Delaware Journal of Public Health - Genetics/Genomics

Delaware Journal of

Volume 7 | Issue 5

December 2021

Public Health A publication of the Delaware Academy of Medicine / Delaware Public Health Association

Public Health/ Population Health

Genetics/Genomics

www.delamed.org | www.djph.org

Delaware Academy of Medicine

Board of Directors: OFFICERS S. John Swanson, M.D. President Lynn Jones, FACHE President-Elect Professor Rita Landgraf Vice President Jeffrey M. Cole, D.D.S., M.B.A. Treasurer Stephen C. Eppes, M.D. Secretary Omar A. Khan, M.D., M.H.S. Immediate Past President Timothy E. Gibbs, M.P.H. Executive Director, Ex-officio DIRECTORS David M. Bercaw, M.D. Lee P. Dresser, M.D. Eric T. Johnson, M.D. Erin M. Kavanaugh, M.D. Joseph Kelly, D.D.S. Joseph F. Kestner, Jr., M.D. Brian W. Little, M.D., Ph.D. Arun V. Malhotra, M.D. Daniel J. Meara, M.D., D.M.D. Ann Painter, M.S.N., R.N. John P. Piper, M.D. Charmaine Wright, M.D., M.S.H.P. EMERITUS Robert B. Flinn, M.D. Barry S. Kayne, D.D.S.

Delaware Public Health Association

Advisory Council:

Omar Khan, M.D., M.H.S. Chair Timothy E. Gibbs, M.P.H. Executive Director Louis E. Bartoshesky, M.D., M.P.H. Gerard Gallucci, M.D., M.H.S. Richard E. Killingsworth, M.P.H. Erin K. Knight, Ph.D., M.P.H. Melissa K. Melby, Ph.D. Mia A. Papas, Ph.D. Karyl T. Rattay, M.D., M.S. William J. Swiatek, M.A., A.I.C.P.

Delaware Journal of Public Health Timothy E. Gibbs, M.P.H. Publisher Omar Khan, M.D., M.H.S. Editor-in-Chief Louis E. Bartoshesky, M.D., M.P.H. Eric B. Kmiec, Ph.D. Guest Editors Liz Healy, M.P.H. Managing Editor Kate Smith, M.D., M.P.H. Copy Editor Suzanne Fields Image Director ISSN 2639-6378

Delaware Journal of

December 2021

Public Health Volume 7 | Issue 5

A publication of the Delaware Academy of Medicine / Delaware Public Health Association

3 | In This Issue Omar A. Khan, M.D., M.H.S. Timothy E. Gibbs, M.P.H.

32 | Development of Cell Lines for use in COVID-19 Drug Development and Research London McGill, M.S.

4 | Guest Editor Louis E. Bartoshesky, M.D., M.P.H., F.A.C.M.G.

5 | Guest Editor Eric B. Kmiec, Ph.D.

6 | Recent Scientific Breakthroughs Applying CRISPR Gene Editing in Neurological Disorders Mitra Assadi-Khansari, M.D., F.A.A.N. London Pamela McGill, M.S.

10 | Impact of Genetic Testing on Human Health: The Current Landscape and Future for Personalized Medicine

36 | Accelerating the Pace of Newborn Screening Research to Advance Disease Understanding and Improve Health Outcomes: Key Efforts of the Newborn Screening Translational Research Network (NBSTRN) Amy Brower, Ph.D. Kee Chan, Ph.D., M.P.H. Jennifer Taylor, Ph.D. Ross Wiebenga Galata Tona, M.S. Yekaterina Unnikumaran, M.S. LaStephanie Barnes

38 | Life Sciences at Delaware Technical Community College

Vicky L. Funanage, Ph.D.

Mark T. Brainard, Ph.D.

12 | Realities of Pharmacogenomic and Minimizing Misconceptions and Medication Misadventures

40 | Impact of the Access to Genetic Counselor Services Act

Benjamin Duong, Pharm.D.

20 | The Genetic Testing Stewardship Program: A Bridge to Precision Diagnostics for the Non-genetics Medical Provider

Carol Nowlen, M.S. Kendra Flores, M.S., C.G.C.

42 | CRISPR In A Box™ and the Journey Toward Inspiring New Scientists Kristen Pisarcik

64 | Disparities in Delaware Caregiver Beliefs about the COVID-19 Vaccine for their Children Thao-Ly Tam Phan, M.D., M.P.H. Paul T. Enlow, Ph.D. Michael K. Wong Amanda M. Lewis, M.P.H. Anne E. Kazak, Ph.D., A.B.P.P. Jonathan M. Miller, M.D.

72 | Characteristics and Outcomes of SARS-CoV-2 Infection Among Adults Living With HIV In Delaware: The Story of a Syndemic During the First 12 Months of the SARS-CoV-2 Pandemic Adam K Skrzynski, M.D. Brooke L Darmstadter, Pharm.D., A.A.H.I.V.P. Sharon P Miner, A.G.P.C.N.P.-B.C. Keshab Subedi, M.S., M.Sc. Deborah Kahal, M.D., M.P.H., F.A.C.P.

80 | Team Up For Quality Care: The Role of Primary Care Teams in Prevention Of Cardiovascular Disease Cindy Biederman, M.S.N., R.N.

92 | History & Archives: Letter to the Editor Sharon Folkenroth-Hess, M.A.

Morgan Thomas, M.G.C., C.G.C. Louise Amlie-Wolf, M.S., C.G.C. Laura Baker, M.G.C., C.G.C. Karen W. Gripp, M.D., F.A.C.M.G.

44 | An Examination of Seasonal Trends in Delaware Drug Overdoses, 2016-2020

94 | Genetics Lexicon

24 | Molecular Genetic Testing for Kidney Disorders During the COVID-19 Pandemic

Aswini Abraham, M.S. Andrew C. Gray, M.A. Jascha Wagner, Ph.D. Tammy L. Anderson, Ph.D.

96 | Genetics More Information

Susan M. Kirwin Katherine M. Robbins, Ph.D. Kathleen M.B. Vinette Lee Hirata Karen W. Gripp, M.D. Vicky L. Funanage, Ph.D.

COVER

52 | Global Health Matters Sept-Oct 2021

96 | Genetics Resources

97 | Index of Advertisers

Fogarty International Center

The convergence of public health and genetics holds the possibility of improved understanding of the etiology, prevention, and management of complex diseases such as diabetes, dementia, heart disease, cancer including oral cancers, dental diseases, and syndromes.

The Delaware Journal of Public Health (DJPH), first published in 2015, is the official journal of the Delaware Academy of Medicine / Delaware Public Health Association (Academy/DPHA).

only the opinions of the authors and do not necessarily reflect the official policy of the Delaware Public Health Association or the institution with which the author(s) is (are) affiliated, unless so specified.

Submissions: Contributions of original unpublished research, social science analysis, scholarly essays, critical commentaries, departments, and letters to the editor are welcome. Questions? Write ehealy@delamed.org or call Liz Healy at 302-733-3989.

Any report, article, or paper prepared by employees of the U.S. government as part of their official duties is, under Copyright Act, a “work of United States Government” for which copyright protection under Title 17 of the U.S. Code is not available. However, the journal format is copyrighted and pages June not be photocopied, except in limited quantities, or posted online, without permission of the Academy/ DPHA. Copying done for other than personal or internal reference use-such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale- without the expressed permission of the Academy/DPHA is prohibited. Requests for special permission should be sent to ehealy@delamed.org.

Advertising: Please write to ehealy@delamed.org or call 302-733-3989 for other advertising opportunities. Ask about special exhibit packages and sponsorships. Acceptance of advertising by the Journal does not imply endorsement of products.

Copyright © 2021 by the Delaware Academy of Medicine / Delaware Public Health Association.

Opinions expressed by authors of articles summarized, quoted, or published in full in this journal represent

I N T H I S I S SU E Welcome to this issue of the Delaware Journal of Public Health, which focuses on Genetics and its relationship to public health. As always, we appreciate your feedback and hope that you find this issue valuable.

The Determinants of Health, as defined by the US Office of Disease Prevention and Health Promotion, include: • Policymaking, • Social Factors, • Health Services, • Individual behavior, and • Biology and genetics.

The more easily modifiable factors are represented in the first three determinants. The modification of individual behavior is much more challenging - health promotion and a variety of individual and community level models and theories of behavior change address this head on. It has only been during the past few decades that we have seen the growth of novel interventions that can act at the biologic and genetic level, including CRISPR gene therapy and gene editing. This new field has great potential, and groups in Delaware – including the Gene Editing Institute at ChristianaCare - are focusing their energy in these areas.

This issue includes articles on newborn screening, genetic counseling, the development of cell lines for use in COVID-19 research, CRISPR technology and use, and higher education and research, as well as articles on seasonal trends in Delaware’s overdose deaths, HIV and SARS-CoV-2 coinfection, and disparities in caregiver beliefs about the COVID-19 vaccine.

Dr. Lou Bartoshesky and Dr. Eric Kmiec are our guest editors for this issue, and have their own introductory articles to help set the stage. We are grateful for their work on this issue of the Journal.

As the Journal concludes its seventh year of publication with inclusion in PubMed, we want to extend our thanks to all past authors, editors, and to you, our readership, for your engagement and support.

Omar A. Khan, M.D., M.H.S. Editor-in-Chief

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Timothy E. Gibbs, M.P.H. Executive Director

3

Public Health Genetics/Genomics Louis E. Bartoshesky, M.D., M.P.H., F.A.C.M.G.

Genetics, according to The American Heritage Dictionary, is that branch of biology that deals with heredity, especially the mechanisms of hereditary transmissions and the variation of hereditary characteristics among organisms.1 Genomics is the study of all of the nucleotide sequences—including structural genes, regulatory sequences and non-coding DNA segments—in the chromosomes of an organism. Genomics is a relatively new concept, as witnessed by the American College of Medical Genetics changing its name to the American College of Medical Genetics and Genomics in 2012. In general, clinical genetics deals with one person, and one gene locus, while genomics deals with all or large segments of the genome (multiple genes) and how all or various parts of the genome interact with one another and with the environment. Down syndrome is a genomic condition associated with an extra copy of 300+ genes on chromosome 21, while cystic fibrosis is generally considered a genetic disorder associated with altered copies of genes at a single locus in a single person. (But perhaps CF could be considered genomic when multiple variants— mutations at that locus—are being studied within a population.)

Public health can be described as the science and art of preventing disease, prolonging life through the organized efforts of society, organizations, and individuals. Public Health Genetics/Genomics has been described as applying genetic and genomic information to improve public health and prevent disease.2 The core functions of public health include assessment, policy development, and assurance that all populations have access to appropriate care.

Public Health genomics is applying such core functions to genomics. For example, core functions in Public Health Genomics might include evaluation of a state run newborn screening program (Assessment) suggesting changes in the panel of disorders screened for (Policy Development) and organizing an appropriate advisory board to assist in assuring the NSP program is reaching all infants (Assurance). Another example might include applying the genomics/public health core functions to a community based molecular breast cancer screening program.

PUBLIC HEALTH AND GENOMICS Traditionally, preventive services have been on the forefront of Public Health activities. Three types of prevention are generally recognized: Primary – the prevention of disease; secondary – reducing the spread of a disease in an individual or population; and tertiary – managing the long term impact of an ongoing disease.3 In clinical genomics, sometimes laboratory reports are uncertain and difficult to interpret. Perhaps there should be a fourth type of prevention: quaternary prevention or identifying a patient or population with an uncertain course putting them at risk for “over medicalization.” A type of prevention to identify and protect those individuals and populations for whom medical intervention is likely to be a risk for more harm than good.4 4 Delaware Journal of Public Health - December 2021

STATUS OF PUBLIC HEALTH GENOMICS Currently public health genomics is being integrated into existing paradigms for the provision of traditional public health services.

We can expect continued alignment with current public health programs in the community designed to benefit the population.5 Clinical genomics is no longer considered only for “rare” conditions, but all disorders and diseases including conditions such as hypertension, various cancers, psychiatric disorders, diabetes etc.have aspects relevant to Clinical Genomics.3 Issues and Concerns There are issues and concerns around Clinical and Research Genomics. Public Health genomics is generating large amounts of data: the human genome includes up to 3.3 billion base pairs: 20,000 or so genes coding for a protein and similar numbers of genes not coding for a protein. Increasingly, sophisticated informatics will be necessary. Recently, a number of helpful clinical resources have become available, including, but not limited to: • Gene Reviews, a comprehensive clinical resource; • OMIM, an online catalogue of human genes and genetic disorders; • The Genetic Alliance, a resource for consumers; • The National Coordinating Center for Regional Networks, designed to improve access to Genomics services; • Clingen, an NIH funded program dedicated to building an authoritative central resource that defines the clinical relevance of gene, genomes and variants; and • Clinvar, a freely accessible public archive of reports of the relationship among human variations and phenotypes.

As genomics matures, the concept of Precision Medicine is being widely considered. Precision Medicine has been defined as “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyles for each person.”6 More simply, it may be considered as providing the right treatments at the right time, every time, to the right person.

Direct to consumer advertising around molecular testing is widely available raising concern about appropriate interpretation of genomic information by consumers. Regulation is being discussed.

Uncertainty around molecular testing interpretation is widely recognized. Unexpected (“secondary”) results are not uncommon; for example diagnostic exome sequencing (determining the sequence of all or most of the base pairs within the coding regions of the chromosomes) done on an infant with developmental delay might inadvertently uncover a mutation associated with high risk for an adult onset cardiomyopathy. How should that be handled?

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Also, molecular testing for a specific disorder might result in the detection of a DNA variant (a mutation) not previously recognized as pathogenic (disease causing). These are labelled as variants of uncertain significance (VUS) and demand interpretation and discussion. Pre- and post-testing counseling by sophisticated genetics professionals such as Masters Level genetic counselors are needed.

Costs for genetics/genomics services are going down, but remain difficult for some consumers to afford and insurance coverage is inconsistent. Does this suggest problems around one of the core principles of public health: assurance; and to one of the basic principles of modern bioethics: justice?

Furthermore, there is not widespread access to genomics services among lower middle income countries (LMIC), and, for that matter, within parts of the United States. These situations again raise the question of Justice.

Confidentiality, privacy, and strict adherence to bioethical principles are essential parts of Public Health Genomics and genetics activities.

HOW SHOULD PUBLIC SECTOR GENOMICS SERVICES BE MONITORED? Translation of lab results to clinical availability and reliability of testing are topics that lend themselves to public health genomics discussions.

The heart of public health today is the recognition that health outcomes in populations and individuals are influenced by a

range of social, cultural, political, economic, environmental, and behavioral factors. Genomics is being added, perhaps near the top of the list.5

REFERENCES 1. The American Heritage Dictionary of the English Language.

4th Ed. (2000). Houghton Mifflin, Boston 2. What is Public Health Genetics? (2021). https://www.phgw.org/wp-2021 3. Khoury, M. (2000). Genetics and Public Health in the 21st Century. Oxford University Press; 2000, New York 4. Burke, W., Burton, H., Hall, A. E., Karmali, M., Khoury, M. J., Knoppers, B., . . . Zimmern, R. L., & the Ickworth Group.

(2010, December). Extending the reach of public health genomics: What should be the agenda for public health in an era of genome-based and “personalized” medicine? Genet Med, 12(12), 785–791. https://doi.org/10.1097/GIM.0b013e3182011222 5. Molster, C. M., Bowman, F. L., Bilkey, G. A., Cho, A. S., Burns, B. L., Nowak, K. J., & Dawkins, H. J. S. (2018, September 4).

The evolution of public health genomics: Exploring its past, present and future. Frontiers in Public Health, 6, 247. https://doi.org/10.3389/fpubh.2018.00247 6. Khoury, M. J. (2018, May). Precision public health: What is it? Centers for Disease Control and Prevention. Genomics and Precision Health. Retrieved from: https://blogs.cdc.gov/genomics/2018/05/15/precision-public-health-2/

Eric B. Kmiec, Ph.D. Director, Gene Editing Institute, ChristianaCare

COVID-19 has disrupted life as we know it. As a pandemic, it affects us here in Delaware and is still thriving throughout the world. The virus responsible for causing COVID-19 is severe acute respiratory syndrome coronavirus 2, referred to as SARSCoV-2 (defined by the World Health Organization). At the time of this writing, over 47 million cases and 771,000 deaths have been reported in the United States, with a case mortality rate of 6%.1 It remains to be seen how effective public health safety measures will be to sidestep a subsequent wave of viral infections, perhaps caused by identical or similar viruses with genetic variants.

While the development, validation and distribution of effective diagnostic tests and physical separation measures have improved over the course of the last year, a rising tide of distrust within the population for the efficacy of vaccines is undeniable. Whether based in fact or fiction, it is a real problem and it is now suspected that a certain percent of the population, most specifically African Americans, will not automatically trust the vaccine. As such, it is critically important that health systems and public health agencies in Delaware and throughout the world provide effective diagnostics and therapies for the relief of this terrible infectious disease.

The breakthrough technology CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is revolutionizing every aspect of our lives by providing novel therapeutic modalities for the treatment of inherited diseases and cancer, accelerating drug discovery, and creating a brand-new class of diagnostics. The extraordinary versatility of CRISPR for gene modification and genetic detection will likely lead to new applications that have not yet been conceived. And very recently, CRISPR’s ability to precisely target RNA and DNA sequences was employed to determine Doi: 10.32481/djph.2021.12.003

if someone is infected with this coronavirus. A CRISPR-based diagnostic kit for COVID-19 was once believed to be a fantasy, yet now the SHERLOCK test and its derivatives hold a special place in the world of COVID-19 testing. It is but one example on novel genetic applications being used to help in a public health crisis.

I am delighted to be a co-editor of this important issue of the Delaware Journal of Public Health, since information provided by these outstanding authors is both timely and appropriate. As we evolve clinal testing, the impact the genetic analyses have on our thinking both as a diagnostic and treatment platform is increasing rapidly. Right now, pharmaceutical and biotechnology companies are utilizing a variety of genetic tools to create cell lines that can help identify effective drugs and therapies for COVID-19 and other public health challenges. The application of CRISPR to drug discovery efforts is a platform improvement opportunity.

The challenge of COVID itself is an opportunity for researchers worldwide to focus their attention on not only COVID, but on infectious diseases in general.

I hope you enjoy reading the articles assembled in this issue, where our investigators and authors describe and inform about the role that genetics and genetic analysis is having on advancing and improving our capability to diagnose, and perhaps treat, any form of external agent that poses a serious public health challenge.

REFERENCES 1. Centers for Disease Control and Prevention. (2021). COVID data tracker weekly review. Retrieved from: https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html 5

Recent Scientific Breakthroughs Applying CRISPR Gene Editing in Neurological Disorders Mitra Assadi-Khansari, M.D., F.A.A.N. London Pamela McGill, M.S.

Over the past three decades, technological advances have revolutionized the diagnosis and management of neurological disorders. No longer mystifying or ambiguous, even the most uncommon afflictions of the nervous system are now easily defined by molecular markers. The opportunity to recognize incurable disorders often puts neurologists in the juxtaposition of having to deliver bad news without any remedies.

if the gRNA sequence has more than six nucleotide mismatches with the target site, the gRNA will not bind and the CRISPR cannot perform the cleavage at that site.2,3 The gRNA acts as a guide for the Cas protein, directing it to the target site, where it then cleaves the DNA creating a double stranded break three base-pairs upstream from the PAM site. Once the break is created one of two repair mechanisms can be utilized.4

Genome editing technology offers a great opportunity for treating numerous fatal neurological ailments caused by genetic etiologies.

The journey in gene editing begins with recognizing the faulty gene causing the disorder, followed by disrupting the gene sequence using a very precise tool called CRISPR/Cas (Clustered Regularly Interspaced Short Palindromic Sequences / CRISPRassociated). Cas comprises a family of nucleases synthetized by bacteria as part of their adaptive immunity against viruses, of which Cas9 (CRISPR-associated protein 9) is the most commonly utilized version for gene editing (see Figure 1).1,2

The “knock out” model utilizes the two double stranded breaks which are created upstream from one another and the DNA is left to repair itself by recombining the blunt ends of DNA. This method is often used to remove codons and shift the open reading frame (ORF) out of frame resulting in a “knockout” of the gene of interest.

The CRISPR/Cas system works by using short RNA sequences known as guide RNA’s (gRNA’s) to recognize the affected allele(s).

This 20-nucleotide sequence follows a PAM (Protospacer Adjacent Motif) sequence which helps to ensure site specific binding and cleavage. If the target PAM site has been disrupted or

The second method, the “knock in” model, uses a single gRNA to open the DNA at the point of interest and a repair template matching the DNA sequence, giving the DNA a blueprint to copy during repair. Figure 2 depicts the process of the CRISPR/Cas complex as it creates a double stranded break promoting either NHEJ or HDR to either create a desired indel (knockout) or create a precise correction such as a knock in or point mutation repair.4 The knock in model introduces new genetic material to correct the point mutations or frameshift mutations.

Figure 1: CRISPR Associated Nucleases (Cas) Briefly Explained 6 Delaware Journal of Public Health - December 2021

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Figure 2: CRISPR Induced Cell Repair

CRISPR technology can be implemented both in-vitro and in-vivo. Figure 3 highlights the steps needed to complete in vitro gene editing for in vivo use. Mesenchymal stem cells are harvested from adipose tissue, they then undergo gene editing and are expanded in vitro until there are a suitable number of cells to be injected back into the human or mouse model.1 The in-vitro model involves harvesting and editing cells, expanding them in a cell culture and delivering them back to the subject.

Stem cell interventions exemplify a major application for CRISPR technology. For instance, for treating ALS or repairing spinal cord injuries, mesenchymal stem cells may be harvested from the adipose tissue, edited, and then delivered intrathecally.

Autologous stem cell interventions are used for treating numerous otherwise untreatable neurological conditions such as leukodystrophies.1,5 The in-vivo model involves delivering the gRNA and Cas9 by means of a vector directly into the subject’s body to correct the genetic abnormality. Without a vector, these particles are

sequestered by the immune cells prior to reaching the target cells. Viral vectors, given their innate ability to infect cells, are particularly useful for this purpose. To this end, a variety of viral vectors lacking pathogenicity have been designed. The choice of viral vector often relies on natural tropism towards specific tissues to optimize delivery of the gene editing complex. As an example, among more than 100 species of adeno associated virus, AAV9 is popular for gene editing in the brain given its ability to cross the blood brain barrier.1,5,6 Other examples of vectors include liposomes or synthetic nanoparticles. These vectors are driven to the cell membranes due to their lipid solubility and as such, enhance the delivery of the gene editing complex.6 Neurodegenerative disorders comprise numerous devastating and often fatal conditions which are a major source of social and economic burden. Figure 4 highlights five common neurological disorders, the genetic cause, and how the disease can be corrected

Figure 3: Stem Cell Interventions in Neurological Disease 7

REFERENCES 1. Madigan, N. N., Staff, N. P., Windebank, A. J., & Benarroch, E. E. (2017, October 17). Genome editing technologies and their potential to treat neurologic disease. Neurology, 89(16), 1739–1748.https://doi.org/10.1212/WNL.0000000000004558

Figure 4: Applications of Gene Editing in Degenerative Disorders

using CRISPR/Cas based therapeutics.5–7 CRISPR-Cas9 has been used to create cell and animal models of the diseases, as well as to target the genes to mitigate the abnormality. The scientific community is intrigued by the progress being made in applying gene editing in a variety of neurodegenerative disorders. These strides begin by correcting the molecular abnormality at the cellular level using CRISPR-Cas9 before applying the intervention to animal models.5,8 The recent application of gene editing in six human subjects with amyloidosis caused by transthyretin mutation demonstrated its safety and efficacy in decreasing the abnormal protein level.7 The major challenges in gene editing include limited efficiency and precision. While scientists hope to target at least 50% of the mutated alleles to rectify the effects of the faulty gene, even in the best cases, the CRISPR-Cas complex edits less than 10% of the alleles. Moreover, due to partial matches between the gRNA and other parts of the genome, off target effects occur frequently.

The PAM mechanism helps to ensure that off-target activity does not occur when making corrections to mutant alleles. The gene editing field continues to work on correcting off target effects as well as further studying the CRISPR/Cas system to make it a more predictable system for therapeutic use.

It is important to note that other viral vectors are available with the larger packaging capacity needed to carry the CRISPR/Cas system in-vivo. Many of these other vectors such as lentivirus, retrovirus, and even some species of AAV come with the risks however, such as random incorporation into the host genome at unintended sites which can lead to dysregulation of nearby genes, chromosomal rearrangement, or even genotoxicity in some tissue types, as well as unstudied effects on brain homeostasis.9,10 Although unintended incorporation of certain AAV vectors is not commonly seen in neurological tissue and disease studies it is still something that should be monitored as new vectors are developed and introduced into the field.

In summary, gene editing is a powerful and promising tool which will revolutionize the treatment of neurogenetic disorders, and given the rapid advances made over the past few years, is expected to come to fruition during our professional lifetime. We aim to educate the providers in our community regarding the existing alternatives and the ongoing research in this field.

These authors can be contacted at london.mcgill@christianacare.org

8 Delaware Journal of Public Health - December 2021

2. Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012, August 17). A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science, 337(6096), 816–821. https://doi.org/10.1126/science.1225829 3. Collias, D., & Beisel, C. L. (2021, January 22).

CRISPR technologies and the search for the PAMfree nuclease. Nature Communications, 12(1), 555. https://doi.org/10.1038/s41467-020-20633-y 4. Hsu, P. D., Lander, E. S., & Zhang, F. (2014, June 5). Development and applications of CRISPR-Cas9 for genome engineering. Cell, 157(6), 1262–1278. https://doi.org/10.1016/j.cell.2014.05.010 5. Kuruvilla, J., Sasmita, A. O., & Ling, A. P. K. (2018, November). Therapeutic potential of combined viral transduction and CRISPR/Cas9 gene editing in treating neurodegenerative diseases. Neurol Sci, 39(11), 1827–1835. https://doi.org/10.1007/s10072-018-3521-0 6. Barman, N. C., Khan, N. M., Islam, M., Nain, Z., Roy, R. K., Haque, A., & Barman, S. K. (2020, December). CRISPR-Cas9: A promising genome editing therapeutic tool for Alzheimer’s disease—A narrative review. Neurology and Therapy, 9(2), 419–434. https://doi.org/10.1007/s40120-020-00218-z 7. Gillmore, J. D., Gane, E., Taubel, J., Kao, J., Fontana, M., Maitland, M. L., . . . Lebwohl, D. (2021, August 5). CRISPRCas9 in vivo gene editing for transthyretin amyloidosis.

The New England Journal of Medicine, 385(6), 493–502. https://doi.org/10.1056/NEJMoa2107454 8. Min, Y. L., Li, H., Rodriguez-Caycedo, C., Mireault, A. A., Huang, J., Shelton, J. M., . . . Olson, E. N. (2019, March 6).

CRISPR-Cas9 corrects Duchenne muscular dystrophy exon 44 deletion mutations in mice and human cells. Science Advances, 5(3), eaav4324.https://doi.org/10.1126/sciadv.aav4324 9. Tosolini, A. P., & Sleigh, J. N. (2020, July 17). Intramuscular delivery of gene therapy for targeting the nervous system. Frontiers in Molecular Neuroscience, 13, 129. https://doi.org/10.3389/fnmol.2020.00129 10. Deyle, D. R., & Russell, D. W. (2009, August).

Adeno-associated virus vector integration. Current Opinion in Molecular Therapeutics, 11(4), 442–447. https://pubmed.ncbi.nlm.nih.gov/19649989

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9

Impact of Genetic Testing on Human Health: The Current Landscape and Future for Personalized Medicine Vicky L. Funanage, Ph.D. Executive Director, Research, Nemours Children’s Health

ABSTRACT Advances in the field of human genetics over the past three decades have led to improvements in human health through development and availability of novel genetic testing approaches for diagnosis, prognosis, treatment therapy, safety, preventive screening and population-based risk assessment. In this commentary, I highlight the current landscape of genetic testing in Delaware with a focus on the genetic etiology and molecular diagnosis of pediatric disease, tailored treatment efficacy and safety through novel clinical trials and pharmacogenomics, and training in the application of genomic approaches to rare and common diseases. Future opportunities include integrating application of genetic information into clinical practice, improving genetics education, focusing on disparities and access, and advancing genomics and digital health technologies.

Applied Clinical Genomics is the application of genetic information to the clinical setting, including improved diagnosis of disease and tailored treatment efficacy and safety. By discovering and defining the genes that underlie susceptibility to disorders, genetic information can be used to identify and better define those genes that play vital roles in human health, disease, and medical conditions. Equally important is the provision of training to physicians in the application of genomic and genetic approaches to studies of human diseases. When transferred directly into drug discovery programs and clinical trials, this knowledge will help to advance diagnosis, individualize treatment, and improve human health.

The mission of the Precision Medicine Program at Nemours Children’s Health is to integrate the application of genetic information into patient care and to provide colleagues across our institution with the resources and knowledge base to adapt to the growing genetic and genomic landscape that impacts modern patient care. In 1993, the first Clinical Laboratory Improvements Amendments (CLIA)-certified pediatric genetic testing lab was established at the Alfred I. duPont campus in Delaware, with an initial focus on the neuromuscular disorders: Duchenne/Becker muscular dystrophy, myotonic dystrophy, Pelizaeus-Merzbacher disease, and spinal muscular atrophy. In addition to providing accurate diagnoses, the availability of these testing platforms led to the development of clinical decision support tools, improved clinical outcomes, and less invasive and expensive diagnostic tests that could replace muscle biopsy and histochemistry, which were the primary means differential diagnosis of neuromuscular diseases in children. The genetic testing platforms also furthered understanding of the molecular etiology of myotonic dystrophy1,2 and Pelizaeus-Merzbacher disease3 and fostered the development of novel gene therapies for spinal muscular atrophy.4 While human genetics has long been known for its role in the diagnosis and management of familial genetic disorders such 10 Delaware Journal of Public Health - December 2021

as cystic fibrosis and neurodevelopmental and neuromuscular disorders, variation in human DNA sequences contributes to risks for more common complex disorders including asthma, obesity, diabetes, autism, and congenital heart malformations.

Response to treatment with medications and other procedures may also be largely determined by individual genetic variation.

With rapidly advancing technologies in genome-wide mutation discovery (e.g., genome-wide association studies and next generation sequencing technologies), elucidation of the genomic risk factors or genetic etiology of complex diseases became possible. Moreover, “biomarker” profiles derived from many sources including patterns of gene activity, specific DNA sequences at important regulatory genes for drug metabolism (pharmacogenomics), or patterns of DNA sequences at other “risk” genes are rich sources of information for personalized approaches to medicine. These biomarker profiles, along with family history and educated practitioner assessments, can influence the management of patients in a positive way. The application of genetic information from bench to bedside, clinic to community, will help to improve diagnosis of disease, individualize treatment, and improve health outcomes.

Precision or Personalized Medicine, which considers individual differences in genes, environments and lifestyles to better understand and manage a patient’s health, disease, or condition, has emerged as a paradigm shift in healthcare, with the intersection of big data and advances in genomics enabling efficient identification of high quality and personalized evidence-based care. The Nemours Precision Medicine Initiative was launched in 2017 to provide high-quality, evidence-based care to children across the Nemours system, expanding the knowledge base for each individual patient to improve the overall safety, quality and cost effectiveness of their care. Several key programmatic pillars were included in this initiative. The Nemours Genetics Testing Stewardship Program was launched to provide consultation services for appropriate genetic testing, interpretation of genetic tests, explanation of test implications to caregivers and family, and diagnosis and management of genetic Doi: 10.32481/djph.2021.12.005

disorders. In a few short years, this program has been shown to increase access to genetic testing and provide prompt diagnoses and supportive care.5 The Nemours Pharmacogenomics Service Program, comprised of trained PharmD specialists, provides education, clinical decision support tools, and best practice alerts in the electronic health record (EHR).6,7 The Nemours Biomedical Research Informatics Center deployed a learning health system model, developing analytic tools to improve use of existing EHR data for outcomes research, and natural language processing and machine learning tools to make maximal use of unstructured medical data.8,9 The Biobank and Molecular Analysis Program offers a biorepository for storage of pediatric tissue samples as well as guidance and scientific support to investigators in the conduct of clinical research. Finally, the Rare Disease Program provides both single gene and next generation sequencing platforms to provide differential diagnoses for rare complex genetic disorders such as chronic kidney disease and leukodystrophies.

As healthcare organizations strive to excel in a value-driven healthcare economy, it will be important to accelerate the delivery of high quality, precise, and efficient care as well as provide cost savings for patients. Demonstration projects will incorporate genomic information into the EHR and provide clinical decision support for implementation of appropriate interventions or clinical advice. Dissemination of these methods through implementation science is a key goal so that the information generated will contribute to the growing knowledge base of using genomic information in patient care. Researchers often advance the practice of precision medicine by studying the genetics of a population, searching for commonalities and anomalies. This approach may unlock medical breakthroughs, enabling us to prevent disease, improve medication safety based on an individual’s unique genetics, and better predict which treatments will be most effective.

Denny and Collins10 have proposed an expansion in seven key areas to enable a data-driven transformation in healthcare: large interoperable longitudinal cohorts, improved diversity and inclusion in science, big data and artificial intelligence, clinical genomics, phenomics, environment, privacy, trust and return of value. These areas provide a roadmap for precision medicine in 2030 and align with the overall goal of the National Academies’ Roundtable on Genomics and Precision Health to ensure that all people benefit from genomics for precision health.11 The Genomics Workforce is prioritizing four action-oriented areas for 2021: innovation, dialog, equity, and adoption. Collectively, these areas of focus provide a roadmap for our state to employ its collective talent and voices to capitalize on the advances in genomics and precision health to improve the health of all Delawareans.

Correspondence: Dr. Funanage can be e-mailed at vicky.funanage@nemours.org

REFERENCES 1. Carango, P., Noble, J. E., Marks, H. G., & Funanage, V. L. (1993, November). Absence of myotonic dystrophy protein kinase (DMPK) mRNA as a result of a triplet repeat expansion in myotonic dystrophy. Genomics, 18(2), 340–348. https://doi.org/10.1006/geno.1993.1474

2. Krahe, R., Ashizawa, T., Abbruzzese, C., Roeder, E., Carango, P., Giacanelli, M., . . . Siciliano, M. J. (1995, July 1). Effect of myotonic dystrophy trinucleotide repeat expansion on DMPK transcription and processing. Genomics, 28(1), 1–14. https://doi.org/10.1006/geno.1995.1099 3. Taube, J. R., Sperle, K., Banser, L., Seeman, P., Cavan, B. C., Garbern, J. Y., & Hobson, G. M. (2014, October 15). PMD patient mutations reveal a long-distance intronic interaction that regulates PLP1/DM20 alternative splicing. Human Molecular Genetics, 23(20), 5464–5478. Epub2014Jun1. https://doi.org/10.1093/hmg/ddu271 4. Finkel, R. S., Chiriboga, C. A., Vajsar, J., Day, J. W., Montes, J., De Vivo, D. C., . . . Farwell, W. (2021, July). Treatment of infantile-onset spinal muscular atrophy with nusinersen: Final report of a phase 2, open-label, multicentre, dose-escalation study. The Lancet. Child & Adolescent Health, 5(7), 491–500.

Epub2021Jun3. https://doi.org/10.1016/S2352-4642(21)00100-0 5. Amlie-Wolf, L., Baker, L., Hiddemen, O., Thomas, M., Burke, C., Gluck, C., . . . Gripp, K. W. (2021, April). Novel genetic testing model: A collaboration between genetic counselors and nephrology. American Journal of Medical Genetics. Part A, 185(4), 1142–1150. Epub2021Jan21. https://doi.org/10.1002/ajmg.a.62088 6. Rahawi, S., Naik, H., Blake, K. V., Owusu Obeng, A., Wasserman, R. M., Seki, Y., . . . Scott, S. A. (2020, May).

Knowledge and attitudes on pharmacogenetics among pediatricians. [published online ahead of print, 2020 Jan 27]. Journal of Human Genetics, 65(5), 437–444. https://doi.org/10.1038/s10038-020-0723-0 7. Cook, K. J., Duong, B. Q., Seligson, N. D., Arn, P., Funanage, V. L., Gripp, K. W., . . . Blake, K. V. (2021, September). Key considerations for selecting a genomic decision support platform for implementing pharmacogenomics. Clinical Pharmacology and Therapeutics, 110(3), 555–558; Epub ahead of print. https://doi.org/10.1002/cpt.2328 8. Lang, J. E., Bunnell, H. T., Lima, J. J., Hossain, M. J., Wysocki, T., Bacharier, L., . . . Forrest, C. B. (2019, November). Effects of age, sex, race/ethnicity, and allergy status in obesity-related pediatric asthma. Pediatric Pulmonology, 54(11), 1684–1693.

Epub2019Aug30. https://doi.org/10.1002/ppul.24470 9. Gupta, M., Bunnell, H. T., Phan, T. T., & Beheshti, R. (2021, August). Concurrent Imputation and Prediction on EHR data using Bi-Directional GANs: Bi-GANs for EHR imputation and prediction. ACM BCB, 2021, 1. https://doi.org/10.1145/3459930.3469512 10. Denny, J. C., & Collins, F. S. (2021, March 18). Precision medicine in 2030-seven ways to transform healthcare. Cell, 184(6), 1415–1419. https://doi.org/10.1016/j.cell.2021.01.015 11. Ginsburg, G., Penny, M., Feero, W. G., Miller, M., Addie, S., & Beachy, S. H. (2021, October 7). The National Academies’ Roundtable on Genomics and Precision Health: Where we have been and where we are heading.

American Journal of Human Genetics, 108(10), 1817–1822. https://doi.org/10.1016/j.ajhg.2021.08.015 11

Realities of Pharmacogenomic and Minimizing Misconceptions and Medication Misadventures Benjamin Duong, Pharm.D. Nemours Children’s Health Delaware, Precision Medicine, Clinical Pharmacogenomics Service

ABSTRACT Pharmacogenetics allows providers to enhance their treatment decisions for common medications used in certain conditions such as depression, gastroesophageal reflux disease (GERD), pain, and acute lymphoblastic leukemia. A precision medicine approach combines pharmacogenetics (when appropriate) with other clinical and environmental factors to minimize trial-and-error of treatment. Public awareness of the impact of pharmacogenetics on treatment decisions is growing, and healthcare should be aware of the resources supporting it. Pharmacogenetics may seem daunting, but the accessibility of pharmacogenetic testing has improved with growing availability of evidence-based clinical recommendations, pharmacogenetic tests, clinical decision support resources, insurance coverage, and digestible education materials. As precision medicine and precision public health expands over the next decade, pharmacogenetic testing will continuously grow to be cheaper and part of routine genetic or genomic screenings, and be another common test—like liver or kidney function tests—that can enhance treatment decisions.

INTRODUCTION Pharmacogenetics (PGx) examines genetic variability as one of many contributing factors in the variability of drug exposure and response (i.e. side effects, treatment failure).1 It is one aspect of “precision medicine,” an approach to improve health by accounting for individual variability in genes, environment, and lifestyle.2 Unlike rare genetic diseases, pharmacogenetic variants warranting dose adjustments are relatively common. In a study containing over 10,000 patients, over 91% will have at least one actionable variant involved in five drug-gene interactions.3 PGx examples to minimize medication misadventures in certain populations include: • TPMT and NUDT15 genotyping in patients requiring thiopurine (used in acute lymphoblastic leukemia, ulcerative colitis, and Crohn’s disease) will identify 10% of the population at risk for severe thiopurineinduced myelosuppression; • CYP2C19 and CYP2D6 genotyping in patients with depression will identify patients at risk of adverse effects or treatment failure to their certain first-life antidepressants; and • Panel-based PGx tests in cancer patients may guide certain supportive care medications such as CYP2D6 for opioids, CYP2D6 for antiemetics, CYP2C19 and CYP2D6 for antidepressants, and CYP2C19 for proton pump inhibitors.

The reality of PGx testing is that PGx is only one piece of the puzzle, and it should be used to enhance, not replace, evidencebased treatment decisions, along with other clinical (e.g., drugdrug interaction, condition) and environmental considerations (e.g., adherence, cost, exercise). It can help the healthcare provider narrow down treatment options or assist in predicting dosage for certain medications by identifying medications with increased 12 Delaware Journal of Public Health - December 2021

risk of adverse effects or therapeutic failure based on their known PGx variants. There are a lot of misconceptions advertising that PGx identify the “magic bullet” that will treat the condition without side effects. However, PGx cannot predict all adverse reactions to medication, predict risk of a specific side effect for all medication, diagnose a disease, or find the perfect regimen with no risk.4 Due to widespread use of direct-to-consumer genetic testing, patients are becoming more informed of how genetics can play a role in their healthcare. They are coming to their health care providers expecting them to be able to order the right test and apply it to their care. Although just under 80% of pediatricians and primary care providers believe PGx can improve care, less than 10% of pediatrician were initially familiar with PGx5 and 26% of adult primary care providers expressed confidence in using PGx in a treatment decision.6 The purpose of this article is to briefly increase awareness of publicly available resources to utilize PGx in treatment decisions, how accessibility is improving using PGx results, and briefly highlight the implementation of a PGx service at Nemours Children’s Health System.

AVAILABLE PGX RESOURCES There are dozens of health systems that have now implemented PGx into their clinical practices across the country with evidencebased recommendations, PGx testing, and clinical decision support platforms in their electronic health records (EHR). The Implementing Genomics in Practice (IGNITE) Network is an NIH-funded network includes over 20 institutions dedicated to support genomic implementation in healthcare.7 The IGNITE Network’s Genomic Medicine Knowledgebase’s IGNITE Toolbox (www.gmkb.org) consists of their collection of genomic implementation resources, clinical decision support examples, and education material publicly available for other institutions to consider. This knowledge base also provides an Implementation Guide that outlines the steps and resources on implementing Doi: 10.32481/djph.2021.12.006

CYP2C19-clopidogrel and CYP2D6-opioids. The implementation science framework that was used to design the implementation guide can be applied other specific drug-gene interactions of interest or a PGx process in general.8 The initial steps identified include ensuring there is sufficient evidence, laboratory testing process, reimbursement, clinical decision support, and education.

CLINICAL EVIDENCE To apply PGx clinically, there should be significant evidence to support the drug-gene interaction. Fortunately, there are multiple established sources with a collection of evidence-based druggene interactions through the Food and Drug Administration (FDA), the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the Pharmacogenomics Knowledge Base (PharmGKB). The FDA provides PGx information and/ or recommendations through their Table of Pharmacogenetic Association, Table of Pharmacogenomic Biomarkers, and within the drug labeling.9,10 CPIC (www.cpicpgx.org) is an international consortium of clinicians and scientists that develops clinical PGx guidelines with structured interpretations and recommendations of evidence-based gene-drug interactions. The CPIC guidelines utilize a rigorous evidence evaluation process and adhere to the Institute of Medicine’s Standards for Developing Trustworthy Clinical Practice Guidelines.11 As of December 2021, there are 26 published CPIC guidelines that correspond to over 80 medications spanning across multiple therapeutic areas such as psychiatry, cardiology, pain management, and hematology/ oncology. Lastly, PharmGKB (www.pharmgkb.org), is a freely available public resource that users can search for a drug or gene, and find any existing evidence and recommendations from the FDA, CPIC, or other expert groups.12 These groups evaluate the evidence and disseminate publicly-available evidence-based recommendations that providers without a genetics background would be able to apply in their practice.

LABORATORY Single and/or multi-gene PGx tests can be obtained through direct-to-consumer genetic testing companies, large clinical laboratory networks with thousands of sites across the country, institutional pathology or molecular diagnostic laboratories, and commercial provider-ordered combinatorial pharmacogenomic testing companies that utilize a proprietary algorithm.

Despite the large availability of PGx tests, the genetic variants, nomenclature, and gene-drug interaction recommendations may be discordant from other laboratories and CPIC’s recommendation and translation.13 Unfortunately, the current challenge to PGx testing is the deviation by most PGx labs from CPIC phenotype translation and recommendations. The misleading information may lead to unnecessary avoidance of first-line agents that do not have enough evidence to have a drug-gene interaction, and increased utilization of medication that is not appropriate for the patient.

Selection of a laboratory should include four domains: pharmacogene selection, logistics, reporting of results, and test costs and reimbursement.14 The pharmacogene selected and results reported should use standardized nomenclature and recommendations as outlined in CPIC’s PGx standardization publication15 and genotype-phenotype translation. The genes and

variants tested should also be representative of the population and cover variants with established reference material on the variant’s impact to the enzyme’s functionality and multi-ethnic frequency as such by the Association of Molecular Pathology for CYP2C19 and CYP2D6.16,17 Logistics that should be considered are the type of sample collection, turnaround time for results, and documentation formed/required. Lastly, cost and reimbursement should be reasonable and covered by insurance.14 Despite possible discrepancies in the recommendations provided, providers can use the genotype results and check with PharmGKB and CPIC for available clinical recommendations.

INTEGRATION/CLINICAL DECISION SUPPORT PGx clinical decision support (CDS) is the integration of PGx results into the electronic medical records to prevents errors and improve health.18 Types of CDS include active CDS and passive CDS. Active CDS are typically interruptive alerts when there is a significant drug-gene interaction or when a drug is ordered and PGx testing is recommended. Passive CDS is available PGx information if the user chooses to seek it (e.g. a PGx profile listing all the possible drug-gene interactions or embedded PGx results within the drug’s order information). CDS usually requires PGx information to be uploaded as discrete variables to enable rule-based decisions. Depending on the institution’s capabilities, they may decide to create PGx CDS using internal resources or outsource with the multiple commercial PGx CDS platforms.

Ideally, PGx CDS are seamlessly integrated with the electronic medical records and provide PGx recommendations concordant with CPIC or FDA recommendations.18,19

INSURANCE COVERAGE Although PGx testing is typically cheaper than traditional diagnostic genetic tests, cost and lack of insurance coverage is a barrier in PGx testing adoption. PGx test cost averages about $300 depending on the laboratory, however most health insurance companies typically deny reimbursement of PGx testing as they are considered investigational and/or experimental. This may change soon as, effective December 12, 2021, PGx testing will be covered by Medicare across 40 of the 50 states as Novitas Solutions, and First Coast Medicare Administrative Contractor (MAC) jurisdiction harmonizes with Molecular Diagnostic Services (MolDx) local coverage determination (LCD) which involves four other MACs.20–22 Novitas Solution and First Coast MACs includes Colorado, New Mexico, Oklahoma, Texas, Arkansas, Louisiana, Mississippi, Delaware, Maryland, Pennsylvania, New Jersey, District of Columbia, and Florida. This marks another milestone in the adoption and accessibility of PGx testing as tool to enhance treatment decisions and minimize risk of treatment failures or adverse effects.

Per the LCD, PGx testing is considered medically reasonable and necessary if the patient is indicated for a medication with a known gene-drug interaction; and the PGx test meets standards (as evaluated by a scientific, transparent, peer-reviewed process) and is determined to demonstrate actionability in clinical decision making (by CPIC guidelines level A or B level of evidence, FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling, the Table of Pharmacogenetic Associations, or FDA drug 13

labeling). PGx testing is not medically reasonable and necessary if the analytical validity, clinical validity, or clinical utility is not established, or the test investigates the duplicative genetic information.20,21 The language from the LCD may restrict coverage for combinatorial PGx tests that rely on proprietary algorithms and provide clinical recommendations on drug-gene interactions classified as low level of evidence by CPIC and PharmGKB. With the new coverage, commercial payers and Medicaid are expected to adopt similar coverages to harmonize with their LCD.

EDUCATION Like with any intervention, the patient should be educated of the benefits and limitations of PGx testing. Education resources for patients should highlight what PGx can and cannot do, such as the fact that PGx testing cannot predict all adverse reactions to medication, specific side effects for all medications, or the perfect “magic pill.”4 If a combinatorial PGx test is used, the patient should be educated that the report may contain low-evidence recommendations, and that categorized pharmacogenomic recommendations with a “Red” indication (“Significant DrugGene Interaction”) may be clinically appropriate more than the “Green” list (“No Drug-Gene Interaction”).

DISCUSSION Accessibility to PGx has grown tremendously over the past decade with stronger evidence supporting utilization and clinical guidelines, increasing availability clinical PGx tests, growing insurance coverage for more affordable tests, and advancing clinical decision support integration. Over the next few years, PGx is expected to transition from a more reactive approach where testing is ordered by specialists and/or when patients have already failed multiple medications, to earlier in the diagnosis using a preemptive panel approach before a medication is indicated. Adoption of preemptive PGx testing will allow for a healthier population by enhancing treatment decisions and minimizing trial and error. This will contribute to one piece of the precision medicine puzzle and the emerging concept of “Precision Public Health,” with the goal of providing right treatment for the right population at the right time.24 In 2030, it is envisioned that precision medicine will have a wealth of data that includes not only genetics but also patient’s environmental factors and medical records. PGx testing will become more routine and stored in “genome-aware” EHR that is standardized and automatically updated from central guidelines, and portable across various institutions.2

PGx education in various health professions is increasing as schools and organizations have been embedding PGx education into their curriculums and continuous education opportunities.

Healthcare professionals seeking formal PGx education on how to effectively apply or implement PGx in their practice can find live or online PGx certificate programs from professional societies (e.g., American Society of Health-System Pharmacists, American College of Clinical Pharmacology) and academic institutions (e.g., University of Pittsburgh, University of Florida).

In conclusion, there is substantial availability of PGx testing and resources that should allow application across the country. There is still a need for harmonization between PGx laboratories with evidence-based interpretation and recommendation as well as coverage in a variety insurance companies, but recently PGx accessibility has become widespread and ready for application as one piece of the puzzle to enhance treatment decisions.

NEMOURS CLINICAL PHARMACOGENOMICS SERVICE

REFERENCES

The resources and considerations above were vital in developing the dedicated Clinical Pharmacogenomic Service at Nemours Children’s Health launching in February 2020, one of only dozen of such services implemented across the country by pediatric health systems.23 This service is managed by pharmacists with clinical PGx residency training to construct PGx resources across the enterprise and assist providers with utilizing PGx with their care. The service’s implementation responsibilities include developing an in-house PGx panel with the Nemours’ CLIAcertified Molecular Diagnostic Laboratory, customizing CDS processes specific to the pediatric population that seamlessly incorporate PGx results into the medical record, fire interruptive drug-gene interaction best practice alerts as a last-line of defense, and patient and provider education. The Nemours Clinical Pharmacogenomics Service direct patient care includes assisting providers to determine how the PGx may be used, coordinating logistics with insurance authorization and DNA sample collection (blood or buccal swab), interpreting any PGx results regardless of the source (direct-to-consumer, commercial, secondary/ incidental findings from diagnostic genetic tests, or the Nemours in-house panel), and reviewing the results with the patient and provider. Many of the patients consulted were patients with mental health conditions, about half of which heard about PGx testing from another parent, family member, or online forum.

14 Delaware Journal of Public Health - December 2021

Correspondence: Dr. Duong can be emailed at benjamin.duong@nemours.org

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Clinically actionable genotypes among 10,000 patients with preemptive pharmacogenomic testing. Clinical Pharmacology and Therapeutics, 95(4), 423–431. Epub2013Nov19. https://doi.org/10.1038/clpt.2013.229 4. Wake, D. T., Ilbawi, N., Dunnenberger, H. M., & Hulick, P. J. (2019, November). Pharmacogenomics: Prescribing Precisely.

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Clinical Pharmacology and Therapeutics, 107(1), 171–175. https://doi.org/10.1002/cpt.1651 12. Gong, L., Whirl-Carrillo, M., & Klein, T. E. (2021).

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Genotype, phenotype, and medication recommendation agreement among commercial pharmacogenetic-based decision support tools. The Pharmacogenomics Journal, 18(5), 613–622. https://doi.org/10.1038/s41397-018-0027-3 14. Vo, T. T., Bell, G. C., Owusu Obeng, A., Hicks, J. K., & Dunnenberger, H. M. (2017, September). Pharmacogenomics implementation: Considerations for selecting a reference laboratory. Pharmacotherapy, 37(9), 1014–1022. https://doi.org/10.1002/phar.1985

16. Pratt, V. M., Del Tredici, A. L., Hachad, H., Ji, Y., Kalman, L. V., Scott, S. A., & Weck, K. E. (2018, May). Recommendations for clinical CYP2C19 genotyping allele selection: A report of the Association for Molecular Pathology. The Journal of molecular diagnostics. J Mol Diagn, 20(3), 269–276. https://doi.org/10.1016/j.jmoldx.2018.01.011 17. Pratt, V. M., Cavallari, L. H., Del Tredici, A. L., Gaedigk, A., Hachad, H., Ji, Y., . . . Weck, K. E. (2021, September).

Recommendations for Clinical CYP2D6 Genotyping Allele Selection: A Joint Consensus Recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, and the European Society for Pharmacogenomics and Personalized Therapy. J Mol Diagn, 23(9), 1047–1064. https://doi.org/10.1016/j.jmoldx.2021.05.013 18. Wake, D. T., Smith, D. M., Kazi, S., & Dunnenberger, H. M. (2021, August 8). (2021). Pharmacogenomic clinical decision support: A review, how-to guide, and future vision. Clinical Pharmacology and Therapeutics; Advance online publication. https://doi.org/10.1002/cpt.2387 19. Cook, K. J., Duong, B. Q., Seligson, N. D., Arn, P., Funanage, V. L., Gripp, K. W., . . . Blake, K. V. (2021, September).

Key considerations for selecting a genomic decision support platform for implementing pharmacogenomics.

Clinical Pharmacology and Therapeutics, 110(3), 555–558. https://doi.org/10.1002/cpt.2328 20.Novitas Solutions, Inc. (2021) Local coverage determination (LCD): pharmacogenomics testing (L39063).

21. Coast Service Options Solutions, Inc. (2021) Local coverage determination (LCD): pharmacogenomics testing (L39073).

22. Palmetto, G.B.A. (2020). Local coverage determination (LCD): MolDX: Pharmacogenomics Testing (L38294).

23. Brown, J. T., Ramsey, L. B., Van Driest, S. L., Aka, I., & Colace, S. I. (2021, March). Characterizing pharmacogenetic testing among children’s hospitals. Clinical and Translational Science, 14(2), 692–701. https://doi.org/10.1111/cts.12931 24. Khoury, M. J., Bowen, M. S., Clyne, M., Dotson, W. D., Gwinn, M. L., Green, R. F., .., & Yu, W. (2018). From public health genomics to precision public health: a 20year journey. Genetics in medicine: official journal of the American College of Medical Genetics, 20(6), 574–582. https://doi.org/10.1038/gim.2017.211

15. Caudle, K. E., Dunnenberger, H. M., Freimuth, R. R., Peterson, J. F., Burlison, J. D., Whirl-Carrillo, M., …, & Hoffman, J. M. (2017). Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genetics in medicine: official journal of the American College of Medical Genetics, 19(2), 215–223. https://doi.org/10.1038/gim.2016.87 15

The DPH Bulletin

From the Delaware Division of Public Health

November 2021 FDA, CDC approve pediatric COVID-19 vaccine for children ages 5-11 years On Nov.2, 2021, the CDC and its advisory committee approved the use of a pediatric dose of the Pfizer-BioNTech COVID-19 vaccine for children ages 5-11. As of Nov. 16, Delaware vaccine providers have administered 4,875 doses of the vaccine. The dosage, reduced by one-third of the adult dose for children under 12, was also approved by the Food and Drug Administration in late October.

There are approximately 77,500 children in this age group in Delaware.

Terrance Banks of Milton received a COVID-19 vaccination during the “Race to End COVID” event held at Dover International Speedway on the weekend of October 16 and 17. He was one of 335 individuals who were vaccinated.

The event was sponsored by the Speedway, DPH, and the CDC Foundation. Photo by Sean Dooley.

FDA/CDC recommend COVID-19 boosters for adults 18+ The Division of Public Health (DPH) is encouraging all fully vaccinated Delawareans 18 and older to get a booster dose of Pfizer, Moderna or Johnson & Johnson (J&J) COVID-19 vaccines.

On Nov. 19, the U.S. Food and Drug Administration expanded booster dose eligibility to all adults 18 and older, who were originally fully vaccinated with either the Pfizer or Moderna COIVD-19 vaccines at least 6 months prior. Those 18 and older who initially received J&J were already approved for a booster vaccine two months after their initial dose.

“We applaud the latest federal action to make all adults eligible for a booster vaccine,” said DPH Director Dr. Karyl Rattay. “COVID-19 cases are again rising and having this tool in our arsenal can help us in holding off another winter surge that could come with people gathering inside more often as the weather turns colder.”

The three authorized vaccines can be administered to qualifying individuals as a booster in a "mix and match" approach to the vaccine originally received.

For more information on second, third, and booster doses of the COVID-19 vaccine, visit de.gov/boosters.

Find a vaccine location near you at de.gov/getmyvaccine.

16 Delaware Journal of Public Health - December 2021

During clinical trials nationwide involving more than 3,000 children ages 5-11, the vaccine was found to be more than 90% protective against developing symptomatic COVID-19. No severe vaccine-related side effects such as myocarditis or severe allergic reactions were identified. Side effects Side effects were found to be similar to, or fewer than, those experienced by adults and included sore arms, fatigue, headaches, muscle pain, chills, and lowgrade fevers lasting a day or two.

Written parental consent is required for people younger than 18, but either a parent or other adult may attend with the child.

Parents or guardians are encouraged to first contact their child’s pediatrician to see if they are administering the vaccine. Vaccines will also be available at Federally Qualified Health Centers (for patients), standing DPH Vaccine sites, and DPH’s communitybased vaccine sites.

Additionally, vaccines are available at major and independent pharmacies.

DPH recommends parents check pharmacy websites for scheduling options and availability before going.

Find vaccine locations for ages 5-11 at https://coronavirus.delaware.gov/vaccineinformation-for-ages-5-11/.

Latest data report: Delaware’s cancer mortality rates continue to decrease

Pediatric case is one of four confirmed flu cases of the 2021-2022 season A Kent County child under the age of 5 was one of the first two laboratory-confirmed influenza cases of the 2021-2022 flu season, the Division of Public Health (DPH) announced. The child, infected with influenza strain B, was hospitalized. The other case occurred in a 26-year-old Sussex County woman, with influenza strain A, who was not hospitalized.

Neither individual had received the flu vaccine.

Since then, the total number of lab-confirmed flu cases has risen to four.

"This first case of the flu is an excellent reminder for us to get our flu vaccine as soon as possible," said DPH Director Dr. Karyl Rattay. "We must not get lulled into a false sense of security with last year's unusually low case numbers.”

Delawareans resuming pre-pandemic activities, the flu is a definite threat to our health. Because hospitals and physicians' offices are already taxed with COVID-19 cases, we must do everything we can to prevent adding more to their burden and the flu vaccine is a very good start."

The flu vaccine is recommended for Delawareans 6 months of age and older and can be administered at the same time as the COVID-19 vaccine. It takes approximately two weeks after vaccination for antibodies that protect against influenza virus infection to develop in the body.

DPH is offering flu vaccine at community-based events where COVID-19 vaccine is offered; visit de.gov/getmyvaccine. Uninsured and underinsured people can find flu vaccine at Public Health clinics (https://dhss.delaware.gov/dhss/dph/fluclinics.html.)

Physician offices, many pharmacies, and some grocery stores also offer flu vaccine.

Children, older adults, and those who have chronic underlying medical conditions are most at risk for complications from the flu and are strongly encouraged to get vaccinated now.

The DPH Bulletin – November 2021

Delaware’s mortality rate for all cancer sites combined (all-site cancer) improved in most categories during the last decade, according to the Division of Public Health’s (DPH) annual data report, Cancer Incidence and Mortality in Delaware, 20132017. The state remains 15th-highest in the U.S. for the period 2013-2017, which is unchanged from 2012-2016. Delaware also remains second-highest nationally for all-site cancer incidence during the same period, which may be partly due to the state’s continued increases in early detection and screening.

This year’s report, presented to the Delaware Cancer Consortium on October 11, analyzes all-site cancer and eight site-specific cancer types: breast, colorectal, lung, cervical, kidney, leukemia, oral, and prostate. DPH also issued a compendium report, Census Tract-Level Cancer Incidence in Delaware, 2013-2017, which presents modified calculations and detailed maps with all-site cancer incidence rates by census tract.

For 2013-2017, the state’s all-site cancer mortality rate (171.0 deaths per 100,000 people) was higher than the U.S. rate (158.3 deaths per 100,000) and higher among both sexes. For all-site cancer incidence in 2013-2017, Delaware saw statistically higher rates (484.3 per 100,000) than the U.S. (435.0 per 100,000) and among both sexes.

Noticeable improvements exist among many racial and ethnic groups, likely due to Delaware’s health equity initiatives.

“In order to address the disparities that persist in cancer incidence and mortality, we must address the circumstances in which people are born, grow up, live, work, and age and the systems put in place to deal with illness,” said DPH Director Dr. Karyl Rattay. “These social determinants of health include housing and neighborhood conditions, educational and economic factors, transportation systems, social connections, and other social factors. We must look at the racial disparities across the cancer continuum from prevention to end-of-life care that result from differences in the social determinants of health as no longer endurable.”

Page 2 of 4 17

Delaware data by cancer type The following data were pulled from Cancer Incidence and Mortality in Delaware, 2013-2017: BREAST CANCER Delaware’s percentage of female breast cancer cases diagnosed at the local stage increased from 42% in 1980-1984 to 68% in 2013-2017.

CERVICAL CANCER In 2013-2017, Delaware ranked 20th in the U.S. for cervical cancer incidence, a six-place improvement from 14th in 2012-2016. Non-Hispanic Caucasians accounted for 70% of Delaware’s cervical cancer cases in 2013-2017.

COLORECTAL CANCER Between 2003-2007 and 2013-2017, incidence rates for colorectal cancer decreased by 26% in Delaware and 21% in the U.S. In the same period, mortality rates for colorectal cancer decreased by 21% both in Delaware and in the U.S.

Cancer Resources Risk factors, screening, state of diagnosis, data trends, and cancer survivorship are included in the Cancer Incidence and Mortality in Delaware, 2013-2017 report.

Learn how to prevent, detect, and treat chronic diseases and obtain assistance with a cancer screening. Visit the Healthy Delaware website at HealthyDelaware.org.

Delaware residents 18 and older who want help quitting smoking should contact the Delaware Quitline at 1-866-4091858 or http://www.quitsupport.com.

KIDNEY AND RENAL PELVIS CANCER From 2003-2007 to 2013-2017, mortality rates for kidney cancer increased 17% in Delaware females and decreased 15% in U.S. females.

Eligible Delaware adults can receive office visits, mammograms and clinical breast exams, Pap tests and screening tests for prostate, colorectal, and lung cancer when recommended by a doctor. Contact the Screening for Life Program at https://www.dhss.delaware.gov/dph/dpc/sf l.html or call 302-401-4212 to speak with a screening nurse navigator.

LEUKEMIA From 2003-2007 to 2013-2017, incidence rates for leukemia increased 19% in Delaware and increased 8% in the U.S.

Delaware Comprehensive Cancer Control Program, 302-744-1020, https://www.dhss.delaware.gov/dhss/dph/ dpc/cancer.html

LUNG AND BRONCHUS CANCER Non-Hispanic Caucasians accounted for 82% of lung cancer cases in 2013-2017. Hispanics had a lower lung cancer incidence rate than nonHispanic Caucasians and non-Hispanic African Americans.

Delaware Cancer Consortium, https://www.healthydelaware.org/Consortium

ORAL CAVITY AND PHARYNX CANCER From 2003-2007 to 2013-2017, incidence rates for oral cancer increased 18% in Delaware and increased 7% in the U.S., with a 19% increase in Delaware males and an 18% increase in Delaware females.

PROSTATE CANCER In 2013-2017, Delaware’s non-Hispanic African Americans had a much higher prostate cancer incidence rate compared to non-Hispanic Caucasians and Hispanics, as well as a higher prostate cancer mortality rate than non-Hispanic Caucasians.

The DPH Bulletin – November 2021 18 Delaware Journal of Public Health - December 2021

For population health, environmental and social determinant of health data at the smallest geographical area available, visit the My Healthy Community data portal at de.gov/healthycommunity.

Health Insurance Marketplace opens Delawareans seeking health insurance, especially those who have lost coverage, can shop for 2022 coverage through the Health Insurance Marketplace. The marketplace's ninth open enrollment period ends Saturday, Jan 15, 2022. Consumers can renew existing coverage or sign up for a new plan at www.HealthCare.gov. Coverage for enrollees who sign up by Dec. 15 and pay their first month's premium will take effect Jan. 1, 2022.

Page 3 of 4

2021 Communicable Diseases Health Summit to be held on December 13 The 2021 Communicable Disease Summit, cosponsored by the Delaware Academy of Medicine/ Delaware Public Health Association and the Division of Public Health, will be held on December 13 as a virtual event.

In-person attendees must show proof of COVID-19 vaccination upon entry.

Dr. Kate Smith, Program Manager of the Immunization Coalition of Delaware, will moderate.

Tropical Storm Isaias damaged many properties on August 4, 2020, such as these homes on New Burton Road in Dover. Pruning trees can lessen damage from severe weather. Photo by Donna Sharp.

Prune trees to withstand winter storms

The fee for health care professionals is $45 and the fee for non-health care professionals is $25. To register, visit https://delamed.org/cd2021/.

“Medicare & You” handbook available in Chinese, Korean, and Vietnamese

Pruning can strengthen trees and minimize damage from severe weather, such as high winds, ice, and snowstorms. While it is best to prune or trim trees in late winter, a tree’s growth may require immediate action.

The Centers for Medicare & Medicaid Services’ (CMS) “Medicare & You” handbook is now available in Chinese, Korean, and Vietnamese. Asian Americans currently represent the fourth largest demographic enrolled in Medicare.

Branches should be pruned if they obstruct visibility for vehicles or pedestrians, if they interfere with power lines, and if they might cause damage to a house or other structure. Determine if there are any dead trees or branches that could become airborne daggers during high winds. Safely remove them with pruners or a tree saw, following directions within the Delaware Department of Agriculture’s 2021 Tree Owner’s Manual.

The handbook is being released as part of this year’s Medicare Open Enrollment Period, which kicked off on December 7, 2021.

The Forest Service advises to hire an arborist if pruning cannot be done with both feet on the ground, or if a chainsaw is required. In addition: • Because electricity flows through branches, never prune trees or branches that are within 10 feet of utility lines. Contact the local utility company.

• Do not remove more than 25 percent of the tree’s live branches (and therefore leaves) at any one time.

To read the 2021 Tree Owner’s Manual, visit https://delawaretrees.com/blog/wpcontent/uploads/2021/03/Tree-Owners-Manual-2021-1.pdf.

To contact the Delaware Forest Service, call 1-800-282-8685 toll-free.

The DPH Bulletin – November 2021

Download the translated CMS handbooks at Medicare.gov or order them from 1-800-MEDICARE for free. Several other documents are available in 23 languages, including Chinese, Korean, and Vietnamese, at https://www.medicare.gov/aboutus/information-in-otherlanguages. These documents provide detailed information about Medicare basics, preventive services, supplemental insurance, and COVID-19 vaccine coverage.

Live assistance is available 24 hours a day, 7 days a week (except some federal holidays), both via Live Chat on Medicare.gov and by phone at 1-800-MEDICARE, which offers language interpreter services.

Page 4 of 4 19

The Genetic Testing Stewardship Program: A Bridge to Precision Diagnostics for the Non-genetics Medical Provider Morgan Thomas, M.G.C., C.G.C. Louise Amlie-Wolf, M.S., C.G.C. Laura Baker, M.G.C., C.G.C. Karen W. Gripp, M.D., F.A.C.M.G. Nemours Children’s Hospital

ABSTRACT Genetic/genomic testing can reveal important diagnostic information, provided the appropriate test is chosen and the results are interpreted accurately. Choosing an informative, cost-effective genetic testing strategy is a complex process. Nemours’ Genetic Testing Stewardship Program (GTSP) is a genetic counselor-staffed consultative service serving the Nemours Children’s Health (NCH) system. This program assists non-genetics providers and their patients access genetic testing for improved patient care and reduced costs. GTSP genetic counselors provide pre- and post-test genetic counseling, obtain informed consent, ensure complete documentation, and provide results interpretation/disclosure support for ordering providers. Implementation of this program began with genetic testing needs assessments and presentations about this novel service at subspecialty division meetings. GTSP expanded at NCH Delaware and NCH Orlando to include review of inpatient genetic testing for medical necessity. GTSP has experienced success from provider satisfaction and cost savings perspectives.

GTSP has produced cost savings of >$400,000, supporting financial sustainability of the program. Additionally, genetic counselors bill for visits, creating the foundation for a future revenue stream which is likely to increase as reimbursement for genetic counseling services improves. GTSP has become integral in the NCH system by improving patient access to genetic testing in a safe, efficient, effective manner.

INTRODUCTION

METHODS

Nemours Children’s Health created the Genetic Testing Stewardship Program (GTSP) in July 2018 as part of the Precision Medicine initiative. The objectives of GTSP include providing genetic counseling support to non-genetics providers while reducing inappropriate genetic test orders and ensuring the medical utility of ordered genetic testing. GTSP genetic counselors offer pre- and post-test genetic counseling, obtain informed consent, and interpret/disclose test results.

Place and Time

The GTSP is a consultative genetic counseling service with utilization management components. An on-call genetic counselor reviews genetic test requests received during business hours and assesses the medical necessity of the requested test.

The genetic counselor then reviews relevant patient history and discusses a recommended genetic testing strategy with the ordering provider to reach a mutually agreed upon plan. When a testing strategy is selected, the genetic counselor provides pre-test genetic counseling, if requested, and obtains informed consent (which is required by Delaware State law) before coordinating the sample collection. The genetic counselor will also ensure proper documentation of counseling, informed consent, and results in the electronic medical record, and will provide direct patient care for results disclosure when needed. Additionally, GTSP reviews all orders for inpatient genetic testing and provides intervention, in addition to the above-described services, when testing is deemed not medically necessary for the admission.

This intervention was targeted towards non-genetics clinicians ordering genetic testing at Nemours Children’s Hospital Delaware and aims to increase diagnostic yield and appropriate test utilization for the pediatric population.

20 Delaware Journal of Public Health - December 2021

GTSP was initiated at Nemours Children’s Hospital Delaware in Wilmington, Delaware in 2018 (previously known as Nemours/ Alfred I. duPont Hospital for Children) and currently operates at multiple sites including Nemours Children’s Hospital, Delaware, Delaware Valley satellite clinics, and Nemours Children’s Hospital, Florida.

Population

Purpose Non-genetics providers often order genetic testing independent of a trained genetics healthcare provider. However, literature suggests an increased error rate in genetic testing ordered without genetics support.1 The Medical Genetics workforce nationally is not sufficient to provide genetic services for all individuals requiring genetic testing.2 The risks associated with erroneous test ordering are numerous, and include reduced clinical relevance, missed diagnoses, incorrect interpretation and increased harm to patients due to improper patient care.1 Risks can be mitigated by including genetic counselors in genetic testing utilization management, which can significantly reduce costs to a healthcare system1 when inappropriate or incorrect orders are modified or cancelled.

Doi: 10.32481/djph.2021.12.007

Genetic counselors are healthcare providers who provide education about genetic conditions and genetic testing to patients.3 This information is provided to help patients and their families understand the risks, benefits and limitations of genetic testing in order to make an informed decision about proceeding with a specific genetic test. GTSP genetic counselors partner with non-genetics physicians, advanced practice nurses, and physician assistants to determine if genetic testing is necessary for a patient, and if so, what genetic testing approach is most appropriate and cost effective. Providers often know which patients would benefit from genetic testing, but are limited by their understanding of evolving testing technologies, access to and experience with laboratories offering testing, and understanding of legal requirements regarding informed and documented consent for genetic testing. Furthermore, providers often lack the administrative support to coordinate ordering, insurance coverage, and billing, as well as to the follow up on results.

Genetic counselors, along with a genetic counseling assistant, can support each of these steps. This allows patients to receive medically indicated genetic testing and genetic counseling ordered by non-genetics providers without a referral to the Medical Genetics Department, which often has a long wait list and may not be needed, depending on the indication for testing.

Lastly, GTSP genetic counselors offer pre- and post-test genetic counseling support to families undergoing genetic testing.

The support and information that genetic counselors provide is integral in helping patients through the decision-making process for genetic testing, as well as during and after results disclosure. Involving genetic counselors in informed consent discussions leads to increased patient knowledge about the testing they receive.3 Additionally, genetic counseling performed by a genetic counselor allows providers more time to focus on a patient’s medical subspecialty care without the additional burden of discussing genetic testing details during their appointment.

Genetic counselors are uniquely suited to improve patient care in pediatric healthcare.

Implementation

The precision medicine initiative at Nemours aims to tailor healthcare based on an individuals’ genetic and health factors.

Staff from medical genetics and genetic counseling recognized the potential value of a genetic testing stewardship program and worked with Nemours leadership at the medical and executive levels to secure funding through the Precision Medicine Initiative. This program design was based loosely on the very successful antibiotic stewardship program. Subsequently, a needs assessment was completed with hospital subspecialty divisions to ensure that the program met the varying needs of providers in different specialties, and to build relationships with the various stakeholders.

Original staffing for the program included a part time (0.5 FTE) genetic counselor manager and a full-time genetic counselor.

Oversight for the program is provided by an American College of Medical Genetics board-certified medical geneticist and pediatrician. During the implementation phase, GTSP staff offered educational presentations to hospital divisions to promote awareness of this new service. The program was well received, and quickly expanded to include a genetic counseling assistant, who is

integral in managing the clerical workload associated with genetic testing, scheduling, and patient communication tasks. Additional genetic counseling staff was hired at the equivalent of one additional full time genetic counselor and an interdepartmental partnership was formed with a part-time (0.5 FTE) genetic counselor dedicated to and funded by pediatric neurology. As of 2021, the GTSP employs the equivalent of 2.0 full time genetic counselors, 0.5 FTEs of genetic counseling manager, one fulltime genetic counseling assistant and 0.5 FTEs of neurology-funded specialty genetic counselor.

RESULTS During the first year of the program, electronic health record (EHR) tools were built to increase provider ease of access to the program and to allow for genetic test order review by the GTSP staff. When the program was initiated, providers could request program assistance in inpatient and outpatient settings through EHR order, email, phone or staff message. In the following year, GTSP added the automatic review of all inpatient genetic test orders for medical appropriateness and cost effectiveness. A 3-tier system to filter these orders was developed in partnership with the Epic EHR development team. Tier 1 tests are molecular tests that may fall outside the GTSP staff expertise, such as HLA typing or pharmacogenomic testing. Tests categorized as tier 2 are automatically routed to the GTSP inbox for review but do not require approval for ordering, such as Factor V Leiden testing and chromosome microarray. Tier 3 classification was reserved for high-cost tests with a high risk for result misinterpretation and high complexity consent process. These tests require approval by a GTSP counselor before ordering and trigger a corresponding EHR alert. This automated review process allowed for identification of high-risk cases and optimization of cost savings opportunities. Attention to relationship building and clinical partnership has led to an overwhelmingly positive reception from providers.

Nemours is a multistate healthcare system, and as staffing for GTSP has increased, the program has extended telehealth services to satellite clinics in PA, NJ, and DE. The program continues to grow and support cross campus collaboration with Nemours Children’s Hospital, Florida.

Evaluation

Since its inception in the last quarter of 2018, GTSP genetic counselors assisted with and reviewed testing for ~1900 cases.

About 25% were completed in the inpatient setting and 75% in the outpatient setting. When genetic testing was ordered, the genetic counselor provided pre- and post-test counseling in 79% of cases. This indicates a major shift in the burden of this work from the ordering provider to the genetic counseling team. The introduction of this service has been met with universal enthusiastic support by Nemours providers. A provider satisfaction survey distributed to Nemours providers utilizing the GTSP service from 2018 to 2020 revealed that providers were significantly more (p<0.0001; OR=86.1) comfortable with all aspects of the genetic testing and counseling process when in partnership with counselors from GTSP, and that almost all (n=41/45) were satisfied or very satisfied with the GTSP service.

Forty-two of the 45 providers indicated that the program had a positive impact on their practice. No providers indicated 21

a negative impact on their practice. When asked to describe their experience with the service in their own words, providers indicated that they were more willing to consider genetic testing for their patients with help from GTSP, that the program made genetic testing more accessible, and that the program allows for valuable genetic counseling services. One provider went so far as to call the program a “game changer for me in my practice.” It is clear that from the perspective of Nemours healthcare providers, the implementation of GTSP has been an unambiguous success.

counselors are not currently recognized by the Centers for Medicare and Medicaid as reimbursable providers, reimbursement for this code varies widely. Impending changes to federal legislation may make billable genetic counseling encounters a more reliable source of revenue. It is a future goal of the program to evaluate revenue generation in addition to cost savings produced by the program.

In addition to these qualitative provider facing improvements, GTSP aids in utilization management efforts by evaluating cases for cost effectiveness and necessity. Modifications to requested testing strategies were recommended in approximately 15% and cancellations of testing occurred approximately 25%. The most common reasons for modification of testing strategy were identification of a more cost-effective test or an improvement to the requested testing strategy based on the patient’s clinical presentation. Approximately 10% of cases were cancelled due to errors, lack of medical necessity, or requests for duplicated testing.

Other reasons for cancellation included deferral of genetic testing for further evaluation (medical genetics or other diagnostic studies necessary to determine proper testing strategy), patient lost to follow up, and families declining testing after proper counseling. In total, alterations to testing (including modifications and cancellations) led to an estimated $380,000 in savings in 2019.

This excludes testing not completed due to lack of family followup. An additional $87,000 of potential revenue captured was through insurance prior authorizations facilitated by GTSP.

In 2015, the United States Precision Medicine Initiative was announced with the long-term goal of expanding precision medicine to all areas of healthcare. In alignment with this goal, Nemours Children’s Health System prioritized the establishment of the Genetic Testing Stewardship Program. Access to genetic testing is an increasingly important component of precision medicine with implications for the diagnosis and treatment of rare and common disease. However, in 2015, 30% of genetics practices reported a wait time of over three months for a new patient visit; a steep increase from 10% of clinics reporting a three month wait time in 2005.2 This concerning trend highlights a severe access deficit for genetics services. The GTSP and non-genetic subspecialist partnership allows for expedient identification and testing of individuals with high suspicion for genetic disease, as well as appropriate triage to a medical geneticist as necessary.

On average, patients referred to GTSP are seen within 20 days of referral, and same day or next day services are available for time-sensitive indications. Programs such as the GTSP could significantly increase access to necessary diagnostic testing and genetic counseling services throughout the healthcare system.

Longitudinal analysis of GTSP case data has shown that the program has been successful in increasing access and proper utilization of genetic testing, allowing for proper consenting and counseling of patients, and reducing potential errors and unnecessary healthcare spending to a significant degree.

Adverse Effects

Implementation of the GTSP at Nemours highlighted inequities in access to genetics services and provided an opportunity to increase equity in access. Genetics services are typically more readily available at major academic medical centers, which may be prohibitive for individuals living in remote or rural communities. As Nemours is the only children’s hospital in the State of Delaware, this information is particularly applicable to Nemours. To combat this inequity, the GTSP has expanded their telehealth program to assist providers seeing patients in satellite clinics throughout the Delaware valley, and the service area of the program now extends to include Pennsylvania, New Jersey, Maryland, and in the future, Florida.

Though there have been few patient facing adverse effects relating to the implementation of the genetic testing stewardship program at Nemours, opportunities for provider education, improvements to the electronic medical record, and areas for increased compliance with state consent laws have been identified and are an active area of focus for the program.

Sustainability

The GTSP is largely self-sustaining, as the program led to an estimated $400,000+ in cost savings to the Nemours system annually. In addition to cost savings, genetic counseling is a billable service under its own CPT code. Because genetic 22 Delaware Journal of Public Health - December 2021

PUBLIC HEALTH SIGNIFICANCE

In addition to the access benefits that the GTSP has shown, genetic counselor involvement in genetic test utilization contributes to significant healthcare savings, increased quality of patient care and reduction of diagnostic errors. Currently, over 75,000 genetic testing products and an estimated 10,000 unique forms of testing are currently available to the medical community on a clinical basis.4 With this oversaturation of testing choices, providers are often overwhelmed when determining an appropriate genetic test for their patients. Previous studies have shown that providers without specialty training in genetics often make errors when ordering genetic testing and often are underequipped to provide accurate and comprehensive interpretation of results.5 This can lead to healthcare waste, and, most importantly, missed or misinterpreted diagnoses. Genetic counselors are uniquely trained to navigate the complex landscape of genetic testing and assist non-genetics providers in making the most effective diagnostic decisions for their patients.

CONCLUSION The GTSP model demonstrates a highly effective and sustainable framework for integrating next generation genetic and genomic diagnostics into pediatric specialty care. This may translate into other areas of healthcare and should be considered by institutions intending to prioritize genetic and genomic diagnostics in primary and specialty care. This approach utilizes the combined expertise of pediatric subspecialists and genetic counselors to increase access to genetics services, improve quality of patient care, and reduce unnecessary healthcare spending.

These authors can be contacted at genetic.testing@nemours.org

REFERENCES 1. Mathias, P. C., Conta, J. H., Konnick, E. Q., Sternen, D. L., Stasi, S. M., Cole, B. L., . . . Dickerson, J. A. (2016, August).

Preventing genetic testing order errors with a laboratory utilization management program. American Journal of Clinical Pathology, 146(2), 221–226. https://doi.org/10.1093/ajcp/aqw105 2. Maiese, D. R., Keehn, A., Lyon, M., Flannery, D., & Watson, M., & the Working Groups of the National Coordinating Center for Seven Regional Genetics Service Collaboratives. (2019, August). Current conditions in medical genetics practice. Genet Med, 21(8), 1874–1877. https://doi.org/10.1038/s41436-018-0417-6 3. Madlensky, L., Trepanier, A. M., Cragun, D., Lerner, B., Shannon, K. M., & Zierhut, H. (2017, June). A rapid systematic review of outcome studies in genetic counseling. Journal of Genetic Counseling, 26(3), 361–378. https://doi.org/10.1007/s10897-017-0067-x 4. Conway, M. E., Kalejta, C. D., Sternen, D. L., & Singh, I. R. (2020, March 9). The importance of genetics experts in optimizing genetic test orders through prospective and retrospective reviews. American Journal of Clinical Pathology, 153(4), 537–547. https://doi.org/10.1093/ajcp/aqz188 5. Haga, S. B., Kim, E., Myers, R. A., & Ginsburg, G. S. (2019, May 24). Primary care physicians’ knowledge, attitudes, and experience with personal genetic testing. Journal of Personalized Medicine, 9(2), 29. https://doi.org/10.3390/jpm9020029

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Molecular Genetic Testing for Kidney Disorders During the COVID-19 Pandemic Susan M. Kirwin Katherine M. Robbins, Ph.D. Kathleen M.B. Vinette Lee Hirata Karen W. Gripp, M.D. Vicky L. Funanage, Ph.D. Nemours Children’s Health, Molecular Diagnostics Laboratory

ABSTRACT Chronic kidney disease (CKD) has major morbidity and mortality for children and adults. While in adults CKD often is associated with diabetic complications, genetic variants can be the underlying cause in both populations.

Beginning in 2016 with the emergence of more affordable next-generation sequencing (NGS) technologies, the Molecular Diagnostics Lab at Nemours Children’s Hospital-Delaware developed the first clinically actionable pediatric NGS kidney panel comprised of 46 genes including APOL1. Apolipoprotein L1 (APOL1) associated nephropathy is reported along a spectrum of non-diabetic kidney disease. It is significantly associated with two “risk alleles” defined as G1 and G2 and typically found in individuals of African descent. In early 2020, as COVID-19 spread across the globe, reports of patients with kidney failure began to emerge. A collapsing glomerulopathy in Black patients with COVID-19 was found to be associated with the APOL1 predisposition of the known G1 and/or G2 risk variants. We identified genetic variants in 11 genes (NPHS1; NPHS2; LAMB2; WT1; COL4A4; COL4A5; COQ8B; CUBN; MEFV; PMM2; SMARCAL1) known to be associated with pediatric onset nephrotic syndrome, or detection of the high-risk haplotype of APOL1, in the majority (78%) of patients tested.

These clinically actionable results guided medical care and improved patient outcomes.

INTRODUCTION

Chronic kidney disease (CKD) has major morbidity and mortality for children and adults. While in adults it often is associated with diabetic complications, genetic variants can be the underlying cause in children and adults alike. With a prevalence of 1.5 - 3 per million, many of the children under age 16 years diagnosed annually with CKD have an underlying genetic cause or predisposition.1–3 While linked to morbidity and mortality, CKD is also associated with an increase in cardiovascular disease.

Focal segmental glomerulosclerosis (FSGS) is a pathologic finding in many renal disorders presenting with proteinuria and declining renal function. Nephrotic syndrome is typically defined by edema, hypoalbuminemia, hyperlipidemia, and proteinuria, and can lead to FSGS and end-stage renal disease (ESRD). These patients can be classified by their response to steroid treatment: steroid sensitive nephrotic syndrome (SSNS) or steroid resistant nephrotic syndrome (SRNS). In children and young adults, approximately 80% respond to steroid treatments.

The remaining SRNS population can progress to CKD and ESRD. Next-generation sequencing (NGS) based sequencing for genetic variants involved in SRNS or FSGS can inform diagnosis and guide the healthcare provider in treatment.

Collapsing glomerulopathy (CG) is a subtype of FSGS and reported to be the most common in individuals of African 24 Delaware Journal of Public Health - December 2021

descent.4 Although CG is not common in young children, 30% of pediatric patients with FSGS have an underlying genetic cause identifiable through next generation sequencing.

Monogenic forms of FSGS are associated with variants in genes expressed in either the podocyte or the glomerular basement membrane. Pediatric forms are typically categorized as: congenital onset (NPHS1, NPHS2, WT1, LAMB2, PLCE1, LMX1B), infantile onset (ACTN4, COQ2, COQ6), or adolescent onset (LAMB2, COL4A3, COL4A4, COL4A5). In addition, several syndromic disorders (Alport syndrome, Denys-Drash syndrome, Alstrom syndrome) often present with kidney disease.

Variants in the gene apolipoprotein L1 (APOL1) are found in individuals of sub-Saharan African ancestry, and these risk variants display a strong association with kidney disease.5 The APOL1 risk haplotypes are defined as G1, comprised of two missense changes (p.Ser358Gly, rs73885319 + p.Ile384Met, rs60910145) and a 6 base-pair deletion (p.Asn388_Tyr389del, rs71785313) resulting in a deletion of two amino acids, designated G2. The G1 variants are in almost complete linkage disequilibrium and found on the same chromosome. The highrisk genotypes are designated G1/G1, G1/G2, and G2/G2 and are considered contributors to the incidence of ESRD in Black children and adults.

Doi: 10.32481/djph.2021.12.008

Approximately 13% of Black Americans carry two risk alleles, markedly increasing their risk for a wide range of nondiabetic kidney disease. Yusuf et al report the frequency of G1 in the U.S. at 20-42%, with G2 detected at approximately 15%.6 These risk alleles have also been reported in populations from western Africa, African and Hispanic Caribbean, and Brazilian and South American ancestry.6 Renal disease in individuals with two APOL1 risk alleles has been described as a “two hit” disease. APOL1 risk variants represent the “first hit,” with the “second hit” being an external trigger such as virus exposure (HIV, CMV, parvovirus B19), medication (interferons, pamidronate, anabolic steroids), or autoimmune disease.4,7,8 Throughout the SARS-CoV2 pandemic, reports of individuals with COVID-19 and acute kidney injury (AKI) with high levels of proteinuria, and in some cases collapsing glomerulopathy, emerged from across the globe. Caza et al report 37% of patients hospitalized with confirmed COVID-19 were diagnosed with AKI.9

METHODS The Molecular Diagnostic Laboratory (MDL) utilized a custom panel designed by the SureSelect Design software (Agilent Technologies, Inc.) to analyze genomic DNA isolated from whole blood (Qiagen). Genomic DNA was sheared using a M220 Ultrasonicator (Covaris, Inc.) prior to library preparation and target enrichment by using the SureSelect XT kit protocol (Agilent Technologies, Inc.). Prepared libraries enriched for the coding exons and exon boundaries of genes associated with steroid resistant nephrotic syndrome and related disorders were sequenced using a MiSeq System (Illumina, Inc.).

Data analysis was performed using NextGENe Sequence Analysis Software (Version 2.4.2.2, SoftGenetics, LLC.) to align patient data to reference sequences (hg19/GRCh37).

Confirmation of all likely pathogenic or pathogenic variants, as well as variants of uncertain significance, was performed using a standard PCR protocol followed by Sanger sequencing (BigDye Terminator v.3.1) and analyzed on a 3500 Genetic Analyzer (ThermoFisher/Applied Biosystems). Sequences were analyzed using MacVector software (MacVector, Inc.). Regions known to have low coverage (<30X) were also analyzed using standard PCR and Sanger sequencing protocols. All variations from the reference sequence(s) were checked against current literature, the NCBI SNP database, and computational and splice predictions websites. Mutation nomenclature follows guidelines of the Human Genome Variation Society (http://www.hgvs.org).

Single gene testing for APOL1 G1/G2 was performed by PCR of the last exon of APOL1, followed by bidirectional sequencing, and compared to the known APOL1 reference sequence using MacVector software.

Variant Analysis

Variant classification follows the American College of Medical Genetics (ACMG) Standards and guidelines for the interpretation of sequence variants. All genetic variants possibly associated with phenotype and incidental findings were classified using NextGENe software (SoftGenetics, LLC).

Variants classified as pathogenic or likely pathogenic were

reported with gene variant assessments. Variants of unknown significance (VUS) were also reported with the information that there was insufficient evidence to support either a likely benign or likely pathogenic classification. APOL1 single gene sequencing was analyzed by alignment to the APOL1 reference sequence and assessed for the G1 or G2 variant.

RESULTS The NGS panel was designed to target 46 genes associated with the rare SRNS disorders. In the small cohort of pediatric patients screened with this FSGS panel over the course of the past two years, we have identified two patients who were initially diagnosed with congenital nephrotic syndrome, at 5 months and 14 months of age respectively. The first patient (unilateral nephrectomy and pathology consistent with mesangial sclerosis) was homozygous for a known pathogenic variant in NPHS1: c.3250dupG, leading to a substitution of glycine for valine and premature stop codon encountered with exon 24. The second child was first diagnosed around 14 months of age with a two-week history of swelling, edema, nephrotic range proteinuria and hypertension. A renal biopsy was inconclusive. The patient underwent research testing and found to have an autosomal dominant WT1 variant c.1384C>T leading to a substitution of tryptophan for an arginine, and the MDL confirmed this result with our clinical NGS panel.

A rare disorder was identified in a 14-year-old with a homozygous variant cubilin (CUBN) associated with Imerslund-Grasbeck syndrome (Megaloblastic anemia 1).

Variants in CUBN cause vitamin B12 malabsorption and proteinuria, and most reported variants are found in the binding domain important for renal protein reabsorption.

The identified CUBN variant, a 7 base pair deletion leading to a frameshift and premature stop within exon 45, was not previously described in a homozygous state, but cited in the literature in compound heterozygosity with another pathogenic variant. The medical management for this patient was changed due to the confirmation of this CUBN variant.

The NPHS2 gene encodes the slit diaphragm protein podocin, and variants in this gene are among the most common causes of childhood and adolescent nephrotic syndrome.10 A 7-yearold with FSGS was compound heterozygous for a known pathogenic variant within exon 7 of NPHS2, and a second variant with pathogenicity dependent upon the location of the first variant. This exon 5 variant replaces an arginine with a glutamine and is reported with variable frequency in European, South Asian, African, and Latino populations. The pathogenicity of the exon 5 missense variant is reported to be dependent upon a second variant. It is considered pathogenic only when it is located in trans with another variant within exon 7 or 8. The pathogenic association is reported to cause a less severe phenotype with slowly progressive FSGS. Alport syndrome (AS), caused by variants in the type IV collagen genes (COL4A3, COL4A4, COL4A5) can be phenotypically diverse with isolated kidney disease, or progressive disease including extrarenal abnormalities with hearing loss and ocular anomalies. Approximately 85% of 25

Alport syndrome is X-linked (COL4A5) with autosomal recessive inheritance (COL4A3, COL4A4) and rare autosomal dominant cases (COL4A3) comprising the remaining 15%.

Two adolescents were found to carry type IV collagen gene variants. The first patient had a history of FSGS (proteinuria, hyperkalemia, and hyponatremia). This same COL4A4 variant had previously been detected in a parent who was reportedly asymptomatic. The second individual diagnosed with Alport syndrome had a history of hematuria, and proteinuria. A variant in the X-linked COL4A5 affected a highly conserved glycine residue in the triple helical region of the COL4A5 protein, where pathogenic missense variants frequently occur.

The high-risk APOL1 haplotypes were detected in several pediatric patients tested by our NGS panel. For one individual with FSGS, previous testing at another laboratory did not provide a molecular diagnosis as APOL1 was not included on the panel. Additional testing at the MDL confirmed a homozygous G2/G2 genotype, therefore explaining the patient’s phenotype.

Overall, 78% of the patients tested had a genetic variant which explained their clinical phenotype with the APOL1 and CUBN genes representing the highest proportion of variants.

As shown in figure 1, eighteen patients were screened for genetic variants in the NGS panel. Fourteen patients were found to carry at least one relevant genetic variant, and the frequency distribution of the affected genes is shown.

Pathogenic or likely pathogenic variants were associated with the following genes: APOL1, apolipoprotein 1; COL4A4/ COL4A5 type IV collagens alpha 4 and 5; COQ8B, co-enzyme Q 8B; CUBN, cubilin; LAMB2, laminin beta-2; MEFV, familial Mediterranean fever; NPHS1, nephrin; NPHS2, podocin; PMM2, phosphomannomutase-2; SMARCAL1, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a like 1; WT1, Wilms tumor suppressor 1.

FSGS Gene Varients in Pediatric Patients

Figure 1. Results of next-generation sequencing (NGS) testing in patients referred for FSGS genetic evaluation.

26 Delaware Journal of Public Health - December 2021

Genotype testing for APOL1 risk alleles is orderable as either a single gene test to confirm risk allele status, or as part of the 46 gene NGS kidney disease panel. Over the course of the pandemic, we have seen an increased interest in APOL1 testing.

As new information emerged that collapsing glomerulopathy was associated in Black patients presenting with COVID-19 and renal issues, the APOL1 gene was likely considered more frequently in clinical requests for diagnostic testing.

In samples received in the MDL from March 2020 – October 2021 for APOL1 genotyping, 30% were positive for two risk alleles, and an additional 39% carried one risk allele. These numbers align with the overall APOL1 testing profile for individuals with one or two risk alleles in all samples tested in the MDL since 2014. This pre-disposition to renal disease has been highlighted during the pandemic, as Black Americans are at higher risk due to their genetic susceptibility associated with the APOL1 high-risk genotype.

DISCUSSION We identified genetic variants in 11 genes (NPHS1, NPHS2, LAMB2, WT1, COL4A4, COL4A5, COQ8B, CUBN, MEFV, PMM2, SMARCAL1) associated with pediatric onset nephrotic syndrome, as well as detection of the high-risk haplotype of APOL1. While NGS panels are an appropriate method for the molecular evaluation of nephrotic syndrome, single gene testing for some disorders (such as APOL1-related nephropathy) remain a relevant screening tool. Clinical testing has previously shown that using NGS for detection of multiple monogenic diseases adds to the diagnostic yield, and can lower the turnaround time for molecular diagnoses, thereby improving care. Differentiating FSGS into SSNS and SRNS can improve clinical management and outcomes, by decreasing exposure to ineffective treatments and prompt use of more appropriate therapies.

In a 2021 consensus statement on APOL1, Freedman et al. determined that APOL1-associated nephropathy includes a range of kidney diseases, which may be present in children as FSGS, or may appear later in life (Hypertensive nephrosclerosis, NDCKD), or after exposure to a “second hit” (autoimmune disease, HIV, another comorbidity).11 Although most individuals with two risk alleles will not develop renal disease, much is unknown regarding the involvement of viral exposure such as SARS-CoV2.12 COVID-19 associated glomerulopathy is discussed in 37 peer-reviewed articles in PubMed (https://pubmed.ncbi.nlm.nih.gov/?term=COVID-19+and+APOL1), and more than 500 articles mention COVID-19 and AKI. While most people experience mild or moderate COVID-19, approximately 5% suffer severe symptoms, including respiratory distress, fatigue, muscle and joint pain, headache, and loss of taste or smell. Other affected organ systems include heart, brain, and kidneys with increased proteinuria and AKI. Throughout the pandemic, analyses of federal, state, and local data continue to indicate that Black and Hispanic patients suffered a disproportionate burden of COVID-19 cases and deaths. Large disparities in the number of COVID-19 cases and deaths in Black communities may be related to socioeconomic factors, but genetic predisposition to AKI

and renal insufficiency could contribute to this burden. Early identification of at-risk patients could lead to proactive drug therapy lessening the impact of COVID-19, for example through use of monoclonal antibodies or the protease inhibitors currently under investigation.

4. Nicholas Cossey, L., Larsen, C. P., & Liapis, H. (2017, August). Collapsing glomerulopathy: A 30-year perspective and single, large center experience. Clinical Kidney Journal, 10(4), 443–449. https://doi.org/10.1093/ckj/sfx029

PUBLIC HEALTH SIGNIFICANCE

5. Genovese, G., Friedman, D. J., Ross, M. D., Lecordier, L., Uzureau, P., Freedman, B. I., . . . Pollak, M. R. (2010, August 13). Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science, 329(5993), 841–845. https://doi.org/10.1126/science.1193032

The ability to diagnose and monitor renal disease progression in the context of comorbidities, such as obesity, diabetes, hypertension, and infectious diseases, has become a public health focus that will benefit from NGS testing strategies.

Future considerations, including testing availability for vulnerable populations, is critical in order to monitor individuals with renal predisposition and a high-risk genotype.

Since 2020, numerous studies reported that patients with two APOL1 risk alleles have an increased likelihood for collapsing glomerulopathy, with COVID-19 representing the “second hit.” Shetty et al reported that a single APOL1 risk allele may be associated with an increased risk of COVID-19 associated nephropathy.12 Knowing that 13% of Black Americans are at high risk of kidney disease due to the APOL1 risk alleles, how do we ensure that underserved communities at the highest risk of CKD are prioritized for COVID-19 testing and treatment? If a healthcare provider is unaware that an individual is positive for risk alleles, they would be unprepared for rapid progression to end stage kidney disease.11 Implications for the Black communities would be to identify those individuals who would most benefit from COVID-19 vaccination and early treatment opportunities.

Consequently, long term outcomes are unknown regarding COVID-19 collapsing glomerulopathy.

ACKNOWLEDGEMENTS We wish to acknowledge support from Erin and Christopher Lee and the Piper’s Kidney Bean Foundation for the development of the NGS gene panel in the MDL and Dr. Joshua Zaritsky for his insightful discussions during the development of the SRNS panel. We thank Morgan Thomas, genetic counselor with the Molecular Diagnostics Laboratory, for assistance with gene variant analysis.

These authors can be contacted at susan.kirwin@nemours.org

REFERENCES 1. Whyte, D. A., & Fine, R. N. (2008, October). Chronic kidney disease in children. Pediatr Rev, 29(10), 335–341. https://doi.org/10.1542/pir.29-10-335 2. Harshman, L. A., & Zepeda-Orozco, D. (2015).

Genetic considerations in pediatric chronic kidney disease. Journal of Pediatric Genetics, 5(1), 43–50. https://doi.org/10.1055/s-0035-1557111

6. Yusuf, A. A., Govender, M. A., Brandenburg, J.-T., & Winkler, C. A. (2021, April 26). Kidney disease and APOL1. Human Molecular Genetics, 30(R1), R129–R137. https://doi.org/10.1093/hmg/ddab024 7. Freedman, B. I., Divers, J., & Palmer, N. D. (2013, December). Population ancestry and genetic risk for diabetes and kidney, cardiovascular, and bone disease: Modifiable environmental factors may produce the cures. Am J Kidney Dis, 62(6), 1165–1175. https://doi.org/10.1053/j.ajkd.2013.05.024 8. Velez, J. C. Q., Caza, T., & Larsen, C. P. (2020, October).

COVAN is the new HIVAN: The re-emergence of collapsing glomerulopathy with COVID-19.

Nature Reviews. Nephrology, 16(10), 565–567. https://doi.org/10.1038/s41581-020-0332-3 9. May, R. M., Cassol, C., Hannoudi, A., Larsen, C. P., Lerma, E. V., Haun, R. S., . . . Caza, T. N. (2021, August 3). A multi-center retrospective cohort study defines the spectrum of kidney pathology in Coronavirus 2019 Disease (COVID-19). Kidney International, 1303-1315. https://doi.org/10.1016/j.kint.2021.07.015 10. Sadowski, C. E., Lovric, S., Ashraf, S., Pabst, W. L., Gee, H. Y., Kohl, S., . . . Hildebrandt, F., & the SRNS Study Group.

(2015, June). A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol, 26(6), 1279–1289. https://doi.org/10.1681/ASN.2014050489 11. Freedman, B. I., Burke, W., Divers, J., Eberhard, L., Gadegbeku, C. A., Gbadegesin, R., . . . Blacksher, E. (2021, April 14). Diagnosis, education, and care of patients with APOL1-associated nephropathy: A Delphi consensus and systematic review. J Am Soc Nephrol, 32(7), 1765–1778. https://doi.org/10.1681/ASN.2020101399 12. Shetty, A. A., Tawhari, I., Safar-Boueri, L., Seif, N., Alahmadi, A., Gargiulo, R., . . . Quaggin, S. E. (2021, January). COVID-19-associated glomerular disease. J Am Soc Nephrol, 32(1), 33–40. https://doi.org/10.1681/ASN.2020060804

3. Amlie-Wolf, L., Baker, L., Hiddemen, O., Thomas, M., Burke, C., Gluck, C., . . . Gripp, K. W. (2021, April).

Novel genetic testing model: A collaboration between genetic counselors and nephrology. American Journal of Medical Genetics. Part A, 185(4), 1142–1150. https://doi.org/10.1002/ajmg.a.62088 27

The DPH Bulletin

From the Delaware Division of Public Health

October 2021 Providers administering booster doses of Pfizer-BioNTech COVID-19 vaccine Vaccine providers can now administer booster doses of the Pfizer-BioNTech COVID-19 vaccine to certain populations recommended by the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices.

Drive the Monster Mile and receive COVID-19 vaccine on October 16 and 17

Up to 800 drivers who pre-register for a COVID-19 vaccination at Dover International Speedway as part of the “Race to End COVID” can drive two laps on the Monster Mile. The free event is sponsored by Dover International Speedway, the Delaware Division of Public Health (DPH) and the CDC Foundation.

Vaccination appointments – with or without driving the track – are available on Saturday, October 16, 2021 between 10:00 a.m. and 5:00 p.m. and on Sunday, October 17, 2021 between 8:00 a.m. and 5:00 p.m. Moderna, Pfizer-BioNTech, and Johnson & Johnson/Janssen COVID-19 vaccines are offered for first or second doses and the additional doses recommended for some groups. Testing (without driving) is also available. Pre-register at https://www.racetoendcovid.org/event/doverinternational-speedway/.

Drivers ages 16 and older with a valid driver’s license, who are vaccinated that weekend, can drive their own vehicle behind the track’s pace car in groups of up to 25 vehicles.

Get vaccinated for flu by October 31

The Division of Public Health (DPH) recommends that Delawareans get their annual flu vaccinations by October 31. Those who did not yet receive a COVID19 vaccination can get the flu vaccine and the COVID-19 vaccine during the same visit.

Flu vaccines are available at pharmacies, participating medical provider offices, and Federally Qualified Health Centers, and DPH’s communitybased COVID-19 vaccination events. Individuals without insurance or those on Medicaid or Medicare may receive flu and COVID-19 vaccinations at Public Health clinics.

For more information about flu vaccines in Delaware, visit flu.delaware.gov or call 1-800-282-8672.

28 Delaware Journal of Public Health - December 2021

Based on CDC recommendations, the following people should receive a booster shot of PfizerBioNTech’s COVID-19 vaccine at least six months after their second dose of Pfizer-BioNTech: • People 65 years and older and residents in longterm care settings • People age 50 to 64 years with underlying medical conditions, which include but are not limited to: cancer, chronic heart, lung, and kidney diseases; dementia, diabetes, down syndrome, HIV, overweight and obesity, pregnancy, organ transplants, and stroke.

CDC recommends the following individuals may also receive Pfizer-BioNTech’s booster shot: • People age 18 to 49 years with underlying medical conditions (the same categories as mentioned above), based on their individual benefits and risk.

• People age 18 to 64 years who are at increased risk for COVID-19 exposure and transmission because of occupational or institutional setting, including health care workers, teachers and day care staff, grocery workers and those in homeless shelters or prisons, among others.

Delawareans with certain Donald A. Williams of immunocompromising Wilmington gets a COVIDconditions including those 19 vaccine in February who have received organ 2021. DPH photo. or stem cell transplants, are undergoing treatment for HIV or cancer, or who are taking medication that suppresses the immune system, are currently eligible to receive an additional (third dose) of either Pfizer or Moderna vaccines if their second dose was administered at least 28 days prior.

Visit de.gov/getmyvaccine for vaccine providers.

Toothbrushing books gifted to pediatricians Literacy and good oral health habits for very young children are being promoted by the Division of Public Health’s Bureau of Oral Health and Dental Services (BOHDS) and the Delaware Chapter of the American Academy of Pediatrics (DEAAP). The DEAAP recently established an Early Literacy Committee tasked with engaging and supporting Delaware primary care pediatricians to promote early literacy from birth to five years.

The organizations are distributing the Brush, Brush, Brush book to pediatric practices that are implementing the evidence-based Reach Out and Read (ROR) literacy program. The book, to be distributed during the 12-month well-child visit, promotes healthy habits using rhyme to engage and inspire little ones to brush their teeth. Its back cover has a sticker with the BOHDS’ Help Line to help families find a dentist for their child by age 1.

“The age 1 dental visit creates an opportunity for early identification of any developmental issues and preventive needs,” said Dr. Nick Conte, DPH dental director. “More importantly, it helps to foster a home environment where oral health is valued, and families have the knowledge and skills necessary to stay healthy and decay free.”

Pediatric practices expressing an interest in distributing the book will be contacted by a dental hygienist who will coordinate book delivery, engage in oral health conversations around available resources and supplies; and training for risk assessment and fluoride varnish application, as requested by the practice.

Stacey G. Fox, MD, FAAP, Chair of the DEAAP Early Literacy Committee said the fun gift provides two essential messages simultaneously: the importance of reading with your child every day and how to keep their brand-new teeth healthy and strong.

COVID-19 vaccination helps protect kids from infection and hospitalization Positive COVID-19 cases in children are rising statewide, especially in areas with low vaccination rates. The Division of Public Health (DPH) reports that as of October 10, 2021, the rate of positive COVID-19 cases per 10,000 population among school age children (5 to 17 years) is 1,299.7 in New Castle County, 1,173.7 in Kent County, and 1,377.6 in Sussex County. According to My Healthy Community, 48.1 percent of 12 to 17 year-old Delawareans were fully vaccinated for COVID-19 as of October 10, 2021.

“If we can prevent children from becoming infected, we should,” said DPH Director Dr. Karyl Rattay, a board-certified pediatrician. “Vaccination is our best tool to prevent COVID-19 infections and unnecessary suffering. Wearing face masks helps protects very young children who cannot yet be vaccinated.”

COVID-19 infection in some children can be so severe that they require hospitalization.

While children with underlying health conditions are most at risk for severe illness, approximately 30 percent of children hospitalized with COVID-19 in the U.S. have no underlying health condition. At least 430 children in the U.S. have died from COVID-19.

Also of concern is Multisystem Inflammatory Syndrome in children (MIS-C), a rare but serious condition associated with COVID-19 that requires hospital care. The Centers for Disease Control and Prevention reports 5,217 MIS-C cases nationwide and 46 deaths since reporting began in 2020. For more information about MIS-C, visit https://www.cdc.gov/mis/mis-c.html.

Click here for a list of COVID-19 vaccination sites.

For dental resources in Delaware, visit https://dhss.delaware.gov/dph/hsm/files/dentalresour ceguide.pdf. For assistance locating a dentist, call the Oral Health Services Help Line at 302-622-4540.

The DPH Bulletin – October 2021

Page 2 of 3 29

Eat fruits, vegetables, and healthy foods to reduce anxiety and boost immunity Consuming ample amounts of fruits, vegetables, and other healthy foods every day can reduce anxiety and boost immunity. The Division of Public Health’s Health Promotion and Disease Prevention Section recommends trying these dietary suggestions from Harvard University: • Beans, fruits, berries, nuts, vegetables, ginger, and turmeric are antioxidants which can help support your immune system and lower anxiety.

• Citrus fruit and red bell peppers are both rich in vitamin C, which in some studies has been shown to support the immune system.

• Spices from ginger, garlic, turmeric, and capsaicin (from chili peppers) are immunity boosters and can be easily added to soups, stews, stir-frys, or salad and salad dressings.

• Stress can deplete magnesium levels, so eat magnesium-rich foods like legumes, nuts, seeds, and leafy greens to feel calmer and support the immune system.

When someone begins to feel increased stress and tension, they should avoid drugs and alcohol which can create additional problems and increase stress levels. Eating healthy, exercising, and getting plenty of sleep are recommended for those for feel anxious or stressed. Instead of over-indulging on a treat you are trying to avoid, vent to a “stress buddy.”

Visit Harvard University at https://www.health.harvard.edu/blog/eating-duringcovid-19-improve-your-mood-and-lower-stress2020040719409) and https://www.health.harvard.edu/blog/nutritionalstrategies-to-ease-anxiety-201604139441.

For more information about healthy diets, read the 9th Edition of the Dietary Guidelines for Americans, 20202025, December 2020, recently released by the U.S. Department of Agriculture and U.S. Department of Health and Human Services.

For tips on coping with stress, visit the CDC at https://www.cdc.gov/violenceprevention/publichealthi ssue/copingwith-stresstips.html.

The DPH Bulletin – October 2021 30 Delaware Journal of Public Health - December 2021

Felicia Cruz, RN, APRN, AG-CNS, RN-BC, a geriatric clinical nurse specialist with Bayhealth provides information and giveaways about preventing falls to Mary Riordan, 69, of Dover.

The Falls Prevention Team organized a resource fair at the Modern Maturity Center on September 22. Photo by Donna Sharp.

Falls Prevention Team shares advice Falls can be disabling and are the leading cause of traumatic brain injuries in the United States, particularly among older adults and young children, according to the Mayo Clinic.

The Delaware Coalition for Injury Prevention’s Falls Prevention Team advises seniors to get regular vision and hearing checkups, eat nutritious foods and beverages, stay hydrated, get regular exercise, and discuss their fall risk with their health care provider.

Delawareans of all ages should wear shoes that fit well and are in good condition. Canes and walkers should be fitted to the user.

The Falls Prevention Team also recommends keeping homes, yards, and public areas clutter free and maintaining walkways to ensure a smooth, nonslippery surface. Use motion-activated lights indoors and outdoors when possible or use night lights inside.

Install handrails, ramps, and automatic doors.

Enroll older Delawareans in classes to improve coordination and balance. For a schedule of A Matter of Balance© classes, call Volunteer Delaware 50+ at 302-255-9882 in New Castle County and 302-5153020 in Kent and Sussex counties. ChristianaCare offers BingoCize, an evidence-based program integrating Bingo and exercise, and ThinkFirst to Prevent Falls©, which can be done virtually or in person. To schedule, contact injuryprevention@christianacare.org.

To learn more about preventing falls, visit the CDC at https://www.cdc.gov/steadi/index.html and the National Council on Aging at https://www.ncoa.org.

Page 3 of 3

The DPH Bulletin – Special flu edition From the Delaware Division of Public Health

October 2021

Find flu vaccine in many places such as DPH’s COVID-19 vaccination sites Flu vaccines are available to the public from pharmacies, participating medical providers, DPH clinics, and Federally Qualified Health Centers.

Flu season is here; get vaccinated The best way to prepare for the 2021-22 flu season is for all Delawareans 6 months of age and older to get their annual flu vaccine, preferably before winter begins. When large numbers of the population get flu vaccinations, they protect vulnerable individuals from flu illness, hospitalization and death. That keeps people from overwhelming emergency departments and hospitals with flu illness.

Vaccination is especially important for people at higher risk of developing serious flu complications, such as those with chronic respiratory conditions, blood disorders, diabetes, heart disease, neurologic conditions, obesity, and weakened immune systems.

Delawareans with chronic health conditions should closely manage their health to avoid unnecessary medical visits and hospitalizations during flu season.

Children younger than 5 years old, older adults, pregnant women, and those who have chronic underlying medical conditions are most at risk from flu complications and are strongly encouraged to get vaccinated now. The Division of Public Health (DPH) also urges vaccination for those who live or work with infants under 6 months of age, as well as those who live or work in congregant settings such as long-term care and correctional facilities.

Individuals without insurance or those on Medicaid or Medicare may receive vaccines for flu and COVID-19 at Public Health clinics. In addition, flu and COVID-19 vaccines are available for all Delawareans, regardless of insurance status, at DPH’s community-based COVID-19 vaccination events. A list of DPH’s community-based vaccination locations can be found at de.gov/getmyvaccine.

Updated guidance from the CDC allows those who have not yet received a COVID-19 vaccination to get both the flu vaccine and the COVID-19 vaccine during the same visit, and even in the same arm!

For more information about flu vaccines in Delaware, visit flu.delaware.gov or call 1-800-282-8672.

More ways to prevent flu • Avoid close contact with sick people.

• Cover coughs and sneezes with a tissue, or cough or sneeze into your inner elbow.

• Wash hands often with soap and water for 20 seconds or use hand sanitizer.

• Do not touch your eyes, nose, and mouth.

• Clean and disinfect frequently touched surfaces.

• If sick with flu-like illness, stay home for 24 hours until the fever is gone without use of fever-reducing medication. If symptoms worsen, call your doctor.

“The flu vaccine is the strongest defense when it comes to keeping yourself and family members safe and preventing severe illness, hospitalization, and possibly death,” said DPH Director Dr. Karyl Rattay.

For more information, visit flu.delaware.gov and cdc.gov/flu, or call 1-800-282-8672.

31

Development of Cell Lines for use in COVID-19 Drug Development and Research London McGill, M.S. Staff Scientist II, Gene Editing Institute, ChristianaCare

BACKGROUND

CRISPR/CAS SYSTEM

In late 2019 the SARS-CoV-2 virus sparked the global COVID-19 pandemic, with the first United States cases being seen in early 2020 eventually leading to over 7 million cases throughout the country, and accounting for over 600,000 COVID-19 related deaths.1,2 To address this novel virus, new testing technologies were developed encompassing the unique RNA and DNA targeting capabilities of the CRISPR/CAS system to detect viral particles. This same CRISPR/CAS technology, however, could also be used to create cell lines modelling COVID-19 which would provide pharmaceutical manufacturers a tool to perform drug screening assays in addition to providing researchers a tool for in vivo research on the mechanism of the SARS-CoV-2 virus that causes COVID-19.

The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/ Cas9 (CRISPR-associated) system is derived from a naturally occurring defense system found in bacteria.8 Bacterial protection from bacteriophage and other viruses is mediated by small RNAs that are present within this system. These RNAs detect and act on foreign DNA from bacteriophage and pathogens that invade the bacteria.8 This adaptive immunity used by bacteria has been well studied and the naturally occurring system has been repurposed into a model that can be used at the bench by scientists to edit the eukaryotic genome. Although the CRISPR/ Cas technology is among the newest of the genome engineering tools, it has proven pivotal to the successful modification of mammalian genomes on a large scale and with a much shorter time frame than seen with previous genome editing technologies such as Zinc Finger Nuclease and TALENS.

In mid-2020 a surge in COVID-19 cases lead New Castle County, Delaware to establish the COVID CARES grant. The grant aimed to provide funding to reduce the impact of SARS-CoV-2 (COVID-19) within the community, help to protect individuals that were deemed vulnerable to the virus, and provide jobs to those impacted by the virus. Using this grant, six target genes believed to be host factors in the COVID-19 virus were identified, and six knock out cell lines that could be pivotal in helping those researching COVID-19 were created. It was believed that cell lines without these genes would be beneficial tools in COVID-19 research. A preliminary study using CRISPR-based loss-of-function screenings within the genome found numerous host genes implemented in the ability of COVID-19 to infect the host.3 The genes identified play roles in viral binding, spike cleavage and membrane fusion, endosome recycling, and Golgi and endoplasmic reticulum trafficking. Another group released a separate study in which a CRISPR genome-wide screening of infection and cell death was done for SARS-CoV-2, SARS-CoV-1, and MERS-CoV using Vero-E6 cells,4 this study brought to light genes implicated as viral receptors, facilitation in viral entry, and genes participating in antiviral activity. These two studies, in addition to others, lead us to move forward with our six genes (Table 1). Vero-E6 (kidney epithelial cells from the African Green Monkey) were used as the host cell line, due to their popularity and common use as cell-based infection models for SARS virus research.4 The Vero cell lines also have an increased presence of ACE2 receptors,7 which was identified as one of the targets for this work.

As the technology has become more popular, new Cas proteins have been identified, each with their own unique capabilities.

Of these proteins, SpCas9, has become the primary protein used for eukaryotic cell genome engineering work.9 This highly studied protein cleaves double-stranded DNA (dsDNA) bluntly, which then allows for an insertion or deletion to be made at the double-strand break or ‘cut site’ due to nonhomologous endjoining (NHEJ). To achieve this, specific RNAs known as gRNAs are designed to carry the SpCas9 to the cleavage site using the same premise originally seen in bacteria. The gRNA contains of a 20-nucleotide sequence that binds to the DNA of interest. PAM restrictive sequences traditionally consist of NGG, where N can be any nucleotide, and repeat with high frequency throughout the genome. The 20 nucleotides that follow act to create a unique binding site and help to prevent the CRISPR/Cas from working elsewhere in the genome.

GRNA DESIGN To develop the most efficient knockout for these targets, a dual gRNA method was used. When using a dual gRNA construct to inhibit or ‘knockout’ a gene, the proximity of the two gRNAs to one another and the reading frame disruption created by the gRNA’s must both be considered. A reading frame consists of a

Table 1. Knock Out Cell Line Targets3,5,6 Gene Symbol

Gene Name

Presumed Mechanism in SARS-CoV-2 (COVID-19)

ACE2

Angiotensin I Converting Enzyme 2

Receptor for binding of SARS-CoV-2 via endocytosis

ARIDIA

AT-Rich Interaction Domain IA

Helicase and ATPase nuclear receptor binding

CTSL

Cathepsin L

Lysosomal cysteine proteinase spike cleavage and membrane fusion

JMJD6

Jumonji Domain-Containing Protein 6

Protein hydroxylases or histone demethylase

KDM6A

Lysine Demethylase 6A

Helicase and ATPase chromatin remodeling

SMARCC1

SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin Subfamily C Member 1

Helicase and ATPase chromatin remodeling

32 Delaware Journal of Public Health - December 2021

Doi: 10.32481/djph.2021.12.009

set of three nucleotides (or nucleotide triplicates) that create a codon and code for an amino acid, whereas an open reading frame (ORF) is considered the segment of triplicates from the start codon (methionine) to the stop codon (nonsense codon: UGA, UAA, or UAG). Any disruption to the genomic sequence can cause a nucleotide change in a triplicate, and then induce an early stop codon downstream which would shorten the ORF. For these projects the gRNAs were designed so that the SpCas9 molecules from each complex would not interfere with one another’s activity when binding to and cleaving the DNA, thus nsuring that both Cas molecules can access the DNA simultaneously and ensuring that they will both actively cleave the DNA without impeding one another’s function. When the gRNAs are located too closely to one another, the gRNAs can work against one another and lead to a lower knockout efficiency, because only one molecule can access the DNA at a time and therefore one gRNA could potentially correct the activity of the other gRNA. These gRNAs were also designed to account for a single base insertion that is commonly seen during the double stranded break repair mechanism after CRISPR/Cas targeting.

This single nucleotide insertion can inadvertently shift the disrupted reading frame back into place, leading to the complete ORF being transcribed and the protein being made. To ensure that a frame shifting deletion was made in the DNA, codons were targeted based on the ‘two thirds rule’, where segments equaling n number of triplicates plus two thirds of a triplicate were targeted (Figure 1). This allowed for the deletion of two nucleotides within the targeted reading frame and would still leave a one nucleotide discrepancy in the reading frame if an additional base pair was added during the double strand break repair mechanism.

In addition to ensuring a frameshift occurs as an outcome of CRISPR technology, the relative location of the frameshift in the coding sequence of the target gene must also be taken into consideration. To avoid the possibility of creating truncated yet functional proteins, gRNAs targeting early exons are selected to generate frameshifts which induce early stop-codons as discussed earlier. This process was carried out by cross-referencing the genomic sequence of each gene of interest with an algorithmic tool created by Synthego Corporation, a CRISPR gene editing company that provides reagents and bioinformatics tools such as the Synthego Knockout gRNA Designer tool. The tool generates gRNA sequences and identifies any repeat sequence found elsewhere in the genome which can lead to off target activity, the anticipated activity level of a gRNA, and the location within the gene that the gRNA will target. gRNAs were selected that had no off-target activity and targeted within the exon of interest (Figure 2). An off-target location is any region within the genome where a gRNA can act on the DNA outside of the anticipated target, typically a gRNA that has fewer than three mismatches in the sequence will be avoided to help ensure that off-target activity does not occur. While aligning the gRNA, the algorithm will show the exact codons that the gRNA will target within the gene, as well as the exon that the codons are within. Finally, the activity level of the gRNA is a measurement of how well the gRNA will act on and cleave the DNA at the target cut site. The algorithm that Synthego’s program uses can predict activity levels, but the gRNA activity is truly tested by doing a single gRNA transfection where only the gRNA of interest is used, and the amount of wild type or untouched DNA is measured within the cell. A gRNA that has a higher activity level is traditionally predicted to work better than a low activity gRNA within the cell, but we have case studies that show otherwise.

Figure 1. Deletion Design

33

Figure 2. Project Guide Designs

CLONAL CELL LINE PRODUCTION To produce our cell lines, the CRISPR/Cas must first be introduced into the cells. In order to do so the CRISPR/Cas is first assembled, using the gRNA designed with the method above and the purified SpCas9 protein. They are complexed into a ribonucleic protein (RNP) and delivered into the cell nuclease via electroporation, a method which uses electrical current to create temporary pores in the cell membrane. These pores allow the RNP to pass through the cell membrane and into the cell nucleus, where it is able to perform the cleavage. From here, the populations of transfected cells are left to recover. Once the cells appear healthy, a sample of the population is taken and analyzed for ‘efficiency,’ or the amount of the population that is showing change to the DNA. In this case, the efficiency was based off the population showing a frameshift, which was determined

by Sanger sequencing at the genomic level. From here this information is used to perform statistical analysis.

In the case of the cell lines being produced here, we used the methodology described above, and were able to achieve a high knockout efficiency across all six projects: with the knockout efficiency in the transfected populations averaging 80.95%, and efficiencies ranging from 63% to 100% knockout of the gene across the different gene targets. Using this information, a statistical estimate for clonal sequencing was made using the known allele number for the parental cell line in addition to the transfection efficiency: Knock Out Efficiencyn = Chance of K0 Clone (where n represents the number of known allele copies in the cell line) From here an estimate was made of how many clones would need to be screened to find one that contained a homozygous knock out of the desired gene, keeping in mind that some cell lines including 34 Delaware Journal of Public Health - December 2021

the Vero-E6 line have a varying allele number (n) meaning the chance must be viewed as a statistical range (Table 2). At this point, the bulk populations of transfected cells were sorted into 96-well plates with a seeding density of one cell per well. The cells once expanded are considered cloned as they are all genetically identical. During the clonal expansion process, some cells are harvested for their DNA, which undergoes Sanger Sequencing to determine if the knockout is present within that clonal cell line. Upon completing Sanger sequencing, an inhouse program called DECODR: Deconvolution of Complex DNA Repair is used to align the clonal sequence to the original parental cell line sequence. This program allows us to see when indel patterns are present and we can then determine if the desired indel pattern has been achieved. When a clone is identified as having a complete or ‘homozygous’ knockout, it was further expanded and banked. At the point of banking the cells are frozen at (-80) degrees Celsius using a controlled freeze method for short term storage and moved into liquid nitrogen where they will remain long term until thawed to be used for research and drug assays.

Table 2 uses ACE2 as an example for the evaluation of the chance of finding a clone. The allele number and the chance of finding a clone are based on the number of alleles present in the cell line.

This is used in determining how many clones to sequence, as well as how many 96 well plates to sort cells into at the beginning of the project. This process was done for all six projects.

At the completion of developing all six cell lines, the number of clones sequenced was compared to the number of clones that were found, this data was then compared to the statistical estimate made in the beginning of the project (Table 3). Discrepancy in actual efficiency seen and estimated efficiency can occur when only a small amount of the clonal population has been sequenced or ‘screened’ like in this case, where only a certain number of clones were needed prior to the sequencing process being terminated.

Discrepancies can occur due to the growth characteristics of the

Table 2. Evaluation of Clonal Chance Gene

Efficiency

Allele Variant

Chances of Finding a Clone

ACE2

.633

2

40.1%

ACE2

.633

3

25.4%

ACE2

.633

4

16.1%

Table 3. NCC Vero-E6 CARES Act Grant Results Gene Symbol

Total Clones Screened

Homozygous Clones Identified

Knock Out Efficiency Estimated from Bulk

Predicted Clonal

Actual Clonal

ACE2

28

6

63%

16.1% - 40.1%

21.4%

ARID1A

12

2

68%

21.3% - 46.2%

16.6%

CTSL

11

3

68.2%

21.6% - 46.5%

27.2%

JMJD6

15

10

100%

100%

66.7%

KDM6A

23

16

95.5%

83.2% - 91.2%

69.5%

SMARCC1

5

4

91%

68.5% - 82%

80%

cells, variance in copy number among cells, the selection process among plates where the healthier looking clonal colonies are expanded out of the 96-well plates first, initial cell death at time of single cell plating, and several other external factors.

REFERENCES 1. Awadasseid, A., Wu, Y., Tanaka, Y., & Zhang, W. (2021, January 1). Current advances in the development of SARS-CoV-2 vaccines. International Journal of Biological Sciences, 17(1), 8–19. https://doi.org/10.7150/ijbs.52569

Table 3 shows the sequencing results and clonality for each of the six projects. Highlighted efficiencies represent those in which fell the estimated efficiency.

2. Centers for Disease Control and Prevention. (2020, April 3).

Provisional Death Counts for Coronavirus Disease (COVID-19). https://www.cdc.gov/nchs/nvss/vsrr/COVID19/index.htm

Clones are sequenced as they expand, meaning when clones containing the desired mutation grow at slower rates than others containing the mutation, the slower growing clone may never make it to the point of sequencing, thus lowering the actual efficiency unless the entire population of clones is screened.

During screening we also find many times that clones will contain allele copies that have the deletion but will also contain one or more allele copies that are non-frameshifting. When these heterozygous clones occur, the gene is still often able to be transcribed and a functional protein is made therefore a knockout is not seen.

3. Daniloski, Z., Jordan, T. X., Wessels, H. H., Hoagland, D. A., Kasela, S., Legut, M., . . . Sanjana, N. E. (2021, January 7). Identification of required host factors for SARSCoV-2 infection in human cells. Cell, 184(1), 92–105.e16. https://doi.org/10.1016/j.cell.2020.10.030

CONCLUSION Genome editing technologies have quickly developed over the years from small reactions that took months, to larger scale reactions that can be done in hours and yield results in just a few days. The CRISPR/Cas technology, the newest and most efficient of these technologies, came into play around 20138 quickly improving the capabilities of gene editing technologies but much is still being learned about it. Harnessing this technology allows for many potential disease cures and research models that will continue to improve the global healthcare system. As part of the fight against genetic disease and viral pathogens, we have proven that it is possible to efficiently knockout the genes that are believed to be responsible for the SARS-CoV-2 virus to infect the host allowing the global pandemic to persist. It is our hope that these cell lines that have been created will be used to help find pharmaceutical therapeutics and uncover the viral mechanisms that will allow the medical field to put an end to the global pandemic that has been responsible for so many deaths.

Ms. McGill can be contacted at London.mcgill@christianacare.org

4. Wei, J., Alfajaro, M. M., DeWeirdt, P. C., Hanna, R. E., LuCulligan, W. J., Cai, W. L., . . . Wilen, C. B. (2021, January 7). Genome-wide CRISPR screens reveal host factors critical for SARS-CoV-2 infection. Cell, 184(1), 76–91.e13. https://doi.org/10.1016/j.cell.2020.10.028 5. Kai, H., & Kai, M. (2020, July). Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19. Hypertens Res, 43(7), 648–654. https://doi.org/10.1038/s41440-020-0455-8 6. National Center for Biotechnology Information. (n.d.). https://www.ncbi.nlm.nih.gov/ 7. Ren, X., Glende, J., Al-Falah, M., de Vries, V., SchwegmannWessels, C., Qu, X., . . . Herrler, G. (2006, June). Analysis of ACE2 in polarized epithelial cells: Surface expression and function as receptor for severe acute respiratory syndromeassociated coronavirus. The Journal of General Virology, 87(6), 1691–1695. https://doi.org/10.1099/vir.0.81749-0 8. Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012, August 17). A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science, 337(6096), 816–821. https://doi.org/10.1126/science.1225829 9. Hsu, P. D., Lander, E. S., & Zhang, F. (2014, June 5). Development and applications of CRISPR-Cas9 for genome engineering. Cell, 157(6), 1262–1278. https://doi.org/10.1016/j.cell.2014.05.010 35

Accelerating the Pace of Newborn Screening Research to Advance Disease Understanding and Improve Health Outcomes: Key Efforts of the Newborn Screening Translational Research Network (NBSTRN) Amy Brower, Ph.D. Kee Chan, Ph.D., M.P.H. Jennifer Taylor, Ph.D. Ross Wiebenga Galata Tona, M.S. Yekaterina Unnikumaran, M.S. LaStephanie Barnes American College of Medical Genetics and Genomics (ACMG)

ABSTRACT Each year in the United States, neonatal screening leads to approximately 1 in 220 newborns being identified with a condition that requires treatment, and in some cases, life-saving interventions. Research that discovers new technologies to screen, diagnose, and treat diseases helps to expand the number of conditions that are candidates for nationwide screening. The National Institute of Child Health and Human Development (NICHD) Hunter Kelly Newborn Screening Research Program funds research to advance newborn screening (NBS). A key effort is the Newborn Screening Translational Research Network (NBSTRN). For fourteen years, the American College of Medical Genetics and Genomics (ACMG) has developed and coordinated the activities of the NBSTRN. This article provides an overview of the NBSTRN.

Newborn screening (NBS) is a multi-component system that involves education, neonatal screening and diagnosis, followed treatment, and in some cases, life-long management.

In the United States (U.S.), approximately 1 in 220 newborns is diagnosed with a condition through NBS. State-based public health departments, like the Delaware Newborn Screening Program (NSP), play a key role in organizing and conducting screening and referral to care. While each state determines which conditions to screen, a federal advisory committee, the Advisory Committee of Heritable Disorders in Newborns and Children (ACHDNC), has established a Recommended Uniform Screening Panel (RUSP) of thirty-five core and twenty-six secondary conditions. ACHDNC has also established a nomination and evidence review system, available to the NBS community of researchers, healthcare professionals, families, and advocacy groups to expand NBS to conditions that are not yet part of screening. NBS research leads to discoveries and pilots of conditions that are candidates for screening, and eventual, RUSP nomination.

NBS began in the 1960s with the discovery that a biomarker for a metabolic disorder could be detected in a newborn’s blood. Elevation of this biomarker led to the diagnosis of phenylketonuria (PKU) and timely interventions that prevented the development of intellectual disability. The enormous benefit of pre-symptomatic diagnosis and treatment of PKU, made possible by NBS, has fostered over six decades of collaborative efforts between research, public health, and clinical care to expand the number of screened conditions. Leading research efforts is 36 Delaware Journal of Public Health - December 2021

the National Institute of Child Health and Human Development (NICHD), one of the twenty-seven institutes and centers at the National Institutes of Health (NIH). NICHD operates the Hunter Kelly Newborn Screening Research Program to fund research to advance NBS. The goals of the Hunter Kelly Newborn Screening Research Program are to identify, develop and test promising new screening technologies; increase the specificity of newborn screening; expand the number of conditions for which screening tests are available; and/or develop experimental treatments and disease management strategies for additional newborn conditions, and other genetic, metabolic, hormonal and or functional conditions that can be detected through newborn screening for which treatment is not yet available. A key effort is the Newborn Screening Translational Research Network (NBSTRN). For fourteen years, the American College of Medical Genetics and Genomics (ACMG) has developed and coordinated the activities of the NBSTRN. NBSTRN develops data tools, resources, and expertise to facilitate and support ground-breaking research to accelerate understanding of genetic disease to increase the number of screened conditions and foster collaborations with clinicians, families, and health professionals to understand and maximize health outcomes. NBSTRN tools are designed to help plan research studies, facilitate efforts, accelerate discoveries, and foster collaborations with key stakeholders and partners. A description of NBSTRN tools highlights the different facets of NBS research and the important role public health plays in advancing disease understanding and improving outcomes for all newborns.

Doi: 10.32481/djph.2021.12.010

LONGITUDINAL FOLLOW-UP WITH THE LPDR Because newborn screening aims to improve health outcomes by identifying and treating affected newborns, NBSTRN created a data tool to facilitate the longitudinal collection of health information on newborns diagnosed with a condition through NBS. The Longitudinal Pediatric Data Resource (LPDR) captures, stores, analyzes, visualizes, and shares genomic and phenotypic data over the lifespan of NBS identified newborns to facilitate understanding of genetic disease and to assess the impact of early identification and treatment.

STATE-BASED NEWBORN SCREENING PROGRAMS WITH THE NBS-VR In the United States, there are 53 newborn screening (NBS) programs located in 50 states, two territories, and the District of Columbia (D.C.). Although there are federal recommendations, each NBS program establishes its policies and procedures, including: which conditions to screen, whether and how to store residual dried blood spots (DBS), whether to obtain consent from parents for the use of DBS, and whether to conduct long-term follow-up of diagnosed cases. NBSTRN created the NBS Virtual Repository of States, Subjects & Samples (NBS-VR) to provide national and state-level views of these policies and procedures.

The NBS-VR facilitates collaboration with NBS programs. The NBS-VR consists of an interactive map of the United States and an interactive table to download data.

101, which summarizes topics related to ELSI in NBS research.

The content addresses common topic areas in ELSI of interest to the NBSTRN community groups: researchers, healthcare professionals, families and advocacy groups, and state NBS programs. Ask ELSA! is an interactive avatar where you can ask a question about ELSI and NBS research. This online resource draws from a database of NBS Research ELSI topics and addresses questions related to the Common Rule, Informed Consent, and Institutional Review Boards (IRB).

For over sixty years, newborn screening has enabled the early identification and treatment of a variety of genetic diseases – both rare and common. Today molecularly designed therapies are revolutionizing treatment and incrementally, and in some cases, dramatically improving health outcomes in conditions like Cystic Fibrosis (C.F.) and Spinal Muscular Atrophy (SMA). In this era of gene-targeted therapies and pre-symptomatic diagnosis, NBS has emerged as a potential mechanism to screen, diagnose and treat potentially all the estimated seven thousand genetic conditions. These rapid advancements in genomic technologies and treatments present even more ways that public health teams, researchers, clinicians, and families can work together to save the lives of infants with a genetic condition.

The authors can be contacted at abrower@acmg.net

NBS CONDITIONS WITH THE NBS-CR Currently, newborns in the U.S. are screened for 81 disorders, 61 by the ACHDNC, and 20 conditions not on the RUSP are screened by at least one state. An additional 35 conditions have been identified as candidates for pilots to determine whether screening is feasible and beneficial. In addition to the screened conditions, thousands of rare disorders may be candidates for NBS. The Newborn Screening Conditions Resource (NBS-CR) provides a centralized resource of facts and statistics on both screened and candidate conditions. The NBS-CR is designed to be an interactive resource for researchers, clinicians, parents, and families to learn more about these disorders and links to National Library of Medicine (NLM) resources, including the National Center for Biotechnology Information (NCBI). NCBI provides access to biomedical and genomic information and maintains MedGen, NCBI’s portal, to information about human disorders and phenotypes having a genetic component. Use the filter tool to sort conditions by nomination status and ACHDNC category.

ETHICAL CONSIDERATIONS IN NBS WITH ELSI ADVANTAGE The ELSI Advantage is a tool developed by the NBSTRN to aid the newborn screening research community in thinking about ethical, legal, and social issues (ELSI) that may arise in the planning and implementation. The content, developed and maintained by the NBSTRN Bioethics and Legal Workgroup, was created to address common topic areas in ELSI of interest to the NBSTRN community groups: researchers, healthcare professionals, families, and advocacy groups, and state NBS programs. ELSI Advantage is organized into different tools and resources, including ELSI 37

Life Sciences at Delaware Technical Community College Mark T. Brainard, Ph.D. Delaware Technical Community College

One of the great strengths of community colleges is their ability to rapidly develop curricula in response to industry needs and provide the hands-on training that prepares students to meet those needs. Here in Delaware, we are fortunate to be part of a strong network of academic and industry partners that assist us in this work.

One of the fast-growing fields relying upon Delaware Technical Community College to prepare a skilled workforce is the life sciences sector, of which genetics plays a critical role. Because it is a vital component of all aspects of biological science, genetics is reflected in the curricula for our biosciences and biotech programs. These concepts are taught and reinforced throughout our biology courses, as well as other required courses in our nursing and allied health programs, such as anatomy and physiology.

This is important because here in Delaware, the number of degrees in life science disciplines expanded 64 percent between 2010 and 2019, rising from 562 to 921, and this sector employs approximately 11,000 people, according to the “Life Sciences in Delaware” report developed by DelawareBio and the Delaware Prosperity Partnership. The report also notes that this sector in Delaware generates at least $2 billion in gross domestic product (GDP) annually.

Thanks to a $1 million grant from the National Science Foundation (NSF), Delaware Tech and the Christiana Care Health System’s Gene Editing Institute began collaborating three years ago to develop a unique gene-editing curriculum now in place not only at Delaware Tech, but also in many other college classrooms across the country. As part of this grant, Delaware Tech has also held a series of workshops to teach gene-editing techniques to community college faculty nationwide so they can develop their own curricula.

The training students receive on the use of gene editing in bioscience and biomedical research as part of this program can accelerate the development of therapies for human diseases such as cancer. This means we are training the next generation on the most important technology of our time.

Last year, the College and the Gene Editing Institute were awarded a second $700,000 grant from NSF to enhance and expand gene editing curriculum development. Related to these efforts, the “CRISPR in a Box” educational tool kit was released to market by partnering with Rockland Immunochemicals.

This training is highly relevant and is used, for example, to instruct students in the ways CRISPR can be used to detect and treat viral infections. This takes on new meaning as we continue to battle a global pandemic that has killed over five million people worldwide. And health care is just one area 38 Delaware Journal of Public Health - December 2021

in which genetics plays a role. Agriculture is also critically important with the study of increased resistance to herbicides and pesticides, as is the field of environmental science.

In addition to the NSF grant, students at Delaware Tech have benefited from our long-standing partnership with the Delaware INBRE (Delaware Idea Network of Biomedical Research Excellence). Through the INBRE partnership network, Delaware Tech students have engaged in biomedical research opportunities and activities with demonstrated increases in student persistence, retention and graduation.

Students from across Delaware Tech have also attended the NIH Community College Day to learn about biomedical and life science research initiatives.

All this work is preparing our students with the skills they need to compete in a rapidly developing field. As noted in the “Life Sciences in Delaware” report, life sciences employment reached a record high in the first quarter of this year, and employment in that sector has grown by 16 percent over the past four years. Delaware’s geographic location, combined with the fact that the state has the nation’s fourth-highest concentration of PhD’s in health, science, and engineering, means we are uniquely positioned to attract even more companies in the life sciences sector. The report also notes that “nearly 30 percent of all biochemists and biophysicists in the United States are employed in Delaware, Maryland, New Jersey, and Pennsylvania, and one out of six U.S. pharmaceutical employees works in the Mid-Atlantic region.” Clearly, we are operating right in the middle of an area of tremendous growth and opportunity for our students.

Thanks to our collaboration with our partners in the public and private sectors, we continue to tailor our curricula to meet industry needs. Our work in the life sciences field is not only ground-breaking, but it will change the lives of people beyond Delaware—in both our nation and the world. The field of gene editing has wide-reaching benefits, from developing new medical treatments for disease to improving the environment around us. We are proud to engage in this critical work with our partners at Christiana Care and throughout Delaware, and we look forward to continuing to share the educational tools we have developed with community colleges nationwide.

Dr. Brainard can be contacted at brainard@dtcc.edu

Doi: 10.32481/djph.2021.12.011

39

Impact of the Access to Genetic Counselor Services Act Carol Nowlen, M.S. Genetic Counselor, ChristianaCare Kendra Flores, M.S., C.G.C. Senior Licensed Genetic Counselor, ChristianaCare

ABSTRACT The goal of this Opinion Editorial is to raise public awareness regarding legislation introduced to Congress, known as the Access to Genetic Counselor Services Act, or HR 2144/S1450. Currently, Medicare policy denies beneficiaries direct access to genetic counselors. This bill aims to rectify this though CMS recognition of genetic counselors. This is of particular importance to Delawareans who rely on genetic counseling service in the subspecialties of cancer, preconception/prenatal, pediatrics, cardiology, and neurology. In this paper, we aim to underscore the importance of this legislation by outlining how genetic counselors impact patient care.

The Access to Genetic Counselor Services Act, known as either S.1450 or HR.2144, is a bill that has been introduced to Congress with the intent to increase access to genetic counselors. Currently, Medicare and Medicaid policy denies beneficiaries access to genetic counselors. S.1450/HR.2144 aims to rectify this by having the Centers for Medicare and Medicaid Services (CMS) recognize genetic counselors as standalone healthcare providers. Due to the rapid expansion of genetic knowledge across medicine, genetic expertise is essential to a growing number of specialties. This bill would help ensure that Delawareans will have reliable access to cost-saving allied health professionals with niche training in this evolving field.

Genetic counselors are highly trained professionals that work collaboratively as members of the medical team. Genetic counselors in the United States obtain a master’s degree from one of 52 programs accredited by the Accreditation Council for Genetic Counseling. Graduation requirements include rigorous coursework, field placement, and completion of a graduatelevel thesis. In addition to genetics expertise, the curriculum emphasizes interpersonal, psychosocial, and counseling skills.

Graduates that pass a board examination administered by the American Board of Genetic Counseling are designated a title of certified genetic counselor. Currently, 28 states grant licensure for the practice of genetic counseling with all but two states working towards establishing licensure in the future.

In an appointment with a genetic counselor, patients can be expected to be asked questions regarding family members and their health history, as well as the patient’s personal health history.

Important things to note when considering personal and family histories are congenital conditions, sudden or unexplained deaths, conditions that occur much earlier in individuals than they do in the general population (such as cancer, aneurysms, strokes, vision and hearing loss, etc.), and any known genetic diagnoses.

It is also important to note any family members that have already had genetic testing, and what kind. Based on personal and family history, the genetic counselor will then review the concept of genetics, the likelihood of a genetic diagnosis for the family, and testing that may be available. The conversation would then 40 Delaware Journal of Public Health - December 2021

be centered around benefits and limitations of testing while facilitating decision making by helping patients evaluate how the testing aligns with their values and concerns.

Genetic counselors work within several subspecialty clinics in Delaware, including: • Cancer: genetic counselors are members of the oncology team that evaluate the risk that an individual has a genetic condition that can cause an increased risk for cancer. Examples include Hereditary Breast and Ovarian Cancer syndrome (BRCA1/BRCA2) and Lynch syndrome.

• Prenatal/Preconception: genetic counselors work with reproductive endocrinologists, obstetricians and gynecologists, and maternal fetal medicine specialists to evaluate the risk that a couple would have a pregnancy affected with a genetic condition.

• Pediatrics: genetic counselors work with a geneticist to care for children that may have genetic conditions.

Common referral reasons include birth defects, diagnoses of autism spectrum disorder, or abnormal newborn screening tests.

• Neurology: genetic counselors that work in neurology can work in a team with a geneticist or a neurologist to see patients with neurological conditions, like seizures or unexplained neuropathy.

• Cardiovascular: genetic counselors work, often with cardiologists, to evaluate various cardiac concerns, including aortic dissections, arrhythmias, cardiomyopathies or family histories of sudden unexplained deaths.

• Transthyretin Amyloidosis: a specialized clinic in Delaware that serves patients with a prevalent but underdiagnosed hereditary form of amyloidosis.

This disease results in a misfolded protein which can cause multisystemic dysfunction. Notably, the diagnosis of this condition can allow for genespecific tailored interventions.

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• Huntington Disease: a multi-disciplinary clinic which includes a genetic counselor, clinical psychologist and neurologists who evaluate the readiness for diagnosis in individuals with symptoms or family histories of Huntington disease.

• General Genetics: genetic counselors work with geneticists to evaluate individuals that may have adultonset genetic conditions that do not fit neatly into a different subspecialty. Examples include mitochondrial conditions and connective tissue disorders.

It is an important point of discussion that CMS recognizes the act of genetic counseling. The procedural (CPT) code 96040 allows providers to bill for the act of analyzing a family history, risk-assessment, and counseling. While CMS will provide payment for this code when billed by a physician, nurse practitioner or physician assistant, reimbursement is not granted when performed by a genetic counselor. This denial is attributed to the fact that CMS does not recognize genetic counselors as medical providers.

While policies vary widely by location, several third-party insurers reimburse genetic counselors for their service since the inception of the procedural code for genetic counseling in 2007. In the greater Delaware area, most private insurance companies recognize the value genetic counselors bring to their subscribers and will reimburse a genetic counselor for this CPT code. However, many private insurance companies look to CMS to inform their coverage policies. As a result, some genetic counselors are not reimbursed by these companies for the service they provide. In cases where insurance will not pay, the facility the genetic counselor is employed through may choose to bill instead.

These facility fees provide significantly less reimbursement than the CPT code and can only be utilized when the appointment occurred within the billing facility. Ergo, even though genetic counseling is perfectly suited for remote healthcare (telemedicine) because the sessions are discussion-based, it is often a noncovered service modality.

Additionally, it has been frequently demonstrated that genetic counselors save healthcare dollars. Genetic counselors are uniquely qualified to ensure the correct test is performed, the correct family member is tested, and results are correctly interpreted. One 2014 study tracked the cost-savings provided by having genetic counselors perform a pre-analytical assessment of the appropriateness of testing, which established that the “test review process resulted in an average reduction in charges to the referring institutions of $48,000.00 per month.”1 Further, S.1450/ HR.2144 proposes reimbursement of genetic counselors at 85% the physician-fee schedule. Consequently, recognition of genetic counselors would save 15% of the federal dollars already being paid for physicians to provide genetic counseling.

In the age of personalized medicine, access to a specialty-trained genetic expert is invaluable. Current federal policy fails to recognize genetic counselors and the role they play in making genetic information accessible and understandable to the public. We urge you to consider contacting your congressional representative in support of S.1450/HR.2144 or visiting https://www.nsgc.org/Policy-Research-and-Publications/Federal-Advocacy to learn more.

Carol Nowlen, MS, CGC can be contacted at Carol.Nowlen@ChristianaCare.org

REFERENCES 1. Miller, C. E., Krautscheid, P., Baldwin, E. E., Tvrdik, T., Openshaw, A. S., Hart, K., & Lagrave, D. (2014, May). Genetic counselor review of genetic test orders in a reference laboratory reduces unnecessary testing. American Journal of Medical Genetics. Part A, 164(5), 1094–1101. https://doi.org/10.1002/ajmg.a.36453

41

SPOTLIGHT

CRISPR In A Box™ and the Journey Toward Inspiring New Scientists Kristen Pisarcik Science Educator, Gene Editing Institute, ChristianaCare; Undergraduate, University of Delaware

It all started with a call from ChristianaCare’s Gene Editing Institute to Delaware Technical Community College looking for a potential student that could help do beta testing on a CRISPR kit. That plan expanded to a National Science Foundation (NSF) grant and an educational kit called CRISPR In A Box™ (see Figure 1). The goal was to test a kit that was very complex and had many moving parts to demonstrate gene editing, but before we got to the fancy experiments, we had to prove that the basic principles of gene editing could be done successfully in a simple microorganism. It was this proof-of-principle experiment that drove the two institutions to submit an NSF grant, which was awarded, called Technical Training in Gene Editing (TTiGE) (NSF ATE DUE awards #1700660 and #2000696).

The grant is designed to teach community college instructors how to incorporate the topic of gene editing into their curricula and give their students a hands-on demonstration. In 2017, CRISPR/Cas gene editing was still a new tool, and most academic institutions were not yet including CRISPR technology discussions into their classes; however, the science is advancing so

rapidly that STEM students are going to start seeing CRISPR/Cas technology in their careers whether or not it is taught to them.

In 2020, the Nobel Prize in Chemistry was awarded to Jennifer Doudna and Emmanuel Charpentier for developing the CRISPR/ Cas method for genome editing – the first women to be awarded the prize without a male counterpart.

The TTiGE grant allows me to work as the Science Educator where I am housed at the Gene Editing Institute (GEI) to watch, listen, and learn everything I can about CRISPR. I get to determine if any possible experiments or scientific discoveries can be adapted into laboratory exercises that students and teachers could study in their classrooms. It was during this time that GEI was creating a gene editing platform to study and understand the mechanisms of CRISPR/Cas reactions. The in vitro gene editing system is a simple reaction using common biological techniques and a cell-free extract that allows the users to conduct the experiment on the benchtop without expensive equipment. The cell-free system allows for students to do the reaction “in a tube” rather than the typical technical setting of a living cell. It is this experimental reaction that led to a renewal of the NSF grant as well as the production of an educational kit – CRISPR In A Box™.

Figure 1. CRISPR in a Box™ 42 Delaware Journal of Public Health - December 2021

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Figure 2. St. Georges Technical School was the first school to teach the CRISPR in a Box™ gene editing experiment in March 2021.

CRISPR In A Box™ is a fully inclusive gene editing laboratory exercise educational kit that can be implemented into a variety of educational settings including high schools, community colleges, and four-year universities (see Figure 2). The primary experiment is based off the in vitro gene editing reaction where students will be able to see their results with a blue-to-white color change on a bacterial plate. While the GEI uses the in vitro reaction to study the mechanisms of CRISPR, students can use that same reaction to experience an innovative gene editing reaction in their classroom.

One important feature of CRISPR In A Box™ is that the students will be gene editing a plasmid, a small circular piece of DNA that can be expressed in bacteria, without actually modifying the bacteria. There are many moments within this kit’s experimental process that can help facilitate the learnings of a biological system, but the most relevant aspect is the kit’s ability to have a diverse readout at the end of the reaction. In gene editing, the final result of an experiment is not often a yes or no answer. Some parts of CRISPR may work perfectly, but overall, perfection is not

regularly achieved in the field yet. This kit is able to show an array of outcomes that are representative of the CRISPR field as a whole when gene editing is being conducted. Gene editing isn’t perfect, and the students will see that within the reactions they perform, leading to the strongest “teachable moment” of them all.

At the GEI, we are using CRISPR In A Box™ to reach a variety of students that may not have previous exposure to gene editing, or even genomics/molecular biology as a subject of interest they could pursue. Our goal is to be a vehicle in bringing cutting edge science to students and communities that may not have had easy access to the fundamentals in the past. Science depends on the future scientists who will think differently and creatively to solve problems that have continuously impacted society. CRISRP/Cas is an important technology, but now we need scientists to figure out how to use that technology to make impactful changes. We hope that CRISPR In a Box™ can be used to spark the next generation of scientists’ interests in gene editing.

Ms. Pisarcik can be contacted at kristen.m.pisarcik@christianacare.org

43

An Examination of Seasonal Trends in Delaware Drug Overdoses, 2016-2020 Aswini Abraham, M.S. Department of Applied Economics and Statistics, University of Delaware Andrew C. Gray, M.A. Department of Sociology & Criminal Justice, University of Delaware Jascha Wagner, Ph.D. Department of Social Sciences, Texas A&M International University Tammy L. Anderson, Ph.D. Department of Sociology & Criminal Justice, University of Delaware

ABSTRACT Objective: To examine whether overdose deaths and related metrics—overdose calls for service to police and non-fatal overdose emergency department visits—in Delaware follow within-year (i.e., seasonal) patterns during the most recent years of the opioid epidemic (2016-2020).

Methods: We begin by providing descriptive statistics on yearly trends in overdose metrics, followed by Analysis of Variance (ANOVA) to analyze whether seasonal variations have a significant impact on the patterns of Delaware’s overdose metrics while controlling for annual variations.

Results: We find yearly variations across the three overdose-related metrics, with overdose deaths reporting the only consistent increases per year. Within-year, or seasonal, variations show the spring months have the most consistent increases in overdose deaths and overdose calls for service across years we studied. Finally, we report significant differences for all overdose metrics across years and seasons.

Conclusions: As in prior studies, we find significant variation in overdose-related metrics by season in Delaware.

Policy Implications: These findings lend support to existing interventions in slowing yearly growth in overdose deaths. However, allocation of resources and interventions to specific times of the year—when overdoses are highest—may further reduce risks and harms.

INTRODUCTION Recently, the News Journal in Delaware published the disappointing news from the State’s Division of Forensic Science that overdose deaths in 2020 increased, yet again, and set a record at 447 lives lost.1 This represents an increase of 3% from 2019 (N = 431). As opioid-related morbidity continues in Delaware and across the nation, professionals, policymakers, and other stakeholders are busy seeking solutions.2 To date, there is a voluminous literature on the factors driving today’s opioid problem as well as past drug crises.3,4 This existing research has most often addressed questions around who, what, where, and why the opioid epidemic is persisting and has also guided policymakers and professionals in formulating and implementing solutions. However, some questions remain understudied and warrant further attention. One question that remains includes how overdose deaths might vary throughout the year or seasonally. In other words, is there a certain time of the year—or a certain season—when drug overdoses, and deaths from them, are likely to be higher or lower in prevalence?

Currently, research focusing on “when” most often investigates yearly variations in overdoses and only a few studies have investigated distinct and shorter time periods, such as variations from season to season. Thus, our knowledge about overdose death trend variations within a given year is generally lacking. Scientific study of within-year (i.e., seasonal, or quarterly) overdose trends can enhance intervention efforts by sharpening best practices, improving budget allocation and resource deployment, and assisting communities when their residents are at greatest risk 44 Delaware Journal of Public Health - December 2021

and most in need. An analysis of seasonal variations over time can, for example, uncover if patterns seen in one year are unique in comparison to others or whether these patterns are part of a consistent trend that interventionists can plan for accordingly.

Given this, our study investigates seasonal trends in overdose metrics for the state of Delaware between 2016 to 2020. We examine three overdose-related metrics to capture the scope of the problem: overdose deaths, non-fatal overdose emergency department visits, and overdose calls for service made to Delaware law enforcement agencies. Our analysis establishes the yearly trends and differences between these metrics before turning to the within-year, or seasonal, variations of them. Based on our findings, we conclude our discussion by offering policy implications that may help to address seasonal variations of overdoses within Delaware.

WITHIN-YEAR VARIATIONS IN SOCIAL AND BEHAVIORAL HEALTH OUTCOMES Overtime, there have been important studies published on seasonal or quarterly variations in numerous behavioral health outcomes, including crime rates, suicide, and substance use. For the most part, seasons and quarters correspond with each other because they are both measured in three-month units that closely align with astronomical seasons and the Gregorian calendar.5,6 For example, the second quarter of the year includes April, May, and June, which overlaps most closely with springtime in the Northern Hemisphere since the summer solstice does not occur until the later part of June—approximately June 21 each year to be Doi: 10.32481/djph.2021.12.014

precise.5,6 Studies to date have generally shown within-year cycles for each of these phenomena, but their fluctuations depend on myriad factors (e.g., weather, type of crime observed). The next sections briefly review existing knowledge about within-year or seasonal variations in crime, suicide, and substance use to inform our research objective.

Crime

In a study of crime rates across US cities, McDowall, Loftin, and Pate found that all major crimes (i.e., violent and property index crimes) showed similar seasonal trends.7 Specifically, most of the crime rates peaked in the summer months (July or August) and dropped to their lowest point during the winter (i.e., December, January, and February). Robbery and murder were exceptions to this pattern. Robbery peaked in December while murder did so in August.7 Notably, they reported that February tended to be the lowest point for crimes in their analysis. In a later analysis, McDowall and Curtis examined the within-year variations in assault and homicide more closely.8 They found patterns for both forms of violence, but that within-year patterns are more pronounced for assaults than for homicides.

Suicide

Suicide is another behavioral health outcome studied through a within-year framework. For example, Rocchi, Miotto, and Preti considered within-year trends in suicide in Italy from 1984 to 2000 and compared these trends to those of overdose deaths.9 Suicide risk for males was higher between March and July, months spanning from late-winter/early-spring to summertime, while female suicide risk was highest during February/March and September. In another study, Rocchi, Sitsi, Cascio, and Preti observed suicide by season in Italy again from 1974 to 2003.10 Based on their analysis, the authors reported a notable suicide peak during the spring relative to other seasons and, also, that this trend persisted over the entire time frame they considered.10 More recently, Yu et al.’s research supported the spring peak and winter decline in suicides across several countries.11

Substance Use and Overdoses

Prior studies of within-year patterns in drug overdoses tend to show fluctuations throughout the year. For example, Rocchi et al. reported drug-involved death trends suggesting a higher risk of death in cooler months with two peaks in the DecemberJanuary.9,12 However, they also found a spike in August. As such, Rocchi et al. conclude there are within-year patterns regarding unintentional overdose deaths in Italy.9,12 Notably, these overdose trends differ from the pattern Rocchi et al. reported for suicides.9 Years later, Sadler and Furr-Holden’s study in Flint and Genesee County in Michigan revealed the summer (110) had the fewest opioid overdose deaths with the most occurring in the spring (151), followed by winter (143), and finally the fall (139).13 Sadler and Furr-Holden (2019) noted these findings offered some contradiction to a study in Ohio conducted by Weiner et al. showing prescriptions for opioids were more common in the summer.13,14 Other studies have examined overdoses in relation to quarterly trends, that closely parallel seasons, with Q1 typically being the winter (January - March), Q2 the spring (April - June), Q3 the summer (July - September) and Q4 the fall (October - December). In doing so, Vivolo-Kantor et al. reported that the highest change rate increase in suspected opioid overdose

emergency department visits happened between Q1 of 2017 and Q2 of 2017 (13.15%), or as winter transitions to spring.15 The second highest change occurred between Q2 of 2017 and Q3 of 2017 (7.68%) (i.e., as spring transitions to summer) when examining National Syndromic Surveillance Program (NSSP) data from July 2016 to September 2017. On the other hand, in their examination of Enhanced State Opioid Overdose Surveillance Program (ESOOSP) data, Vivolo-Kantor et al. found that the highest growth rate increase occurred between Q1 and Q2 of 2017 (13.06%) (i.e., as winter transitions to spring) with the changes between Q3 and Q4 of 2016 (8.91%) (i.e., as summer transitions to fall) and Q4 of 2016 and Q1 of 2017 (9.09%) (i.e., fall transitions to winter) close behind.15 Based on these studies, opioid-related complications appear to be more prominent during the spring (Q2 in 2017) and summer, with some escalation in fall months (Q3 of 2017). These findings coincide with overdose death trends to some degree with the spring having a relatively higher prevalence of emergency visits and overdose deaths and the emergency visits increasing further in the summer.9,12,13 Overall, for opioid-related emergency department visits, there were increases between each quarter or season, but the only statistically significant change occurred for the entire time frame under study—from Q3 (or fall) of 2016 to Q3 of 2017.15 Thus, quarter-to-quarter fluctuations were not significantly different from one another.

In another examination of suspected heroin overdose emergency visits, Vivolo-Kantor, Hoots, David, & Gladden reported seasonal or quarterly changes between 2017 to 2018.16 They found a significant increase between Q1 and Q2 of 2017 (i.e., as winter transitions to spring), a significant decrease between Q3 and Q4 of 2017 (i.e., as summer transitions to fall), another significant decrease between Q4 of 2017 and Q1 of 2018 (i.e., as fall transitions to winter), and a significant increase between Q1 of 2018 and Q2 of 2018 (i.e., as winter transitions to spring).

These results suggest emergency room visits relating to heroin use are most prevalent during Q2 (April, May, June or the spring) and tend to decline throughout the remainder of the year. Thus, a national sample of heroin emergency visits appear more prevalent during spring months similar to overdose deaths according to Sadler and Furr-Holden’s study.13 Finally, in a study of Cincinnati, Ohio examining overdose emergency calls that were heroin-involved, there were three reported spikes during the period of study: September of 2016, March of 2017, and July of 2018.17 In addition, Li et al. included measures of temperature and precipitation to account for seasonal variations in monthly overdose calls and found higher temperatures were positively related to the prevalence of calls for heroin overdoses.17 In sum, research confirms the existence of within-year or seasonal patterns for substance use and overdose-related phenomena. However, there are important variations depending on the measures considered and location of the study. In Italy, overdose deaths were higher in December-January and August, which appears to be partially inconsistent with findings from US settings regarding emergency visits for overdoses.9,12 On the one hand, Vivolo-Kantor et al. found the largest increase in opioid-related overdose emergency department visits occurred between winter and spring (i.e., Q1 and Q2) in 2017, but a further increase between spring and summer (i.e., Q2 and Q3) of 2017, making the summer months those with the most visits.15 45

Their conclusion about this additional increase appears less pronounced when examining the ESOOSP data relative to NSSP data. Since Q3 includes the month of August, the Vivolo-Kantor et al. finding suggests possible overlap with the overdose death spike Rocchi et al. found.9,12,15 On the other hand, using ESOOSP data, Vivolo-Kantor et al. report the highest increases in heroininvolved emergency calls from Q1-Q2 (i.e., winter to spring) in both 2017 and 2018, which includes the months transitioning from winter to spring.16 Notably, Vivolo-Kantor et al.’s Q2 (spring) finding is consistent with what Sadler and Furr-Holden found in Flint, Michigan where they reported opioid-related overdose deaths to be highest in the spring and lowest in the summer; however, this is inconsistent with opioid prescription patterns in OH and overdose deaths in Italy since both had a higher prevalence in the summer.9,12–14,16

Overdose Emergency Department Visits in Delaware

Notably, two of the studies discussed above included opioid overdose data from Delaware.15,16 First, the state-specific change rate trends using the ESOOSP data from Q3 (i.e., fall) of 2016 to Q3 of 2017 for Delaware showed increases between each season or quarter.15 Their limited timeframe study found the largest increases in emergency visits for opioid-related overdoses between Q1 (i.e., January, February, March) and Q2 (i.e., April, May, June) or as winter transitions to spring (43.00%) in 2017, but the prevalence of visits increases even further as spring (Q2) gives way to summer (Q3: July, August, September) (18.76%).

Using ESOOSP data, Vivolo-Kantor et al. also examined change trends in suspected heroin overdoses across states from Q1 (winter) of 2017 to Q2 (spring) of 2018.16 For Delaware, there was a significant increase between Q1 (winter) and Q2 (spring) of 2018 (37.4%) and a further significant increase of 22.9% from Q2-Q3 (i.e., spring to summer) of 2017. In contrast, there were declines in suspected overdoses from Q3-Q4 (2017) and Q4 of 2017 to Q1 of 2018, and a nonsignificant increase from Q1-Q2 of 2018. These results suggest that suspected heroin overdoses increase in Delaware as the winter becomes spring and again as the spring becomes summer before declining throughout the fall and winter. These seasonal patterns are partially consistent with previous findings relating to overdose deaths and other related measures.9,12,14,17 Given the patterns and inconsistencies reported, we further investigate the within-year trends in Delaware using a wider time frame across three overdose metrics to determine if there are similarities or differences with these past studies.

Explanations of Within-Year Trends

Several possible explanations have been hypothesized about these seasonal fluctuations in behavioral health outcomes. Temperatureaggression theories propose higher temperatures and humidity levels lead to irritability among people in ways that may increase rates of violence, especially in summer months (i.e., or Q3).7 Other arguments draw on routine activities theory and suggest weather changes influence how people behave and structure their activities.7,18 Pleasant weather may motivate outdoor activities away from home, thus increasing exposure to victimization. Thus, differences in routine social activities, not just weather patterns, may influence patterns of social and behavioral health outcomes throughout the year.7 For overdose deaths specifically, within-year trends could also be a result of fluctuations in illicit substance availability or the ability of others to respond to an overdose.9,12,19 46 Delaware Journal of Public Health - December 2021

Both the temperature-aggression and routine activities theories posit increased spikes of behavioral health outcomes in the warmer months (i.e., spring and summer).

Psychosocial explanations also explain seasonal variations via individual expectations about events and holidays. For example, the increased likelihood of suicide escalating in the spring (or Q2), on weekends, or around holidays may result from failed expectations of them, leading to increased individual risk.20 Rocchi et al. also used a psychosocial framework and suggested some parts of the year (i.e., Christmas, New Year’s arrival, end of school year) are more likely to create a discrepancy between experiences and expectations, resulting in substance use and increased overdose risk.9,12

Our Study

As detailed above, existing research suggests that overdoses and related social phenomena have a within-year pattern related to seasons or quarters. However, such patterns may vary by other factors including location or year.9,12–14,18 We build on this existing literature by considering the within-year variation of overdose deaths, non-fatal overdose emergency department visits, and calls for service related to overdoses in Delaware from 2016 to 2020.

Our approach studies seasonal fluctuations that approximate the Gregorian calendar: winter, spring, summer, and fall.9,12,20 Next, we discuss our methodological approach to exploring questions about the seasonality of overdose deaths and related phenomena in Delaware before reporting our findings and offering possible solutions to the seasonal variations we report in our findings.

DATA AND METHODS We analyze yearly and quarterly trends between 2016 and 2020 using multiple overdose indicators in the state of Delaware.

Specifically, we examine trends in drug overdose deaths, calls for service made to the police concerning overdoses, and emergency room visits for overdoses that do not result in death. We consider these separate estimates since comparing metrics from multiple datasets allows us to draw more valid conclusions about overdose trends.

Data

The overdose death data for this study come from toxicology files and death reports from the Delaware Department of Forensic Sciences from 2016 to 2020. We produced quarterly counts for each year based on the recorded day of death for each fatal overdose. All deaths were included in these counts (e.g., out of state residents or persons under 18 years of age).

Separate from overdose deaths, police overdose calls for service data were provided by the Delaware Justice Information System (DELJIS). Delaware police respond to overdoses and DELJIS codes them accordingly with the date of the incident. We used this information to calculate quarterly counts of calls for service for overdose incidents also spanning the years of 2016 to 2020.

Monthly data on non-fatal overdose emergency room visits were reported by the Delaware Department of Health and Social Services during a presentation.21 We then aggregated these data to quarterly/seasonal counts to match our other metrics. Whether an emergency room visit is related to a drug overdose is determined using syndromic surveillance definitions found in the National Syndromic Surveillance Platform. Non-fatal overdose emergency room visits are expressed as cases per 10,000 emergency room visits given the format in which these data were made available.

Analytic Strategy

Our analysis begins with descriptive statistics of yearly trends spanning 2016 to 2020 and subsequently analyzes seasonal variation within the three overdose measures. As such, the seasons are winter (January, February, March), spring (April, May, June), summer (July, August, September), and fall (October, November, December). We use the Analysis of Variance (ANOVA) approach to test whether within-year variations have a significant impact on the variability of Delaware’s overdose metrics, controlling for annual variations. ANOVA partitions the variability in each of the overdose metrics into components that are caused by the factors tested (years and quarters). The contribution of each component to the total variability in the metrics is then tested for significance.22,23 The analysis assumes the model fits the data well and the errors are normally and independently distributed with mean zero and constant, but unknown variance.24 Violations of assumptions and model adequacy were evaluated through the examination of probability distributions of the overdose metrics and residual plots of the fitted model (i.e., normal quantile plots, distribution of residuals over time, residual vs predicted values plot). Visual inspection as well as additional statistical indicators indicate normal distributions of residuals and compliance with all modelling assumptions.

As an omnibus test, ANOVA helps us to detect the impact of within-year variations on the overdose metrics, but further analyses need to be performed to answer the following questions.

First, which quarters/seasons differ significantly from the overall mean of the respective response variable? Second, which quarters/ seasons differ from each other? The first question is answered using the Analysis of Means (ANOM) approach. It identifies quarters with means that differ significantly from the overall mean of all quarters, with annual variations controlled. The second question is answered using Tukey’s honestly significant difference (HSD) method.25 It performs all pairwise comparisons between the quarterly means using the q-distribution (i.e., the exact sampling distribution based on the largest differences of two means from the same population). Controlling for annual variations, our analysis approach allows us to determine not only which quarters/seasons are significantly different from the Delaware average, but also whether they are significantly different from each other. For example, controlling for annual variation, we can determine whether the months of Q3, which includes two of the warmer/summer months of the year, are significantly different from the Q4, Q2, or Q1.

Figure 1. Yearly Trend and Percentage Change of Overdose-Related Metrics (2016-2020) 47

RESULTS

Seasonality of Overdose-Related Metrics

Yearly Trends in Overdose-Related Metrics

Figure 1 shows a steady and rising trend for all three overdoserelated metrics for 2016 and 2017. However, these trends start to diverge in 2018. Between 2018 and 2019, both calls for service and total overdose deaths continue to increase—though at a smaller rate than in previous years. At the same time, non-fatal overdose emergency visits began to decline—down 6.0% from 2018 to 2019—and continued to decline from 2019 to 2020 at a rate of 15.0%. Between 2019 and 2020, calls for service also slow down and start to decline. Specifically, despite yearly increases ranging from 118.0% (2016-2017) at the highest and 4.0% (2018-2019) at the lowest increase, the trend in calls for service declined by 7.0% from 2019 to 2020. On the other hand, overdose deaths continued to increase between 2019 and 2020, but at a smaller rate than previous years. Specifically, there was a 3.0% increase in overdose deaths from 2019 to 2020 compared to the 8.0% (20182019), 16.0% (2017-2018), and 13.0% (2016-2017) increases in the previous ones.

Overall, overdose deaths are the only measure to increase consistently across the time-period under observation, with deaths ranging from 306 in 2016 to 446 in 2020. As these trends suggest, there is considerable yearly variation in calls for service to police, non-fatal overdose emergency department visits, and overdose deaths. That is, the trends across these measures are not parallel; they do not share a similar pattern from year-to-year during the 2016 to 2020 timeframe. It is these divergences that we explore further next through a within-year seasonal analysis.

Figure 2 displays seasonal variations in the three overdose-related metrics by year. Specifically, each seasonal data point reflects its three-month average value for its respective year. The flat and solid straight lines running through each square of Figure 2 represent the overall mean (x–) of each variable (i.e., overdose deaths = 32.13 per month, calls for service = 101.65, and non-fatal overdose emergency visits = 126.5). Monthly average values of the response variables for each season are shown using a straight dashed line and the 95% confidence intervals of each average are represented by the grey bands. The upper and lower confidence limits are mentioned at the respective boundaries of the bands.

Thus, as an example, the average calls for service for overdoses is 105.3 in the winter (January, February, and March), and 162.2 is the upper limit of this average while 48.3 is the lower 95% confidence limit.

Figure 2 shows quarterly differences in the three overdoserelated metrics. For the Winter, (January, February, March), non-fatal drug overdose emergency visits increased in the early years (2016 and 2017) but declined and leveled-off by 2018. In contrast, both overdose calls for services and deaths increased in the winter, except for a slight decline for both from 2018 to 2019.

That said, overdose deaths during the winter have increased to the point of falling slightly beyond the upper-95% confidence interval for this quarter. As for spring (April, May, June), nonfatal overdose emergency visits have been stable since 2017 while the other two estimates have seen increases throughout this quarter. Specifically, calls for service to police have seen an

Figure 2. Seasonal Overdose-Related Metrics by Year (2016-2020) 48 Delaware Journal of Public Health - December 2021

upward trend since 2016, but this appears to be leveling-off some in later years for this season. On the other hand, overdose deaths in the spring have been rising since 2017, and this upward trend appears more substantial than calls for service and overdose deaths in this quarter of 2020, escalating beyond the upper limit of the 95% confidence interval again. Moving onto summer (July, August, September), all three measures increased early on but have leveled-off or even declined since 2018. Specifically, overdose deaths in the summer have been stable since 2018, nonfatal overdose emergency visits have been declining since 2018, with calls for service declining in 2019 after steadily increasing before then.

Table 2. Tukey’s HSD Results Assessing Differences between Specific Seasons

Finally, fall (October, November, December) has seen increases and declines in all three measures over the years of study. Both calls for service and non-fatal overdose emergency visits increased substantially between 2016 and 2017 but remained fairly stable afterwards. On the other hand, overdose deaths did not spike upwards in the winter until 2019. However, all three overdose measures declined significantly between 2019 and 2020 during the winter, suggesting that this season is not as problematic in overdose-related measures in Delaware compared to studies from other locations.9,12 Overall, the spring months (Q2) report increases in calls for service and overdose deaths beyond the other seasons. However, winter has also seen increases in both of these measures for most years.

* p<.05 **p<.01 ***p<.001

Tables 1 and 2 show the results of the ANOVA tests, determining which of the overdose-related measures had significant variation across the years and seasons we studied. At the 95% confidence level, we can conclude that there is significant variation in our measures across years and across quarters for at least two groups.

Regarding overdose deaths, we find both yearly differences (p < 0.001) and seasonal differences (p < 0.05) are significant.

Similarly, calls for service to police for overdose deaths significantly varied by year p < .001 and p < 0.001. Finally, non-fatal overdose emergency room visits also varied by both year p < 0.001 and season p < 0.001.

Table 1. ANOVA Results Assessing Differences across Years and Seasons

Total OD Deaths

Calls for Service

Non-Fatal OD

Winter

Spring

0.0383*

0.0110*

0.0008***

Winter

Summer

0.0499*

0.0005***

<.0001***

Winter

Fall

0.4348

0.3951

0.2748

Spring

Summer

0.9995

0.7374

0.7781

Spring

Fall

0.6008

0.3598

0.1112

Summer

Fall

0.6681

0.0478*

0.0106*

Pairwise comparisons between the seasons, using Tukey HSD, enabled us to uncover significant variations at the 95% confidence level. When comparing winter and spring, we found overdose deaths, calls for service, and non-fatal overdose emergency visits all differ significantly between these two seasons. Similarly, when comparing winter and fall, we again found significant variation across all three measures. When comparing fall and winter, we found differences in two of the three overdose measures.

Specifically, calls for service to police for overdoses and non-fatal overdose emergency visits significantly varied between fall and winter, while total overdose deaths did not vary significantly between these two seasons. On the other hand, when comparing winter with spring, summer and fall, and spring with winter, there were no significant differences for any of the three overdoserelated measures.

DISCUSSION Within-year trends have been a topic of public health and safety scholarship over time for many behavioral health outcomes.

There is significant value in studying within-year variations to help create effective policies and interventions to halt today’s stubborn opioid epidemic. Yet, this existing literature has important gaps. In this study, we sought to address these gaps by investigating seasonal variations in three overdose metrics across a five-year period.

* p<.05 **p<.01 ***p<.001

Our study reports yearly differences between the three overdoserelated metrics we studied, suggesting they are separate but related phenomena. For example, the trendline divergence of emergency room mentions and police service calls for overdoses from overdose deaths (since 2018 and 2019) suggests the independent nature of these three metrics in recent years. From these data, we might alternatively ask if overdoses are slowing down as even the overdose death metric reported a modest uptick (i.e., 3%) in 2020 compared to previous years.

We also explored the degree to which the seasonal measures varied from their overall mean. Regarding overdose deaths, we find that only the winter is significantly lower than the overall average at the 95% confidence level while the remaining seasons are not significantly different from the average. As for calls for service and non-fatal overdoses emergency visits, both are significantly higher in the summer, but significantly lower in the winter when compared to their respective means. In sum, these findings support the variation we saw in the trends from Figures 1 and 2. While the results discussed so far are notable in and of themselves, we now turn to which quarters are significantly different from each other (see Table 2).

Next, we found significant differences in within-year or seasonal variation in the three overdose-related metrics we studied, which is another indication that they are independent phenomena. We found the number of overdose emergency room visits, police calls for service, and deaths was consistently lower in the winter months compared to the spring and summer, but not compared to fall. Summer consistently reported the highest averages for all three metrics across the years we studied, with a small exception for spring overdose deaths. Even though summer reported the highest seasonal averages across the years we studied, summer averages were only significantly different from the winter for all three metrics and from the fall months for two of the three metrics studied.

Years (p-value)

Seasons (p-value)

Total OD Deaths

0.0003***

0.0272*

Calls for Service

<0.0001***

0.0005***

All Drug-Non-Fatal ODs

<0.0001***

<0.0001***

49

PUBLIC HEALTH IMPLICATIONS The findings reported from our study have implications for public health and safety efforts underway in Delaware and beyond to combat its opioid crisis. The yearly decline or slowing of overdose metrics in the state since 2016 may offer support for some of Delaware’s efforts in addressing the problem, including its reformation of prescription drug monitoring program (PDMP) laws and opioid prescribing practices; its expansion of naloxone distribution and medications for opioid use disorders; and its partnerships between public health and law enforcement agencies to divert individuals with substance use disorders to treatment instead of the criminal justice system. Yet, as we begin seeing a rise in opioid use in combination with other drugs (e.g., cocaine and methamphetamines),26–30 Delaware should expand existing efforts to address poly-drug use. Further, the results here also suggest that state officials may want to expand and focus these interventions and others in the summer months since that season presents the greatest risk of overdose in the state. This may be challenging since the summer often marks the end of the fiscal year and a period when many, including first responders and others, take vacation.

ACKNOWLEDGEMENTS This study is part of the “Delaware Opioid Metric Intelligence Project.” DOMIP is supported by the National Institute of Justice (Grant No. 2017-IJ-CX-0016). The findings and discussion reported here do not necessarily reflect the views of NIJ. Tammy L. Anderson can be contacted at tammya@udel.edu

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26. Al-Tayyib, A., Koester, S., Langegger, S., & Raville, L. (2017, July 3). Heroin and methamphetamine injection: An emerging drug use pattern. Substance Use & Misuse, 52(8), 1051–1058. https://doi.org/10.1080/10826084.2016.1271432 27. Hedegaard, H., Miniño, A. M., & Warner, M. (2020). Drug overdose deaths in the United States, 1999-2018. NCHS Data Brief, No. 356. Retrieved May 3, 2021 from https://www.cdc.gov/nchs/products/databriefs/db356.htm 28. McCall Jones, C., Baldwin, G. T., & Compton, W. M. (2017, March). Recent increases in cocaine-related overdose deaths and the role of opioids. American Journal of Public Health, 107(3), 430–432. https://doi.org/10.2105/AJPH.2016.303627 29. Jones, C. M., Bekheet, F., Park, J. N., & Alexander, G. C. (2020, January 31). The evolving overdose epidemic: Synthetic opioids and rising stimulant-related harms. Epidemiologic Reviews, 42(1), 154–166. https://doi.org/10.1093/epirev/mxaa011 30. Vestal, C. (2019, May 13). As the opioid crisis peaks, meth and cocaine deaths explode. Stateline, an initiative of The Pew Charitable Trusts. https://www.pewtrusts.org/en/research-and-analysis/blogs/ stateline/2019/05/13/as-the-opioid-crisis-peaks-meth-and-cocainedeaths-explode

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www.fic.nih.gov www.fic.nih.gov www.fic.nih.gov

GLOBAL GLOBAL HEALTH GLOBAL HEALTH M HEALTH M AT AT TERS TERS M AT TERS

Inside this issue Inside this issue GEOHealth hub studies Inside this issue SEPT/OCT 2021 SEPT/OCT 2021

GEOHealth hub studies climate change in four GEOHealth hubinstudies climate change four East African countries...p. 3 climate change in four East African countries...p.

3

FOGARTY INTERNATIONAL CENTER • NATIONAL INSTITUTES OF HEALTH OF HEALTH AND54 East African countries...p.

3HUMAN SERVICES SEPT/OCT 2021 • DEPARTMENT FOGARTY INTERNATIONAL CENTER • NATIONAL INSTITUTES OF HEALTH • DEPARTMENT OF HEALTH AND HUMAN SERVICES

NIH awards $75M to boost data science in Africa NIH awards $75M to boost data science in Africa NIH awards $75M to boost data science in Africa

FOGARTY INTERNATIONAL CENTER • NATIONAL INSTITUTES OF HEALTH • DEPARTMENT OF HEALTH AND HUMAN SERVICES

PhotoPhoto courtesy courtesy Photo of UCT courtesy of UCTof UCT

The NIH is investing about $74.5 million over five years to advance data science, catalyze innovation andfive spur health The NIH is investing about $74.5 million over years to discoveries across Africa.

Under its new Harnessing Data advance data science, catalyze innovation and spur health The NIH is investing about $74.5 million over five years to Science for Health Discovery andits Innovation in AfricaData (DS-I discoveries across Africa.

Under new Harnessing advance data science, catalyze innovation and spur health Africa) program, the NIH is issuing 19 awardsintoAfrica support Science for Health Discovery and Innovation (DS-I discoveries across Africa. Under its new Harnessing Data research and training activities.

DS-I is an NIH Africa) program, the NIH is issuing 19Africa awards to support Science for Health Discovery and Innovation in Africa (DS-I Common and Fund program that is supported research training activities.

DS-I Africabyisthe an Office NIH of Africa) program, the NIH is issuing 19 awards to support the Director andprogram 11 NIH Institutes, Centersbyand Common Fund that is supported theOffices.

Office of research and training activities. DS-I Africa is an NIH Awards will establish a consortium consisting of Offices. a data the Director and 11 NIH Institutes, Centers and Common Fund program that is supported by the Office of science platform and coordinating seven Awards will establish a consortiumcenter, consisting of research a data the Director and 11 NIH Institutes, Centers and Offices. hubs, seven data science research training programs science platform and coordinating center, seven research Awards will establish a consortium consisting of a data and four projects focused research on studying the ethical, legal hubs, seven data science training programs science platform and coordinating center, seven research socialprojects implications (ELSI) of data science research. and four focused on studying the ethical, legal hubs, seven data science research training programs Awardees a robust(ELSI) network of partnerships across and socialhave implications of data science research. and four projects focused on studying the ethical, legal the Africanhave continent and in the U.S., including numerous Awardees a robust network of partnerships across and social implications (ELSI) of data science research. national health ministries, nongovernmental organizations, the African continent and in the U.S., including numerous Awardees have a robust network of partnerships across corporations and other academic institutions.organizations, national health ministries, nongovernmental the African continent and in the U.S., including numerous corporations and other academic institutions. national health ministries, nongovernmental organizations, corporations and other academic institutions.

The University of Cape Town (UCT) will develop and manage the open data science platform and coordinating center of the NIH’s new Data Science in Africa program.

The University of Cape Town (UCT) will develop and manage the open data science platform and coordinating of the NIH’s new Data Science in Africa program.

“This initiative has center generated tremendous enthusiasm in The University of Cape Town (UCT) will develop and manage the open data science all sectors of Africa’s biomedical research community,” said “This initiative has generated tremendous enthusiasm in platform and coordinating center of the NIH’s new Data Science in Africa program.

. . . continued on said p. 2 all sectors of Africa’s biomedical research community,” “This initiative has generated tremendous enthusiasm in .. . .. .continued continued on 2 on nextp.page all sectors of Africa’s biomedical research community,” said . . . continued on p. 2

NIH Director Collins will step down at end of 2021 NIH Director Collins will step down at end of 2021 NIH Director Collins will step down at end of 2021 Dr. Francis S. Collins has announced will endhas his Dr. Francis he S. Collins tenure as NIH announced he director will end by his Dr. Francis S. Collins has the endas of NIH the year.

Collins tenure director by announced he will end his is the longest the end of the serving year. Collins tenure as NIH director by presidentially appointed is the longest serving the end of the year. Collins NIH director, having served presidentially appointed is the longest serving in three administrations.

NIH director, having served Dr. Roger Glass (left) and Dr. Francis presidentially appointed Collins (right) During his 12-year leaderin three administrations.

Dr. Roger Glass (left) and Dr. Francis NIH director, having served ship, NIH’s budget grew by 38%, fromhis $3012-year billion leaderCollins (right) During in three administrations.

Dr. Roger Glass (left) and Dr. Francis in 2009 to $41.3 billion ship, NIH’s budget grew in by2021.

38%, from $30 billion Collins (right) During his 12-year leaderin 2009 to $41.3 billion in 2021. ship, NIH’s budget grew by 38%, from $30 billion “It has been an incredible privilege to lead this great in 2009 to $41.3 billion in 2021. agency for more than a decade," said "I love “It has been an incredible privilege to Dr. leadCollins. this great this agency and its people so deeply the decision to agency for more than a decade," saidthat Dr. Collins.

"I love “It has been an incredible privilege to lead this great step agency down was difficult this andaits peopleone.” so deeply that the decision to agency for more than a decade," said Dr. Collins. "I love step down was a difficult one.” this agency and its people so deeply that the decision to A physician-geneticist, Collins previously served as the step down was a difficult one.”

A physician-geneticist, Collins previously served as the A physician-geneticist, Collins previously served as the

FOCUS FOCUS FOCUS 52 Delaware Journal of Public Health - December 2021

director of the National Human Genome Research Institute from 1993-2008, where Human he led the international Human director of the National Genome Research Institute Genome Project, which in a finished Human sequence from 1993-2008, where culminated he led the international director of the National Human Genome Research Institute of the human DNA instruction book.in a finished sequence Genome Project, which culminated from 1993-2008, where he led the international Human of the human DNA instruction book.

Genome Project, which culminated in a finished sequence As NIH Director, Collins travelled widely and supported a of the human DNA instruction book. number of significant global health research training As NIH Director, Collins travelled widely and and supported a initiatives, including the Human Heredity and Health number of significant global health research and training As NIH Director, Collins travelled widely and supported a in Africa (H3Africa) the Heredity Medical Education initiatives, includingprogram, the Human and Health number of significant global health research and training Partnership Initiative (MEPI), the Health-Professional in Africa (H3Africa) program, the Medical Education initiatives, including the Human Heredity and Health Education Partnership Initiative and the new Data Partnership Initiative (MEPI), the(HEPI) Health-Professional in Africa (H3Africa) program, the Medical Education Science in Africa (DS-I Africa) program.

Education Partnership Initiative (HEPI) and the new Data Partnership Initiative (MEPI), the Health-Professional Science in Africa (DS-I Africa) program.

Education Partnership Initiative (HEPI) and the new Data “I am proud of all we've accomplished,” Collins said. “I'm Science in Africa (DS-I Africa) program. most proudaccomplished,” of the NIH staffCollins and the scientific “I am grateful proud ofand all we've said.

“I'm community, extraordinary commitment to scientific lifesaving most gratefulwhose and proud of the NIH staff and the “I am proud of all we've accomplished,” Collins said. “I'm research delivers hope to the American people and the community, whose extraordinary commitment to lifesaving most grateful and proud of the NIH staff and the scientific world every day.” research delivers hope to the American people and the community, whose extraordinary commitment to lifesaving world every day.” research delivers hope to the American people and the world every day.”

Fogarty awards $3.3 million in COVID-19-related grant supplements Fogarty awards $3.3 million in COVID-19-related supplements • Scientists will study vaccine hesitancy, antibody responsegrant and other topics Some funds support research for pandemic • Scientists willwill study vaccine hesitancy, antibody responseresponse and other topics Fogarty awards $3.3 million in training COVID-19-related grant supplements Funding will will aid support researchers whose projects interrupted • Some funds research training forwere pandemic response • Scientists will study vaccine hesitancy, antibody response and other topics • Funding will aid researchers whose projects Read were more interrupted on pages 57-60 6–9 More on • Some funds will support research training forRead pandemic response Read more on pages 6–9 • Funding will aid researchers whose projects were interrupted Read more on pages 6 – 9

SEPTEMBER/OCTOBER 2021 SEPTEMBER/OCTOBER 2021

NIH awards $75M to boost data science in Africa NIH awards $75M to boost data science in Africa from previous .. .. ..continued continued from p.1 page . . . continued from p.1 NIH Director Dr. Francis S. Collins. “Big data and Artificial NIH Director(AI) Dr.have Francis Collins.to“Big data and Intelligence the S. potential transform theArtificial conduct Intelligence (AI) have potentialwhile to transform conduct of research across thethe continent, investingthe in research of research continent, while investing in research training willacross help tothe support Africa’s future data science trainingand will ensure help to sustainable support Africa’s future science leaders progress in data this promising leaders and ensure sustainable progress in this promising field.” field.”

The University of Cape Town (UCT) will develop and manage The initiative’s University open of Cape Town (UCT) will develop and manage the data science platform and coordinating the initiative’s open data science platform and coordinating center, building on previous NIH investments in UCT’s data center, building on previous made NIH investments UCT’s data and informatics capabilities through theinHuman and informatics capabilities through the Human Heredity and Health in Africamade (H3Africa) program.

UCT Heredity anda Health Africa (H3Africa) program.

UCT will provide flexible,inscalable platform for the DS-I Africa will provide aso flexible, scalable platform the select DS-I Africa researchers, they can find and accessfor data, tools researchers, so and they run can analyses find and through access data, select tools and workflows, collaborative and workflows, and run analyses through workspaces.

UCT will also administer and collaborative support core workspaces. also administer and support core resources, asUCT well will as coordinate consortium activities. resources, as well as coordinate consortium activities.

The research hubs, all of which are led by African instituThe research hubs, allapproaches of which aretoled by analysis African institutions, will apply novel data and AI tions, will apply novel approaches to data analysis and to address critical health issues. Scientists in Kenya willAI to address critical health issues.

Scientists Kenya will leverage large, existing data sets to develop in and validate leverage large, existing data sets to develop validate AI models to identify women at risk for poorand pregnancy AI models to identify women at risk forand pooryoung pregnancy outcomes; and to identify adolescents healthcare outcomes; adolescents andideation. young healthcare workers at and risk to of identify depression and suicide A hub workers at risk of depression and suicide ideation. hubof in Nigeria will study SARS-CoV-2 and HIV with the Agoal in Nigeria study SARS-CoV-2 and HIV with In theUganda, goal of using datawill to improve pandemic preparedness. using data towill improve pandemic preparedness.

In imaging Uganda, researchers advance data science for medical researchers will advance data science fordisease medical imaging with efforts to improve diagnoses of eye and cervical with efforts to improve diagnoses of eye disease and cervical cancer.

Scientists in Nigeria will also study anti-microbial cancer. Scientists Nigeria will also study anti-microbial resistance and thein dynamics of disease transmission, resistance and the screening dynamics tool of disease transmission, develop a portable for bacterial infections develop tool for bacterial infections and testaaportable potentialscreening anti-microbial compound.

A project and test a potential anti-microbial compound.

A project based in Cameroon will investigate ways to decrease the based inofCameroon willsurgical investigate ways to the burden injuries and diseases, asdecrease well as improve burdento ofquality injuriessurgical and surgical diseases, well as improve access care across the as continent.

From access toSouth qualityAfrica, surgical care across continent.

From a hub in researchers willthe study multi-disease a hub in South Africa, researchers studydata multi-disease morbidity by analyzing clinical and will genomic with morbidity analyzing clinical and genomic data with the goal ofby providing actionable insights to reduce disease the goaland of providing insights to reduce disease burden improve actionable overall health.

Finally, another project burden improve overall innovative health. Finally, another project in Southand Africa will develop solutions to mitigate in South Africa will develop innovative solutions to mitigate the health impacts of climate change throughout the region, the health climate outcomes change throughout the region, with initial impacts studies of clinical of heat exposure. with initial studies of clinical outcomes of heat exposure.

The research training programs, which leverage partnerThe research training programs, which multi-tiered leverage partnerships with U.S. institutions, will create ships withtoU.S. institutions, will create multi-tiered curricula build skills in foundational health data science, curricula to build skills in master’s foundational data science, with options ranging from and health doctoral degree with options ranging from master’s doctoral degree tracks, to postdoctoral training and and faculty development. tracks, postdoctoral and faculty A mix oftoin-person and training remote training will development. be offered A mix of skills in-person and such remote be offered to build in topics astraining applied will mathematics, to build skills in topics such as applied mathematics,

2 2

biostatistics, epidemiology, clinical informatics, analytics, biostatistics, epidemiology, clinical informatics, analytics, computational omics, biomedical imaging, machine computational omics, biomedical machine intelligence, computer science andimaging, engineering.

Trainees intelligence, computermentoring science and Trainees will receive intensive andengineering. participate in will receive intensive mentoring and participate in internships to learn how to apply data science concepts internships to learn how to apply sciencethe concepts to medical and public health areasdata including social to medical andofpublic health areas including the social determinants health, climate change, infectious determinants of health, climate change, infectious diseases, noncommunicable diseases and health diseases, noncommunicable diseases and health surveillance. surveillance.

Recognizing that data science research may uncover Recognizing that data research may uncover potential ethical, legal science and social implications (ELSI), potential ethical,will legal and social implications (ELSI), the consortium include dedicated ELSI research the consortium willembedded include dedicated ELSI research teams that will be in the research hubs teams that these will betopics. embedded in the research hubs to address This will include efforts to to address these topics. This willspecific includeguidance efforts to for develop evidence-based, context develop evidence-based, context specific guidance for the conduct and governance of data science initiatives. the conduct and governance of data science initiatives.

Researchers will evaluate current legal instruments and Researchers evaluate legal instruments guidelines to will develop new current and innovative governanceand guidelines tofor develop new and innovative governance frameworks data science health research in Africa. frameworks for data science healthacross research in Africa.

They will explore legal differences regions of Theycontinent, will explore differences across regions of the as legal well as investigate public attitudes the continent, well as investigatefor public attitudes regarding data as science approaches healthcare. regarding data science approaches for healthcare.

A second phase of the program is being planned to A second phase the program is being planned to encourage more of researchers to join the consortium, encourage more researchers to join the consortium, foster the formation of new partnerships and address foster the formation of new partnerships and address additional capacity building needs. A concept under additional capacity needs. Aresearch concept under development would building support discrete projects development support who discrete research projects led

by Africanwould investigators propose innovative led by African investigators innovative health data science researchwho andpropose solutions with a new health data science research and solutions with a new non-academic partner.

To enhance the career pipeline non-academic partner. enhance the in career pipeline and retention of health To data scientists Africa, at least and retention of health data scientists in Africa, at least half of the awards would go to new and early-stage half of the awards wouldconcept go to new andenhance early-stage investigators.

A second would the investigators.

A second concept would enhance the existing research training programs. existing research training programs.

In addition to the Common Fund, the DS-I Africa awards In addition to the Common Fund,the theNational DS-I Africa awards are being supported

by Fogarty, Cancer are being the supported byHuman Fogarty, the National Cancer Institute, National Genome Research Human Genome Research Institute, the National Institute of Allergy and Infectious Institute, the National Institute of Allergy and Imaging Infectious Diseases, the National Institute of Biomedical Diseases, the National of Biomedical Imaging and Bioengineering, theInstitute Eunice Kennedy Shriver National and Bioengineering, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Institute Institute of Child Health andand Human Development, the National of Dental Craniofacial Research, National Institute of Dental and Craniofacial Research, the National Institute of Environmental Health Sciences, Environmental Health Sciences, the National Institute of Mental Health, the National the National Institute of the Mental National Library of Medicine and NIHHealth, Office ofthe Data Science Library of Medicine and the NIH Office of Data Science Strategy.

Strategy.

More info at https://commonfund.nih.gov/AfricaData.

More info at https://commonfund.nih.gov/AfricaData.

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SEPTEMBER/OCTOBER 2021

GEOHealth hub studies climate change in East Africa Climate change-related health problems due to droughts, floods, heat waves, and vector- and water-borne diseases are increasingly affecting the world’s most vulnerable populations. Scientists in four East African countries have conducted studies of these complex issues, developed needs assessments and provided guidance to policymakers on how to address them. The research projects—which may serve as models for other countries—were supported by the Fogarty-led Global Environmental and Occupational Health (GEOHealth) program.

Hotter temperatures also spur climate-sensitive illnesses, including vector-borne diseases that require optimal ground, air and water temperature for the survival and reproduction of insects, Simane said. “The more the temperature increases, let’s say, 0.5° Celsius every 10 years, the larger the area of vector-borne disease—and the longer the transmission period—becomes.” Malaria, customarily prevalent in the lowlands, is moving into the highlands. The WHO estimates 68% of Ethiopians are now at risk of malaria. Other vector-borne diseases, notably dengue and visceral leishmaniasis, are already escalating due to climate change, Simane observed.

Water-borne and zoonotic diseases are increasing as well. Bacteria that live in water are more apt to multiply in warmer temperatures, while helminthic infections like hookworm (transmitted through soil) follow a similar pattern, said Simane. Zoonotic infections are already escalating. Currently, the nation has the fourth highest burden of zoonoses, which cause an estimated one-fifth of all human infectious diseases in low-income countries.

Four East African countries have produced climate change needs assessments for their countries through the Fogarty-managed GEOHealth program.

Add to this the fact that global warming intensifies humidity and dust levels, two factors that increase the risk of meningitis outbreaks. Ethiopia sits within sub-Saharan Africa’s “meningitis belt” and Simane’s study reported certain types of meningitis have been diagnosed beyond those regions traditionally prone to the disease.

Yet, it is climate change’s effects on agriculture and nutrition that pose the greatest threat, said Simane. Heat stress has a negative impact on the crops themselves while also curtailing workers’ productivity. Some crops are no longer viable in higher temperatures, forcing a reliance on carbohydrates. The number of people sickened due to malnutrition will be greater than those affected by malaria and other climate-sensitive diseases, stated Simane.

Addis Ababa University leads the eastern Africa GEOHealth hub, which includes universities in Kenya, Rwanda and Uganda. The hub’s members meet regularly to share findings and all have completed similar national situational and needs assessment studies. The hub’s Principal Investigator, Dr. Abera Kumie, believes these reports can serve as blueprints for other low-resource countries seeking to clarify the impact of climate change and identify gaps in research, training and capacity.

The need for more research—and researchers—is urgent so that interventions can be developed and implemented, said Kumie. “The whole point of our project, our research, is to produce evidence that could influence policy change.”

The East Africa hub has been supported by Fogarty, the NIH’s National Institute of Environmental Health Sciences, the CDC’s National Institute for Occupational Study and Health, and Canada’s International Development Research Centre.

RESOURCES https://bit.ly/climate_EAfrica

54 Delaware Journal of Public Health - December 2021

Photo by Nancy McNally/Catholic Relief Services

Rising temperatures have already begun to take their toll on Ethiopian health, said Dr. Belay Simane, the lead author of his country’s study, which was published in the Ethiopian Journal of Health Development. Ethiopia’s annual temperature has already risen more than 1.3° Celsius since 1960 and models suggest it could climb as much as 2.9° Celsius more by the 2050s. A warming planet has caused repeated droughts, floods and extreme temperature events in Ethiopia over the past few decades, explained Simane, who is a scientist at Addis Ababa University. Water scarcity leads to inadequate hygiene, which results in fecal-oral transmission of diseases. Meanwhile, floods are expected to become more frequent and more severe under most scenarios. Given that Ethiopia relies heavily on pit latrines, flooding can contaminate surface, ground and drinking water. An epidemic of cholera followed flooding in 2006, leading to widespread illness and loss of life. Diarrhea, a leading cause of infant mortality, is becoming a growing health risk, noted Simane.

3

PROFILE PROFILE Fogarty Fellow investigates Fogarty Fellow investigates trauma care in Tanzania trauma care in Tanzania

By Mariah Felipe

By Mariah Felipe

Rapid urbanization in many low- and middle-income countries (LMICs) is resulting a growing number Rapid urbanization in many in lowand middle-income of trauma injuries to traffic in accidents. bone countries (LMICs)due is resulting a growingShin number of trauma due to trafficbroken accidents.

Shin bone and fractures areinjuries the most common bones globally fractures the most common broken bones and have a high are infection rate, up to 40%.

There areglobally currently a highways infection rate,the upfractures to 40%. There are currently twohave common to treat surgically— two common treat the fractures surgically— placing a nail orways platetointernally to stabilize the bone or placing a nail or with plate pins internally to stabilize bone or fixing it externally and rods.

While the external fixing is it far externally with pins and rods.a While fixation less invasive, it requires muchexternal longer fixation is far less is invasive, requires a much longer healing time, which difficultit for working patients whose healing time, which is difficult for working patients whose jobs require mobility. jobs require mobility.

Fogarty Fellow Dr. Abigail Cortez spent a year studying Fogarty Fellow Dr. Abigail Cortez spent a year studying surgical outcomes of patients with tibia fractures in surgical outcomes of patients with tibia fractures in Tanzania to see which treatment method had better Tanzania to see which treatment method had better results. Cortez, now an orthopedic surgery resident at results. Cortez, now an orthopedic surgery resident at the University of California, Los Angeles, was forced to the University of California, Los Angeles, was forced to work remotely from her home base due to the COVID-19 work remotely from her home base due to the COVID-19 pandemic.

She relied heavily pandemic.

She relied heavilyononher herteam teamofofresearch research coordinators in Tanzania.

They followed coordinators in Tanzania. They followedup upwith withabout about 240 patients who were offered 240 patients who were offeredin-person in-personappointments, appointments, which involved x-rays and a aclinical which involved x-rays and clinicalassessment, assessment,or oraa phone consultation.

To work around COVID restrictions, phone consultation. To work around COVID restrictions, thethe research team research teamdeveloped developeda adetailed detailedquestionnaire questionnaire to to trytry and elicit thethe same level and elicit same levelofofinformation, information,even eventhough though they couldn’t physically bebewith they couldn’t physically withthe thepatient. patient. study found that there areno nofundamental fundamentaldifferences differences HerHer study found that there are between two surgical approaches,even eventwo twoto tofive five between thethe two surgical approaches, years after initial surgery.This Thisproved provedthat thatthe the years after thethe initial surgery. internally applied nail did notcause causehigher higherrates ratesof of internally applied nail did not infection and a viable alternativetotoexternal externalfixation, fixation, infection and is is a viable alternative which is often preferred LMICs.Eight Eightofofthe thepatients patients which is often preferred inin LMICs. reported persistent or complex complications after their reported persistent or complex complications after their surgery, and these patients were seen to have overall lower surgery, and these patients were seen to have overall lower quality of life.

Four of them had received the internal nail, quality of life. Four of them had received the internal nail, and four had received external fixation. The quality-ofand four had received external fixation. The quality-oflife scores they shared were comparable to some chronic life scores they shared were comparable to some chronic illnesses, which highlighted the importance of complication illnesses, which highlighted the importance of complication and infection prevention and continuity of care. and infection prevention and continuity of care.

“We should be focusing on how best to prevent infection “We should be focusing on how best to prevent infection prior to surgery so that we can avoid the burden of prior to surgery so thatafter we can avoidsaid the burden of those complications surgery,” Cortez. “Chronic those complications after surgery,” said Cortez.

“Chronic complications will ultimately cost a lot more to the healthcomplications will ultimately cost a lot more to the health-

4

Abigail Cortez, M.D. Abigail Cortez,2020-21 M.D. Fogarty Fellow: Fogarty Fellow: 2020-21 US Institution: University of California, San Francisco US Institution: University of California, San Francisco Foreign Institutions: Muhimbili Orthopedic Institute, Tanzania Foreign Institutions: Muhimbili Orthopedic Institute, Tanzania Research area: Trauma care in low- and middle-income countries Research area: Trauma care in low- and middle-income countries

care system, and this is true in both low- and highcare system, and this is true in both low- and highincome countries.” income countries.”

During her fellowship, Cortez trained in biostatistics During her fellowship, Cortez trained in biostatistics and learned how to work with online data capturing and learned how to work with online data capturing tools, in addition to practicing fundamentals such as tools, in addition to practicing fundamentals such as study design and manuscript writing. “This was a very study design and manuscript writing. “This was a very impactful year and I gained a lot of tools in my research impactful year and I gained a lot of tools in my research toolbox,” she said. said.“Now, “Now,I Ifeel feelaalot lotmore moreconfident confident toolbox,” she conducting research independently, and I think it's only conducting research independently, and I think it's only going to help my career.” going to help my career.”

Logistics were aa considerable considerablepart partofofCortez's Cortez'sstudy study Logistics were because she was was working workingremotely remotelyininthe theU.S. U.S. She because she She learned to to communicate communicateeffectively effectivelywith withher herresearch research coordinators and trained trainedthem theminindata datacollection, collection, a skill coordinators and a skill they'll be be able able to to use usein infuture futurestudies. studies.

“During this this process, process,you yourealize realizehow howlong longresearch research takes, from from the the inception inceptionofofan anidea, idea,testing testingyour your hypothesis, formulating nailing hypothesis, formulatingyour yourstudy studydesign designand and nailing down the down the logistics logistics for forimplementation,” implementation,”Cortz Cortzobserved. observed.

She recently She recently helped helpeddevelop developtwo twoprojects projectsthat thatallowed allowed her to employ the skills she learned during Fogarty her to employ the skills she learned duringher her Fogarty experience. One the impact experience.

One will willexamine examineamputation amputationand and the impact of prosthetic devices in LMICs and the second will study of prosthetic devices in LMICs and the second will study post-surgical infection rates. post-surgical infection rates.

“I feel like my life has changed for the better because “I feel like my life has changed for the better because of the Fogarty fellowship. I learned so much, and I also of the Fogarty fellowship. I learned so much, and I also made so many valuable connections,” she said. “The made so many valuable connections,” she said. “The global health community is a close one. Now I know that global health community is a close one. Now I know that if I have any questions or any new research interests, if I havewho anytoquestions or any new research interests, I know contact, and I’ll be able to find the right Iperson know in who to contact, and I’ll be able to find the right any country.” person in any country.”

4 55

Q&A

N ANDINI KUMAR, MBBS, DCP, MHSC

Dr. Nandini Kumar completed a medical degree in clinical pathology from India’s Trivandrum Medical College, where she also completed post-graduate training in pathology and gastroenterology. Later, she participated in the first cohort of Fogarty's research ethics training program in 2001. While at the Indian Council of Medical Research, she held a Fogarty grant to establish a national bioethics training program and helped formulate India’s national research ethics guidelines. She has also served on the WHO’s Forum for Ethics Review Committees in India and chaired the bioethics committee at Manipal University.

What led you to Fogarty?

I was chosen to participate in Fogarty’s new bioethics research training program by the director of the Indian Council of Medical Research because I’d done bioethics work in the past. With Fogarty support, I completed a master’s course at the University of Toronto. We studied the philosophical and historical approaches to bioethics, regulatory codes and case studies that illustrated the complexity of bioethics research issues. As trainees, we felt that we were given every opportunity to develop as bioethicists.

And that happened in many regions. My program was meant for mid-career people but one of our trainees was a medical college dean who then started a two-year diploma program. Other trainees innovated in smaller ways.

Did the pandemic influence Indian bioethics?

For example, one of the exercises was to write a grant to establish a bioethics training program at home. It was a challenge—the application process was unfamiliar to me. But I knew that India could really benefit and I also knew that my position at the Council, the apex of Indian biomedical research, was the best ground in which to initiate bioethics training.

Some prestigious people in our biomedical community were already talking about ethics, so I asked them if I could use parts of their programs for my project. I never imagined they would encourage me, but they did and that helped. Writing that grant became a stepping stone for me, another important lesson from my training.

We received a large number of proposals related to COVID-19 and this led to changes at the Ministry of Ayurveda, Yoga, Unani, Siddha, Sowa-Rigpa and Homeopathy (AYUSH). I was chair of that ministry’s safety monitoring group and, during COVID, the concept of data safety and evidence was applied to traditional medicine for the first time. It used to be said that our plants don’t have safety issues because they’ve been used for centuries, but we required evidence around claims related to COVID drugs. So, you could say the pandemic led to an integration of ideas between modern and traditional medicine. And the Ministry of AYUSH actually came out with two products to use for mild to moderate COVID cases. Another problem was: How exactly do ethics committees review COVID proposals?

With everything online, scientists had to produce certificates proving they’d received all the necessary training in ethics. You could say COVID compelled investigators to become more sensitized to ethics.

How did you begin ethics training in India?

What impact has ethics training had?

I thought very seriously about how to train people in a way that is suitable to India. The training was a step-by-step “upscaling” process. First, we held oneday workshops. Then we held three-day workshops and that evolved into five-day workshops, five-week training programs and eventually degree programs.

Researchers are spread out across India and some cannot travel or take a leave from their jobs for longterm training. My thought was that our program could encourage mentorships and then when trainees returned home, both trainee and mentor could work together to plan bioethics programs and workshops.

I’m very happy to announce that we recently launched a Good Clinical Practice (GCP) program—certified by the International Organization for Standardization—which is the first of its kind. The initiative includes standard principles of ethics and GCP within the Indian context.

It is a train-the-trainer program so, importantly, people will have to pass an exam and only then will they be able to train others. So just like there are certified ethics committee members, we will also have certified professionals for GCP. That is a very big step.

RESOURCES https://bit.ly/Kumar_bioethics

56 Delaware Journal of Public Health - December 2021

5

OCCUUSS FFO

Fogartyawards awards $3.3M $3.3M Fogarty COVID-19supplements supplements ininCOVID-19 forresearch, research, training training for

Photo courtesy of NIAID Photo courtesy of NIAID

LL

ow-resource nations have faced significant challenges in responding to the COVID-19 pandemic and numerous researchersnations have had their projects disrupted.

To helpin address these to issues, Fogarty has awardedand nearly $3.3 ow-resource have faced significant challenges responding the COVID-19 pandemic numerous million in 42 administrative supplements to existing awards for these one year of support. researchers have had their projects disrupted.

To help address issues, Fogarty has awarded nearly $3.3 million in 42 administrative supplements to existing awards for one year of support.

Priority was given to COVID-19-related projects that address unique scientific questions associated with the pandemic in the was low-resource country where the projects research that is conducted.

Precedence was also shownassociated for COVID-19-related Priority given to COVID-19-related address unique scientific questions with the pandemic research training conducted in LMICs. Fogarty also provided supplementary support to researchers who were unable in the low-resource country where the research is conducted. Precedence was also shown for COVID-19-related to complete theirconducted projects due to pandemic lockdowns. research training in LMICs. Fogarty also provided supplementary support to researchers who were unable to complete their projects due to pandemic lockdowns.

The supplements will support research and training in a broad range of COVID-related topics. Several projects willsupplements examine the will mental health aspectsand of COVID-19, among people living with HIV.Several Others will study The support research training inparticularly a broad range of COVID-related topics. projects interactions between SARS-Co-V-2 and other infectious diseases such as HIV and TB. In addition, supplements will will examine the mental health aspects of COVID-19, particularly among people living with HIV. Others will study fund COVID-19-related investigations into vaccine hesitancy, intimate partner violence, stigma and other topics. interactions between SARS-Co-V-2 and other infectious diseases such as HIV and TB. In addition, supplements will

fund COVID-19-related investigations into vaccine hesitancy, intimate partner violence, stigma and other topics.

The NIH Office of AIDS Research and the NIH Common Fund provided significant support for the awards. Several project examples are described below.

The NIH Office of AIDS Research and the NIH Common Fund provided significant support for the awards. Several project examples are described below.

Investigating vaccine hesitancy in Kenya The COVID-19 vaccine is safe for people living with Investigating vaccine hesitancy in Kenya HIV (PLHIV), yet vaccination rates within this group The COVID-19 vaccine is safe for people living with have been lower than expected in Kenya. University HIV (PLHIV), yet vaccination rates within this group of Washington’s Dr. Carey Farquhar received a have been lower than expected Kenya.

University supplementary award to defineinboth barriers and of facilitators Washington’s Dr. Carey Farquhar received a PLHIV of COVID-19 vaccine uptake among supplementary define both barriers and in Kenya. Her award team’s to proposal also aims to identify facilitators of COVID-19 vaccine uptake among PLHIV strategies to overcome vaccine hesitancy while building inresearch Kenya. Her team’s proposal also aims to identify capacity at Kenyatta National Hospital (KNH) strategies to overcome vaccine hesitancy while building in Nairobi. research capacity at Kenyatta National Hospital (KNH) inVaccine Nairobi.hesitancy among PLHIV is not well understood.

During the first phase of the study, baseline surveys Vaccine is not well understood. will be hesitancy conductedamong amongPLHIV patients accessing care at During the first comprehensive phase of the study, baseline the hospital’s HIV care centersurveys and the will be conducted patients accessing care at outpatient units.among This will be followed by in-depth interviews and a survey administered health care the hospital’s comprehensive HIV care to center and the workers. These knowledge outpatient units. will Thisidentify will be attitudes followed and by in-depth about theand COVID-19 vaccine.

“Understanding interviews a survey administered to healththe care workers. These will identify attitudes and knowledge about the COVID-19 vaccine. “Understanding the

6

6

patient-health care worker interaction will be key in promoting use of the COVID-19 vaccine,” patient-health care worker interaction will be said team member Dr. Nancy Ngumbau of KNH. key in promoting use of the COVID-19 vaccine,” Research capacity at the national hospital will be said team member Dr. Nancy Ngumbau of KNH. strengthened with four trainees gaining experience Research capacity at thevia national hospital will be in research methodology hands-on experience, strengthened with four trainees gaining experience mentorships, workshops and courses. in research methodology via hands-on experience, mentorships, and courses.

During phase workshops two, stakeholders will participate in a two-day workshop to identify strategies for During phase two, stakeholders will participate optimizing COVID-19 vaccine uptake among PLHIV. in a two-day will workshop identify strategies for Participants includeto health ministry leadership, optimizing COVID-19 vaccine among PLHIV. NGOs, health care workers anduptake networks of PLHIV. Participants health ministry leadership, The study willwill useinclude an integrated, implementation NGOs, caretoworkers of PLHIV. sciencehealth approach “ensure and thatnetworks interventions, The study and will policies use an integrated, implementation strategies will be developed to increase science approach to “ensure that interventions, uptake of vaccination,” said Ngumbau.

“Therefore, the resultsand of this studywill canbe bedeveloped rapidly adopted and strategies policies to increase used to of influence optimal COVID-19 vaccine delivery uptake vaccination,” said Ngumbau.

“Therefore, for PLHIV the resultsinofKenya.” this study can be rapidly adopted and used to influence optimal COVID-19 vaccine delivery for PLHIV in Kenya.”

Resources: https://bit.ly/COVIDsupplements

Resources: https://bit.ly/COVIDsupplements

57

FOCUS ON COVID AWARDS

Studying intimate partner violence in India Across the globe, an unintended consequence of COVID19-related lockdowns has been an uptick in domestic violence. In India, roughly a third of married women experience intimate partner violence even during normal times, according to University of Iowa professor Dr. William Story.

When the pandemic began, Story’s colleagues, Dr. Nancy Angeline Gnanaselvam and Dr. Avita Johnson, were in the Bangalore suburbs collecting data on attitudes surrounding violence against women for a Fogarty-funded study. “We were able to interview women both before the COVID-19 lockdown and then after,” said Story. His supplemental grant from Fogarty will enable him to analyze this data and also re-interview some women given that initial trends were “curious.”

“Intimate partner violence in some populations decreased after the lockdown, when we expected to see an increase,” he said.

Since many people moved during the pandemic, he noted, someone in an abusive relationship may have relocated away from their partner. With liquor stores and bars closed, alcohol consumption might have decreased. “It’s a complex pattern that we want to look into more deeply,” Story said.

“Supplements are great for being able to look at a question that maybe we weren’t expecting to come up during a study,” Story said. “COVID has put us in a position of asking extra questions and looking at things a little bit differently and I want to continue to practice that moving forward.”

Examining antibody response to SARS-CoV-2 in Sierra Leone Sierra Leone has experienced much lower COVID-19 caseloads and much less disease severity than countries in other parts of Africa. Preliminary testing done on blood samples collected prior to the pandemic showed Sierra Leoneans had a higher antibody response to SARS-CoV-2, SARS-CoV, MERS and and other human coronavirus strains than their U.S. counterparts.

58 Delaware Journal of Public Health - December 2021

Vanderbilt and its partners at Tulane have been using a Fogarty grant to help build research capacity in Sierra Leone in the wake of the 2014-16 Ebola outbreak.

With supplemental funding, Moon and his colleagues will expand on this preliminary data to determine the percentage of participants who are seropositive to different human coronaviruses, including SARSCoV-2, both before and during the pandemic, but prior to vaccination. In addition the team will determine the proportion of positive-testing patients whose serum has neutralizing antibodies against SARS-CoV-2. Finally, the team will determine if this pre-existing immunity has any impact on the immune response in their cohort of participants following COVID-19 vaccination.

The onsite work will be led by Sierra Leonean investigator Dr. Robert Samuels, who recently trained at Vanderbilt as a scholar with support from the original Fogarty grant. Samuels will apply his newly acquired knowledge of research methods and management to lead and oversee the day-to-day implementation of the study, while gaining hands-on experience.

Moon believes this research could provide essential clues to further understand how coronaviruses operate.

“I think it opens up many questions as we try to better understand our immune response and coexistence with different respiratory pathogens and how that affects us at different time points when we see different illnesses,” he noted. “This is now the third pathologic coronavirus epidemic we've seen and one that probably will be with us for a long time. This is not going to be the last time we hear from coronaviruses.”

Scientists in India are using supplemental funds to analyze partner violence during the pandemic lock-down.

Photo courtesy of St. John’s Medical College

Peri-urban neighborhoods—created by the settling of previously rural areas near cities—are appearing throughout Southeast Asia and in other regions. For this reason, Story believes his work will be applicable to settings beyond India. Story hopes his data will also inform his work developing an intervention for teens that addresses patterns of behavior around concepts of masculinity. The new funding will also support data analysis instruction for the research team at St. John’s Medical College in India.

“One theory is that there may be other circulating coronaviruses in that part of the world that don’t necessarily cause disease—or severe disease—yet may be providing some level of protection,” said Vanderbilt University’s Dr. Troy Moon.

FOCUS FOCUS ON ON COVID COVID AWARDS AWARDS F O C U S O N C O V I D AWA R D S

Training Training researchers researchers at at Rakai Rakai Training researchers at Rakai The The COVID-19 COVID-19 pandemic pandemic has has interrupted interrupted HIV HIV treatment treatment

The COVID-19 pandemic has interrupted HIV treatment and and prevention prevention services services throughout throughout Africa.

Africa.

Given Given thethe and prevention services throughout Africa. Given the limited limited number number of health of health workers workers and and researchers researchers on on limited number of health workers and researchers on thethe continent, continent, a clear a clear need need exists exists forfor immediate immediate capacity capacity the continent, a clear need exists for immediate capacity building building and and research research training training specific specific to the to the HIV/ HIV/ building and research training specific to the HIV/ COVID-19 COVID-19 syndemic. syndemic.

To To help help meet meet that that need, need, Johns Johns COVID-19 syndemic. To help meet that need, Johns Hopkins Hopkins University’s University’s Dr.Dr. Larry Larry Chang Chang and and Rakai Rakai Health Health Hopkins University’s Dr. Larry Chang and Rakai Health Sciences Sciences Program’s Program’s Drs. Drs. Fred Fred Nalugoda Nalugoda and and Godfrey Godfrey Sciences Program’s Drs. Fred Nalugoda and Godfrey Kigozi Kigozi willwill establish establish anan HIV/COVID-19 HIV/COVID-19 Training Training and and Kigozi will establish an HIV/COVID-19 Training and Research Research Initiative Initiative at at the the Rakai Rakai Health Health Sciences Sciences Program Research Initiative at the Rakai Health Sciences Program Program in in Uganda Uganda through through a supplement a to the to existing existing grant. grant. in Uganda through a supplement supplement to the the existing grant.

The The Rakai Rakai Health Health Sciences Sciences Program Program is an is extramural extramural The Rakai Health Sciences Program is an an extramural training training sitesite forfor Makerere Makerere University University that that provides provides field field training training forfor Ugandan Ugandan and and U.S. U.S. students. students.

The The program program cancan implement implement and and support support HIV/COVID-19 HIV/COVID-19 research research and and capacity capacity building building through through thethe Rakai Rakai Community Community Cohort Cohort Study, Study, which which has has been been collecting collecting sociodemographic, sociodemographic, behavioral, health and other data since 1994. behavioral, behavioral, health health and and other other data data since since 1994.

1994.

The supplement, parent grant, aims The The supplement, supplement, likelike like its its its parent parent grant, grant, aims aims to to to support support support locally relevant research.

Planned activities include locally locally relevant relevant research. research.

Planned Planned activities activities include include didactics and discussions, mentored research, online didactics didactics and and discussions, discussions, mentored mentored research, research, online online writing accountability groups, data science training and writing writing accountability accountability groups, groups, data data science science training training and and in-country mini-sabbaticals. in-country in-country mini-sabbaticals. mini-sabbaticals.

COVID-19 disease, when combined with existing high

Building Building biostatistical capacity capacity inthreatens in South South Africa Africa rates of biostatistical HIV/AIDS and tuberculosis, fragile

COVID-19 COVID-19 disease, disease, when when combined with with existing existing high high healthcare systems andcombined infrastructures in sub-Saharan rates rates of HIV/AIDS of HIV/AIDS and and tuberculosis, tuberculosis, threatens threatens fragile fragile 8 healthcare healthcare systems systems and and infrastructures infrastructures in in sub-Saharan sub-Saharan

Africa. Policymakers require quality evidence to prevent Africa.

Africa.

Policymakers Policymakers require require quality quality evidence to to prevent prevent and treat COVID-19.

Instead, theyevidence face an “infodemic”— and and treat treat COVID-19.

COVID-19.

Instead, Instead, they they face face an an “infodemic”— “infodemic”— innumerable studies conducted across the globe, many of innumerable innumerable studies studies conducted conducted across across thefindings, the globe, globe, many many ofDr. of poor quality, plenty with contradictory noted poor poor quality, quality, plenty plenty with with contradictory contradictory findings, findings, noted noted Dr. Dr. Taryn Young of Stellenbosch University.

Taryn Taryn Young Young of Stellenbosch of Stellenbosch University.

University.

With her supplementary grant, Young will develop training With With herher supplementary supplementary grant, grant, Young Young willwill develop develop training training to support evidence synthesis and network meta-analysis to to support support evidence synthesis synthesis and and network network meta-analysis meta-analysis informevidence COVID-19 and HIV policy and practice decisions.

Young’s team plans to increase capacity by developing an to to inform inform COVID-19 COVID-19 and and HIV HIV policy policy and and practice practice decisions. decisions. onlineteam course thattoinstructs participants to developing find, appraise, Young’s Young’s team plans plans to increase increase capacity capacity by by developing anan interpret and consider theparticipants use of network meta-analysis online online course course that that instructs instructs participants to to find, find, appraise, appraise, and systematic reviews.

The South African team will also interpret interpret and and consider consider thethe use use of network of network meta-analysis meta-analysis develop a global network meta-analysis master class for and and systematic systematic reviews. reviews.

The The South South African African team team will will also also researchers, decisionmakers and students in HIV/AIDS. develop develop a global a global network network meta-analysis meta-analysis master master class class forfor This onlinedecisionmakers workshop will build regional capacity and researchers, researchers, decisionmakers and and students students in in HIV/AIDS. HIV/AIDS. cultivate analysis and systematic review skills. and “We are busy This This online online workshop workshop willwill build build regional regional capacity capacity and registering the short courses and developing content,” said cultivate cultivate analysis analysis and and systematic systematic review review skills. skills.

“We “We areare busy busy Young, noting that the courses will be offered early in 2022. registering registering thethe short short courses courses and and developing developing content,” content,” said said Young, Young, noting noting that that thethe courses courses willwill be be offered offered early early in in 2022.

2022.

Having seen the pandemic’s disruption of care delivery systems, she believes that the pandemic will likely Having Having seen seen thethe pandemic’s pandemic’s disruption disruption of care of care delivery delivery reverse gains achieved over decades by HIV programs. systems, systems, she she believes believes that that the the pandemic pandemic will will likely likely Young’s supplementary project aligns with her parent reverse reverse gains achieved achieved over decades decades by HIV HIV programs. programs. grant,gains which aims toover establish an by Africa Center for Young’s Young’s supplementary supplementary project project aligns aligns with with her her parent Biostatistical Excellence. “There is an urgentparent need for data grant, grant, which which aims aims to to establish establish anan Africa Africa Center Center for driven interventions to address these threats to for African Biostatistical Biostatistical Excellence.

Excellence.

“There “There is an is an urgent urgent need need forfor data data populations.” driven driven interventions interventions to to address address these these threats threats to African to African populations.” populations.”

Photo by Mckina Jackie/Rakai Health Sciences Program

Malaysia—spared in the earliest days of the pandemic— Malaysia—spared Malaysia—spared in in thethe earliest earliest days days of the of the pandemic— pandemic— had the largest COVID-19 case load per capita by the had had the the largest largest COVID-19 COVID-19 case case load load per per capita capita bynation by thethe is spring of 2021. Concurrently, this Asia-Pacific spring spring of 2021. of 2021.

Concurrently, Concurrently, this this Asia-Pacific Asia-Pacific nation nation is is battling a rapidly expanding HIV epidemic. COVID-19 has battling battling a rapidly a rapidly expanding expanding HIV HIV epidemic. epidemic.

COVID-19 COVID-19 has has been an “implementation disruptor,” stalling research and been been an an “implementation “implementation disruptor,” disruptor,” stalling stalling research research and and the prevention and treatment of HIV in Malaysia, noted thethe prevention prevention and and treatment of HIV ofAltice HIV in in Malaysia, noted noted Yale University’s Dr.treatment Frederick in Malaysia, his supplement Yale Yale University’s University’s Dr.Dr. Frederick Frederick Altice Altice in in hishis supplement supplement proposal. proposal. proposal.

With the additional support, Altice and his colleague Dr.the Adeeba Kamarulzaman will establish COVID-19With With the additional additional support, support, Altice Altice and and hishis colleague colleague related trainings and activities through an existing Dr.Dr. Adeeba Adeeba Kamarulzaman Kamarulzaman willwill establish establish COVID-19COVID-19implementation science training program.

These will related related trainings trainings and and activities activities through through anan existing existing include a series of lectures on program.

COVID-19 and an implementation implementation science science training training program.

These These willwill expansion of the bootcamp to and address include include a series a series of lectures ofsummer lectures on on COVID-19 COVID-19 and ananissues directly related to COVID-19.

In addition, research expansion expansion of the of the summer summer bootcamp bootcamp to address to address issues issues funding will be so In faculty members can conduct directly directly related related to provided to COVID-19.

COVID-19.

In addition, addition, research research pilot projects focused on both COVID-19 and HIV. funding funding willwill be be provided provided so so faculty faculty members members cancan conduct conduct pilot pilot projects projects focused focused on on both both COVID-19 COVID-19 and and HIV. HIV. The nation of 32.8 million people has more than 100,000 cumulative cases of HIV. Recent rapid growth is attributed The The nation nation of 32.8 of 32.8 million million people people has has more more than than 100,000 100,000 to an inadequate scale-up of evidence-based interventions, cumulative cumulative cases cases of HIV. of HIV. Recent Recent rapid rapid growth growth is attributed is attributed including access to HIV testing, pre-exposure prophylaxis, to an to an inadequate inadequate scale-up scale-up of evidence-based of evidence-based interventions, interventions, antiretroviral therapy and syringe exchange programs. including including access access to to HIV HIV testing, testing, pre-exposure pre-exposure prophylaxis, prophylaxis, antiretroviral antiretroviral therapy therapy and and syringe syringe exchange exchange programs. programs.

Building biostatistical capacity in South Africa

Fogarty grant supplements will support an array of COVID-19-related activities Fogarty Fogarty grant supplements supplements will will support support anRakai, array an array of COVID-19-related of COVID-19-related activities activities such grant as mentored research training in Uganda. suchsuch as mentored as mentored research research training training in Rakai, in Rakai, Uganda.

Uganda.

8 8 59

Photo Photo by by Mckina Mckina Jackie/Rakai Jackie/Rakai Health Health Sciences Sciences Program Program

Advancing implementation science in Malaysia Advancing Advancing implementation implementation science science in in Malaysia Malaysia

Determining the mental health of Ugandan youth Uganda responded to the COVID-19 pandemic with stern measures, including a lockdown, shelter-in-place requirements and school closures. This strict approach exposed youth living with HIV (YLHIV) and their families to a variety of stressors, including social isolation, anxiety, loneliness, difficulty accessing medications and disruptions in economic activities, explained Dr. Fred Ssewamala of Makerere University. With supplementary support from Fogarty, he plans to examine the pandemic’s impact on the mental health of YLHIV in Uganda.

Ssewamala and his team will interview 500 YLHIV across 39 health facilities in the greater Masaka region of Southwestern Uganda. Prevalence of HIV and AIDS in this region is 8% compared to about 6% nationally.

His primary aim is to gain a clearer understanding of “the intersectionality of the consequences of two viral infections at a physiological level: HIV and COVID-19,” he said. “We need to understand the psychological impact of the pandemic in real time in order to design appropriate measures to address any challenges.”

Ssewamala’s team anticipates seeing increased depression, anxiety and post-traumatic stress disorder in study participants. “We know that prior large-scale disasters— such as Ebola and SARS—had a negative impact on the psychological wellbeing of patients and healthcare providers,” he noted. “However, we have never witnessed such drastic control measures before.”

During the project, Ssewamala and his colleagues will be training and mentoring the cadre of 18 Ugandan scientists chosen under his original research training grant. Participants will learn “rigorous and culturally-congruent research methods,” he said. He hopes to exchange data and lessons learned with other Fogarty awardees and, eventually, plans to disseminate his findings among the broader scientific community. “The lessons are potentially transferable to other low-resource settings in sub-Saharan Africa.”

Understanding stigma in Nigeria Nigeria has a high burden of HIV-related brain disorders, including mental health illnesses and neurological impairment. Dr. Babefemi O. Taiwo of Northwestern University in Chicago estimates that HIV-associated neurocognitive disorders alone affect many Nigerians living with HIV, but exact numbers are not known. Taiwo, supported by an award attached to his HIV Research training grant, will look at the intersection of COVID-19 and HIV amongst people living with HIV (PLHIV) in Nigeria. “We have a particular interest in how mental health issues have been impacted, which will include how stigma might have played into that.”

PLHIV historically bear a disproportionate share of mental

health challenges caused by both the diagnosis itself and the environment, he explained. Pockets of stigma still exist in Nigeria—like in many parts of the world— and COVID-19 has added to this psychological burden.

Meanwhile, the lockdown complicated pre-existing mental health issues and restricted access to treatment.

“Testing for COVID-19 is not widespread and there is a lot of misinformation, fear and stigma,” Taiwo noted.

“So what you have now is a confluence of mental health challenges from COVID-19 and HIV that, for PLHIV, can be quite significant.” This “entanglement” often leads to poor adherence to treatment, the cornerstone of success.

Ongoing research includes longitudinal data on depressive symptoms and HIV care adherence both before and after the onset of the pandemic, explained Dr. Bibilola Oladeji, Taiwo’s colleague who will lead the research team in Ibadan. “We want to leverage this data to explore the effects of the COVID-19 pandemicrelated lockdowns and movement restrictions on depressive symptoms.” The team expects to gain a better understanding of how COVID-19 is impacting the mental health of PLHIV, which age groups are most affected and how to use that information to develop interventions.

Progress is underway. The team has selected trainees and brought together key stakeholders. Currently, they are developing lectures, courses and other educational experiences. Oladeji said, “Trainees will explore available data and develop qualitative data as part of their handson training and to fulfill the program’s capacity building activities.” Taiwo concluded, “This supplement will help nurture another group of investigators with an interest in the mental health and neurologic complications of HIV infection.”

9 60 Delaware Journal of Public Health - December 2021

OPINION

By Dr. Roger I. Glass, Director, Fogarty International Center

Investing in Africa will improve economy and health The 20th century has demonstrated that innovations in technology and investments in research have been among the most powerful and costeffective ways to advance economic development and improve health and prosperity. I was delighted to participate in a recent event hosted by the African Business Coalition and the U.N. Economic Commission for Africa (ECA), where we explored the tremendous opportunities for progress across their continent. COVID-19 has clearly shown us the need to strengthen African research capacity to respond to health issues with African solutions.

through the Medical Education Partnership Initiative and for genomics research through the Human Health and Heredity in Africa program.

Sustainable advances usually require a well-developed research agenda and a solid workforce trained in science, technology, engineering and mathematics (STEM) capable of carrying it out. We must think about things differently.

First, we need to refocus our training in STEM from rote memory learning to problem solving. We need to think about how to foster creativity, innovation and leadership.

In addition to strengthening its pandemic preparedness, Africa must also prepare to address the rising tide of noncommunicable diseases such as mental illness, diabetes, stroke and lung cancer. These illnesses have overlapping risk factors—hypertension, high fasting plasma glucose, high body mass index, tobacco use and ambient air pollution. Some of these diseases and risk factors are also predisposing factors for more severe and prolonged cases of COVID-19. Through our implementation science efforts, we are trying to leverage the HIV research and care platforms for NCDs, but much more is needed.

Second, we must recognize that team science is critical.

It’s not just the health scientists who are important but it’s the engineers, the data scientists, the businesspeople and the marketers. It’s understanding where we can identify local priorities for health research and find solutions that will make a difference. We’re now investing in teams to do this kind of research, where each member brings different perspectives to the table not just to conduct research, publish papers and push out academic promotions but to develop products, find solutions and bring these solutions and products to market.

Third, governments and industry have to come together to develop activities like biotech parks, filled with spaces where new ideas from academia can be incubated and accelerated into products that improve health and can be brought to scale.

Partnerships are absolutely critical to all these endeavors.

South-South partnerships should be encouraged, so that new skills acquired are shared regionally and across the continent. North-South partnerships remain important to bring new technologies and help discover how they could be adapted for local use. NIH has contributed by establishing African networks for research training

Finally, we should consider ways to engage diaspora scientists with Africa, so their knowledge, perspectives and networks can be leveraged for progress. We are encouraged by the example of Dr. John Nkengasong. Early in his career, he received Fogarty training in the U.S., spent time at the American CDC and now has gone on to be a truly outstanding leader of the Africa CDC. We need to train more people for leadership positions who understand research, who can make policies that respond to the science and can move this agenda forward.

We see huge opportunities with Africa’s rapidly expanding population of young people who will be the stimulus for these activities in the future. We need to encourage them as they progress in scientific careers, find ways to keep them on the continent and make them part of the solution.

We believe that in the next few decades economic advances in Africa will be driven by innovations in science and technology, leading to improvements in health. Much of that will come from local solutions to local problems aided by global collaborations and partnerships.

NIH plans to remain an active participant. This month we are launching a $75 million data science in Africa initiative. Through this investment, we will be creating a network of research and training hubs in data science and innovation across Africa to stimulate innovation, advance data science and spur health discoveries.

We realize progress is measured over decades and we are committed for the long haul.

RESOURCES

10

www.abchealth.com 61

PEOPLE AAMC honors scientists for integrity during pandemic Three NIH-affiliated scientists are being honored by the Association of American Medical Colleges for their leadership in biomedical research and contributions during the pandemic.

NIH Director Dr. Francis Collins is cited for engaging the full capabilities of the NIH to combat coronavirus and for managing the international Human Genome project.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, is being acknowledged for his commitment to scientific integrity and public health during the COVID19 pandemic. In addition to his role as a respected government spokesperson, Fauci is also recognized for overseeing the rapid development of the COVID-19 vaccines. He is also one of the principal architects of the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR).

Finally, the AAMC is presenting its 2021 Robert Wood Johnson Foundation David E. Rogers Award to NIH grantee and former Fogarty board member, Dr. Peter Hotez. Dean of Tropical Medicine at Baylor College, Hotez is honored for his work in countering anti-vaccine messaging during the pandemic and leading efforts to confront anti-COVID-19-vaccine aggression.

NHGRI names Rotimi as scientific director The NIH’s National Human Genome Research Institute has selected Dr. Charles Rotimi as its next scientific director and head of its intramural research program. Rotimi—the first African-born scientific director of an NIH Institute—was a key architect and major participant in the Human Heredity and Health in Africa (H3Africa) Initiative.

Global Health Council names new President and CEO The Global Health Council recently announced the appointment of Elisha Dunn-Georgiou as its new president and CEO. Previously, she was vice president for policy and advocacy at Population Action International (PAI). She holds a master’s degree in epidemiology and a law degree from the State University of New York at Buffalo.

Bhutta receives 2021 Roux Prize Agha Khan University Professor Zulfiqar Bhutta has been awarded the 2021 Roux Prize for turning evidence into health impact. Bhutta’s work has focused on newborn and child survival and undernutrition, with an emphasis on reducing health disparities. The award is administered by the Institute for Health Metrics and Evaluation at the University of Washington.

Jirair Ratevosian tapped as senior PEPFAR advisor Jirair Ratevosian, MPH, has been named by the White House to serve as a senior advisor in the State Department’s Office of the U.S. Global AIDS Coordinator and Health Diplomacy. Ratevosian, a Boston University graduate, will help oversee the President’s Emergency Plan for AIDS Relief (PEPFAR).

Global HEALTH Briefs HHS requests input on new strategic plan

The U.S. Department of Health and Human Services, of which NIH is a part, has released a new draft strategic plan open for comment until Nov. 7. One goal addresses global health and calls for improved capabilities to prevent and respond to threats, protect populations from disease, promote healthy behaviors and mitigate climate change.

Website: https://bit.ly/HHS_plan

HHS establishes climate change office

HHS has announced it is forming an Office of Climate Change and Health Equity (OCCHE), tasked with the mission of protecting vulnerable communities that disproportionately bear the brunt of pollution and climate-driven disasters, at the expense of public health. OCCHE’s interim director is the NIH’s Dr. John Balbus.

Website: www.hhs.gov/ocche

NIH launches stigma research toolkit

NIH has developed a stigma and discrimination research toolkit that contains information about theories, models, frameworks, measures, methods and interventions that can be applied to reduce the impact of stigma and discrimination. Hosted by the National Institute of Mental Health, partners include the National Institute on Drug Abuse and Fogarty.

Website: https://bit.ly/stigma_toolkit

WHO recommends malaria vax for kids

The WHO is calling for widespread use of a groundbreaking malaria vaccine for children in sub-Saharan Africa and other regions with moderate to high malaria transmission. The WHO said the RTS,S/AS01 vaccine should be provided in a schedule of 4 doses in children 5 months of age and older.

News release: https://bit.ly/WHO_malaria_vax

PMI releases plan to end malaria faster

The U.S. President’s Malaria Initiative (PMI) has announced its new five-year strategy to end malaria faster. PMI said it will work with partners to maximize program efficiency by addressing five focus areas: reach the unreached, strengthen community health systems, keep malaria services resilient, invest locally, and innovate and lead.

Full plan: https://bit.ly/PMI_Plan

11 62 Delaware Journal of Public Health - December 2021

SEPTEMBER/OCTOBER 2021

Funding Opportunity Announcement

Deadline

Details

Global Infectious Disease (GID) Research Training D71 Clinical Trials Not Allowed

Oct 28, 2021

http://bit.ly/IDtraining

Emerging Global Leader Award K43 Independent Clinical Trials Required K43 Independent Clinical Trials Not Allowed

Nov 3, 2021

https://bit.ly/E_Lead

Mobile Health: Technology and Outcomes in Low and Middle Income Countries R21 Clinical Trials Optional R33 Clinical Trials Optional

Nov 15, 2021

https://bit.ly/NIH_mHealth

Ecology and Evolution of Infectious Diseases (EEID)

Nov 17, 2021

http://bit.ly/EEIDNIH

HIV-associated Noncommunicable Diseases Research at LMIC Institutions

Dec 8, 2021

https://bit.ly/FogartyHIVNCD

Global Brain and Nervous System Disorders Research Across the Lifespan R21 Clinical Trials Optional R01 Clinical Trials Optional

Dec 9, 2021

http://bit.ly/NIHGlobalBrain

International Research Scientist Development Award K01 Independent Clinical Trials Required K01 Independent Clinical Trials Not Allowed

Mar 9, 2022

https://bit.ly/IRSDAK01

For more information, visit www.fic.nih.gov/funding

Global Health Matters September/October 2021 Volume 20, No. 5 ISSN: 1938-5935 Fogarty International Center National Institutes of Health Department of Health and Human Services Managing editor: Ann Puderbaugh Ann.Puderbaugh@nih.gov Writer/editor: Mariah Felipe Mariah.Felipe@nih.gov Writer/editor: Susan Scutti Susan.Scutti@nih.gov Designer: Carla Conway

All text produced in Global Health Matters is in the public domain and may be reprinted. Please credit Fogarty International Center. Images must be cleared for use with the individual source, as indicated.

SUBSCRIBE: www.fic.nih.gov/subscribe

World Report used to detail US-India partnerships The U.S. Health Attaché in India Dr. Preetha Rajaraman has scored a trifecta using World Report, a tool illustrating global research funding. With simple query terms, she was able to quickly generate scene-setting information and start a conversation about India’s role in global biomedical research.

World Report helped her highlight the expansion of collaborative health research for a recent report titled “The US-India Partnership: Ambition and Achievement,” to brief the Indian Minister of Human Resource Development and provide introductory remarks for U.S. Chargé d’Affaires at a bilateral workshop on vision research.

“World Report has been a great resource to help advance our goals of initiating and facilitating regional cooperation in health and biomedical research,” Rajaraman observed. “It is easy to use and updated specifically for global biomedical research, allowing me to quickly locate where collaborations are happening in South Asia.”

R ESOURCE worldreport.nih.gov 63

Disparities in Delaware Caregiver Beliefs about the COVID-19 Vaccine for their Children Thao-Ly Tam Phan, M.D., M.P.H. Associate Professor of Pediatrics, Thomas Jefferson University; Research Scientist, Nemours Center for Healthcare Delivery Science Paul T. Enlow, Ph.D. Assistant Professor of Pediatrics, Thomas Jefferson University; Assistant Research Scientist, Nemours Center for Healthcare Delivery Science Michael K. Wong Medical Student, Thomas Jefferson University Amanda M. Lewis, M.P.H. Data Analyst, Nemours Center for Healthcare Delivery Science Anne E. Kazak, Ph.D., A.B.P.P. Professor of Pediatrics, Thomas Jefferson University; Director, Nemours Center for Healthcare Delivery Science Jonathan M. Miller, M.D. Medical Director, Nemours Value-Based Services Organization; Chief of Primary Care Pediatrics, Nemours Children’s Health - Delaware Valley

ABSTRACT Objective: To describe sociodemographic disparities in caregiver beliefs about the COVID-19 vaccine for their children.

Methods: This was a cross-sectional study, linking caregiver-reported data to geocoded sociodemographic data from child EHRs. Caregivers of children receiving care in a Delaware pediatric healthcare system were invited to complete a survey about COVID-19 vaccine beliefs from March 19 to April 16, 2021.

Results: 1499 caregivers participated (18% Black, 11% Hispanic, 32% public insurance, 12% rural). 54% of caregivers intended to vaccinate their children, while 34% were unsure and 12% would not. Caregivers of younger children (aOR 3.70, CI 2.36-5.79), Black children (aOR 2.11, CI 1.50-2.96), and from disadvantaged communities (aOR 1.59, CI 1.05-2.42) were more likely to be unsure and not vaccinate their children. Caregivers from rural communities were more likely not to vaccinate their children (aOR 2.51, CI 1.56-4.05). Fewer caregivers of younger children, Black children, and from disadvantaged communities believed in the safety or efficacy of the vaccines (p < 0.001), while fewer caregivers of younger children and from rural communities believed in their children’s susceptibility to COVID-19 or risk of getting severe disease from COVID-19 (p < 0.05). While the majority (72%) of caregivers were influenced by health experts, fewer from communities of color and disadvantaged communities were (p<0.001).

Conclusions: Caregivers of younger children and from communities of color, rural communities, and disadvantaged communities in Delaware expressed more COVID-19 vaccine hesitancy.

Policy implications: This study explores beliefs of different communities in Delaware, which are important to tailoring public health messaging and strategies to increase vaccine uptake in these communities.

INTRODUCTION The COVID-19 pandemic has exacerbated disparities in Delaware and across the United States, with communities of color, rural communities, and disadvantaged communities experiencing higher rates of COVID-19 transmission, morbidity and mortality1–3 and reduced rates of COVID-19 vaccination.4,5 The United States is still far from achieving herd immunity, with about 54% of Delawareans being fully vaccinated and uptake for COVID-19 vaccines declining.6–8 Several studies in adults have demonstrated that Black adults, adults from rural areas, and adults from households with lower incomes have higher rates of COVID-19 vaccine hesitancy6,9–13 exacerbated by systemic issues of institutional racism, distrust of the healthcare system, misinformation, and complacency with the pandemic.14,15 However, there have been only a handful of studies assessing caregiver hesitancy towards a COVID-19 vaccine for their children,6,16–20 with the most recent national survey showing that less than half of caregivers in the United States were likely to vaccinate their children against COVID-19 and increased hesitancy among parents of younger children those with lower educational status and non-Democratic affiliations.20 64 Delaware Journal of Public Health - December 2021

With the COVID-19 vaccine increasingly becoming available for children,21,22 understanding factors that impact caregiver acceptance of COVID-19 vaccines for their children is critical to informing public health interventions and messaging.7 The Health Belief Model (HBM) is a validated conceptual framework used to describe factors, including beliefs about vaccine safety/efficacy, severity of/susceptibility to disease, and cues to action, that have impacted caregiver acceptance of the seasonal and H1N1 influenza vaccines for their children.23–25 Studies evaluating HBM constructs that impact adult acceptance of the COVID-19 vaccine for themselves26–30 have demonstrated the value in identifying what beliefs are commonly associated with vaccine hesitancy. Despite this there have been no studies formally evaluating the impact of HBM constructs on caregiver acceptance of the COVID-19 vaccine for their children. In addition, recent studies that have evaluated caregiver beliefs (e.g about vaccine safety) have not described differences in these beliefs between different demographic subgroups.20 Doi: 10.32481/djph.2021.12.015

Therefore, the objective of this study was to describe disparities in caregiver intention to vaccinate their children against COVID-19 in Delaware and differences among sociodemographic groups in caregiver beliefs that influence intention to vaccinate their children against COVID-19 through the lens of the HBM, leveraging linked EHR data and geocoded variables to define social determinants of health. Identification of hesitant populations and modifiable beliefs is critically important to developing tailored public health strategies in the state to promote equitable uptake of COVID-19 vaccines among children.

METHODS

Study Design and Participants

A cross-sectional study was conducted, linking caregiver-reported survey data to child electronic health record (EHR) data. Families (N=2403) received an invitation to complete the survey for this study if they had consented to participating in a prospective cohort study about the impact of COVID-19 on families and pediatric healthcare delivery in October and November of 2020.

Families (N=15,000) were invited to participate in the prospective cohort study and were eligible if they had a scheduled outpatient visit in April 2020 to a large pediatric healthcare system in the Delaware Valley region of the United States. Families were excluded if the child was older than 21 years, if the caregiver was not proficient in English or Spanish, if a mobile phone number was not listed in the EHR, if the family had opted out of research participation, or if the child was not an established patient of the healthcare system (defined as having at least one other visit to the healthcare system in the prior 12 months). Families of children who were of Black race or Hispanic ethnicity, who had public insurance, or who were from rural neighborhoods [Rural Urban Commuting Area (RUCA) code ≥ 4]31 were oversampled, with all eligible families from these subgroups receiving an invitation to participate in the original study, and a random sample of eligible families from other subgroups receiving an invitation to participate. If a mobile number was available for more than one caregiver per family, both caregivers were invited to participate.

This study was approved by the healthcare system’s institutional review board (number 1613768), with caregivers of participating families signing an e-consent.

Procedures

A study identifier was created for all eligible participants in a REDCap database32 and information from each child’s EHR was imported into the database. Text messages containing a hyperlink to the REDCap survey, unique to each eligible participant, were sent every three days to caregivers of all eligible families at the mobile number listed in the child’s EHR from March 19, 2021 to April 16, 2021 until the survey was completed. An e-mail message describing the study and alerting the eligible participant to anticipate a text message with the survey link was sent at the beginning and at the end of the survey time period to increase survey response rates.33

Caregiver Beliefs about the COVID-19 Vaccine for their Children

Ten questions were included in a REDCap survey. In addition to a question about intention to vaccinate, an additional set of questions asked about five potential cues to action that might influence caregiver decisions to vaccinate their child against COVID-19, adapted for the pediatric population from a validated survey conducted among adults about the COVID-19 vaccine.29 A question representing each of the four primary HBM constructs

(perceived susceptibility, severity, benefits, and barriers) was also included. Questions were adapted from a study of caregiver beliefs about the influenza vaccine for their child, with questions selected based on the strength of their association in the original study with child influenza vaccination.24 1) Do you plan to vaccinate your child(ren) against COVID-19 when they are eligible? (intention to vaccinate) 2) My decision to have my child(ren) vaccinated against COVID-19 is affected by (cues to action) a. What I have seen/read on media (including social media) b. What my friends and family say c. What health experts think d. What my or my child’s doctor says e. What my child’s school says 3) My child(ren) would get sick more easily from COVID-19 than other child(ren) (perceived susceptibility) 4) COVID-19 could make my child(ren) very sick (perceived severity) 5) If my child(ren) get the vaccine, they won’t get sick from COVID-19 (perceived benefit) 6) COVID-19 vaccines are unsafe for children (perceived barrier) Response options for question 1 included yes, no, and not sure.

Response options for the remainder of the questions included strongly disagree, disagree, neither agree nor disagree, agree, and strongly agree. For the purpose of analyses, these responses were categorized as agree (including agree and strongly agree) or not.

Child Sociodemographics

Information on child race, ethnicity, age, insurance, and ZIP code were extracted from the child’s EHR. For the purpose of analyses, child race and ethnicity were categorized as NonHispanic Black, Hispanic, Non-Hispanic White, or Non-Hispanic Other. Child age was categorized as 0-1 years, 2-11 years, 1215 years, and 16 years or older to correspond to current and anticipated COVID-19 vaccine approval stages. Insurance status was categorized as private insurance, public insurance, or selfpay. ZIP code was used to categorize child neighborhoods as rural (RUCA code ≥ 4) or not (RUCA code < 4) and to categorize child neighborhood inequity based on overall Child Opportunity Index (COI, state-normed). The COI combines indicators of educational (e.g., early childhood education enrollment, high school graduation rate), health and environment (e.g., access to healthy food, health insurance coverage), and social and economic opportunity (e.g., employment rate, median household income) for all United States neighborhoods.34 These indicators are then used to categorize COI as very low, low, moderate, high, and very high.

Analysis

Descriptive analyses of child sociodemographics and caregiver responses to the survey items were performed. Pearson’s ChiSquare tests were conducted to describe the association between caregiver intention to vaccinate and child sociodemographics.

Multinomial logistic regression was conducted to further describe the association between intention to vaccinate as the primary outcome variable and child sociodemographics, 65

including any variables in the analyses that were found to be significant with Pearson’s Chi-Square testing and excluding any variables that were significantly associated with one another on tests of collinearity. Finally, Pearson’s Chi-Square tests were conducted to describe the association between caregiver beliefs about the COVID-19 vaccine for their children and child sociodemographics. All tests were performed with SPSS v27 and at a significance level of p<0.05.

RESULTS Participant Sociodemographics

1549 caregivers responded to the survey (60% of those who received the survey). The large majority were female (83%) and with a preferred language of English (96%). One hundred participants were caregivers for the same child and therefore 1449 children were represented in this survey (Table 1). The children in this sample were diverse and representative of the population, with 18% Black, 11% Hispanic, 32% having public insurance, and 12% from rural neighborhoods. There was a wide range of child ages and COI scores. 56% were patients seen in a primary care clinic of the pediatric healthcare system.

Table 1. Participant Characteristics Sociodemographic Variable Total Families

No. (%) 1449 (100)

Child sex Female

721 (50)

Male

728 (50)

Child age range 0-1 years

163 (11)

2-11 years

705 (47)

12-15 years

341 (23)

16 years and older

290 (19)

Child race/ethnicity Hispanic

167 (11)

Black

270 (18)

White

869 (58)

Other

193 (13)

Child insurance Public

484 (32)

Private

972 (65)

Self-Pay

43 (3)

Child Opportunity Index Very low

196 (13)

Low

289 (19)

Moderate

234 (16)

High

265 (18)

Very high

515 (34)

Neighborhood rurality Non-Rural (RUCA < 4) Rural (RUCA ≥ 4)

66 Delaware Journal of Public Health - December 2021

1321 (88) 178 (12)

Caregiver Intention to Vaccinate Child against COVID-19 by Child Sociodemographics

54% of caregivers intended to vaccinate their children against COVID-19, while 34% were not sure and 12% would not (Table 2). Of the one hundred participants who were caregivers for the same child, 82% were in agreement about their intention to vaccinate their children against COVID-19 (e.g., both parents said they would vaccinate their child). There were significant differences by child sociodemographics, with fewer caregivers of children under 16 years, of Black race, with public insurance, from neighborhoods with lower COI, and from rural neighborhoods reporting they intended to vaccinate their children against COVID-19 (p < 0.001 for all variables, Table 2).

In multinomial logistic regression analysis (Table 3), the pattern of associations was similar to the univariate analyses. Caregivers of younger children, Black children, children with public insurance, and children from neighborhoods with lower COI were more likely to both be unsure and report that they would not vaccinate their children against COVID-19. Caregivers from rural neighborhoods with lower COI were more likely to report that they would not vaccinate their children against COVID-19.

Caregiver Health Behavior Beliefs about COVID-19 Vaccination for their Child by Sociodemographics

The majority of caregivers agreed that COVID-19 could make their child very sick (53%) and that healthcare experts (72%) and their child’s doctor (70%) affect their decision to vaccinate their children (Table 4). Only 431 (29%) of participants agreed that the media and only 340 (23%) of participants agreed that friends and family affected their decision to vaccinate their children, with no differences among subgroups so these are not reported in Table 4. However, there were significant differences between sociodemographic subgroups in other beliefs (Table 4).

Fewer caregivers of younger children believed that their children are susceptible to COVID-19, that COVID could be severe in their children, and that the COVID-19 vaccines are safe. Fewer caregivers of Black children believed that the COVID-19 vaccines are effective, and fewer caregivers of Black and Hispanic children believed that COVID-19 vaccines are safe and were influenced by health experts or doctors. Fewer caregivers of children with public insurance believed that their child was susceptible to COVID-19, that the COVID-19 vaccines are safe or effective, or were influenced by health experts, doctors, or schools. Similarly, fewer caregivers of children from neighborhoods with lower COI scores believed that the COVID-19 vaccines are safe or effective or were influenced by health experts or doctors. Finally, fewer caregivers from rural neighborhoods believed that COVID-19 could be severe in their children or were influenced by their child’s school.

DISCUSSION This is the first study that comprehensively evaluates disparities in caregiver attitudes and beliefs about the COVID-19 vaccine for their children in Delaware. This is also the first study to evaluate these disparities leveraging EHR and geocoded data to assess individual and neighborhood level sociodemographics and evaluating constructs from the HBM. Fifty-four percent of caregivers in this representative sample intended to vaccinate their children against COVID-19, lower than what was described

by Kelly and colleagues at the start of the pandemic and higher than what was reported in a recent Kaiser Family Foundation

Table 2. Caregiver Intention to Vaccinate their Children Against COVID-19 by Sociodemographic Group

Total

Yes N (%)

No N (%)

Not Sure N (%)

808 (54)

180 (12)

511 (34)

Child age range

< 0.001

0-1 years

72 (44)

20 (12)

71 (44)

2-11 years

358 (51)

95 (14)

252 (36)

12-15 years

176 (52)

39 (11)

126 (37)

16 years and older

202 (70)

26 (9)

62 (21)

Child race/ethnicity

< 0.001

Hispanic

94 (56)

17 (10)

56 (34)

Non-Hispanic Black

98 (36)

47 (17)

125 (46)

Non-Hispanic White

515 (59)

96 (11)

258 (30)

Non-Hispanic Other

101 (52)

20 (10)

72 (37)

Public

200 (41)

78 (16)

206 (43)

Private

585 (60)

97 (10)

290 (30)

Self-Pay

23 (54)

5 (12)

15 (35)

Child insurance

< 0.001

Child Opportunity Index Very low

< 0.001 71 (36)

42 (21)

83 (42)

Low

148 (51)

44 (15)

97 (34)

Moderate

111 (47)

26 (11)

97 (42)

High

143 (54)

35 (13)

87 (33)

Very high

335 (65)

33 (6)

147 (29)

Neighborhood rurality Non-Rural (RUCA < 4) Rural (RUCA ≥ 4)

P

< 0.001 736 (56)

139 (11)

446 (34)

72 (40)

41 (23)

65 (37)

poll.6,18 Importantly, 46% of caregivers were unsure or would not vaccinate their children against COVID-19, with caregivers of younger children and from communities of color, rural communities, and disadvantaged communities being more hesitant. It is among these groups that public health strategies to improve COVID-19 vaccine uptake will be critical. This study is also the first to explore which caregiver health beliefs and cues to action are related to intention to vaccinate children in these subgroups, which is important when tailoring communication strategies to increase pediatric COVID-19 vaccine uptake in these communities.

There were significant differences in intention to vaccinate by child sociodemographics, with caregivers of children under 16 years, of Black race, with public insurance, from rural neighborhoods, and from neighborhoods with lower COI being less likely to intend to vaccinate their children against COVID-19.

These findings support the racial and socioeconomic disparities in COVID-19 vaccine hesitancy found in adult studies and the few pediatric studies among caregivers of children in the United States.15,25–28 This study adds to prior studies by using EHR and geocoded variables to better understand the impact of a child’s neighborhood on intention to vaccinate, including highlighting

the impact of social determinants of health and rurality on intent to vaccinate and health beliefs. While these sociodemographic variables often have complex relationships with one another, this study also highlights the need to recognize each as important and independent contributors to beliefs about COVID-19 vaccination.

Similar to recent studies,20 age was an important factor influencing caregiver intention to vaccinate their children against COVID-19. At the time of the survey, the vaccine was available to youth 16 years of age and older, and caregivers of children 16 years of age and older were more likely than caregivers of younger children to intend to vaccinate their children. This finding provides hope that as the COVID-19 vaccines become available to younger children, including now being available to children 12 years of age and older, caregivers may become more confident about vaccination for their children.

Similar to HBM studies evaluating caregiver beliefs about the seasonal and H1N1 influenza vaccine and to those evaluating adult beliefs about the COVID-19 vaccine for themselves,23–30 this study highlights the concerns about vaccine safety and efficacy that caregivers of all backgrounds have when considering whether to vaccinate their children. This study also demonstrates that fewer caregivers of younger children, compared to caregivers 67

of older children, believed that their children are susceptible to COVID-19 and would have severe disease from COVID-19, which are messages emphasized by early epidemiological studies and amplified by the media. Fewer caregivers from rural neighborhoods also believed that their child would have severe disease from COVID-19. These findings point to modifiable beliefs that should be targeted with more focused messaging, both emphasizing the efficacy and safety of the COVID-19 vaccine in a way that is relatable and relevant to families but also stressing the transmissibility and burden of COVID-19 among younger children and the importance of herd immunity to public health.

Not surprisingly, the overwhelming majority of caregivers in this study would be influenced by messaging from health experts and doctors, so it is important to leverage these communicators for general public health messaging. However, fewer caregivers from communities of color and disadvantaged communities were influenced by health experts and doctors, a finding likely driven by structural racism, mistrust of the medical system, systematic inequities, and a history of discrimination in research that have led to distrust in the healthcare system.14,35 Therefore it is critically important to develop a deeper understanding of how to reach these communities, including ways to improve access and trust and reduce structural racism within the healthcare system, such as identifying trusted champions within these communities and

developing a more diverse healthcare workforce.

There were some limitations to this study. While 60% of eligible families who received the vaccine survey completed it, if we take into account the number of eligible families who received an invitation to participate in the original study the overall participation rate was 10%. While this is not unexpected for a large-scale electronic survey study, it may lend itself to sampling bias. However, by oversampling for certain subgroups this study was able to achieve a sample otherwise very representative of the population. Notably, this study was conducted in four states in the Delaware Valley region of the United States. While the population was diverse, it is possible that there are geographic and political differences that are not accounted for in this study.

Another limitation is that youth health beliefs were not assessed.

Caregivers of older youth may include their child in deciding whether or not to receive the COVID-19 vaccine; therefore, future studies should also evaluate youth and adolescent beliefs. Finally, this study utilized EHR data like race/ethnicity and geocoded data to evaluate social determinants of health. While it is possible that self-reported data may have provided a more accurate picture of a family’s sociodemographics, the fact that the disparities found in this study were consistent with other studies and that

Table 3. Multinomial Logistic Regression Predicting Caregiver Intention to Vaccinate their Children Against COVID-19 No vs. Yes aOR (95% CI)

Not Sure vs. Yes aOR (95% CI)

Child age range 0-1 years

2.51 (1.56-4.05)

3.70 (2.36-5.79)

2-11 years

2.10 (1.30-3.40)

2.31 (1.65-3.30)

12-15 years

1.78 (1.02-3.09)

2.41 (1.65-3.51)

1 [Reference]

1 [Reference]

Hispanic

0.68 (0.37-1.23)

0.88 (0.59-1.30)

Non-Hispanic Black

1.75 (1.10-2.80)

2.11 (1.50-2.96)

Other

0.99 (0.57-1.71)

1.36 (0.96-1.93)

1 [Reference]

1 [Reference]

Public

1.82 (1.26-2.65)

1.82 (1.39-2.37)

Self-Pay

1.29 (0.47-3.56)

1.27 (0.64-2.52)

1 [Reference]

1 [Reference]

Very Low

3.65 (2.04-6.53)

1.59 (1.05-2.42)

Low

1.82 (1.05-3.16)

1.11 (0.77-1.60)

Moderate

1.83 (1.03-3.25)

1.66 (1.17-2.37)

High

2.13 (1.26-3.62)

1.25 (0.89-1.76)

1 [Reference]

1 [Reference]

2.51 (1.56-4.05)

1.42 (0.96-2.11)

1 [Reference]

1 [Reference]

16 years and older Child race/ethnicity

Non-Hispanic White Child insurance

Private Child Opportunity Index

Very High Neighborhood rurality Rural (RUCA < 4) Non-rural (RUCA ≥ 4) 68 Delaware Journal of Public Health - December 2021

Table 4. Caregiver Agreement with Health Belief Model Items by Child Sociodemographic Group Susceptible to COVID N (%)

Severity of COVID N (%)

Vaccine effective N (%)

Vaccine unsafe N (%)

Cue - health experts N (%)

Cue- child’s doctor N (%)

Cue – school N (%)

462 (31)

792 (53)

375 (25)

154 (10)

1073 (72)

1055 (70)

416 (28)

Total Child age range 0-1 years

20 (13)

73 (47)

41 (26)

17 (11)

114 (72)

112 (70)

55 (35)

2-11 years

210 (31)

376 (55)

165 (24)

89 (13)

496 (72)

488 (70)

199 (29)

12-15 years

106 (32)

170 (52)

88 (27)

29 (9)

246 (73)

243 (73)

101 (30)

16 and older

127 (45)

173 (62)

81 (29)

19 (7)

217 (75)

212 (74)

61 (21)

p

< 0.001

< 0.05

0.77

< 0.001

0.77

0.91

0.15

Hispanic

47 (31)

75 (49)

38 (25)

21 (14)

83 (52)

77 (48)

38 (25)

Non-Hispanic Black

90 (35)

140 (54)

41 (16)

39 (15)

161 (60)

149 (55)

73 (27)

Non-Hispanic White

268 (31)

471 (55)

248 (29)

70 (8)

691 (80)

693 (81)

240 (28)

Non-Hispanic Other

58 (31)

106 (57)

48 (26)

24 (13)

138 (74)

136 (73)

65 (35)

p

< 0.05

0.38

< 0.01

< 0.001

< 0.001

< 0.001

0.28

Public

179 (39)

244 (53)

80 (17)

68 (15)

263 (56)

254 (54)

106 (23)

Private

273 (29)

526 (55)

286 (30)

79 (8)

781 (81)

769 (80)

294 (31)

Self-Pay

11 (26)

22 (51)

9 (21)

7 (16)

29 (67)

32 (74)

16 (37)

< 0.001

0.24

< 0.001

< 0.001

< 0.001

< 0.001

< 0.001

Child race/ethnicity

Child insurance

p

Child Opportunity Index Very low

64 (34)

100 (54)

35 (19)

30 (16)

113 (58)

103 (53)

50 (26)

Low

80 (29)

132 (48)

54 (19)

37 (13)

192 (68)

187 (66)

65 (23)

Moderate

81 (36)

124 (54)

50 (22)

23 (10)

154 (67)

152 (66)

58 (25)

High Very high p

85 (33)

144 (56)

75 (29)

32 (13)

196 (75)

190 (73)

76 (29)

153 (30)

292 (58)

161 (32)

32 (6)

418 (82)

423 (83)

167 (33)

0.32

0.26

< 0.001

< 0.001

< 0.001

< 0.001

0.13

Neighborhood Rurality Non-Rural (RUCA < 4)

412 (32)

710 (55)

343 (27)

134 (11)

949 (73)

934 (72)

379 (29)

Rural (RUCA ≥ 4)

51 (30)

82 (48)

32 (19)

20 (12)

124 (71)

121 (69)

37 (21)

0.56

< 0.05

0.06

0.10

0.43

0.19

< 0.05

p

69

neighborhood indicators of social determinants of health like RUCA codes and COI performed as well as individual indicators like insurance status validates the use of the EHR in this study and underscores the importance of evaluating community-level factors. It also highlights the potential to use linked EHR data to evaluate the associations between health factors like prior child vaccination history and disease risk factors like obesity with caregiver beliefs about the COVID-19 vaccine for their children.

CONCLUSION This study describes the sociodemographic disparities in Delaware caregiver intention to vaccinate their children against COVID-19 and beliefs influencing this decision at a critical time when vaccines are more available to children, leveraging both caregiver-reported and EHR data. This study highlights the need to tailor COVID-19 vaccine public health messaging and strategies in Delaware for communities of color, rural communities, disadvantaged communities, and caregivers of young children in order to promote equitable pediatric vaccine uptake.

ACKNOWLEDGEMENTS We would like to thank Dr. Kara Odom Walker, MD, MPH, MSHS for her review of this manuscript and the team at the Nemours Center for Healthcare Delivery Science for their input on the parent study, The Impact of COVID-19 on Families and Pediatric Healthcare Delivery. This work was supported by the ACCEL/Delaware Clinical and Translational Research Program (grant number NIGMS U54 GM104941) [to TP and PE]. The National Institute of General Medical Sciences had no role in the design and conduct of the study.

Dr. Phan can be contacted at tphan@nemours.org

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Characteristics and Outcomes of SARS-CoV-2 Infection Among Adults Living With HIV In Delaware: The Story of a Syndemic During the First 12 Months of the SARS-CoV-2 Pandemic Adam K Skrzynski, M.D. Brooke L Darmstadter, Pharm.D., A.A.H.I.V.P. Sharon P Miner, A.G.P.C.N.P.-B.C. Deborah Kahal, M.D., M.P.H., F.A.C.P. ChristianaCare, William J. Holloway Community Program Keshab Subedi, M.S., M.Sc. ChristianaCare, Value Institute

ABSTRACT Objective: To better characterize the intersection of the HIV and SARS-CoV-2 pandemics, including our robust statewide panel of people living with HIV, in the State of Delaware. Methods: We conducted a retrospective descriptive case-series that identified people living with HIV ≥ 18 years old co-infected with SARS-CoV-2 from 1 March 2020 through 9 March 2021 who attended our ambulatory HIV program, through review of testing results, electronic medical records and external clinical records. Results: There were 105 confirmed cases of SARS-CoV-2 infection and 4 attributable deaths from COVID-19 among adult people living with HIV from 1 March 2020 through 9 March 2021. Co-infected patients had very high rates of ART prescription and virologic suppression, with robust CD4 counts. 24/105 (22.9%) SARS-CoV-2 cases were hospitalized due to COVID-19 and had a significant burden of co-morbidities; a vast majority were AIDS-defined. Age, BMI >30 kg/m2, cardiovascular disease, chronic kidney disease and cirrhosis were independently associated with hospitalization by logistic regression. Black patients appeared to have lower rates of testing and higher rates of hospitalization.

Additionally, those with history of natural immunity to hepatitis B virus exhibited a low rate of hospitalization.

Conclusions: Our cohort data is the first to capture the experience of patients co-infected with HIV/SARS-CoV-2 in Delaware, demonstrating the risk of long-term immunosuppression and burden of comorbid disease, even in the setting of virologic suppression. Although not reaching statistical significance, we identified high rates of resolved hepatitis B virus infection amongst non-hospitalized co-infected patients and postulate there may be an underlying immunologic mechanism to this hypothesis-generating observation. Our results also highlight the role that healthcare disparities have played during these overlapping pandemics. Policy Implications: Pronounced healthcare disparities are known to worsen outcomes in a variety of disease states. From our descriptive data, we suggest continued efforts to address the social determinants of health, especially as they pertain to common chronic comorbid conditions and certain Black communities.

BACKGROUND The intersection of the human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus-2 (SARSCoV-2) pandemics has opened a Pandora’s box of unanswered questions within medicine. As of this writing, SARS-CoV-2 has infected 210 million individuals worldwide, including many people living with HIV (PLWH), of whom there are estimated to be 37.9 million individuals at present. Due to the immunosuppressive and inflammatory effects of HIV, concern has emerged over the possibility of worse outcomes in PLWH affected by COVID-19. Worldwide studies have yielded variable associations between HIV and increased risk of morbidity and 72 Delaware Journal of Public Health - December 2021

mortality from SARS-CoV-2/HIV co-infection when compared to people without HIV infection.1–12 Delaware has been severely affected by overlapping HIV and SARS-CoV-2 pandemics, including our robust statewide panel of PLWH. We hope to better characterize this intersection amongst PLWH in Delaware as captured through the first year of the SARS-CoV-2 pandemic.

Of great concern, the COVID-19 pandemic has disproportionately and more severely affected communities of color and lower socioeconomic status, both in the United States6,9,10,12–15 and abroad.2,16,17 In similar fashion to non-HIV infected individuals, PLWH with COVID-19 tend to have at least one high-risk co-morbidity associated with severe disease,5,15,18 Doi: 10.32481/djph.2021.12.016

including older age,1,17–20 male sex,1,6,17 diabetes mellitus type 2 (DM),1,6,10,14,17,21 hypertension (HTN),1,6,10,14,15,17,19,21 hyperlipidemia (HLD),14 chronic lung disease (CLD),6,9,10,19,21 chronic kidney disease (CKD),6,17 obesity,4,6,10,15 cardiovascular disease (CVD),6,15 tobacco use,6,10,11 and chronic liver disease.4 It is the hope that PLWH, who are adherent to an effective anti-retroviral treatment (ART) regimen with adequate CD4+ cell count and virologic suppression, incur no excess morbidity or mortality beyond that imposed by their other comorbid conditions and demographic risk factors. However, the evidence is not yet definitive in either direction. Here, we present a cohort of co-infected patients from the ChristianaCare William J. Holloway Community Program, located at multiple sites in Delaware, with a hope to shed more light on this question.

STUDY POPULATION, SETTING AND DESIGN The William J. Holloway Community Program serves as the sole Ryan White-funded HIV clinical program in Delaware.

The program cares for 1754 of the state’s 3050 HIV-infected individuals currently accessing care (57.5%), at six clinical sites: three sites in New Castle County (with the largest at the Wilmington Hospital campus), two in Kent County and one in Sussex County. Patients from all clinical sites were eligible for study inclusion. This retrospective descriptive case-series identified PLWH ≥ 18 years old co-infected with SARS-CoV-2 from 1 March 2020 through 9 March 2021 who attended any of our ambulatory HIV programs. Infections were confirmed by documentation of positive SARS-CoV-2 nasopharyngeal polymerase chain reaction (PCR) or reactive SARS-CoV-2 IgG antibody testing following compatible clinical presentation for COVID-19. Patients were identified during the study period through review of individual testing results, the ChristianaCare electronic medical record (EMR) and external inpatient and/or outpatient clinical records. The William J. Holloway Program is electronically notified in real-time whenever a program-participating patient presents to a ChristianaCareaffiliated emergency department or is hospitalized within the ChristianaCare health system. Patients with self-reported SARS-CoV-2 required confirmation of definitive infection by way of review of all available EMR and external data.

Patients for whom SARS-CoV-2 infection could not be laboratory confirmed were excluded from the study, including presumptive or probable COVID-19 cases. The study received ChristianaCare Internal Review Board approval. Utilizing The R Project for Statistical Computing online software environment, Chi-Square and t-tests compared categorical and continuous variables respectively between hospitalized and non-hospitalized patients; logistic regression modeling evaluated co-variates associated with hospitalization.

DATA COLLECTION AND ANALYSIS Pre-defined individual data categories were collected in secure fashion with removal of all personal identifiers. All chart review and data extraction were completed by two study authors with the a priori development of all study definitions and terms.

To characterize patients co-infected with HIV/SARS-CoV-2, we collected demographic data, clinical data related to HIV diagnosis, relevant medical history including co-morbidities,

and medication history including ART, as well as data pertaining to SARS-CoV-2 diagnosis and management. Data of all PLWH attending the William J Holloway Program was extracted through pre-existing 2020 HIV CareWare data.

Descriptive data analysis was performed on this case series.

Data regarding the general HIV clinic population is provided for context; however, a case-control study was not undertaken.

Mean values were calculated for non-skewed variables. Attempts were made to uniformly calculate and present measures of patients co-infected with HIV/SARS-CoV-2 and those requiring hospitalization across multiple tables.

RESULTS There were 105 cases of SARS-CoV-2/HIV co-infection with 24 (22.9%) hospitalizations (with nine of these patients requiring ICU-level care) and four attributable deaths due to COVID-19 among our program’s adult PLWH from 1 March 2020 through 9 March 2021. One hundred four (104) cases were identified through positive SARS-CoV-2 nasopharyngeal PCR testing.

One case was identified in a patient with a compatible clinical syndrome followed by positive SARS-CoV-2 IgG antibody testing three months after resolution of symptoms. Baseline demographic and HIV characteristics of adults co-infected with HIV/SARS-CoV-2 are presented in Table 1. Overall, the cohort had high rates of ART utilization (95.2%, on predominantly INSTI-based regimens with TAF-based NRTI backbone), virologic suppression (89.4% with viral load <200 cells/mL) and robust CD4 counts (mean 549 cells/m3) preceding SARSCoV-2 co-infection. Sixty-seven percent of co-infected patients were AIDS-defined based on historical nadir CD4 count and/ or history of opportunistic infection, and had been living with HIV for a mean of 13 years. Thirty-two percent of all co-infected patients with available data had significant ART resistance.

Most hospitalized patients were male and Black (Table 2).

Hospitalized patients tended to have less virologic suppression as well as lower proximal and nadir CD4 cell counts, in the setting of high levels of ART resistance. Notably, 20/24 (87.0%) of hospitalized individuals were historically AIDS-defined and had been living with HIV for a mean duration of 15.8 years.

Hospitalized versus non-hospitalized co-infected individuals demonstrated statistically significant differences across multiple variables: mean age (59.0 versus 47.6 years), utilization of public insurance (82.6% versus 50.6%), mean CD4 count (444 cells/ m3 versus 579 cells/m3), nadir CD4 count ≤200 cells/m3 (70.8% versus 39.5%), AIDS-defined status (87.0% versus 61.0%).

Hospitalized co-infected patients also demonstrated a statistically significant higher proportion of several key comorbid conditions versus their non-hospitalized counterparts including cardiovascular disease (58.3% versus 9.9%), diabetes (41.7% versus 13.6%), hypertension (70.8% versus 44.4%), chronic kidney disease (41.7% versus 7.4%) and cirrhosis (20.8% versus 2.5%).

Half of hospitalized patients had known clinically significant ART resistance. Age, BMI >30 kg/m2, cardiovascular disease, chronic kidney disease and cirrhosis were independently associated with hospitalization by logistic regression (Table 3).

Comparing infection and hospitalization rates across racial and ethnic groups, White co-infected patients were slightly underrepresented when compared to their share 73

Table 1. Baseline Characteristics of HIV/SARS-CoV-2 Co-Infected Patients and HIV Program Population (n)(%) Total

105

Sex, biologic Male

(n)(%) Mean CD4 Count (cells/mm3) (SD) CD4 Count ≤ 200 cells/mm3

71 (67.6)

Race

548.9 (257.2) 10 (9.6)

CD4 Count Nadir Range (cells/mm3) <50 cells/mm3

20 (19.0)

Black

66 (62.9)

51-100 cells/mm3

11 (10.5)

White

26 (24.8)

101-200 cells/mm3

18 (17.1)

Hispanic

10 (9.5)

>200 cells/mm3

35 (33.3)

Other

3 (2.9)

CD4 Count Nadir ≤200 cells/mm3

49 (46.7)

AIDS-Defined

67 (67.0)

HIV ART Resistance c

32 (38.6)

Mean Age (SD)

50.2 (12.5)

Age Range

Hepatitis B Infection

18-24 years old

1 (1.0)

25-40 years old

22 (21.0)

Chronic Hepatitis B Infection

41-50 years old

23 (21.9)

Resolved Hepatitis B Infection d

>60 years old

22 (21.0)

Hepatitis C Infection

Insurance

4 (3.8)

Treatment with Cure

9 (8.6) 9 (8.6)

3 (2.9)

Private

41 (39.4)

Spontaneous Clearance

Public

60 (57.7)

Comorbidities

INSTI

75 (75.0)

15 (14.3)

Chronic Hepatitis C Infection

None

ART Classa

8 (7.6)

BMI (mean)(SD)

31.4 (8.1)

Cardiovascular Disease (%)

22 (21.0)

INSTI + NNRTI

6 (6.0)

Diabetes (%)

21 (20.0)

INSTI + PI

6 (6.0)

Hypertension (%)

53 (50.5)

INSTI + PI + NNRTI

2 (2.0)

Dyslipidemia (%)

51 (48.6)

NNRTI

3 (3.0)

Chronic Kidney Disease (%)

16 (15.2)

PI

7 (7.0)

Chronic Lung Disease (%)

24 (22.9)

PI + EIb

1 (1.0)

Cirrhosis (%)

7 (6.7)

13.3 (9.3)

Hospitalized

24 (22.9)

ICU Admission (%)

9 (13.6)

Mean Years Living with HIV (SD) HIV Viral Load Range <200 (copies/mL)

93 (89.4)

200-1000 (copies/mL)

1 (1.0)

>1000 (copies/mL)

4 (3.8)

>5000 (copies/mL)

6 (5.8)

74 Delaware Journal of Public Health - December 2021

Note: a = in addition to NRTI backbone (F/TAF in vast majority of patients); b = entry inhibitor, i.e. maraviroc; c = defined as clinically significant resistance to ART in one or more drug class; d = either isolated anti-HBc (with negative HBV DNA) or anti-HBc + anti-HBs

Table 2. Historical Immunologic and Virologic Characteristics of HIV/SARS-CoV-2 Co-Infected Patients

Total (n)

Hospitalized (n)(%)

Not Hospitalized (n)(%)

24

81

17 (70.8)

54 (66.7)

p-Value

Sex, biologic Male Race

0.265

Black

19 (79.2)

47 (58.0)

White

4 (16.7)

22 (27.2)

Hispanic

1 (4.2)

9 (11.1)

Other

0 (0.0)

3 (3.7)

59.0 (11.3)

47.6 (11.7)

Mean Age (years) (SD) Age Range

0 (0.0)

1 (1.2)

25-40 years old

2 (8.3)

20 (24.7)

41-50 years old

2 (8.3)

21 (25.9)

51-60 years old

9 (37.5)

28 (34.6)

>60 years old

11 (45.8)

11 (13.6)

Insurance

0.022

None

0 (0.0)

3 (3.7)

Private

4 (17.4)

37 (45.7)

19 (82.6)

41 (50.6)

Public ART Class

<0.001 0.006

18-24 years old

0.646

a

INSTI

14 (63.6)

61 (78.2)

INSTI + NNRTI

2 (9.1)

4 (5.1)

INSTI + PI

1 (4.5)

5 (6.4)

INSTI + PI + NNRTI

1 (4.5)

1 (1.3)

NNRTI

1 (4.5)

2 (2.6)

3 (13.6)

4 (5.1)

PI PI + EI

0.893

b

Years Living With HIV (mean)(SD)

0 (0.0)

1 (1.3)

15.8 (8.7)

12.6 (9.4)

HIV Viral Load Range <200 (copies/mL)

0.165 0.037

19 (82.6)

74 (91.4)

200-1000 (copies/mL)

0 (0.0)

1 (1.2)

>1000 (copies/mL)

0 (0.0)

4 (4.9)

>5000 (copies/mL)

4 (17.4)

2 (2.5)

444.3 (243.8)

578.6 (254.6)

0.026

4 (17.4)

6 (7.4)

0.302

Mean CD4 Count (SD) CD4 Count ≤ 200 cells/mm3 CD4 Count Nadir Range (cells/mm3)

0.053

<50 cells/mm3

7 (29.2)

13 (16.0)

51-100 cells/mm3

5 (20.8)

6 (7.4)

101-200 cells/mm3

5 (20.8)

13 (16.0)

>200 cells/mm3

3 (12.5)

32 (39.5)

Table 2 continued on next page.

75

Table 2 continued.

Hospitalized (n)(%)

Not Hospitalized (n)(%)

p-Value

CD4 Count Nadir ≤200 cells/mm3

17 (70.8)

32 (39.5)

0.014

AIDS-Defined

20 (87.0)

47 (61.0)

0.039

10 (50.0)

22 (34.9)

0.345

ART Resistance

c

Hepatitis B Infection

0.417

Chronic Hepatitis B Infection Resolved Hepatitis B Infection

d

3 (12.5)

5 (6.2)

2 (8.3)

13 (16.0)

Hepatitis C Infection =

0.128

Chronic Hepatitis C Infection

2 (8.3)

2 (2.5)

Treatment with Cure

4 (16.7)

5 (6.2)

Spontaneous Clearance

3 (12.5)

6 (7.4)

BMI (mean (SD))

30.6 (8.2)

31.6 (8.1)

0.609

Cardiovascular Disease (%)

14 (58.3)

8 (9.9)

<0.001

Diabetes (%)

10 (41.7)

11 (13.6)

0.006

Hypertension (%)

17 (70.8)

36 (44.4)

0.041

Dyslipidemia (%)

14 (58.3)

37 (45.7)

0.391

Chronic Kidney Disease (%)

10 (41.7)

6 (7.4)

<0.001

Chronic Lung Disease (%)

7 (29.2)

17 (21.0)

0.575

Cirrhosis (%)

5 (20.8)

2 (2.5)

0.007

Comorbidities

Note: a = in addition to NRTI backbone (F/TAF in vast majority of patients); b = entry inhibitor, i.e. maraviroc; c = defined as clinically significant resistance to ART in one or more drug class; d = either isolated anti-HBc (with negative HBV DNA) or anti-HBc + anti-HBs

Table 3. Logistic Regression Model of Hospitalization Variable

Odds Ratio

95% Confidence Intervals

p-Value

Age

1.12

[1.01;1.23]

0.029

Male sex

0.15

[0.02;1.38]

0.092

Black race

0.86

[0.11;6.63]

0.885

BMI >30

7.36

[0.99;54.79]

0.051

Cardiovascular Disease

26.30

[2.73;253.53]

0.004

Diabetes

1.21

[0.16;8.91]

0.854

Hypertension

0.28

[0.03;2.46]

0.250

Chronic Kidney Disease

44.96

[2.75;735.55]

0.007

Cirrhosis

61.36

[1.81;2081.76]

0.022

AIDS-Defined

0.17

[0.02;1.61]

0.122

INSTI-Based ART

0.79

[0.11;5.51]

0.808

HIV Viral Load ≤ 200

0.41

[0.02;7.04]

0.541

Private Insurance

0.45

[0.05;3.95]

0.472

76 Delaware Journal of Public Health - December 2021

of the overall clinic population (24.8% versus 30.2% clinic population), but significantly underrepresented in terms of the proportion that were hospitalized (16.7%). Conversely, Black patients were far more likely to be hospitalized as compared to White patients (with 79.2% of co-infected Black patients being hospitalized), while their overall rate of co-infection remained proportional to their share of the clinic population (62.9% versus 60% clinic population).

in this population, especially given there are consistently reported increased rates of SARS-CoV-2 infection amongst other Black communities in the United States.9,10,13,14,26 The above observations suggest that Black PLWH in Delaware are testing less frequently for COVID-19 and presenting to care with more severe disease.

Sadly, this picture mirrors the national pattern regarding HIV itself, with Black patients presenting later to care and with more advanced HIV disease.27

In addition to the co-morbidities addressed above, we assessed the hepatitis B status of all PLWH infected with SARS-CoV-2. While not statistically significant, a lower rate of hospitalization was seen in individuals with a history of naturally resolved HBV. Amongst those hospitalized, 2/24 (8.3%) patients had a history of resolved HBV, compared to 13/81 (16%) non-hospitalized patients.

While our descriptive analysis is potentially suggestive of wider trends, our analysis was limited by a small sample size, incomplete historical data for some variables, and wide confidence intervals.

While every attempt was made to identify PLWH with SARSCoV-2 co-infection in our program population, we certainly did not capture every positive test during the study period. It is possible that not all our clinic patients were tagged/recognized in the EMR, consequently preventing us from receiving electronic notification of SARS-CoV-2 infection. There were instances in which patients reported positive SARS-CoV-2 test results that were unable to be confirmed, as well as several cases of presumptive COVID-19 diagnoses with either no testing or negative testing. We also acknowledge that at the start of the pandemic, testing availability was very limited which resulted in the initial testing of only symptomatic cases. Even as access to testing has expanded throughout Delaware, there remain many barriers to testing that disproportionately affect different communities. In summary, the presented confirmed positive SARS-CoV-2 cases represent our best – albeit imperfect – attempt to capture all cases amongst our clinic population. Larger studies are needed to further investigate the roles of long-term immunosuppression and inflammation, burden of comorbidities, and early and late immunologic responses in COVID-19 outcomes amongst PLWH.

DISCUSSION AND PUBLIC HEALTH IMPLICATIONS Our cohort data is the first to capture the experience of PLWH co-infected with SARS-CoV-2 in the State of Delaware, during the first year of the COVID-19 pandemic. In keeping with previously published data, increasing age and the presence of well-defined co-morbidities in the setting of HIV/SARSCoV-2 co-infection are independently associated with higher odds of hospitalization.1,6,11,17,22 Whether HIV itself represents an independent risk factor for severe COVID-19 remains a matter of debate:1,23 our study patients’ immunologic profiles and HIV-specific histories (including nadir CD4 count, virologic suppression, AIDS-defined status and known ART resistance) were not found to be independently associated with hospitalization. However, from an immunological perspective, we observed that AIDS-defined individuals were over-represented amongst PLWH hospitalized with SARS-CoV-2 co-infection, and historical nadir CD4 counts as well as proximal CD4 counts were lower in hospitalized than non-hospitalized SARS-CoV-2 cases. These observations, along with high rates of ART resistance and significant time living with HIV amongst hospitalized patients, altogether buttress the idea that cumulative lifetime immunosuppression and/or HIV viremia, with the expected associated changes in the underlying immunologic profiles of these patients, may be associated with higher rates of progression to severe COVID-19 in PLWH. Recent data further supports this biologically plausible hypothesis.,10,22,26 Furthermore, our data highlight the seeming risk of underlying chronic inflammation that is either a direct result of HIV itself and/or multi-morbidity.14,16,17,21 We hypothesize that this increased, underlying, chronic inflammation amongst hospitalized co-infected patients may contribute to a more severe presentation of COVID-19. Although not reaching statistical significance, we identified high rates of naturally resolved HBV infection amongst non-hospitalized co-infected patients and postulate there may be an underlying immunologic mechanism to this hypothesis-generating observation.24,25 Unfortunately, the social determinants of health that so deeply impacted PLWH prior to the COVID-19 pandemic once again affected our clinic population, with a higher percentage of Black patients being hospitalized versus their White counterparts. The observation that the rate of Black patients diagnosed with HIV/ SARS-CoV-2 co-infection was similar to that of Black patients in our general clinic population raises concern for decreased testing

ACKNOWLEDGMENTS We give thanks to all our patients for their strength and perseverance throughout these pandemics, as well as to the Holloway Program’s entire staff for their ongoing dedication to patient care.

The authors can be contacted at adam.skrzynski@christianacare.org

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2. Bhaskaran, K., Rentsch, C. T., MacKenna, B., Schultze, A., Mehrkar, A., Bates, C. J., . . . Goldacre, B. (2021, January). HIV infection and COVID-19 death: A population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform. The Lancet. HIV, 8(1), e24–e32. https://doi.org/10.1016/S2352-3018(20)30305-2 3. Western Cape Department of Health in collaboration with the National Institute for Communicable Diseases, South Africa. (. (2021). Risk factors for COVID-19 death in a population cohort study from the Western Cape Province, South Africa. Clin Infect Dis, 73(7), e2005–e2015. https://doi.org/10.1093/cid/ciaa1198 77

4. Geretti, A. M., Stockdale, A. J., Kelly, S. H., Cevik, M., Collins, S., Waters, L., . . . Semple, M. G. (2020). Outcomes of COVID-19 related hospitalization among people with HIV in the ISARIC WHO Clinical Characterization Protocol (UK): A prospective observational study. Clin Infect Dis. https://doi.org/10.1093/cid/ciaa1605

16. Childs, K., Post, F. A., Norcross, C., Ottaway, Z., Hamlyn, E., Quinn, K., . . . Taylor, C. (2020, November 5). Hospitalized patients with COVID-19 and human immunodeficiency virus: A case series. Clin Infect Diss, 71(8), 2021–2022. https://doi.org/10.1093/cid/ciaa657

5. Gervasoni, C., Meraviglia, P., Riva, A., Giacomelli, A., Oreni, L., Minisci, D., . . . Cattaneo, D. (2020). Clinical features and outcomes of HIV patients with coronavirus disease 2019. Clin Infect Dis, 71(16), 2276–2278. https://doi.org/10.1093/cid/ciaa579

17. Etienne, N., Karmochkine, M., Slama, L., Pavie, J., Batisse, D., Usubillaga, R., . . . Salmon, D., & the COVID-19 ID Team.

(2020, October 1). HIV infection and COVID-19: Risk factors for severe disease. AIDS (London, England), 34(12), 1771– 1774. https://doi.org/10.1097/QAD.0000000000002651

6. Hadi, Y. B., Naqvi, S. F. Z., Kupec, J. T., & Sarwari, A. R. (2020, November 1). Characteristics and outcomes of COVID-19 in patients with HIV: A multicentre research network study. AIDS (London, England), 34(13), F3–F8. https://doi.org/10.1097/QAD.0000000000002666

18. Nomah, D. K., Reyes-Uruena, J., Diaz, Y., Moreno, S., Aceiton, J., Bruguera, A., . . . Miro, H. M. (2021, Jul 18-21).

Unsuppressed plasma HIV-RNA viral load is associated with worse COVID-19 outcomes among people living with HIV. 11th IAS Conference on HIV Science; virtual conference.

7. Härter, G., Spinner, C. D., Roider, J., Bickel, M., Krznaric, I., Grunwald, S., . . . Hoffmann, C. (2020, October). COVID-19 in people living with human immunodeficiency virus: A case series of 33 patients. Infection, 48(5), 681–686. https://doi.org/10.1007/s15010-020-01438-z

19. Dandachi, D., Geiger, G., Montgomery, M. W., KarmenTuohhy, S., Golzy, M., Antar, A. A. R., . . . Sax, P. E. (2021). Characteristics, comorbidities, and outcomes in a multicenter registry of patients with HIV and coronavirus disease 2019. Clin Infect Dis, 73(7), e1964–e1972. https://doi.org/10.1093/cid/ciaa1339

8. Huang, J., Xie, N., Hu, X., Yan, H., Ding, J., Liu, P., . . . Wang, X. (2021). Epidemiological, virological and serological features of COVID-19 cases in people living with HIV in Wuhan City: A population-based cohort study. Clin Infect Dis, e2086. https://doi.org/10.1093/cid/ciaa1186 9. Mascolini, M. (2020, Jul 6-10). COVID-19 rate no higher with HIV in largest US HIV+/HIVCohort. AIDS 2020: 23rd International AIDS Conference Virtual.

10. Shalev, N., Scherer, M., LaSota, E. D., Antoniou, P., Yin, M. T., Zucker, J., & Sobieszczyk, M. E. (2020). Clinical characteristics and outcomes in people living with HIV hospitalized for COVID-19. Clin Infect Dis, 71(16), 2294–2297. https://doi.org/10.1093/cid/ciaa635 11. Sigel, K., Swartz, T., Golden, E., Paranjpe, I., Somani, S., Richter, F., . . . Glicksberg, B. S. (2020). Covid-19 and people with HIV infection: Outcomes for hospitalized patients in New York City. Clin Infect Dis, 71(11), 2933–2938. https://doi.org/10.1093/cid/ciaa880 12. Stoeckle, K., Johnston, C. D., Jannat-Khah, D. P., Williams, S. C., Ellman, T. M., Vogler, M. A., . . . Choi, J. J. (2020, August 1). COVID-19 in hospitalized adults with HIV. Open Forum Infectious Diseases, 7(8), ofaa327. https://doi.org/10.1093/ofid/ofaa327 13. Byrd, K. M., Beckwith, C. G., Garland, J. M., Johnson, J. E., Aung, S., Cu-Uvin, S., . . . Kantor, R. (2020, July). SARS-CoV-2 and HIV coinfection: Clinical experience from Rhode Island, United States. Journal of the International AIDS Society, 23(7), e25573. https://doi.org/10.1002/jia2.25573 14. Collins, L. F., Moran, C. A., Oliver, N. T., Moanna, A., Lahiri, C. D., Colasanti, J. A., . . . Sheth, A. N. (2020, October 1).

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20. Maggiolo, F., Zoboli, F., Arosio, M., Valenti, D., Guarneri, D., Sangiorgio, L., . . . Callegaro, A. (2021, February). SARSCoV-2 infection in persons living with HIV: A single center prospective cohort. Journal of Medical Virology, 93(2), 1145–1149. https://doi.org/10.1002/jmv.26352 21. Vizcarra, P., Pérez-Elías, M. J., Quereda, C., Moreno, A., Vivancos, M. J., Dronda, F., & Casado, J. L., & the COVID-19 ID Team. (2020, August). Description of COVID-19 in HIV-infected individuals: A single-centre, prospective cohort. The Lancet. HIV, 7(8), e554–e564. https://doi.org/10.1016/S2352-3018(20)30164-8 22. Karmen-Tuohy, S., Carlucci, P. M., Zervou, F. N., Zacharioudakis, I. M., Rebick, G., Klein, E., . . . Rahimian, J. (2020, September 1). Outcomes among HIV-positive patients hospitalized with COVID-19. J Acquir Immune Defic Syndr, 85(1), 6–10. https://doi.org/10.1097/QAI.0000000000002423 23. Durstenfeld, M. S., Sun, K., Ma, Y., Rodriguez, F., Secemsky, E. A., Parikh, R. V., & Hsue, P. Y. (2021). Impact of HIV infection on COVID-19 outcomes among hospitalized adults in the U.S. medRxiv. doi: https://doi.org/10.1101/2021.04.05.21254938 24. Anugwom, C. M., Aby, E. S., & Debes, J. D. (2021, January 23). inverse association between chronic hepatitis b infection and coronavirus disease 2019 (COVID-19): Immune exhaustion or coincidence? Clin Infect Dis, 72(1), 180–182. https://doi.org/10.1093/cid/ciaa592 25. Fajgenbaum, D. C., & June, C. H. (2020, December 3).

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Team Up For Quality Care: The Role of Primary Care Teams in Prevention Of Cardiovascular Disease Cindy Biederman, M.S.N., R.N. Practice Transformation Specialist, Quality Insights

ABSTRACT Healthcare providers appreciate the value of evidence-based guidelines such as the American College of Cardiology/American Heart Association Guideline on the Primary Prevention of Cardiovascular Disease (Guideline). In a busy clinical practice, however, many competing demands can create barriers to full implementation of these protocols. A solution is to embrace a newer model of practice that engages the interdisciplinary care team with all staff working at the top of their licensure/training. The care team approach is backed by strong evidence supporting improved patient outcomes, such as hypertension control. By appropriately sharing responsibilities, the practice delivers a unified health promotion message, and physicians are able to focus on the care requiring their medical expertise. When all staff members have clear roles and responsibilities, the practice can more easily implement the Guideline fully and work together to deliver highquality, evidence-based primary prevention of cardiovascular disease.

BACKGROUND Historically, preventive interventions have yielded improvements in population health. Such interventions largely fall to practitioners of primary care medicine, who must manage many competing demands.1 In recent years there has been a proliferation of clinical protocols and care guidelines intended to assist providers deliver evidence-based care, but implementation of these guidelines can be challenging for busy clinicians.

CARDIOVASCULAR DISEASE PREVENTION Cardiovascular disease prevention is a high priority in primary care. According to the Centers for Disease Control and Prevention (CDC), heart disease is the leading cause of death for men, women, and people of most racial and ethnic groups in the United States.2 One in every four deaths in the U.S. is related to heart disease. In fact, an American dies from cardiovascular disease every 36 seconds, and about 655,000 Americans die from heart disease annually. According to a 2019 report from the Delaware Division of Public Health on chronic disease in Delaware, heart diseases represent 22% of all deaths annually.3 The impetus for prevention of these diseases is clear to society, the health system at large, and especially in primary care.

Hypertension is a major modifiable risk factor for cardiovascular disease. In the U.S., hypertension accounts for more cardiovascular disease deaths than any other modifiable risk factor.4 Improving hypertension control is a strategic pillar in national initiatives such as Million Hearts® 2022 which aim to control hypertension in adults. While uncontrolled hypertension has improved significantly from 1999 to 2014, the burden remains high.5 Raised total cholesterol is another strong modifiable risk factor for cardiovascular disease. CDC reports that about 38% of adults have total cholesterol higher than 200 mg/dl.2 In Delaware, about 35% of adults reported having high cholesterol in 2019.6 Strong 80 Delaware Journal of Public Health - December 2021

evidence exists demonstrating the role of statin therapy risk reduction by lowering low-density lipoprotein cholesterol levels in diverse populations, yet it is estimated that only about half of the U.S. adults who could benefit from cholesterol medicine are currently taking it.2

2019 GUIDELINE ON THE PRIMARY PREVENTION OF CARDIOVASCULAR DISEASE Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. The ACC/AHA Clinical Practice Guideline on the Primary Prevention of Cardiovascular Disease (Guideline) is based on systematic methods to evaluate and classify evidence and provide a foundation for the delivery of quality cardiovascular care. The purpose of the Guideline is to review and consolidate existing recommendations into a single guidance document focused on the primary prevention of cardiovascular disease (CVD).4 ACC/AHA describe the Guideline as a resource for the clinical and public health practice communities. It addresses the primary prevention of cardiovascular disease in adults over age 18. The 2019 update (most recent available) includes new recommendations for aspirin use, exercise and physical activity and tobacco use, as well as recommendations related to shared decision making, assessment of social determinants of health, and team-based care.4 Appendix A provides the Guideline’s Top Things to Know which summarizes the overarching recommendations in patient-centered approaches to prevention, assessment of cardiovascular risk, lifestyle factors, and other factors affecting risk. The Top Things to Know are categorized in Table 1 as Heart-Healthy Lifestyles, Social Determinants of Health, and Risk Assessment/Pharmacotherapy.

Doi: 10.32481/djph.2021.12.017

THE VITAL ROLE OF PRIMARY CARE In the expensive and specialized U.S. health system, primary care is the key to both increasing cost-effectiveness and providing foundational patient-centered care. The Agency for Healthcare Research and Quality (AHRQ) describes highquality primary care as first-contact/accessible; coordinated; continuous; and comprehensive.7 High quality primary care services optimize patient health in a cost-effective manner. This vital role will continue to grow as the U.S. population ages and the prevalence and complexity of chronic disease increases.7 High-performing primary care engages well-organized, multi-disciplinary practice teams to deliver comprehensive, evidence-based services. Examples include identification of potential care gaps, medication management, referral/transition management, and clinic/community linkages.8

Team-Based Care

The American Medical Association (AMA) defines team-based care as a collaborative system in which team members share responsibilities to achieve high-quality patient care. AMA believes that physician-led teams of multidisciplinary health care professionals should involve collaboration and sharing decisions and information for the benefit of patients. Members of the care team should work together depending on the specific training and strengths of each member.9 In the most effective teams, individuals are encouraged to utilize their full skill set to enhance patient care and increase effectiveness and efficiency.10 Well-implemented team-based care can improve comprehensiveness, coordination, efficiency, effectiveness, and value of care, as well as satisfaction of patients and providers.

Team-based care offers expanded access and more effective and efficient delivery of essential services, such as patient education, behavioral health, self-management support, and care coordination. Patient-centered care is linked to improved physician-patient communication and relationships, higher patient satisfaction, improved recall of information and treatment adherence, better recovery, and improved health outcomes.10 Team-based care benefits providers and other members of the care team as well as their patients. A 2018 National Academy of Medicine discussion paper, Implementing Optimal Team-Based Care to Reduce Clinician Burnout, highlights a number of studies demonstrating strong evidence in support of high-functioning teams and their link to increased physician well-being as well as cost-effectiveness.11 Promoting a strong sense of team unity and collective responsibility for patient care can benefit every member of the staff, both clinical and clerical. All members of the team can view themselves as important contributors with a crucial role in promoting patient health.8

Core and Extended Teams in Primary Care

In primary care, a team is the providers and staff in a practice that collaborate to provide care to a defined panel of patients.8 It includes engaged, strong leadership and both core staff who work primarily with individual providers or a small group of providers and patients and an extended team of centralized staff that serve all providers and panels in the practice. The extended team might also include collaborating organizations such as pharmacists, academic institutions, and community agencies. Large or health system-affiliated practices may have

greater access to extended contributors such as social workers, dieticians, care coordinators, and health educators, while smaller practices often leverage the skills of internal staff and external community resources to fill these roles.

The role of the physician as the leader of the health care team is important. Physicians have the highest level of training in patient care and often set the agenda for the practice.9 Physician leaders must review and approve clinical protocols, workflow modifications, staff training, and patient education resources.

As engaged leaders, they must be committed to improving their care teams. In this practice model, every member of the team is recognized and valued for their skills and contributions, enabling the practice to support unified implementation of quality care.

Healthy care teams exhibit common traits including shared goals, clear roles, mutual trust, effective communication, and measurable processes and outcomes.8 Individual care teams are unique in team member disciplines and training, preferred communication styles, patient populations, and personalities.

The workflow modifications discussed in this document should be considered as examples that must be adapted to individual settings.

Role of the Patient

In patient-centered care, patients and their families are key parts of the care team and contribute to decision making. Patients partner with trusted healthcare providers, and patient and family preferences, values, cultural traditions, and socioeconomic conditions are respected.8 Providers use diverse strategies, including technology-based tools, to empower patients to take ownership of their health care outside the clinical setting.

Patients benefit from this model are reflected in higher satisfaction scores, improved self-management and adherence to treatment plans, increased morale and productivity of clinicians and ancillary staff, and better resource allocation.12 Patients are the core of high-quality primary care,8 including primary prevention of cardiovascular disease. While not specifically identified in the workflow modifications presented in this document, patients are team members around whom all recommendations revolve.

Technology as Care Team Support

The proliferation of electronic health records (EHRs) and health information exchanges (HIEs) in recent years creates both demands on and opportunities for clinicians. Many feel that documentation creates barriers to relationship development when providers appear more focused on screens than on patients.13 However, strategic use of the EHR can create efficiencies that free up provider time. Practices should utilize the many tools at their disposal with most modern EHRs, such as patient portals, the ability to create registries for priority areas of care, clinical decision support systems to enhance decision making, and structured data fields that facilitate the documentation process, consulting individual EHR vendors for specific guidance.

CARE TEAMS: PRIMARY PREVENTION OF CARDIOVASCULAR DISEASE The 2019 update of the ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease promotes team-based care supports such as clinical decision making based on treatment 81

algorithms, collaboration among different clinicians, and patient and family member participation to facilitate treatment goals.4 Randomized control trials and systematic reviews with metaanalyses demonstrated greater risk reduction with team-based care than usual care in patients with hypertension, diabetes and hyperlipidemia. Appendix B provides an example of improved blood pressure control attributable to team-based care. Further, a team-based approach may result in significant improvements in patient outcomes and often meets patient needs better than standard care, especially in low-resource settings and among vulnerable populations.4 The Guideline recommendations address both universal health measures such as diet and exercise and specific cardiac risk factors including tobacco use, hypertension, and cholesterol.4 To fully integrate and implement the Guideline’s Top Things to Know primary prevention strategies in a primary care practice, every member of the core and extended care team can creatively and effectively play a role.

HEART-HEALTHY LIFESTYLE RECOMMENDATIONS The Guideline recommends that every patient visit start by promoting primary prevention of cardiovascular disease.

Two of the Top Things to Know advocate for prevention of cardiovascular disease by providing direction on heart-healthy diets, including achieving and maintaining normal weight, and physical activity recommendations.4 These universal, important messages can and should be shared and reinforced by every member of the practice team, from the front desk to the physician, in order to present a strong, unified message of health promotion and disease prevention.

Heart Healthy Diets After four decades of decline, heart disease deaths rose by 1% in 2015, a trend that may be attributable to the obesity epidemic.14 Therefore all patients should receive guidance about heart-healthy diets. Those with overweight or obesity should be encouraged to attain clinically meaningful weight loss (>=5% of initial weight), which is associated with moderate improvement in blood pressure, LDL-C, triglycerides, and glucose levels as well as reducing or delaying development of type 2 diabetes.4 The Guideline states that existing clinical guidance strongly recommends face-to-face or telephonic weight loss programs that provide regular contact with a trained interventionist.4 Patients who need assistance with weight management can be referred to a nutritionist or to appropriate evidence-based lifestyle change programs, such as WW (Weight Watchers) or the National Diabetes Prevention Program.

Patient education materials on heart-healthy diet and physical activity recommendations, available from sources such as AHA and CDC, are the starting point for implementing lifestyle messaging. Materials can be made available in various locations in the medical office such as waiting areas and exam rooms and can be used by clinicians as conversational guides. These materials should address healthy weight, blood cholesterol levels, and blood pressure. Appendix C provides examples of resources.

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Physical Activity

Regular exercise is known to confer numerous health benefits, and physical activity is a cornerstone of maintaining and improving cardiovascular disease. However, approximately half of adults in the U.S. do not meet the minimum physical activity recommendations.4 Physical activity assessment and counseling in the healthcare setting have important complementary roles in promoting increased compliance. Ascertaining physical activity patterns during a standard clinical visit is a first step in effective counseling. This data can be collected during patient rooming and recorded in the EHR along with parameters such as weight and blood pressure.4 Counseling by clinicians can result in modest improvement in physical activity levels and might include an exercise prescription that consists of recommended frequency, intensity, time (duration), and type of exercise.15

Tobacco Screening and Cessation

Since tobacco use is the leading preventable cause of disease, disability, and death in the United States, clinicians should ask all adults about tobacco use at every visit.16 Treating tobacco use status as a vital sign and recording it in the health record not only increases the rate of tobacco treatment but also improves abstinence. Tobacco users are more likely to quit after six months when clinicians strongly advise adults to quit, compared to no advice or usual care.16 For tobacco cessation, multiple behavioral interventions and seven FDA-approved cessation medications exist. Patients can be referred for telephonic or text-message counseling. Appendix C provides examples of resources.

Suggested workflows for care team roles and responsibilities for heart-healthy lifestyle recommendations are presented in Table 2.

SOCIAL DETERMINANTS OF HEALTH According to the CDC, social determinants of health (SDOH) are the conditions in the places where people live, learn, work and play, that affect a wide range of health risks and outcomes.

These factors exist “upstream” in that they occur and interrelate with each other to influence characteristics that manifest “downstream,” such as health behaviors, health conditions, and health outcomes.17 While primary care providers and care teams are essential to optimizing health for their patients by providing evidence-based, patient-centered care in medical homes, most providers are well aware of the impact of SDOH on their patients.

In fact, the Robert Wood Johnson Foundation estimates that only 20% of health outcomes can be attributed to clinical care, with the remaining 80% attributable to upstream factors such as social and economic factors and health behaviors.18 Although social determinants are most often invoked in discussions of inequalities or disparities in health, AHA takes a broader view that social factors can and do affect cardiovascular health. AHA acknowledges the evidence of association of earlylife socioeconomic factors on the development of conventional cardiovascular disease risk factors, such as blood pressure, lipid levels, BMI, smoking, physical activity, and alcohol consumption.

The organization’s 2030 U.S. impact goal to equitably increase healthy life expectancy includes an emphasis on health equity.19 When care teams collect SDOH data such as housing status and food security, they get a clearer picture of the needs

Table 1. ACC/AHA Primary Prevention of Cardiovascular Disease – Top Things to Know, Categorized Category Heart-healthy lifestyles

Message The most important way to prevent atherosclerotic vascular disease, heart failure, and atrial fibrillation is to promote a healthy lifestyle throughout life.

All adults should consume a healthy diet that emphasizes the intake of vegetables, fruits, nuts, whole grains, lean vegetable or animal protein, and fish and minimizes the intake of trans fats, red meat and processed meats, refined carbohydrates, and sweetened beverages. For adults with overweight and obesity, counseling and caloric restriction are recommended for achieving and maintaining weight loss.

Adults should engage in at least 150 minutes per week of accumulated moderate-intensity physical activity or 75 minutes per week of vigorous-intensity physical activity.

All adults should be assessed at every healthcare visit for tobacco use, and those who use tobacco should be assisted and strongly advised to quit.

Social determinants of health

Clinicians should evaluate the social determinants of health that affect individuals to inform treatment decisions.

Risk assessment and Pharmacotherapy

Adults who are 40 to 75 years of age and are being evaluated for cardiovascular disease prevention should undergo 10-year atherosclerotic cardiovascular disease (ASCVD) risk estimation and have a clinician-patient risk discussion before starting on pharmacological therapy such as antihypertensive therapy, a statin, or aspirin. In addition, assessing for other risk-enhancing factors can help guide decisions about preventive interventions in select individuals, as can coronary artery calcium scanning.

For adults with type 2 diabetes mellitus, lifestyle changes such as improving dietary habits and achieving exercise recommendations, are crucial. If medication is indicated, metformin is first-line therapy, followed by consideration of a sodium glucose cotransporter 2 inhibitor or a glucagonlike peptide-1 receptor agonist.

Nonpharmacological interventions are recommended for all adults with elevated blood pressure or hypertension. For those requiring pharmacotherapy, the target blood pressure should generally be < 130/80 mm Hg. Aspirin should be used infrequently in the routine primary prevention of ASCVD because of lack of net benefits.

Statin therapy is first-line treatment for primary prevention of ASCVD in patients with elevated low-density lipoprotein cholesterol levels (LDL-C) (>= 190 mg//dL), those with diabetes mellitus, who are 40 to 75 years of age, and those determined to be at sufficient risk after a clinician-patient risk discussion.

Table 2. ACC/AHA Primary Prevention of Cardiovascular Disease Recommendations – Suggested Care Team Roles and Responsibilities for Heart-Healthy Lifestyles Team Up Members/Roles

Actions

Administrative staff

• Ensure selected educational resources available in paper or electronic (patient portal) form • Track quality measures and share with staff • Ensure all staff is trained in health promotion messaging and evidence-based lifestyle programs • Provide staff training on BP measurement techniques

Front office

• Disseminate selected resources to patients at check-in • Schedule follow-up appointments for office and to community programs • Ensure information about evidence-based lifestyle programs is readily available

MAs and/or nurses

• Assess and document BMI, tobacco use, and physical activity level • Query patient about concerns; share with provider • Provide information on evidence-based programs for weight management and tobacco cessation • Ensure referrals made to provider-recommended programs

Provider

• Select educational resources and evidence-based lifestyle change programs • Counsel on healthy diet and physical activity; emphasize value of lifestyle change • Provide brief intervention/counsel on tobacco cessation • Recommend evidence-based lifestyle change programs • Discuss patient concerns and respond to questions

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of their patients both individually and as a population. As the AMA points out, “Ensuring patients get equitable care is difficult if you aren’t sure who your patients really are.”20 The AMA’s Commission to End Health Care Disparities is investigating best practices in collecting race, ethnicity and preferred language data from patients in ambulatory settings with the goal of integrating services to meet identified needs of patients. Primary care providers can help their patients and communities achieve improved outcomes by serving as integrators among clinical care, public health, behavioral health, and community-based services.20 Getting started with SDOH is a valuable but complex project for a busy practice. Involving the full staff is integral, with both clinical and non-clinical staff needed to optimize processes.

Data can be collected in a number of ways, at the point in the workflow and by the staff members deemed most appropriate.

Systemizing the process begins by defining clear guidelines on roles and responsibilities.21 Organizations may wish to consider adopting a standardized, validated tool for collecting SDOH data, such as Protocol for Responding to and Assessing Patients’ Risks and Experiences (PRAPARE).21 By using PRAPARE, providers can better target clinical and non-clinical care, often in partnership with other community based organizations, to drive care transformation and delivery system integration as well as improved health and cost reductions.21 According to the American Hospital Association, the ICD-10 code system is a tool for capturing data on the social needs of patients.22 Codes Z55-65 document non-medical factors that may influence a patient’s health status. These Z codes identify issues related to a patient’s socioeconomic situation, including education and literacy, employment, housing, lack of adequate food or water or occupational exposure to risk factors such as dust, radiation, or toxic agents. Using these Z codes allows for better tracking needs and identification of solutions to improve community health.22 The American Hospital Association notes that any clinician involved in a patient’s care can document a patient’s social needs, according to a 2018 coding rules clarification.

“Clinician” is defined as anyone who meets the requirements to document in the official medical record, including but not limited to social workers, community health workers, case managers, nurses, or other providers.22 Assessing and addressing social determinants of health are important to comprehensive patient care, including primary prevention of cardiovascular disease. It is important to achieve buy-in from the full staff and to share responsibilities appropriately. Suggested workflows for care team roles and responsibilities for social determinant of health recommendations are presented in Table 3.

RISK ASSESSMENT AND PHARMACOTHERAPY Assessment of risk is the foundation of primary prevention of cardiovascular disease and is a key domain of medical providers.4 The ten-year risk estimate is used to guide decision making for many preventive interventions, including lipid and blood pressure management. It should be the start of a 84 Delaware Journal of Public Health - December 2021

conversation with the patient about risk reduction strategies and one decision factor for the initiation of pharmacotherapy.

For patients with borderline or intermediate estimated 10year risk, assessment of coronary artery calcium is a tool to reclassify risk either upward or downward.4 The American College of Cardiology’s ASCVD Risk Estimator Plus is recommended for assessing a patient’s ten-year risk and is available online or in a dedicated app.4 Initiation of pharmacotherapy, such as aspirin, antihypertensives, or statins is the role of the provider using clinical judgment of individual patients’ unique needs.

Aspirin was previously recommended for selected primary prevention for adults with elevated risk based on traditional factors, but the updated Guideline recommends that low-dose prophylactic aspirin be used for persons at high ASCVD risk who cannot achieve optimal control of other risk factors.

Providers must evaluate use of aspirin therapy based on individual patient considerations.4

Undiagnosed Hypertension

A priority area of the Million Hearts® initiative is identifying patients with undiagnosed hypertension.23 Million Hearts® estimates that one in three U.S. adults (approximately 71 million people) has high blood pressure, and almost half of these individuals (48.2%) do not have their condition under control. Closer examination of the population with uncontrolled hypertension reveals that 36.2% (estimated at approximately 13 million people) are neither aware of the condition nor taking antihypertensive medications. The majority of these individuals have health insurance, a usual source of care, and have received care two or more times in the past year.23 The care team can play a valuable role in addressing undiagnosed hypertension using the process and tools created by Million Hearts®, such as searching the EHR for patients who meet the clinical criteria and calculating the practice’s hypertension prevalence compared with local data.

Hypertension Control (including Self-Measured Blood Pressure)

A Community Guide Systematic Review found that team-based care is effective for improving blood pressure outcomes, including reducing both systolic and diastolic pressures, especially when pharmacists and nurses were part of the care team.24 Appendix B shows examples of changes in proportion of patients with controlled blood pressure attributable to team-based care.

The CDC promotes team-based care to improve blood pressure control and cites evidence supporting strong effectiveness of a multidisciplinary team working in collaboration to educate patients, identify risk factors, prescribe and modify treatments, and maintain an ongoing dialog with patients about their health and care. These teams may include doctors, nurses, pharmacists, primary care providers, community health workers, and others. Team-based care is a cost-effective strategy for increasing medication adherence and lowering blood pressure among diverse populations in various settings. Suggested strategies include use of registries and leveraging EHRs to improve patientprovider communication.25

Table 3. ACC/AHA Primary Prevention of Cardiovascular Disease Recommendations – Suggested Care Team Roles and Responsibilities for Social Determinants of Health Team Up Members/ Roles

Actions

Administrative staff

• Support integration of SDOH tools into EHR • Train staff about SDOH • Track data for evaluation • Communicate outcomes to team

Front office

• Disseminate paper or electronic materials to patients via portal or mail • Provide assessment materials at check-in • Collect race, ethnicity, and language at check-in registration • Ensure data entered into EHR; alert clinical staff as needed • Maintain resource lists and provide to patients

MAs and/or nurses

• Verbally interview patients and enter responses into EHR • Discuss patient needs and assess for readiness to address • Discuss community resources and schedule per practice workflow • Enter Z codes into patient record (social needs codes Z55-Z65 can be entered by any clinician involved in patient’s care) • Follow up on referrals

Provider

• Select assessment tool; determine workflow • Verbally interview patients and enter responses into EHR • Refer patients to other team members for supplemental counseling, using warm handoff where possible

Table 4. ACC/AHA Primary Prevention of Cardiovascular Disease Recommendations – Suggested Care Team Roles and Responsibilities – Risk Assessment/Pharmacotherapy Team Members/Roles

Actions

Administrative staff

• Search EHR to identify patients with possible undiagnosed hypertension • Maintain registry of patients with diagnosed hypertension and elevated cholesterol • Coordinate SMBP program • Track data for evaluation and share with staff

MAs and/or nurses

• Provide patient education on hypertension, elevated cholesterol, and medication adherence • Assist patients with Statin Choice decision aid • Perform medication reconciliation; explore barriers and communicate to provider • Provide nurse appointments for blood pressure monitoring • Facilitate SMBP, train patients on techniques

Provider

• Establish criteria to identify undiagnosed/uncontrolled hypertension • Recommend self-measured blood pressure monitoring • Risk-benefit discussions when initiating pharmacotherapy • When initiating pharmacotherapy, administer Adherence Estimator to assess for medication adherence; discuss results • Use risk estimation and decision aid tools • Initiate and monitor pharmacotherapy as clinically appropriate • Collaborate with pharmacist with referring eligible patients for medication therapy management

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Nonpharmacological interventions are effective in lowering blood pressure and may be sufficient to prevent hypertension and to achieve goal measures in some individuals, and they are integral in the management of those on antihypertensive medications. Combining nonpharmacological interventions is the preferred therapy for adults with elevated blood pressure and an appropriate first-line therapy for adults with stage one hypertension who have an estimated 10-year ASCVD risk of <10%. The Guideline provides recommendations for assessing adherence to and impact of nonpharmacological therapy within three to six months as well as recommended goals and approximate impact on systolic blood pressure.4 Strong scientific evidence shows that self-measured blood pressure monitoring (SMBP) plus clinical support helps people with hypertension lower their blood pressure.26 SMBP plus clinical support can improve access to care and quality of care for individuals with hypertension while making blood pressure control more convenient and accessible to patients.

Clinical support includes regular one-on-one counseling, webbased or telephonic support tools, and educational classes.

For patients with hypertension, the practice can implement SMBP, as recommended by Million Hearts®.26 Staff members can educate patients about blood pressure, train on accurate measurement technique, maintain the SMBP registry, and document measurements for providers.

Appendix C shows examples of resources that can be integrated in many workflows.

Statin Therapy

Statin therapy is first-line treatment for primary prevention of cardiovascular disease in patients with elevated low-density lipoprotein cholesterol levels (>190 mg/dL), those ages 40-75 who have diabetes, and those determined to be at sufficient risk after a clinician-patient risk discussion. A useful tool is the Statin Choice Decision Aid, which can be administered by the provider, a nurse, health educator, or pharmacist.27

Medication Adherence

Medication adherence is a long-recognized challenge with costly impacts. Million Hearts® relates that about 20-30% of prescriptions are unfilled and another 50% of patients discontinue the prescribed treatment regimen.28 The Adherence Estimator®, which can be administered by any clinician and shared with the provider, is a patient-centered resource designed to help gauge a patient’s likelihood of adhering to newly prescribed oral medication for certain chronic, asymptomatic conditions, such as high cholesterol.

Patients respond to three quick statements that provide a score indicating the probability of medication nonadherence, with conversational prompts that guide the provider to explore and address potential barriers.29

CONCLUSION Cardiovascular disease is the leading cause of death in the United States2 and the second leading cause of death in Delaware.3 Primary care providers, highly engaged in care for cardiovascular and other diseases as well as regular preventive care, must contend with the rapidly changing healthcare landscape that makes it difficult to manage a patient population and fully implement evidence-based protocols such as the ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. Team-based models of primary care engage the interdisciplinary team with members working at the top of licensure/training to support providers and patients. When all staff members have clear roles to play, the practice can more easily fully implement the Guideline and work together to deliver high-quality, evidence-based primary prevention of cardiovascular disease.

DISCLOSURE This publication was supported by the Cooperative Agreement Number NU58DP006516 from the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention. Publication number DEDPH-HD-041321A Ms. Biederman can be contacted at: cbiederman@qualityinsights.org

APPENDIX A ACC/AHA Guideline on Primary Prevention of Cardiovascular Disease: Top Things to Know31

1. The most important way to prevent atherosclerotic vascular disease, heart failure, and atrial fibrillation is to promote a healthy lifestyle throughout life.

2. A team-based approach is an effective strategy for the prevention of cardiovascular disease. Clinicians should evaluate the social determinants of health that affect individuals to inform treatment decisions.

3. Adults who are 40 to 75 years of age and are being evaluated for cardiovascular disease prevention should undergo 10year atherosclerotic cardiovascular disease (ASCVD) risk estimation and have a clinician-patient risk discussion before starting on pharmacological therapy, such as antihypertensive therapy, a statin or aspirin. In addition, assessing for other risk-enhancing factors can help guide decisions about preventive interventions in select individuals, as can coronary artery calcium scanning.

While a pharmacist may not be an existing part of the practice core team, providers in Delaware can take advantage of collaboration through a Delaware Division of Public Health/ Delaware Pharmacists Society program that provides nocost medication therapy management for patients taking antihypertensive and cholesterol- lowering medications.30

4. All adults should consume a healthy diet that emphasizes the intake of vegetables, fruits, legumes, nuts, whole grains, lean vegetable or animal protein, and fish and minimizes the intake of trans fats, processed meats, refined carbohydrates, and sweetened beverages. For adults with overweight/obesity, comprehensive lifestyle interventions, including counseling and caloric restriction, are recommended for achieving and maintaining weight loss.

Suggested workflows for care team roles and responsibilities for risk assessment/ pharmacotherapy recommendations are presented in Table 4.

5. Adults should engage in at least 150 minutes per week of accumulated moderate-intensity physical activity or 75 minutes per week of vigorous-intensity physical activity.

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6. For adults with type 2 diabetes mellitus, lifestyle changes, such as improving dietary habits and achieving exercise recommendations, are crucial. If medication is indicated, metformin is first-line therapy, followed by consideration of a sodium-glucose cotransporter 2 inhibitor or a glucagon-like peptide-1 receptor agonist.

7. All adults should be assessed at every healthcare visit for tobacco use, and those who use tobacco should be assisted and strongly advised to quit.

8. Aspirin should be used infrequently in the routine primary prevention of ASCVD because of lack of net benefit.

9. Statin therapy is first-line treatment for primary prevention of ASCVD in patients with elevated low-density lipoprotein cholesterol levels (>190 mg/dL), those with diabetes mellitus, who are 40 to 75 years of age, and those determined to be at sufficient ASCVD risk after a clinician-patient risk discussion.

10. Nonpharmacological interventions are recommended for all adults with elevated blood pressure or hypertension. For those requiring pharmacological therapy, the target blood pressure should generally be <130/80 mm Hg.

APPENDIX B Community Guide Systematic Review: Changes in proportion of patients with controlled BP attributable to team-based care32

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APPENDIX C Sample Resources to Implement ACC/AHA CVD Primary Prevention Guidelines ACC/AHA Guideline

Action

Resources

Prevent atherosclerotic vascular disease, heart failure, and atrial fibrillation by promoting healthy lifestyles throughout life Use a team-based approach to prevent CVD Evaluate the social determinants of health (SDOH) that affect individuals to inform treatment decisions

Provide all patients with information about heart healthy programs

• AHA: Be Healthy for Good with Life’s Simple 7

Collect race/ethnicity from all patients.

Implement validated SDOH screening tool

• Quality Insights practice module: Social Determinants of Health and Workflow Modifications • PRAPARE Toolkit

Adults 40-75 years being evaluated for CVD prevention should undergo 10-year risk estimation and should have clinician-patient risk discussion before starting on pharmacological therapy, such as antihypertensive or statin

Screen for risk factors and apply race- and sexspecific modifiers for asymptomatic adults. Manage hypertension and blood cholesterol, use clinical guidelines. Where appropriate, assess risk using coronary artery calcium scanning

• American College of Cardiology ASCVD Risk Estimator Tool

Adults 40-75 years being evaluated for CVD prevention should undergo 10-year risk estimation and should have clinician-patient risk discussion before starting on pharmacological therapy, such as antihypertensive or statin

Screen for risk factors and apply race- and sexspecific modifiers for asymptomatic adults. Manage hypertension and blood cholesterol, use clinical guidelines. Where appropriate, assess risk using coronary artery calcium scanning

• American College of Cardiology ASCVD Risk Estimator Tool

All adults should consume a healthy diet For adults with overweight/ obesity, comprehensive lifestyle interventions, including counseling and caloric restrictions, are recommended for achieving and maintaining weight loss

Provide all patients with nutrition information For patients with hypertension, provide DASH diet information and promote self-monitoring of blood pressure For patients with overweight/ obesity, administer prediabetes risk tests and offer information on weight management For patients with prediabetes, refer to National Diabetes Prevention Program (National DPP)

• AHA’s Life Simple 7 – Eat Better • AHA: Life’s Simple 7 – Manage Weight • Quality Insights: Take Control of Hypertension with WW and TOPS • DASH Your Way to Lower Blood Pressure • Tips for Taking Your Own Blood Pressure Readings • CDC Prediabetes Risk Test • Refer Your Patients with Prediabetes to a National DPP • CDC’s Recognized Lifestyle Change Programs

Adults should engage in at least 150 min./week of accumulated moderate-intensity physical activity or 75 min./ week of vigorous- intensity physical activity.

Counsel all patients about physical activity recommendations. Provide educational materials.

• AHAs Life’s Simple 7 –Move More

For adults with type 2 diabetes mellitus, lifestyle changes, such as improving dietary habits and achieving exercise recommendations, are crucial.

Refer patients to Diabetes Self-Management Education and Support (DSMES).

• DSMES (Sussex)* • DSMES (Kent)* • DSMES (NCC)* *Includes virtual programming

All adults should be assessed at every healthcare visit for tobacco use, and those who use tobacco should be assisted and strongly advised to quit.

Aspirin should be used infrequently in routine primary prevention of ASCVD because of lack of net benefit.

Ask every patient about tobacco use. Provide cessation assistance.

• AHA: Life’s Simple 7 – How to Quit Tobacco • Delaware QuitLine • 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease

Statin therapy is first-line treatment for primary prevention of ASCVD in patients with elevated LDL-C, those with diabetes who are age 40-75, and those at sufficient ASCVD risk after clinician-patient risk discussion.

Nonpharmacological interventions are recommended for all adults with elevated BP or HTN. For those requiring pharmacological therapy, target BP should generally be <130/80 mm Hg.

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Evaluate use of aspirin therapy based on patient age and risk-enhancing factors such as family history, ability to achieve lipid, BP, or glucose targets.

Assess LDL-C and related risk factors. Initiate risk/benefit discussion.

Assess BP for all patients and recommend evidencebased lifestyle programs where appropriate.

• 2018 Guideline on the Management of Blood Cholesterol • Statin Choice Decision Aid • Adherence Estimator©

• Million Hearts® Hypertension Control Change Package

REFERENCES 1. , C., McCormack, J., Kolber, M. R., Garrison, S., & Allan, G. M. (2017). Competing demands and opportunities in primary care. Canadian Family Physician. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597006/ 2. Centers for Disease Control and Prevention. (2020). Heart disease facts. https://www.cdc.gov/heartdisease/facts.htm

12. New England Journal of Medicine Catalyst. (2017). What is patient-centered care? https://catalyst.nejm.org/doi/full/10.1056/CAT.17.0559 13. Tsai, C. H., Eghdam, A., Davoody, N., Wright, G., Flowerday, S., & Koch, S. (2020, December 4). Effects of electronic health record implementation and barriers to adoption and use: A scoping review and qualitative analysis of the content. Life (Basel), 10(12), 327. https://doi.org/10.3390/life10120327

4. Arnett, D. K., Khera, A., & Blumenthal, R. S. (2019, October 1). 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease. JAMA Cardiology, 4(10), 1043–1044. https://doi.org/10.1001/jamacardio.2019.2604

14. Virani, S. S., Alonso, A., Benjamin, E. J., Bittencourt, M. S., Callaway, C. W., Carson, A. P., . . . Tsao, C. W., & the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee.

(2020, March 3). Heart disease and stroke statistics—2020 update: A report from the American Heart Association.

Circulation, 141(9), e139–e596. Retrieved from https://www.ahajournals.org/doi/10.1161/CIR.0000000000000757 https://doi.org/10.1161/CIR.0000000000000757

5. Egan, B. M., Sutherland, S. E., Rakotz, M., Yang, J., Hanlin, R. B., Davis, R. A., & Wozniak, G. (2018, December). Improving hypertension control in primary care with the Measure Accurately, Act Rapidly, and Partner with Patients protocol.

Hypertension, 72(6), 1320–1327. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221423/pdf/hyp72-1320.pdf https://doi.org/10.1161/HYPERTENSIONAHA.118.11558

15. Krist, A. H., Davidson, K. W., Mangione, C. M., Barry, M. J., Cabana, M., Caughey, A. B., . . . Wong, J. B., & the US Preventive Services Task Force. (2020, November 24).

Behavioral counseling interventions to promote a healthy diet and physical activity for cardiovascular disease prevention in adults with cardiovascular risk factors. U.S. Preventive Services Task Force recommendation sheet. JAMA, 324(20), 2069–2075. https://doi.org/10.1001/jama.2020.21749

6. Delaware Health and Social Services, Division of Public Health. (2019). Update on high cholesterol data. https://www.dhss.delaware.gov/dhss/dph/dpc/cholesterol_update.html

16. U.S. Department of Health and Human Services. (2020).

Smoking cessation. A report of the Surgeon General. https://www.hhs.gov/sites/default/files/2020-cessation-sgr-fullreport.pdf

3. Delaware Health and Social Services. (2019). Chronic disease in Delaware: Facts and figures. https://dhss.delaware.gov/dhss/dph/dpc/ files/2019chronicdiseasefactsfigures.pdf

7. Coleman, K., Wagner, E., Schaefer, J., Reid, R., & LeRoy, L. (2016). Redefining primary care for the 21st century. Agency for Healthcare Research and Quality. https://www.ahrq.gov/ncepcr/primary-care-research/workforcefinancing/white-paper.html 8. Schottenfeld, L., Petersen, D., Peikes, D., Ricciardi, R., Burak, H., McNelis, R., & Genevro, J. (2016). Creating patientcentered team-based primary care. Agency for Healthcare Research and Quality. https://pcmh.ahrq.gov/page/creating-patient-centered-team-basedprimary-care 9. American Medical Association. (2019). Physician-led teambased care. https://www.ama-assn.org/practice-management/payment-deliverymodels/physician-led-team-based-care 10. MacColl Center for Health Care Innovation. (2015).

Improving primary care team guide. http://improvingprimarycare.org/ 11. Smith, C., Balatbat, C., Corbridge, S., Dopp, A., Fried, J., Harter, R., . . . Sinsky, C. (2018). Implementing optimal teambased care to reduce clinician burnout. National Academy of Medicine Perspectives. https://nam.edu/implementing-optimal-team-based-care-to-reduceclinician-burnout/

17. Centers for Disease Control and Prevention. (2020). Social determinants of health. https://www.cdc.gov/socialdeterminants/index.htm 18. McGovern, L., Miller, G., & Hughes-Cromwick, P. (2014).

What determines how healthy you are? Robert Wood Johnson Foundation. https://www.rwjf.org/en/library/research/2014/08/the-relativecontribution-of-multiple-determinants-to-health-out.html 19. Angell, S. Y., McConnell, M. V., Anderson, C. A., BibbinsDomingo, K., & Boyle, D. S. Captewell, … & Warner, J.J. (2020). The American Heart Association 2030 impact goal: A presidential advisory from the American Heart Association.

Circulation, 141(8). https://www.ahajournals.org/doi/epub/10.1161/ CIR.0000000000000758 20. American Medical Association. (2015). Why race, ethnicity and language data is crucial to quality care. https://www.ama-assn.org/delivering-care/patient-support-advocacy/ why-race-ethnicity-and-language-data-crucial-quality-care 21. Weir, R. C., & Jester, M. (2018). Addressing the relationship between social determinants of health and outcomes: Findings from the PRAPARE pilot. National Association of Community Health Centers. http://www.nachc.org/wp-content/uploads/2019/01/PRAPARE-DataFindings-HIgh-Risk-General-slides-for-Toolkit.pdf 89

22. American Hospital Association. (2019). Social determinants of health. 2019. https://www.aha.org/system/files/2018-04/value-initiative-icd-10code-social-determinants-of-health.pdf 23. Wall, H. K., Hannan, J. A., & Wright, J. S. (2014). Patients with undiagnosed hypertension: Hiding in plain sight. Journal of the American Medical Association. https://jamanetwork.com/journals/jama/fullarticle/1935131 24. Community Preventive Services Task Force. (2014). Teambased care to improve blood pressure control. Journal of Preventive Medicine. https://www.thecommunityguide.org/sites/default/files/publications/ cvd-AJPM-recs-team-based-care.pdf 25. Centers for Disease Control and Prevention. (2020). Selfmeasured blood pressure monitoring with clinical support. https://www.cdc.gov/dhdsp/pubs/guides/best-practices/smbp.htm 26. Centers for Disease Control and Prevention. (2020). Million Hearts® hypertension control change package, 2nd edition. https://millionhearts.hhs.gov/tools-protocols/action-guides/htnchange-package/index.html 27. Mayo Foundation for Medical Education and Research. (n.d.).

Statin choice decision aid. https://statindecisionaid.mayoclinic.org/

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28. Centers for Disease Control and Prevention. (2016). Million Hearts® medication adherence action steps for public health practitioners. https://millionhearts.hhs.gov/files/Medication-Adherence-ActionGuide-for-PHPs.pdf 29. Merck. (2020). Use the adherence estimator. Adherence Estimator®. https://www.adherenceestimator.com/default.aspx 30. Delaware Health and Social Services and Quality Insights.

(2020). Medication therapy management: Evidence-based collaboration to improve blood pressure control. https://qualityinsights.org 31. Arnett, D. K., Khera, A., & Blumenthal, R. S. (2019, October 1). 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease. JAMA Cardiology, 4(10), 1043–1044. https://doi.org/10.1001/jamacardio.2019.2604 32. Proia, K. K., Thota, A. B., Njie, G. J., Finnie, R. K. C., Hopkins, D. P., Mukhtar, Q., . . . Cooksey, T., & the Community Preventive Services Task Force. (2014, July).

Team-based care and improved blood pressure control: A community guide systematic review. American Journal of Preventive Medicine, 47(1), 86–99. https://doi.org/10.1016/j.amepre.2014.03.004

FIGHT FLU Get your family vaccinated against flu this season. It’s the best way to protect you and your loved ones from getting the flu.

www.cdc.gov/fightflu 91

From the History, Archives, and Collection

Letter to the Editor Sharon Folkenroth-Hess, M.A. Archivist, Delaware Academy of Medicine/Delaware Public Health Association

There is no denying that digitized newspapers are a precious tool for researchers. Centuries-old news once forgotten is now available at any time. Keyword searches make finding relevant information easy—all without needing to leave home. The Delaware Academy of Medicine Archives is joining this digital revolution to share our rich collections with the world. However, for those willing to brave the dust and the occasional desiccated bug carcass, flipping through the physical copy of an old paper can lead to valuable and surprising discoveries. For example, by unpacking one letter to the editor tucked away in the stacks, the ugly history of Delaware’s Title 16, Chapter 57 law was revealed.

On February 5, 1929, Wilmingtonian George A. Donahue wrote: CHALLENGES LAW AND STATEMENTS ON STERILIZATION

Permit me space in your esteemed paper to say a few words in defense of the insane, feeble-minded, and epileptic. After reading the sterilization report in the Every Evening of the 4th instant, by former Lieut. Gov. J. Hall Anderson, as secretary of the State Board of Charities, in reference to that abominable, unchristian sterilization law, put upon the books of Delaware, the same, in my humble opinion is the blackest work it will ever receive from the hands of Christians and civilization, and the day will come by the grace of God, just as sure as dawn follows the night, when Delaware, with loud wailing and lamentation, will bow its head in shame to hide the infamy due to it.1 Mr. Donahue continues to denounce the report and Anderson for three more paragraphs, ending with a call to loyal Christian soldiers and broad-minded citizens to combat legislation that put down the laws of God. It is difficult to gauge how many Delawareans shared Mr. Donahue’s opinion. One thing is sure: public health officials, administrators, and legislators embraced the new “science” of eugenics and allowed it to determine the extent of civil liberties afforded the “genetically unfit.”

Eugenics is the pseudo-scientific idea that humans can be improved or perfected by “breeding out” disease, disabilities, deviant social behavior, and other undesirable characteristics.

Positive eugenics promotes the breeding of “superior hereditary stock.” Many eugenists believed that education campaigns would lead to voluntary public participation (Figure 1). Negative eugenics restricts or prevents reproduction for those deemed genetically “unfit” by discouraging or prohibiting marriage, 92 Delaware Journal of Public Health - December 2021

restrictions on immigration, or through sexual segregation, sterilization, or euthanasia. For some religions, eugenics is akin to abortion and contraceptives, in that it is a sin against nature to interfere with human reproduction. The law Mr. Donahue refers to is an example of negative eugenics.

Earlier in 1929, representatives from the Delaware State Hospital at Farnhurst and the Delaware Hospital for the Mentally Retarded lobbied the state legislature to enlarge the scope of the 1923 law known as “An act to provide for the sterilization of certain defectives.” Under this law, inmates at mental institutions could be sterilized. The proposed 1929 amendments included criminals with mental abnormalities, the chronically insane, promiscuous women, and gay men.

Dr. Mesrop A. Tarumianz, Superintendent of Farnhurst, argued that the amendments were vital to the hospital’s needs. The overcrowded conditions led to neglect and the lack of proper treatment. Additionally, these amendments would save the taxpayers money. According to Tarumianz, one Delaware family alone had cost taxpayers $125,000 ($2,005,190 today) over the last 35 years.2 The cost savings argument was used successfully throughout the 1930s, thanks in part to the economic depression.

Lieutenant Governor Anderson clearly stated that the proposed amendments were about more than simply cost saving measures and concerns over treatment of wards of the state. His report to the State Board of Charities ends with the conclusion that: “The great social menace, however, of the feeble-minded and insane cannot be computed in money. We cannot afford longer to sit idly by and permit the blood of our people to be longer contaminated by the rapid reproduction of mental defectives whose children will later, in ever increasing numbers, fill our jails with criminals and our hospitals and institutions with insane, feeble-minded and pauper dependents.”3 On March 29, 1929, the amendments passed. Dr. Tarumianz informed the General Assembly that Farnhurst intended to sterilize 150 to 200 Delawareans each year until imbecile, insane, or feeble-minded children in the state were a thing of the past.4 In the 1930s, Delaware was the only state that outpaced California in per capita sterilizations with a rate ranging between about 80 and 100 sterilizations per 100,000 individuals.5 Though the law stated that the patient had to give consent, many were likely coerced.

Even though Nazi sterilization and extermination programs created a distaste for eugenics in America, many sterilization laws remained. In Delaware, sterilizations not only continued, but saw Doi: 10.32481/djph.2021.12.018

an uptick in the 1960s.6 The law (Title 16, Chapter 57) was last updated in 2006, and includes a robust definition of informed consent along with stronger restrictions on who is deemed unable to give consent.

In early fall 2020, news broke that migrant women in an ICE detention center in Georgia were allegedly sterilized without their consent.7 A few months later, pop superstar Brittney Spears divulged to her fans that she was forced to have an intrauterine device implanted under the conservatorship of her father.8 Ms. Hess can be contacted at shess@delamed.org

REFERENCES 1.Newspapers.com. (n.d.). Clipped from the News Journal.

Retrieved from: https://www.newspapers.com/clip/88337778/the-news-journal/ 2. Newspapers.com. (n.d.). Feb16 Luncheon. Retrieved from: https://www.newspapers.com/clip/88332797/feb16-luncheon/ 3. Newspapers.com. (n.d.). Asking for amendments. Retrieved from: https://www.newspapers.com/clip/88332685/asking-for-amendments/

4. Staff. (1929, Jan 26). Show needs of hospital at Farnhurst. The Evening Journal, 1-14. Retrieved from: https://www.newspapers.com/image/160347423/ 5. Stern, A. M. (2005, July). Sterilized in the name of public health. American Journal of Public Health, 95(7), 1128–1138. https://doi.org/10.2105/AJPH.2004.041608 6. Paul, J. (1965). “Three generations of imbeciles are enough:” state eugenic sterilization laws in American thought and practice. (Unpublished manuscript). Washington D.C.: Walter Reed Army Institute of Research. Retrieved from: http://buckvbell.com/pdf/JPaulmss.pdf 7. Powers, L. (2020, Oct). Could forced sterilization still be legal in the US? Syracuse Law Review. Retrieved from: https://lawreview.syr.edu/could-forced-sterilization-still-belegal-in-the-us/ 8. Herstik, L. (2021, Sep). Britney Spears is released from her father’s oversight. The New York Times. Retrieved from: https://www.nytimes.com/2021/09/29/arts/music/britney-spearscourt-decision-conservatorship.html

Figure 1. The American Eugenics Society, “The Triangle of Life,” presented at the Kansas Free Fair.

American Philosophical Society

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GENETICS – LEXICON A Priori Reasoning or knowledge based on theory (not observation).

Adipose Tissue used for fat storage.

Cirrhosis A chronic disease of the liver marked by degeneration of cells, inflammation, and fibrous thickening of tissue.

Comorbidity The simultaneous presence of two or more diseases or medical conditions in a patient.

Etiology The cause, set of causes, or manner of causation of a disease or condition.

Eugenics The study of how to arrange reproduction within a human population to increase the occurrence of heritable characteristics regarded as desirable.

Exome All of the exons within the genome of an organism.

Exome Sequencing Determining the order of all (or almost all) of the nucleotides in the specific exome of an organism.

Gene A distinct sequence of nucleotides that code for a protein or regulates other genes’ functions.

Genome The entire set of genes in an organism.

Genome Sequencing Determining the order of all (or almost all) of the nucleotides of the entire genome of an organism.

Genomics A field of biology that focuses on the structure, function, evolution, mapping and editing of the complete set of genes in an organism and how the genome interacts with other genomes and the environment.

Genotoxicity The property of chemical agents that damages the genetic information within a cell causing mutations, which may lead to cancer.

Genotyping Investigating the genetic constitution of an individual.

Intrathecal A route of administration for drugs via an injection into the spinal canal.

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Lipoprotein Substances made of protein and fat that carry cholesterol through your bloodstream.

Locus The location of a gene on a chromosome.

Mesenchymal Embryonic connective tissue that is derived from the mesoderm and that differentiates into blood and connective tissue

Nanoparticle A small particle that ranges between 1 to 100 nanometres in size.

Nasopharyngeal The upper part of the pharynx throat behind the nose.

Nucleotides Molecules (adenine, thymine, guanine, cytosine) consisting of a nitrogen containing base, a phosphate group and a sugar (desoxyribose or ribose) which, when arranged in sequence, are the building blocks of DNA (deoxyribose) or RNA (ribose).

Pathogenicity The ability to cause disease.

Pharmacogenetics The branch of pharmacology concerned with the effect of genetic factors on reactions to drugs.

Precision Medicine An emerging approach to disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle for each person.

Precision Public Health An emerging approach to utilizing genomic and environmental factors and their interactions to deliver care and prevention to a population.

Prospective Concerned with or applying to the future. A prospective study looks forward in time.

Retrospective Concerned with or applying to the past. A retrospective study looks backwards in time.

Variations of Uncertain Significance (VUS) Usually applied to genetic variants (mutations) which are uncovered during diagnostic sequencing whose clinical importance in disease states is uncertain.

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GENETICS – RESOURCES American College of Medical Genetics and Genomics https://www.acmg.net/ Delaware Center for Maternal and Fetal Medicine https://www.dcmfm.com/genetics Delaware’s Newborn Screening Program https://www.dhss.delaware.gov/dhss/dph/chca/dphnsp1.html Delaware Public Health Laboratory: Genomic Identification and Surveillance https://dhss.delaware.gov/dhss/dph/lab/wgs.html

Delaware State University Center for Integrated Biological and Environmental Research: Molecular Genetics and Epigenomics https://ciber.desu.edu/molecular-genetics-epigenomics-mgel/ Gene Editing Institute at ChristianaCare https://research.christianacare.org/geneeditinginstitute/ University of Delaware School of Agriculture and Natural Resources: Genetics and Genomics https://www.udel.edu/academics/colleges/canr/research/college-strengths/genomics/

GENETICS – MORE INFORMATION This issue of the Delaware Journal of Public health goes into great detail about statistical analyses and genomic sequencing. For background information on these topics please visit the following websites.

The Gene Editing Institute’s CRISPR in the Classroom Video Series https://research.christianacare.org/geneeditinginstitute/education/

Introduction to CRISPR in the Classroom by Dr. Janice Nevin and exploration of care for patients with Sickle Cell Disease: https://youtu.be/oDMTJczo3Qo Dr. Eric Kmiec discusses the “Gene Editing Revolution:” https://youtu.be/eTYjkpo-3EQ A demonstration of the CRISPR in a Box gene editing experimental protocol: https://youtu.be/Qj7iP67otHo

Race, Gender and Science Roundtable Discussion: https://youtu.be/J94N8dGUr8U Genomic Sequencing Transcription and Translation: From DNA to Protein (Professor Dave Explains): https://www.youtube.com/watch?v=bKIpDtJdK8Q Genomic Sequencing (the Mayo Clinic): https://www.youtube.com/watch?v=2JUu1WqidC4 What is CRISPR? (Bozeman Science): https://www.youtube.com/watch?v=MnYppmstxIs CRISPR: A Gene-Editing Superpower (SciShow): https://www.youtube.com/watch?v=UfA_jAKV29g CRISPR and Gene Editing (Delaware Mini Medical School presentation

by Dr. Brett Sansbury of the Gene Editing Institute):

https://www.youtube.com/watch?v=BcFY4FgDHWU

Statistical Concepts https://www.scribbr.com/statistics/statistical-tests/ Statistics Made Easy: https://www.youtube.com/watch?v=I10q6fjPxJ0 96 Delaware Journal of Public Health - December 2021

Index of Advertisers The Nation's Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 American Public Health Association The DPH Bulletin - November 2021 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Delaware Division of Public Health ChristianaCare's Continuing Medical Education. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 ChristianaCare The DPH Bulletin - October 2021 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Delaware Division of Public Health Making the Decision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Public Health Communications Collaborative Quality Improvement Initiative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 ChristianaCare Submission Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 Delaware Journal of Public Health

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Delaware Journal of

Public Health

Submission Guidelines

updated April, 2020

About the Journal Established in 2015, The Delaware Journal of Public Health is a bi-monthly, peer-reviewed electronic publication, created by the Delaware Academy of Medicine/Delaware Public Health Association. The publication acts as a repository of news for the medical, dental, and public health communities, and is comprised of upcoming event announcements, past conference synopses, local resources, peer-reviewed content ranging from manuscripts and research papers to opinion editorials and personal interest pieces, relating to the public health sector. Each issue is largely devoted to an overarching theme or current issue in public health.

The content in the Journal is informed by the interest of our readers and contributors. If you have an event coming up, would like to contribute an Op-Ed, would like to share a job posting, or have a topic in public health you would like to see covered in an upcoming issue, please let us know.

If you are interested in submitting an article to the Delaware Journal of Public Health, or have any additional inquiries regarding the publication, please contact DJPH Deputy Editor Elizabeth Healy at ehealy@delamed.org, or the Executive Director of The Delaware Academy of Medicine and Delaware Public Health Association, Timothy Gibbs, at tgibbs@delamed.org

Information for Authors Submission Requirements The DJPH accepts a wide variety of submission formats including brief essays, opinion editorials pieces, research articles and findings, analytic essays, news pieces, historical pieces, images, advertisements pertaining to relevant, upcoming public health events, and presentation reviews. If there is an additional type of submission not previously mentioned that you would like to submit, please contact a staff member.

Cover Letters must address the following four article requirements: 1. A description of what the paper adds to current knowledge, in particular with respect to material previously published in DJPH, and if systematic reviews exist on the topic.

2. The public health importance of the paper.

3. One sentence summarizing the main message(s) of the paper, which may be used to disseminate the paper on social media.

The initial submission should be clean and complete, without edits or markups, and contain both the title and author(s) fulls name(s). Submissions should be 1.5 or 4. For individual or group randomized trials, provide the double spaced with a font size of 12. Initial submissions date of trial registration and the NCT number from must also contain a cover letter with concise text www.Clinicaltrials.gov or other approved registry. (maximum 150 words). Once completed, articles In the cover letter only, not in the paper. Do NOT should be submitted via email to Elizabeth Healy at include the trial registration or NCT number in the ehealy@delamed.org as an attachment. Graphics, images, abstract or the body of the manuscript during the info-graphics, tables, and charts, are welcome and initial submission. encouraged to be included in articles. Please ensure that all pieces are in their final format, and all edits and track All manuscripts must be submitted via email to Elizabeth Healy at ehealy@delamed.org. changes have been implemented prior to submission.

98 Delaware Journal of Public Health - December 2021

To view additional information for online submission requirements, please refer to the website for the Delaware Journal of Public Health: https://djph.org/sample-page/submit-an-article/.

Submission Length While there is no prescribed word length, full articles will generally be in the 2500-4000-word range, and editorials or brief reports will be in the 1500-2500-word range. If you have any questions regarding the length of a submission, or APA guidelines, please contact a staff member.

Copyright Opinions expressed by contributors and authors do not necessarily reflect the opinions of the DJPH or affiliated institutions of authors. Copying for uses other than personal reference or interest without the consent of the DJPH is prohibited. All material submitted alongside written work, including graphics, charts, tables, diagrams, etc., must be referenced properly in accordance with APA formatting.

Conflicts of Interest Any conflicts of interest, including political, financial, personal, or academic conflicts, must be declared prior to the submission of the article, or in conjunction with a submission. Conflicts of interest are any competing interests that may leave readers feeling misled or deceived, and/or alter their perception of subject matter. Declared conflicts of interest may be published alongside articles in the final electronic publication.

Additional Documents and Information for Authors Please Note: All authors and contributors are asked to submit a brief personal biography (3 sentences maximum) and a headshot along submissions. These will be published alongside final submissions in the final electronic publication. For pieces with multiple authors, these additional documents are requested for all contributors.

Abstracts Authors must submit a structured or unstructured abstract along with their article.

The word limit is 200 words, including headings. A title page should be submitted with this abstract as well.

Structured abstracts should employ 4-5 headings: Objectives (begins with “To…”) Methods Results Conclusions A fifth heading, Policy Implications, may be used if relevant to the article.

Trial Registration information is required for clinical trials and must be included in the final version abstract All abstracts should provide the dates(s) and location(s) of the study is applicable.

Note: There is no Background heading.

Nondiscriminatory Language Use of nondiscriminatory language is required in all DJPH submissions. The DJPH reserves the right to reject any submission found to be using sexist, racist, or heterosexist language, as well as unethical or defamatory statements.

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Delaware Academy of Medicine / DPHA 4765 Ogletown-Stanton Road Suite L10 Newark, DE 19713

www.delamed.org | www.djph.org Follow Us:

The Delaware Academy of Medicine is a private, nonprofit organization founded in 1930. Our mission is to enhance the well being of our community through medical education and the promotion ofpublic health. Our educational initiatives span the spectrum from consumer health education tocontinuing medical education conferences and symposia.

The Delaware Public Health Association was officially reborn at the 141st Annual Meeting of the American Public Health Association (AHPA) held in Boston, MA in November, 2013. At this meeting, affiliation of the DPHA was transferred to the Delaware Academy of Medicine officially on November 5, 2013 by action of the APHA Governing Council. The Delaware Academy of Medicine, who’s mission statement is “to promote the well-being of our community through education and the promotion of public health,” is honored to take on this responsibility in the First State.

ISSN 2639-6378