Penn Healthcare Review Spring 2022 by Publications of the Wharton Undergraduate Healthcare Club

WHARTON UNDERGRADUATE HEALTHCARE CLUB

SPRING 2022

PENN HEALTHCARE REVIEW L O G BA E H

NEW AGE OF MEDICINE

E C VAN

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From Facebook to Flo: Patient Empowerment Through Digital Health Apps Sahiba Baveja

MedTech in Your Pocket: The Increasing Portability of Diagnostic Medical Devices Om Gandhi

Renewal: The "Pluri"potential of Yamanaka Factors

Kyne Wang

Dear Readers,

EDITORS-IN-CHIEFS Kyne Wang Claudia Hejazi-Garcia

At Penn, this semester has felt the closest to normal for the first time since Spring 2019. Students are finally back to holding gatherings, going

WRITERS Annabelle Jin Austin Pothikamjorn Farhaanah Mohideen Kyne Wang Om Gandhi Sahiba Baveja Saraswati Sridhar Shahana Banerjee

to classes, and exploring Philadelphia. We have learned how it feels to eat in dining halls and even how people look without a mask on. This year has certainly not been quiet. Former President Amy Gutmann stepped down and has been sworn in as the U.S. Ambassador to Germany, and Path@Penn is making a turbulent entrance to take over PennInTouch. Yet, the Penn Healthcare Review wanted to take a look outside of our small bubble here in University City and explore how the world has also changed throughout these past few years. The New Age of Medicine: The Global Advance is Penn Healthcare Review’s first publication exploring the novel decisions that are being made in healthcare outside Locust Walk. From handheld ultrasound devices to artificial intelligence, this issue explores the implications of healthcare innovation on a global scale.

EDITORS Austin Pothikamjorn Amarachi Mbadugha Adanna Mogbo Borna Shani Eesha Balar Erin Lee Om Gandhi Saraswati Sridhar Shahana Banerjee

We are also very fortunate to welcome our first industry-insight this semester. The Penn Healthcare Review is grateful for Dr. Todd Fruchterman—the CEO of Butterfly Network, mentioned in one of our articles—who has, kindly, taken the time to offer his insight on the trajectory of MedTech innovation and Butterfly's vision. With the effects of the pandemic slowly diminishing, we look forward to sharing our analyses and investigation of the future of healthcare in the United States and abroad as we pivot to a new age, the New Age of Medicine.

We hope you enjoy, Kyne and Claudia

DESIGNERS Ashleigh Huang Chloe Yue Divyesh Nagarajan Elaine Sun Farhaanah Mohideen Julia Gerbino Please note: There articles were prepared by members of the Wharton Undergraduate Healthcare Club. The opinions do not represent the school or club's official positions on the issues. The Wharton Undergraduate Healthcare Club is an independent, student-led organization of the Wharton School of the University of Pennsylvania. All content is the responsibility of the club.

Dr. Todd. M. Fruchterman C'92 M'96

Dr. Fruchterman is currently the Chief Executive Officer for Butterfly Network, a digital health company transforming care with handheld, whole-body ultrasound. Dr. Fruchterman has dedicated his career to improving patient outcomes and expanding access to care through innovative technologies that benefit all patients and healthcare providers. Dr. Fruchterman received his Bachelor's and M.D. from Penn and his Ph.D. in Physiology & Biophysics from the University of Louisville.

Healthcare is being challenged unlike almost any other time in history. The need to shift care to less expensive venues and meet the patient where they are in their respective communities is paramount to unlocking access to care, globally. Accuracy, speed, and cost efficiency is a premium, and the need to be right at the initial access point to care is critical to both the patient and the doctor. Butterfly Network puts advanced imaging in the pocket of practitioners everywhere to inform clinical thinking at the point of care assessment, guide the differential, the diagnosis, the treatment, and follow up plan. Butterfly enables the practical application of ultrasound information into the clinical workflow. Our technology has the potential to transform diagnostics across many care settings by delivering powerful imaging insights to close information gaps regardless of care setting or geography. And, because the Butterfly IQ+ can be easily transported and linked to smartphones, the value is not only in accessibility at the bedside, but in transcending some of healthcare’s most ingrained geographic barriers. For example, for 2/3 of the world medical imaging is absent altogether, [1] because it is either unaffordable, too far away, or both – a single probe that enables whole body, handheld ultrasound is not just about closing information gaps fast, it’s enabling access to a care modality that does not otherwise exist. This is true in low-mid income nations and in parts of higher income countries in rural settings. With such a pocket-based tool, imaging can be accessible anywhere, fitting easily and affordably in the pocket of every clinician, so they can see what they need to know. By expanding the settings in which medical imaging can be done, Butterfly may provide opportunities for earlier detection and prevention of disease, while reducing cost. This aligns with the focus on consumer health empowerment, wellness, and acceleration of value-based care, all of which are important themes in the healthcare industry today and have become increasingly more important during the COVID-19 pandemic. Our platform is about using ultrasound information in clinical decision making versus doing ultrasound. We are helping to catalyze a paradigm shift in care delivery by helping to inform clinical decision making with information rather than confirming it. The portability and accessibility of Butterfly’s handheld diagnosing imaging tool unlocks tremendous potential to advance global health equity, close gaps in rural care settings, and enhance what’s possible across other low-resourced as well as home care scenarios. In time, we also believe this technology can lead to a new standard of care, one that makes handheld, whole body ultrasound as ubiquitous as the stethoscope. Read more about Butterfly Network on Page 14

[1] PAHO/WHO | World Radiography Day: Two-Thirds of the World's Population has no Access to Diagnostic Imaging

CONTENTS 5

In Utero Gene Therapy: The Promise of Prenatal Modification Written by Annabelle Jin, Designed by Julia Gerbino

From Facebook to Flo: Patient Empowerment Through Digital Health Apps Written by Sahiba Baveja, Designed by Divyesh Nagarajan

CAR-T in Canines: The Future of Cancer Treatment in Dogs Written by Austin Pothikamjorn, Designed by Elaine Sun

Telehealth: A Call to Action Written by Saraswati Sridhar, Designed by Julia Gerbino

MedTech in Your Pocket: The Increasing Portability of Diagnostic Medical Devices Written by Om Gandhi, Designed by Chloe Yue

AI: The Machine of Global Health Written by Shahana Banerjee, Designed by Ashleigh Huang

The Rise of FemTech: Market Overview & Strategic Frameworks for Commercial Adoption Written and Designed by Farhaanah Mohideen

Renewal: The "Pluri"-potential of Yamanaka Factors Written by Kyne Wang, Designed by Chloe Yue

IN UTERO GENE THERAPY: THE PROMISE OF PRENATAL MODIFICATIO N

written BY Annabelle Jin DESIGNED BY JULIA GERBINO

What if you could treat a devastating genetic disease in the womb, such that the baby would never have to suffer from it? That is the promise of in utero gene therapy (IUGT), a cutting edge technology that would alter disease-causing gene mutations by injecting viral vectors carrying the correct gene into the fetus. [1,2]. It is the epitome of the Hippocratic ideal of preventing suffering. A person could live their whole life free from disease due to this early intervention. Although IUGT is still in its early stages of research, it holds great potential for overcoming the challenges of postnatal gene therapy. A central obstacle is the possibility of the vector provoking an immune response, since the body would recognize it as foreign and attack it. This can lead to severe inflammation and even organ failure [2]. In fact, gene therapy clinical trials were derailed for a decade in 1999 when Jesse Gelsinger, an 18-year-old with ornithine transcarbamylase deficiency, became the first patient to die in a clinical trial due to his catastrophic immune response to gene therapy [3,4]. However, in contrast to postnatal gene therapy, IUGT would have a lower risk of an adverse immune response, as fetuses have immature immune systems that allow them to tolerate the vector [1]. IUGT is particularly well-suited for neurological diseases, since the blood-brain barrier develops fully after birth, preventing the vector from entering the brain. It is also compatible with diseases whose pathology begins in the womb, as this would make postnatal treatments futile [5]. One prime example fulfilling both criteria is acute neuronopathic Gaucher’s disease, a metabolic condition in which mutations in the GBA gene prevent production of the enzyme glucocerebrosidase in the brain [1]. This results in toxic buildup of glucosylceramide lipids that begins in utero and shortens lifespan to two years [1,4]. This makes Gaucher’s an ideal candidate for IUGT. A landmark study conducted by Giulia Massaro, a postdoctoral FIG. 1. Advantages of the fetus for delivery of gene therapeutics. fellow at University College London, and her team injected a virus carrying the correct GBA gene into mouse embryos with GBA mutations. The study found that the DNA successfully integrated into the embryos, resulting in normal glucocerebrosidase expression in the brains of treated mice. These mice also lived significantly longer than untreated ones — 18 weeks rather than the usual 2 [1,6]. They had normal brain pathology and a follow-up investigation in macaque fetuses, which closely approximate humans, found that the therapy was effective with no serious side effects [1,6]. This study, described as “bulletproof” by W. Mark Saltzmann, the biomedical engineering department chair at Yale University, is the most sophisticated example of IUGT in animals to date [4]. Treated mice had greatly improved outcomes compared to untreated mice, and this experiment and other similar ones serve as proof of concept for IUGT. They give hope to hundreds of thousands of patients around the world with genetic diseases like hemophilia, ꞵ-thalassemia, and fetal growth restriction, which are all prime candidates for similar treatments [1,4].

However, the study did expose drawbacks to the technique. Treated mice performed worse than normal mice on movement tests, weighed less, and had higher levels of brain inflammation [4,6]. It is unknown whether production of glucocerebrosidase would be permanent and last throughout adulthood, which is critical for preventing neurodegeneration [4]. Gaucher’s is also rarely screened for in prenatal genetic tests, making it impractical to find mothers willing to undergo IUGT [4]. Looking deeper into the implications of IUGT, ethical considerations abound. Like postnatal gene therapy, there is a risk that the vector will insert DNA in the wrong place and trigger cancer, turning an already destructive disease into something truly catastrophic [1]. IUGT in particular compounds ethical concerns because it involves not just the fetus, but also the mother. Although the procedures for injecting gene therapy into the fetus are safe, they do risk infection, preterm labor, and miscarriage, similar to amniocentesis, a common procedure in which amniotic fluid is removed from the uterus to screen for diseases [1,15]. Moreover, if the gene therapy enters the mother’s bloodstream, it could provoke an immune response in the mother, leading to devastating outcomes [1]. Additionally, genetics is full of uncertainty. Not all genetic diseases are clearly visible in the fetal genome, and many are caused by multiple gene variations. This is a question of genotype-phenotype correlation: how likely is it that a given genetic mutation will result in life-threatening disease? [7]. Physicians would have to determine whether the mutation would result in a disease severe enough for IUGT and then communicate those uncertainties to the mother to allow her to make an informed decision [1]. Each step of this process is fraught with ethical considerations. As such, in 2018, the International Fetal Transplantation and Immunology Society (IFeTIS) recommended that IUGT only be considered for diseases in which the genotype and phenotype are highly correlated with clinical outcomes [12,13]. The news in 2018 of a Chinese scientist, He Jiankui, announcing that he had produced the world’s first geneedited babies underscored how we are treading on uncharted territory with IUGT [8]. Jiankui’s hope was that by editing genes to make HIV-resistant embryos, he could help people suffering from HIV/AIDS [8]. However, he faced swift condemnation by other scientists, including Jennifer Doudna, the co-inventor of the CRISPRCas9 technology he used, criticizing him for “ignor[ing] the basic medical mantra of ‘do no harm’ ” [14]. Jiankui was subsequently sentenced to three years in jail [8]. Clearly, IUGT has a long way to go before being considered scientifically effective and ethically safe enough to be implemented on a global scale. Even so, the field of IUGT is moving forward at a breakneck pace. The EVERREST Clinical Trial at University College London, an observational study that followed the pregnancies of women with severe early onset fetal growth restriction from 2014 to 2020, is moving into Phase I human clinical trials [4,9,12]. While gene therapy trials have primarily been conducted in the US and Europe, they are increasingly being conducted around the world, with China becoming the “principal” location for these trials [16]. IUGT would be a gamechanger for patients living with currently untreatable genetic diseases, with the potential to improve quality of life for people globally. At the same time, the technology’s ethical concerns merit rigorous regulatory oversight from institutional review boards, along with the establishment of standardized procedures and methods [12]. With proper caution and consideration of the implications of IUGT, however, the treatment will be transforming people’s lives before we know it.

FROM FACEBOOK TO FLO

PATIENT EMPOWERMENT THROUGH DIGITAL HEALTH APPS WRITTEN BY: SAHIBA BAVEJA

Patient-led initiatives are taking the world of digital health by storm, allowing patients greater transparency and control over their healthcare plans. Giving patients the ability to monitor their health, wellness, and medical spending from their smartphone has the potential to advance medicine into a more efficient space, with patients able to address potential concerns without having to even step into the office. Digital apps have the power to shift transparency in different aspects of healthcare, including women’s health, as well as improve the level of decision-making that patients have when it comes to prescription drug pricing. Women’s health is one area that has seen rapid growth in patient-centered digital usage. Flo, an Android and iOS app to support women on their menstrual cycle, recently raised $50m in a Series B funding round, allowing for greater personalization within the app, more accurate tracking, and expanded services [1]. Flo alone holds about 32 million active users, many of whom use the app to review trends in their menstrual cycle, review predictions on their cycle, and identify potential concerns that can be brought up to a doctor [2]. In promoting user-friendly apps like Flo and Clue, another menstrual cycle tracking app, patients are able to become more educated and responsible for their medical decisions, especially as apps like Flo can provide guidance regarding birth control options. The integration of health into users' digital lives contributes to the destigmatization of health topics that are often avoided, like menstrual and mental health. Knowing that you can switch seamlessly between Facebook and Flo creates an environment where conversation surrounding all aspects of health.

Prescription services are another realm where medicine has expanded to allow patients more transparency in their prescriptions, pricing, and options. GoodRx is a free-to-use telemedicine app that allows patients to find discounts & coupons for their prescription drugs [3]. As of August 2021, GoodRx had an estimated 7.5 million users, but the frequency of usage is dependent on frequency of prescriptions. As the most downloaded medical app on the Apple App Store in 2021, it is largely responsible for the decisionmaking aspect of health & wellness that patients have previously lacked. Such decisions include substituting branded drugs for generics if coupons are available, working with providers to select higher quality/cost drugs, and transparency regarding spending, thanks to advanced technology that allows for drug pricing consolidation. In the past, drug pricing has been a topic confined to the doctor’s office, if affordability is even something that your provider discusses, but with the introduction of digital apps, we have the power to integrate the decisions in your daily lives and better understand how to maximize value per price point. A recent study in Israel found that promotion of different drugs through direct-to-consumer (DTC) marketing allowed patients to feel more empowered about their prescriptions, and encouraged patients to inquire about different drug offerings that might be more affordable [4]. While beneficial outcomes are extremely important, patient empowerment is becoming increasingly valued as we see the growth of more accessible platforms like apps and DTC marketing.

While we see more and more apps like Flo and GoodRx appearing, it’s important to recognize that these digital advances disproportionately benefit certain groups. Though advancements in the new age of medicine are geared towards patient empowerment, there is still a lack of geographical advancement due to limited smartphone access on a global scale. The Iron Triangle of Medicine represents the tradeoff between quality, access & cost, and is used as a framework for evaluating different treatments [5]. In the case of patient-centered apps, we see more advanced and high-quality technology limiting the patients who can actually use it. In 2022, only 54% of Indian citizens owned a smartphone, and in 2022, around 57% of Chinese citizens held smartphones []. With two of the largest countries only having just over half of their populations hold access to smartphones, one cannot say that these patient-driven initiatives contribute to a global advancement of medicine. While we allow for apps and technologies to grow in quality and lower costs, we inherently limit access at a global scale.

The National Health Service (NHS) of England has seen over 16 million citizens engage in their digital health initiatives, most notably in digital apps that allow users to view medical records and directly connect to telehealth appointments [6]. The primary goal of this app was to allow patients to have greater access and control over their medical decisions, and a review from the NHS in November 2021 confirmed that the app did so. The key findings report claims “52% said they could see [the medical information that] they were looking for,” including test results and General Physician notes [7]. While the multi-payer system of the United States makes a consolidated medical information app more difficult to implement, the findings from the NHS show that the work of apps like GoodRx and Flo are accomplishing their goals. Does giving up your 64GB storage for the top medical apps make you as qualified as your peers studying for the MCAT and your family’s longtime physician? Probably not. These apps have shown that the inefficiencies and information asymmetry in the world of healthcare can be minimized, but as we shift into the new age of medicine, digital apps must find a way to make their services more accessible, and target ways to improve health outcomes.

CAR-T in Canines: The Future of Cancer Treatment in Dogs Written by: Austin Pothikamjorn Designed by: Elaine Sun Introduction Canine cancer is a pressing issue that affects dogs all around the globe. Cancer is very common in canines, affecting one in every four dogs; 50 percent of dogs over 10 years diagnosed typically die. [1] Its lethality is especially concerning given its prevalence on the worldwide scale. A University of Cambridge study reports canine transmissible venereal tumor (CTVT), an infectious cancer to be endemic in 90+ countries.[2] With this, cancer is the number one killer of dogs, even ahead of trauma-related deaths.[3] Despite these alarming rates, the amount of resources and funding towards canine cancer research is significantly behind those in humans. The latest cancer treatment innovations in humans have been sluggish to translate to the dog world. Instead, canine cancer is typically treated with chemotherapy which, although not as debilitating as in humans, causes weakening side effects and lowers the dog’s quality of life. In order to provide more effective cancer treatment for dogs, increased funding and resources should be provided to canine oncology research, allowing experts to explore more novel cancer treatment advancements. One treatment that deserves particular attention is CAR T-cell therapy, which has seen success in human trials and is beginning to be tested in dogs. By examining the detrimental effects of canine cancer and lack of respective research, this paper will draw

FIG. 1 CAR T-cell attacking cancer cell

attention to the breakthrough science of CAR T-cell therapy and its implications for the future of canine cancer treatment.

Possible Solution: CAR T-cell Therapy

Once bound, it expels signaling proteins called cytokines, which inflict harmful inflammation on the target cell, and signals the rest of the immune system to eliminate the

CAR T-cell therapy, a type of cancer immunotherapy, has recently seen positive results in human trials globally. The first CAR T-cell therapy was approved by the Federal Drug Administration (FDA) in

potential threat. This antigen-receptor binding complex is highly specific in that each antigen can only bind to one

2017.[4] Other countries, including China, Australia, and Singapore followed suit in 2021.[5] The treatment aims to alter a type of white blood cell in the body, called T cells. The job of T-cells is to

particular receptor. In CAR T-cell therapy, the receptors on an individual’s T-cells are modified to specifically recognize a cancer cell’s antigens. These modified receptors are referred to

recognize and attack foreign particles that enter the body. T-cells contain receptors that bind to protein structures (antigens) on the

as chimeric antigen receptors (CARs). With this technology, scientists can equip T-cells to attack many different kinds of cancer including lymphoma and leukemia. [6]

surface of those cells.

The preparation for CAR T-cell therapy is as follows: 1. T-cells are obtained from the patient by leukapheresis 2. In the lab, T-cells are genetically altered to express the chimeric antigen receptor 3. The cells multiply 4. T-cells are reintroduced back into the individual 5. T-cells detect and attack cancer cells

Not only should these results propel its research in dogs, but it also acts as a reminder to the potentiality of countless treatment options that could arise given appropriate funding and attention. CAR T-cell therapy in canines Though still relatively novel, CAR T-cell therapy has been investigated for quite some time and its earliest forms have been FDA approved for over five years. Yet, explorations into the implications of CAR T-cell therapy in canines are mainly foundational and still in their preclinical stages. Some early tests performed in vitro aim to test the feasibility of modifying canine T-cells, highlighting how far behind its research is. Nevertheless, studies confirmed stable canine CAR T-cell generation is attainable and functioning as intended in destroying cancer cells.[10,11] One study, specifically, reported that tested canine CAR T-cells released more pathogen-killing cytokines to remove cancer cells and exercised great ability in removing them.[12] Significant inflammation in the cancer cell inflicted upon by the T-cells and cytokines, causes the cancer cell to die. Various other scientists have performed similar experiments, which have also shown canine T-cell effectiveness. The tests demonstrate that canine CAR T-cells, similarly to humans, may undergo widespread multiplication, which is an essential basis for CAR T-cell treatment.[13] This mechanical similarity between the two species suggests the translational potential, and should be a key indicator to researchers and investors of the feasibility of bringing this technology for use in dogs. Another notable study was able to examine the performance and safety of CAR T-cell therapy in a canine subject. After CAR T-cell infusion, there were zero serious side effects besides a mild fever. Following the treatment, the researchers reported decreases in cancer B cells, suggesting CAR T-cell activity. Researchers at the University of Pennsylvania have even attempted infusing human T cells into dogs with help of CRISPR technology.[14]

FIG.2 Graphical Overview of CAR-T cell Therapy

Though side effects do exist, such as headaches, fatigue, and dizziness, the treatment has shown great success. In a study performed in 2020, more than 85 percent of the sample children diagnosed with acute lymphoblastic leukemia (ALL) had complete remission and more than half of those remained cancer free after one year of CAR T-cell therapy.[7] Nine out of ten individuals whose cancer didn’t respond to other cancer therapy or didn’t experience complete remission had full remission in another study.[8] In addition to its effectiveness, CAR T-cell therapy boasts many other advantages compared to traditional methods. The treatment itself requires a shorter inpatient care

Although current studies are still in their alpha stages, the results indicate that CAR T-cell treatment can be applied to canines.The resources and research power is available, but require substantial funding for these experiments to begin seeing clinical trials and, ultimately, approval from the government health institutions. Dogs are an invaluable part of a vast majority of households across the world. It is time that the research towards their well being reflected it.

period (a maximum of two weeks versus chemotherapy’s multiple month duration) and is a superior long term method. The modified T-cells continue living in the body, so if cancer cells do reappear after remission, they will still be attacked. MD Anderson reports about 42 percent of lymphoma patients continued to be in remission 15 months after treatment.[9]

TELEHEALTH: A CALL TO ACTION WRITTEN BY SARASWATI SRIDHAR DESIGNED BY JULIA GERBINO The COVID-19 pandemic upended many of our day-to-day functions, especially in healthcare. One field of healthcare that has experienced tremendous growth since the start of the pandemic is telehealth, which is defined by NEJM as “the delivery and facilitation of health and health-related services including medical care, provider and patient education, health information services, and self-care via telecommunication and digital communication technologies.” Telehealth encompasses the use of varying tools, including video conferencing, remote patient monitoring, mobile devices (also known as mHealth, and remote exams, and “store and forward” electronic transmission [1]. According to an analysis conducted by McKinsey, telehealth was used 38 times more during the pandemic than before. This has also been coupled with more positive consumer and provider attitudes towards telehealth. These trends are largely dependent on the field of medicine being practiced, with psychiatry being the most common type of care sought out on telehealth platforms. According to a survey conducted by McKinsey, 40% of healthcare consumers who responded to the survey see telehealth as an option they would continue to use for their care in the near future. This same study showed that 40-60% of respondents were interested in a broader suite of telehealth tools and services. From the standpoint of the provider, 58% of physicians viewed telehealth in a more favorable light, compared to only 11% of physicians at the beginning of the pandemic and 57% of physicians preferred to continue virtual appointments [2]. Moreovers, studies have shown that employers prefer telehealth-based care, largely thanks to its lower costs and association with increased productivity in workers. Because the presence of Covid-19 and protection measures against the virus have now become ubiquitous, consumers’ view of telehealth is likely to evolve, causing it to become embedded into both individual healthcare choices and national/ global markets.

FIG. 1. Variation of Telehealth Claims Across Specialties

Regulatory changes, such as an expansion of reimbursable telehealth codes and a tripling of venture capital available in this field, have been instrumental in both the evolution and proliferation of virtual healthcare and business models. Total investment in the digital health market in the first half of 2021 equaled $14.7 billion; this increase in investment continues to expand, with a projected annualized investment of $30 billion by the end of 2021. At the global scale, the telehealth market is expected to be worth about $224.8 billion by 2030 [3]. While reimbursement may have been the common standard for physician pay prior to the pandemic, the rise of telehealth services is likely to cause an incorporation of data transmission and communication into the overhead of the costs of conducting a medical practice.

Since the advent of the pandemic, 48 states have decided to cover video conference appointments through Medicaid. In addition, 19 states have approved Medicaid for Remote Patient Monitoring (RPM). CMS has approved more than 80 new telehealth-based services and incorporated standardized risk assessments into telehealth that is supported by the platform [4]. McKinsey also estimates that 20% of all healthcare spending could eventually become virtualized. Furthermore, several states have created telehealth parity laws that compel private payers to cover services that are present in both in-person and virtual care [2]. Although the full accommodation of telemedicine in the healthcare system has ample room for growth and improvement, healthcare providers and entities have been flexible and responsive to the lack of in-person care during times of high Covid transmissibility.

FIG. 2. Method of appointment visits

As referenced previously, while telehealth used to be a tool predominantly used in North America, the use of international collaboration in telehealth expanded during the pandemic, mostly in higher-income countries. This can be attributed partly to rapid development of IT, artificial intelligence, and telecommunications infrastructure in these regions [5]. While telehealth is more likely to be used for the assessment and treatment of chronic conditions in the West, it is more often used for acute access to expertise in Europe and Asia. It can also significantly reduce the financial and logistical burden of receiving care in developing countries, while increasing access to care for underserved communities in developing countries [6]. However, telehealth does not come with its own barriers and disadvantages. For example, because it is a relatively new aspect of healthcare, privacy and cybersecurity regulations are under-developed. Any security breaches, large or small-scale, can result in significant financial losses for both private practitioners and large managed-care organizations. Minimizing and managing data security risks would likely require an intricate multi-sector framework to establish an overarching culture of security.

Other barriers in the expansion of telehealth to an international setting include a lack of uniform international certifications and standards, cultural and language barriers, lack of awareness, and reduced internet access in underserved communities. It has also led to major changes in interaction between multiple health practices and entities; earlier, government-sponsored programs utilized “hub” models where large amounts of information are collected from multiple small entities and sent to a larger, centralized entity such as a hospital. However, telemedicine has led to more peer-to-peer interactions, at times on an international level, between individual practices and companies. One notable example of this type of peer-to-peer interaction is the collaboration between Ontario Telehealth Network in Canada and Arizona Telemedicine Program in the United States [7]. Telehealth also faces challenges in data integration across multiple role-players including both patients and physicians, integration of virtual elements into a physician’s routine practice, increasing awareness of telehealth offerings, and transitioning from fee-for-service-based care to value-based care.

FIG. 3. Potential of telehealth

In order to maximize telehealth’s potential, various goals need to be met; these include successfully integrating telehealth into conventional practice, expanding access to telehealth in underprivileged communities, and reinforcing technological foundations. This can be largely accomplished with creating quantifiable methods to value telehealth services using clinical outcomes, prioritizing consumer integration by expanding virtual health options beyond what it has included during the pandemic, regularly developing and incorporating new product designs to meet consumer needs, reinforcing physicians’ and hospitals’ big data skills and capacities, and developing and prognosticating scenarios for the growth of telehealth in the future during the pandemic [2]. The ultimate aim of fully harnessing telehealth’s potential is to make healthcare more efficient by increasing access to healthcare for underserved populations especially during a global pandemic, improve patient experience and compliance, and improve health outcomes.

IN YOUR POCKET:

DIAGNOSTIC MEDICAL DEVICES WRITTEN BY: OM GANDHI

edical technologies have had groundbreaking impacts on healthcare and patient outcomes. From a computerized tomography scanner that meticulously images an internal target through a series of angled X-rays to pacemakers that help control irregular heartbeats, innovations in the medical technology industry have led to higher life expectancy, increased cost savings, and more precise diagnoses[1]. However, these benefits have not been realized by all corners of the world. Accurate diagnostic technologies like magnetic resonance imaging (MRI) or angiogram machines are large, expensive, and bulky. For example, the price of MRIs ranges from $150,000 to $3,000,000[2], and ultrasound machines can cost up to $200,000[3]. Transportation and assembly of these machines is also arduous and costly— for instance, an MRI can weigh up to 80,000 pounds, and the MRI’s magnet must be “supercooled” to approximately –460°F using liquid nitrogen or helium[4]. This creates major accessibility issues for smaller clinics and remote communities that wish to provide a high standard of care. In fact, according to the Organization for Economic Cooperation and Development (OECD), approximately 70% of the world has little or no access to MRIs, with 4.7 billion people lacking access to any form of medical imaging[5]. Fortunately, inventions and innovations that address the barriers to diagnostic medtech accessibility have been brought to market.

One innovation that increases the accessibility of MRIs is Hyperfine’s “Swoop” Portable MRI. It utilizes low strength magnetic fields in a compact form-factor to provide imaging data directly to a wireless tablet. It can be plugged into a standard electrical wall outlet, and it uses 35 times less energy than a traditional MRI. As with many portable versions of established technologies, the major concern with portable MRIs is their accuracy– whether or not they can render images as medically useful as those produced by high-field, superconducting MRIs[6]. Although the imaging data isn’t as sharp as the gold standard, it received FDA approval as the first bedside MRI scanner in 2020, and a recent study has shown that it can help to accurately spot hemorrhagic stroke with 96.6% specificity. Furthermore, advancements in deep learning can allow for future optimization of the images. Nonetheless, at its current level of accuracy, Swoop is still effective for base-level consideration. Swoop benefitted from the value created by Hyperfine merging with Luminal Sciences, a company that develops technology that measures factors like intracranial pressure, via a $580 million reverse Special Purpose Acquisition Company (SPAC) merger[7,8].

Swoop is not alone in developing a portable MRI. Researchers at the University of Hong Kong have developed a compact ultralow-field MRI scanner. This technology utilizes a samarium-cobalt (SmCo) magnet, and it builds upon standard fluidattenuated inversion recovery and diffusion-weighted imaging methods to produce a scan. One key issue with this portable technology is the presence of electromagnetic interference (EMI), but the researchers also built an AI model to distinguish between EMI and MRI signals, effectively removing the interference. Since the portable MRI inevitably produces lower quality images (because low field strength leads to lower magnetic resonance strength), like Swoop, this technology can be used as a preliminary diagnostic tool. In other words, the technology can identify which patients need a closer diagnostic look, thus streamlining clinic workflow and reducing wait-times[9].

One innovation that increases accessibility of ultrasound machines is the Butterfly iQ+, a system produced by Butterfly Network that utilizes semiconductor technology and artificial intelligence to produce and store accurate imaging data. The best part? The hand-held probe can fit in your pocket and connects directly to your phone and the cloud.

Here’s how it works: A traditional ultrasound relies on tiny, vibrating piezoelectric crystals to send sound waves through your body and record the waves that bounce back. Butterfly iQ+, on the other hand, produces sound waves using 9,000 tiny drums carved into a semiconductor chip via a proprietary “Ultrasound-on-Chip” technology. The data is immediately relayed to an application on a mobile phone or tablet for a real-time view of the imaging, and then the data is stored on the cloud and available to share easily across platforms. Butterfly Network has also developed software called “Blueprint” that integrates the ultrasound data from Butterfly iQ+ into clinical and administrative infrastructure to create a more efficient workflow[10, 11]. This technology has been impactful for patient care. The Butterfly iQ+ technology has become FDA approved for 14 different conditions, and costs $2,399 USD compared to a traditional ultrasound machine which starts at $20,000 and goes up to $200,000. The portable form factor also allows it to be used for in-home care and veterinary medicine while also serving lowresource, remote communities at both a domestic and global scale. But the impacts of this technology span beyond increasing access to ultrasounds in remote communities. Butterfly also opens the doors for novices to use the technology since their ultrasound isn’t restricted to sonographers alone. Butterfly’s TeleGuidance coupled with a user-friendly interface allow for healthcare practitioners to virtually assist novices at the bedside and even control the ultrasound remotely. This creates a seamless, one-stop digital health solution, facilitating the highest standard of care regardless of location or healthcare proficiency[12]. The COVID-19 pandemic has propelled innovations in the biotechnology, healthcare, and medical device industries. The pandemic’s severe impact on the ability of hospitals, clinics, and practitioners to see patients in a clinical setting has accordingly stimulated innovations that focus on portable medical technologies that can be brought directly to patients. The MRIs and ultrasounds mentioned above have all decreased costs and increased convenience. It is therefore no surprise that firms which produce portable medical equipment have seen growth and increased venture funding, as investors and entrepreneurs became aware firsthand of the importance of biotech solutions in tackling public health crises. Overall, portable medical technologies are currently undergoing an unprecedented research revolution. With luck, they will change the clinical landscape for the better forever.

ARTIFICIAL INTELLIGENCE THE MACHINE OF GLOBAL HEALTH WRITTEN BY: SHAHANA BANERJEE

AI is marking the next phase of industrialization – and every industry knows this. However, only 5% of global enterprises have the capital ready to expand AI across borders and make it accessible to the organizations that can reap its benefits [1]. Making scalability a linchpin, it will take a concerted effort to launch AI equitably in healthcare and fully cultivate the advantages of its proven innovation. Without scale, the drive of AI may not succeed, especially in low- and middle-income communities, which have the most to gain from the advancement in healthcare services. Through deep research and policies regarding healthcare accessibility, we can better understand how machine learning can address health disparities between LMICs (low-to-middle-income countries) and HICs (high income countries) to inform the future design of AI innovation at the individual, community, health care systems, and provider levels to proselytize health equity [2].

PAGE 01

AI is ushering a new era of healthcare quality & efficient breakthroughs

With payment structures evolving, patient demands accelerating, and volumes of available data growing unexpectedly and rapidly, AI has gradually been recognized as the machine that will drive improvements across the healthcare continuum. From interfacing the brain and the machine to enabling the next generation of radiology tools, reducing the burden on Electronic Health Record use to transforming the makeup of bedside tools, AI is ushering in a new era of healthcare quality and efficient breakthroughs in patient care. It’s already begun to revolutionize both the science and delivery of healthcare, and we may not have even realized it yet.

How AI Is Serving The Gaps One of the more critical conversations that has been brought up regarding the implementation of AI is its implications on underserved populations. Developing countries have been seeing a lack of trained healthcare professionals, such as radiologists and ultrasound technologists, which has impacted the quality of longterm care. AI has been identified as one of the tools that can help relieve the strain on global healthcare systems that are burdened by deficits of qualified staff. Tasks typically allocated to humans, such as diagnosis, can now be controlled by AI. The potential to expand access to global care is prodigious. For example, AI tools can diagnose tuberculosis in chest x-rays at a precision rate that is competitive to that of human-conducted diagnoses such as 88.0% precision, 87.0% sensitivity, and 87.0% accuracy as recorded in an AI machine learning model [3]. Experts say AI in this form can be deployed through an app that reduces the strain of the lack of diagnostic radiologists in LMICs [4].

In 2020, a few hospitals in India used the, government-subsidized app called qXR to scan patient x-rays and assign a risk score if TB was detected. qXR detected TB with an accuracy of 95%, according to the appdeveloping company’s chief executive, Prashant Warier. However, the TB program may be less precise in the US or westernized European countries compared to India [5].

Global Accountability While deriving such a machine is truly transformative, it’s essential to consider that each community and ethnic group is likely to have different physiological factors and environmental elements impacting the path of disease. As explained by Jayashree Kalpathy-Cramer, Assistant in Neuroscience at Massachusetts General Hospital and Associate Professor of Radiology at Harvard Medical School, “[t]he course of a disease and population affected by the disease may look very different in India than in the US…” [4]. When evaluating the scalability of artificial intelligence and its influence on healthcare accessibility, especially in administering to LMICs, the AI data and its relative policies must represent a diverse population and disease expanse. Relying on a single population will inevitably detract from the care of others. While AI is an advanced technology, we can see the necessity of testing for benefits in heterogeneous communities, even through common medical devices. In 2007, a study testing pulse oximeters concluded that the devices can overestimate arterial hemoglobin saturation at low SaO2 in patients with darker pigmented skins, translating to some patients not receiving the proper amounts of supplemental oxygen needed to avoid damage to vital organs [6]. Disparate statistics like these in even the earliest-patented global medical innovations elucidate how important it is for AI to go beyond narrow metrics and monitor representative global populations.

INCREASES IN AI INVESTMENT DURING 2020 AND THE COVID-19 PANDEMIC

Figure 1. Even during the COVID-19 pandemic where most industries reduced their total expenses to stay afloat, many companies actually increased their AI investments in 2020

Political-Framework Solutions While we live in such an unequal world, where the US is

Presenting political leaders with such research-driven

seeing exponential growth in the incorporation of AI

policies can ensure that people who can benefit the

with reduction in human intervention in healthcare,

most from AI will not be the ones excluded from its

and some LMICs are left to detrimental environments

utility [7]. By balancing the scientific and political

that are undoubtedly affecting their citizens’

advocacy of artificial intelligence, stakeholders at

livelihoods, what solution can be provided to ensure

global healthcare forums, like the World Health

that the machine is eliminating these global health

Summit, can understand how AI progression and

disparities? Frankly, this issue isn’t a lack of

global-based policies can be scaled to effectuate a

innovation, but rather a lack of accessibility. In such a

less-burdened, more technological, and more globally

competitive system, the only way to win the battle of

equitable tomorrow.

innovation discrimination against communities that desperately need such engines is to fight the science and political conflicts. Identification of health gaps is critical, but it doesn’t stop there–policies aligning with AI implementation in vulnerable communities should be tried and tested to confirm how it can change the world.

FEM TECH WRITTEN & DESIGNED BY FARHAANAH MOHIDEEN In the past three decades, women's health has emerged as a high growth target for venture capital (VC) investment, with products and services in this sector commonly referred to as “FemTech.” The term FemTech has come to describe the fast-growing subset of medical products and services dedicated to servicing health needs historically associated with cisgender women[1]. As Paljit Sohal, principal consultant at Frost & Sullivan, explains, “women’s healthcare issues are coming to the forefront with an increased focus to differentiate care provided for the healthcare issues specific to women, which no longer fit into the frameworks of men’s health[2].”

Introduction Coined in 2016 by Ida Tin, co-founder and CEO of the menstrual health app Clue, the term FemTech comprises sexual health, pregnancy care, menstruation, and menopausal care products and services. Figure 1 below illustrates a high-level market map of the industry’s eight largest service categories, however many firms like Maven Clinic provide services across caretypes[3]. FemTech encompasses not only technologies seeking to service conditions unique to women (e.g., menstruation, pregnancy, menopausal care) but also existing technologies design with female anatomy in mind. For example, Zimmer Biomet (ZBH), a global medical device company, set to launch its Gender Solutions high-flex knee–the first knee replacement of its kind designed specifically with female anatomical considerations in mind. In 2018, Tin elaborated: “Investors can say, ‘I have four FemTech companies in my portfolio’ instead of, ‘I have a company for women peeing in their pants.’ That’s hard for a male investor to say[1].”

Maven Clinic: FemTech’s First Unicorn Maven Clinic is the first FemTech company to reach unicorn status, that is, to exceed a valuation of $1 billion as a privately owned startup[4]. Launched in 2014, Maven Clinic is a virtual clinic that specializes in women’s health and family planning and has since supported over 10 million users. The company offers 24/7 access to individualized telehealth services delivered by personal care advocates and over 30 provider types[4]. A Maven member in their final trimester of pregnancy, for example, may have a care team composed of an OBGYN, nutritionist, mental health provider, and lactation consultant.

In February of 2021, the company began Maven Rx, a members-only fertility drug delivery program made possible through partnerships with pharmacies Alto and SMP[5]. As Sonia Millsom, chief commercial officer at Maven, explained, the new delivery program could address two of the most challenging aspects of fertility support: high costs of treatments and inability to manage the complexity of selfadministered injections[5]. A key driver of Maven’s success is the company’s strategic partnerships with payers. Maven Clinic sells its services to both individuals and employers, in a B2B2C model. Employers offering Maven services to their employees seek to both attract and retain top talent through the clinic’s evidence-based claims: 70% of employees who use Maven feel more productive at work, while 80% of members are more loyal to their employers after using the service[6]. By offering access to holistic, hands-on care to employees while they are off the clock or on parental leave, employers can

see longitudinal returns from their human capital. Conversely, with trends showing increasing competitiveness in employee benefit packages, health and parental support can be a deciding factor for prospective hires when selecting an offer. With a recent partnership with Fertility Partners, a Canadian fertility services provider, Maven now operates in over 70 countries[7]. The remarkable scale of the FemTech giant points to future global commoditization of critical women’s health services, giving millions of women new access to preventative and interventional care.

Lia Diagnostics: A Disruptive Innovation Lia is the world’s first biodegradable, flushable, and FDA-cleared home pregnancy test[8]. By replacing clinical lab tests, the original at-home pregnancy test was an incredible disruptor, delivering revolutionary privacy and agency to women. Still, the plastic hardware of present-day pregnancy tests cannot be flushed or recycled, unavoidably leaving material evidence of a used test. Developed to maintain testing privacy while also reducing plastic landfill waste, Lia is designed from the same natural fibers found in most toilet paper to be flushed or composted after use. The composable device was developed using a custommade dispensing technique by which the test remains rigid when used before then breaking down like toilet paper when flushed–all while maintaining 99% accuracy[9]. While Lia has received FDA approval for US sales, the product’s affordability and compactibility have widespread implications for global access. An early, positive pregnancy result may be the catalyst for prenatal health monitoring to ensure healthy progression of a pregnancy and enable early interventions to potential complications. By cutting the costs of standard tests in half, Lia may be the ideal candidate for humanitarian distribution efforts addressing global healthcare deserts.

FemTech's Future It is estimated that over 80% of healthcare decisions are made by women, yet satisfying women’s health needs continues to be a daunting challenge for today’s female-centric startups to take on[10]. The growing traction of FemTech, however, be it from unicorns like Maven Clinic looking to rapidly expand or innovations like Lia carving out new market niches, means exciting possibilities for lowering barriers to care access. With continuing progress towards equitable care for all, FemTech founders, funders, and communities of activism may be the key to closing healthcare’s glass ceiling. 22

RENEWAL

F THE "PLURI"POTENTIAL OF YAMANAKA A C L T O R S WRITTEN BY: KYNE WANG DESIGNED BY: CHLOE YUE

arge strides in quality healthcare—from vaccines to antibiotics—may have prolonged the average life expectancy but have also given way to chronic,

degenerative diseases. These diseases often accumulate, where the average 80-year old male can have up to 4 or 5

diseases concurrently [1]. When we age, cells in our body age, losing functionalities and becoming more vulnerable to such diseases. Is there a way to live longer without these chronic illnesses wreaking havoc?

Immortality and time travel have always been a concept of fantasy. Movies, comics, even classic literature reveal that aging has been something humanity has never had a grasp of, so when Shinya Yamanaka announced that he discovered a way to “reverse aging”, the scientific community stared in awe. While in theory, Yamanaka factors are able to reverse

cells back to their embryonic stem-cell stage, there is still a long way to go before this breakthrough enters the market. Dr. Shinya Yamanaka is a Japanese physician and researcher who was

Differentiated Cells

awarded the Nobel Breakthrough Prize in Life Sciences in 2012 for his discovery of a specific number of genes that are able to reprogram a cell into its immature stem cell state [2,3]. These cells are pluripotent, which means they are able to subdivide into various cell types. This was termed Induced Pluripotent Stem Cells (iPSCs, for short).

YFs OCT4 SOX2 KLF4 C-MYC

Full REprogramming

Partial reprogramming

iPSCs are like Embryonic Stem (ES) Cells, the starting point of life [4]. Embryonic differentiation is where these cells specialize into different tissue structures and, eventually, organs [4]. Once stem cells differentiate, their genetic material will upregulate lineage-specific genes [4]. These lineage-specific genes are the identity of the cell, making them—up until this point—irreversible [5]. The research into iPSCs revealed their ability to reverse the differentiated cell back to its pluripotent state.

iPSCs were discovered when Drs. Yamanaka and Takahashi investigated 24 transcription factors that played a vital role in characterizing embryonic stem cells [3]. They tested each of the 24 genes in mouse embryonic fibroblasts (the most common differentiated connective𝛃ge o/ 𝛃 geo tissue cell) from the Fbx15 mouse line [3]. The Fbx15 gene in ES cells demonstrated resistance to high concentrations of the G418 antibiotic, which would be seen as an indication of pluripotency [3]. Using the experiment results from this mouse line, Yamanaka and Takahashi were able to narrow down the 24 genes to four key transcription factors: Oct 4, Sox2, Klf4, and c-Myc (OSKM) [3].

Epigenetically "younger" that retain original identity

Epigenetically "younger" cells that loses identity, forming teratomas

FIG. 1. Partial and Full Reprogramming of Differentiated Cells

For the next decade, the properties of OKSM, now termed “Yamanaka factors,” were being further investigated. However, research is revealing that the overexpression of the four transcription factors (specifically cMyc) often led to a complete reversal to ES cell pluripotent state, leading to potential tumor development (teratoma formation) and the eradication of a cell’s identity [6].

To address this, some studies are finding that even a single short-term expression of OSKM can result in epigenetic, transcriptomic, and metabolomic changes to reverse markers of aging and prolong lifespans in mouse models [6, 7]. Others are hailing partial reprogramming as an effective source for cellular and physiological amelioration without tumor development, where only OKS would be used. Moving forward, the community can look forward to some potentially groundbreaking applications of iPSC technology that leverages its ability to reverse the aging of a cell: disease modeling and clinical applications such as cell transplantation. iPSCs have already begun and will continue to enhance the accuracy and effectiveness of disease modeling [8]. Using patient-specific iPSCs, researchers can direct specific differentiation to study diseases or a drug’s efficacy in various organoids [8]. Using iPSCs can also reduce potential differences between the animal models conventionally used pre-clinically, increasing efficiency and accuracy in drug development that will profoundly shape medicine worldwide.

Target validation

Autologous therapy

New drugs Healthy specialized cells Organoids

Activity readout

Drug screening

Somatic cells

OCT4 SOX2 KLF4 C-MYC

Diseased specialized cells

Directed differentiation

Chimeras

Repaired iPSCs

Patient-specific iPSCs Directed differentiation

Gene correction

FIG. 2. Outline of iPSC applications in cell-based therapies and drug development

Another potential application of iPSCs is cell transplantation.

Eye Institute are spearheading phase 2 clinical trials to evaluate

Conventional transplants involve transferring tissues or

the safety of iPSC-based therapy to treat “dry” form age-

organs from a donor [9]. With a national shortage of organ

related macular degeneration—an age-related illness with no

supply and the risk of hyperacute rejection—where the host’s

cure [13]. In addition, Life Biosciences currently has two OSK

immune system attacks the transplanted organ—iPSCs have

(no c-Myc factor) compounds in development, with one in

enormous potential for revolutionizing organ and cell

preclinical studies [14]. The lack of the c-Myc factor is being

transplants [9,10]. In February 2022, a woman appeared

tested for oncogenic potential at varying expression periods

cured of HIV after stem cells from a family member and

[14]. However, Altos Labs drew a lot of attention after raising a

umbilical-cord blood from a non-related newborn were

$3B, fueling cellular rejuvenation programming and being

transplanted [11]. The emphasis on minimizing rejection

hailed as the largest seed investment ever [15,16]. Investors

played a vital role in searching for donors for the HIV

ranging from industry veterans to Jeff Bezos back a team

therapy. In the future, there may not even be a need to

consisting of GSK’s Chief Scientific Officer, the aforementioned

search. With iPSCs, genetic modifications to autologous cells

Nobel Laureate Shinya Yamanaka, and Spanish biochemist

—cells from the patient themself—mitigates the risks of

Juan Carlos Izpisúa Belmonte—a prominent figure in

rejection when undergoing therapy [8,9]. In the case of HIV

researching methods to develop Yamanaka factors [15,17].

itself, transplants usually are sourced from individuals with the Δ32 variant of the CCR5 co-receptor, which confers

In the next decade, one can expect extraordinary strides in

resistance to HIV [12]. In the future, gene editing in iPSCs to

iPSC research. Further refinements of Yamanaka development

induce the Δ32 mutation may make autologous therapy a

and use, breakthroughs in research, and venture interest may

feasible path to curing the incurable.

fuel the transition to a sustainable technique that can be applied across a plethora of therapies and treatments. The

Finally, iPSCs have remarkable potential in the clinical

immortality of pursuing scientific innovation will continue to

setting. Currently, there are several pipelines investigating

push for the applicability of Yamanaka Factors into medicine,

clinical applications of iPSCs. Researchers at the National

revolutionizing therapeutics across the world. 24

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Wharton Undergraduate Healthcare Club