MN Physician February 2017

MINNESOTA

FEBRUARY 2017

PHYSICIAN

THE INDEPENDENT MEDICAL BUSINESS JOURNAL

Volume XXX, No. 11

Reforming health care reform A look at proposed options

BY STEPHEN WARCH, JD, AND LINDSAY MCLAUGHLIN, JD, MPH

P

resident Donald Trump and a Republicancontrolled House and Senate are in the process of repealing the Affordable Care Act (ACA). At the time of this writing, both the Senate and House approved a budget resolution to begin the repeal. This article examines what lawmakers can legally change and potential policy proposals that would change the future of the health care industry.

What can lawmakers legally change under the ACA?

Precision medicine Translating bioscience into individualized clinical practice

BY DAVID R. BROWN, MD, FACE

T

he foundation that will truly transform health care to meet the individualized needs of patients rests on two concepts: 1) human biology is complex, and 2) medicine is information science. Precision medicine (P4), coupled with the application of molecular-based technologies and digital information to define personalized biologic expression, will be the disruptive innovation medicine has been striving for. P4 will have an impact on diagnostics and therapeutics, as well as enhancing the etiology, pathogenesis, and prognosis of clinical conditions. This revolution in health care is driven by the simultaneous emergence and advancement of multidisciplinary digital Precision medicine to page 164

On Jan. 12, 2017, the Senate passed a non-binding budget resolution that instructs committees with jurisdiction over the ACA to draft repeal legislation.

The House passed the resolution the next day, allowing Congress to start the “reconciliation� process. This process requires just 51 votes to pass a measure in the Senate, not the usual 60 for a Reforming health care reform to page 184

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FEBRUARY 2017 MINNESOTA PHYSICIAN

FEBRUARY 2017

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Volume XXX, Number 11

WWW.MPPUB.COM

COVER FEATURES Precision medicine Translating bioscience into individualized clinical practice

Reforming health care reform A look at proposed options

By Stephen Warch, JD, and Lindsay McLaughlin, JD, MPH

By David R. Brown, MD, FACE

DEPARTMENTS CAPSULES

10

MEDICUS

13

Treating obesity A multidisciplinary approach

INTERVIEW

14

By Charles J. Billington, MD, and Daniel B. Leslie, MD

Bouncing back from burnout

CHRONIC DISEASE

32

Corey Martin, MD, Buffalo Hospital

PROFESSIONAL UPDATE: 28 GENOMICS CFTR modulator therapy New hope for treating cystic fibrosis

By Terri Laguna, MD, MSCS

RESEARCH

36

Autism and genetic discoveries The search for clinical biomarkers

By Madhumathi Rao, MD, MS, and Suma Jacob, MD, PhD

SPECIAL FOCUS: MEDICAL DEVICES Treating patients who have medical devices What to keep in mind

20

By Stuart Steichen, DO New assistive devices Meeting the patient’s needs

22

By Gary Goldish, MD; Eric Nickel, MS; and Andrew Hansen, PhD The hybrid closed loop therapy system A step closer to an artificial pancreas

26

By Amy B. Criego, MD; Anders L. Carlson, MD; and Richard M. Bergenstal, MD

PUBLISHER

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Mike Starnes, mstarnes@mppub.com

EDITOR________________________________________________ Lisa McGowan, lmcgowan@mppub.com ASSOCIATE EDITOR_____________________________ Richard Ericson, rericson@mppub.com ART DIRECTOR_______________________________________Sunshine Sevigny, sunny@mppub.com OFFICE ADMINISTRATOR______________ Amanda Marlow, amarlow@mppub.com

Minnesota Physician is published once a month by Minnesota Physician Publishing, Inc. Our address is 2812 East 26th Street, Minneapolis, MN 55406; email mpp@mppub.com; phone 612.728.8600; fax 612.728.8601. We welcome the submission of manuscripts and letters for possible publication. All views and opinions expressed by authors of published articles are solely those of the authors and do not necessarily represent or express the views of Minnesota Physician Publishing, Inc. or this publication. The contents herein are believed accurate but are not intended to replace medical, legal, tax, business, or other professional advice and counsel.

No part of the publication may be reprinted or reproduced without written permission of the publisher. Annual subscriptions (12 copies) are $48.00/ Individual copies are $5.00.

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FEBRUARY 2017 MINNESOTA PHYSICIAN

It clicked when my doctor and I discussed Trulicity ÂŽ1,2

Trulicity is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy that offers unbeaten A1C reduction* in 6 head-to-head trials, once-weekly dosing, and the Trulicity pen.1,3 If you have patients who struggle with the idea of adding an injectable, consider Trulicity as an option for the next step in their care.1,4 Recommended starting dose is 0.75 mg. Dose can be increased to 1.5 mg for additional A1C reduction. *In clinical studies, the range of A1C reduction from baseline was 0.7% to 1.6% for the 0.75 mg dose and 0.8% to 1.6% for the 1.5 mg dose.1,3

For more information on 6 head-to-head trials, see the following page.

Trulicity is a GLP-1 RA that is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Limitations of Use: Not recommended as first-line therapy for patients inadequately controlled on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans. Prescribe only if potential benefits outweigh potential risks.

Has not been studied in patients with a history of pancreatitis; consider another antidiabetic therapy.

Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. Not a substitute for insulin.

Has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. Not for patients with pre-existing severe gastrointestinal disease. Has not been studied in combination with basal insulin.

Select Important Safety Information WARNING: RISK OF THYROID C-CELL TUMORS In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure.

It is unknown whether Trulicity causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.

Trulicity is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of Trulicity and inform them of symptoms of thyroid tumors (eg, mass in the neck, dysphagia, dyspnea, persistent hoarseness).

Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Trulicity.

Please see Important Safety Information for Trulicity, including Boxed Warning about possible thyroid tumors including thyroid cancer, on inside spread and accompanying Brief Summary of Prescribing Information.

Please see Instructions for Use included with the pen.

Learn about unbeaten A1C reduction at Trulicity.com

MINNESOTA PHYSICIAN FEBRUARY 2017

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Mean A1C change from ba

-0.6

-0.6

-0.8 -1.0 -1.2

-0.8

-1.1 * Unbeaten A1C reduction across 6 head-to-head trials -1.4

-1.6

Lantus® (100 mg) (n=262; Baseline A1C: 8.1%)

Trulicity® (0.75 mg) (n=272; Baseline A1C: 8.1%)

Trulicity® (1.5 mg) (n=273; Baseline A1C:1,3 8.2%)

Data represent least-squares mean ± standard error.

*In clinical studies, the range of A1C reduction from baseline was 0.7% to 1.6% for the 0.75 mg dose and 0.8% to 1.6% for the 1.5 mg dose.1,3 Recommended starting dose is 0.75 mg. Dose can be increased to 1.5 mg for additional A1C reduction.

A1C reduction from baseline

MeanA1C A1Cchange change from from baseline Mean baseline(%) (%)

0.0

Add-on to metformin (26 weeks)

Add-on to metformin (52 weeks)

Add-on to metformin and Actos® (26 weeks)

Add-on to metformin and Amaryl® (52 weeks)

Compared to Victoza®3

Compared to Januvia®1,5,6

Compared to Byetta®1,7

Compared to Lantus®1,8-10

-0.2 -0.4

-0.39

-0.6

-0.46

-0.63

-0.8 -1.0

-0.87

-1.2

-0.99

-1.10

-1.4

-1.51

-1.8 Victoza (1.8 mg) (n=300; Baseline A1C: 8.1%)

Januvia (100 mg) (n=273; Baseline A1C: 8.0%)

Placebo (n=141; Baseline A1C: 8.1%)

Lantus (n=262; Baseline A1C: 8.1%)

Trulicity® (1.5 mg) (n=299; Baseline A1C: 8.1%)

Trulicity® (0.75 mg) (n=281; Baseline A1C: 8.2%)

Byetta (10 mcg BID) (n=276; Baseline A1C: 8.1%)

Trulicity (0.75 mg) (n=272; Baseline A1C: 8.1%)

Trulicity (1.5 mg) (n=279; Baseline A1C: 8.1%)

Trulicity (0.75 mg) (n=280; Baseline A1C: 8.1%)

Trulicity (1.5 mg) (n=273; Baseline A1C: 8.2%)

Trulicity (1.5 mg) (n=279; Baseline A1C: 8.1%)

Data represent least-squares mean ± standard error.

•

26-week, randomized, open-label comparator phase 3 study of adult patients with type 2 diabetes treated with metformin ≥1500 mg/day

•

104-week, randomized, placebocontrolled, double-blind phase 3 study of adult patients with type 2 diabetes treated with metformin ≥1500 mg/day

•

Primary objective was to demonstrate noninferiority of Trulicity 1.5 mg vs Victoza 1.8 mg on A1C change from baseline at 26 weeks (-1.42% vs -1.36%, respectively; difference of -0.06%; 95% CI [-0.19, 0.07]; 2-sided alpha level of 0.05 for noninferiority margin 0.4%; mixed model repeated measures analysis)

•

Primary objective was to demonstrate noninferiority of Trulicity 1.5 mg vs Januvia on A1C change from baseline at 52 weeks (-1.1% vs -0.4%, respectively; difference of -0.7%; 95% CI [-0.9, -0.5]; multiplicity-adjusted 1-sided alpha level of 0.025 for noninferiority with 0.25% margin; analysis of covariance using last observation carried forward [LOCF]); primary objective met

•

-1.08

-1.30

-1.36 -1.42

-1.6

-0.76

Primary objective of noninferiority for A1C reduction was met; secondary endpoint of superiority was not met

•

Key secondary objectives of superiority of both dulaglutide doses vs Januvia were met

Superiority was only demonstrated in the studies versus Byetta and Januvia.

Additional study results Although this was a monotherapy study, Trulicity is not recommended as a first-line therapy. In a 52-week randomized, double-blind phase 3 study, adult patients with type 2 diabetes were treated with monotherapy. Baseline A1C=7.6% for each of metformin (n=268), Trulicity 0.75 mg (n=270), and Trulicity 1.5 mg (n=269). At the 26-week primary endpoint, mean A1C reductions were metformin: 0.6%; Trulicity 0.75 mg: 0.7%; Trulicity 1.5 mg: 0.8%. Primary objective was to demonstrate noninferiority of Trulicity 1.5 mg vs metformin on A1C change from baseline at 26 weeks (-0.8% vs -0.6%, respectively; multiplicity-adjusted 1-sided alpha level of 0.025 for noninferiority with 0.4% margin; analysis of covariance using LOCF); primary objective met.1,11

78-week, randomized, open-label comparator phase 3 study (double-blind with respect to Trulicity dose assignment) of adult patients with type 2 diabetes treated with maximally tolerated metformin (≥1500 mg/day) and Amaryl (≥4 mg/day)

•

52-week, randomized, placebo-controlled phase 3 study (open-label assignment to Byetta or blinded assignment to Trulicity or placebo) of adult patients with type 2 diabetes treated with maximally tolerated metformin (≥1500 mg/day) and Actos (up to 45 mg/day)

•

•

Primary objective was to demonstrate superiority of Trulicity 1.5 mg vs placebo on change in A1C from baseline at 26 weeks (-1.5% vs -0.5%, respectively; difference of -1.1%; 95% CI [-1.2, -0.9]; multiplicity-adjusted 1-sided alpha level of 0.025; analysis of covariance using LOCF); primary objective met

• Starting dose of Lantus was 10 units daily.

Key secondary objectives of superiority of both dulaglutide doses vs Byetta were met

•

•

Lantus titration was based on self-measured fasting plasma glucose utilizing an algorithm with a target of <100 mg/dL; 24% of patients were titrated to goal at the 52-week primary endpoint.

Mean daily dose of insulin glargine was 29 units at the primary endpoint Primary objective was to demonstrate noninferiority of Trulicity 1.5 mg vs Lantus titrated to target on A1C change from baseline at 52 weeks (-1.1% vs -0.6%, respectively; multiplicity-adjusted 1-sided alpha level of 0.025 for noninferiority with 0.4% margin; analysis of covariance using LOCF); primary objective met

In a 52-week randomized, open-label comparator phase 3 study (double-blind with respect to Trulicity dose assignment) of adult patients, Trulicity was studied in combination with Humalog® with or without metformin ≥1500 mg/day. Humalog was titrated based on preprandial and bedtime glucose, and Lantus was titrated based on fasting glucose; 36% of patients randomized to glargine were titrated to the fasting glucose goal at the 26-week time point. Baseline A1C=8.5% for Lantus (n=296), baseline A1C=8.4% for Trulicity 0.75 mg (n=293), and baseline A1C=8.5% for Trulicity 1.5 mg (n=295). At the 26-week primary endpoint, mean A1C reductions were Lantus: 1.4%; Trulicity 0.75 mg: 1.6%; Trulicity 1.5 mg: 1.6%. Primary objective was to demonstrate noninferiority of Trulicity 1.5 mg vs Lantus titrated to target on A1C change from baseline at 26 weeks (-1.6% vs -1.4%, respectively; multiplicity-adjusted 1-sided alpha level of 0.025 for noninferiority with 0.4% margin; analysis of covariance using LOCF); primary objective met.1,12,13

Please see Important Safety Information for Trulicity, including Boxed Warning about possible thyroid tumors including thyroid cancer, on the following page and accompanying Brief Summary of Prescribing Information. Please see Instructions for Use included with the pen.

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FEBRUARY 2017 MINNESOTA PHYSICIAN

Important Safety Information WARNING: RISK OF THYROID C-CELL TUMORS

In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. It is unknown whether Trulicity causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.

Trulicity is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of Trulicity and inform them of symptoms of thyroid tumors (eg, mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Trulicity.

Trulicity is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2, and in patients with a prior serious hypersensitivity reaction to dulaglutide or any of the product components.

diarrhea (6.7%, 8.9%, 12.6%), vomiting (2.3%, 6.0%, 12.7%), abdominal pain (4.9%, 6.5%, 9.4%), decreased appetite (1.6%, 4.9%, 8.6%), dyspepsia (2.3%, 4.1%, 5.8%), and fatigue (2.6%, 4.2%, 5.6%).

Gastric emptying is slowed by Trulicity, which may impact absorption of concomitantly administered oral medications.

Use caution when oral medications are used with Trulicity. Drug levels of oral medications with a narrow therapeutic index should be adequately monitored when concomitantly administered with Trulicity. In clinical pharmacology studies, Trulicity did not affect the absorption of the tested, orally administered medications to a clinically relevant degree.

Pregnancy: There are no adequate and well-controlled studies of Trulicity in pregnant women. Use only if potential benefit outweighs potential risk to fetus.

Nursing Mothers: It is not known whether Trulicity is excreted in human milk. A decision should be made whether to discontinue nursing or to discontinue Trulicity, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of Trulicity have not been established and use is not recommended in patients less than 18 years of age.

Risk of Thyroid C-cell Tumors: Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist (GLP-1 RA), have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 RA use in humans. If serum calcitonin is measured and found to be elevated or thyroid nodules are noted on physical examination or neck imaging, the patient should be further evaluated.

Pancreatitis: Has been reported in clinical trials. Observe patients for signs and symptoms including persistent severe abdominal pain. If pancreatitis is suspected, discontinue Trulicity promptly. Do not restart if pancreatitis is confirmed.

Consider other antidiabetic therapies in patients with a history of pancreatitis.

Hypoglycemia: The risk of hypoglycemia is increased when Trulicity is used in combination with insulin secretagogues (eg, sulfonylureas) or insulin. Patients may require a lower dose of the sulfonylurea or insulin to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: Systemic reactions were observed in patients receiving Trulicity in clinical trials. Instruct patients who experience symptoms to discontinue Trulicity and promptly seek medical advice.

Renal Impairment: In patients treated with GLP-1 RAs, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, sometimes requiring hemodialysis. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration.

In patients with renal impairment, use caution when initiating or escalating doses of Trulicity and monitor renal function in patients experiencing severe adverse gastrointestinal reactions.

Severe Gastrointestinal Disease: Use of Trulicity may be associated with gastrointestinal adverse reactions, sometimes severe. Trulicity has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Trulicity or any other antidiabetic drug.

Please see Brief Summary of Prescribing Information, including Boxed Warning about possible thyroid tumors including thyroid cancer, on following pages. Please see Instructions for Use included with the pen.

DG HCP ISI 20APR2015 Trulicity® and Humalog® are registered trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

Actos® is a registered trademark of Takeda Pharmaceutical Company Limited.

Byetta® is a registered trademark of the AstraZeneca group of companies.

Amaryl® and Lantus® are registered trademarks of Sanofi-Aventis.

Januvia® is a registered trademark of Merck & Co., Inc. Victoza® is a registered trademark of Novo Nordisk A/S. Other product/company names mentioned herein are the trademarks of their respective owners.

References 1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015.

2. Trulicity [Instructions for Use]. Indianapolis, IN: Lilly USA, LLC; 2014.

3. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial [published correction appears in Lancet. 2014;384:1348]. Lancet. 2014;384:1349-1357.

4. Polonsky WH, Hajos TR, Dain MP, Snoek FJ. Are patients with type 2 diabetes reluctant to start insulin therapy? An examination of the scope and underpinnings of psychological insulin resistance in a large, international population. Curr Med Res Opin. 2011;27(6):1169-74. doi: 10.1185/03007995.2011.573623. Epub Apr 6, 2011.

5. Data on file, Lilly USA, LLC. TRU20150203A. 6. Data on file, Lilly USA, LLC. TRU20150203B. 7. Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1) [published correction appears in Diabetes Care. 2014;37:2895]. Diabetes Care. 2014;37:2159-2167.

8. Giorgino F, Benroubi M, Sun JH, et al. Efficacy and safety of once-weekly dulaglutide versus insulin glargine in patients with type 2 diabetes on metformin and glimepiride (AWARD-2) [published online ahead of print June 18, 2015].

Diabetes Care. doi:10.2337/dc14-1625.

9. Data on file, Lilly USA, LLC. TRU20140912A. 10. Data on file, Lilly USA, LLC. TRU20150313A. 11. Umpierrez G, Tofé Povedano S, Pérez Manghi F, et al. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care. 2014;37:2168-2176.

12. Blonde L, Jendle J, Gross J, et al. Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study.

Lancet. 2015;385:2057-2066.

13. Data on file, Lilly USA, LLC. TRU20150313B.

The most common adverse reactions reported in ≥5% of Trulicitytreated patients in placebo-controlled trials (placebo, Trulicity 0.75 mg, and Trulicity 1.5 mg) were nausea (5.3%, 12.4%, 21.1%),

PP-DG-US-0393

01/2016

©Lilly USA, LLC 2016. All rights reserved.

MINNESOTA PHYSICIAN FEBRUARY 2017

7

TrulicityTM (dulaglutide) Brief Summary: Consult the package insert for complete prescribing information.

WARNING: RISK OF THYROID C-CELL TUMORS • In male and female rats, dulaglutide causes a dose-related and treatmentduration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. It is unknown whether Trulicity causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.

• Trulicity is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of Trulicity and inform them of symptoms of thyroid tumors (eg, mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Trulicity.

insulin secretagogues (eg, sulfonylureas) or insulin. Patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting. Hypersensitivity Reactions: Systemic hypersensitivity reactions were observed in patients receiving Trulicity in clinical trials. If a hypersensitivity reaction occurs, the patient should discontinue Trulicity and promptly seek medical advice. Renal Impairment: In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Because these reactions may worsen renal failure, use caution when initiating or escalating doses of Trulicity in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions.

Severe Gastrointestinal Disease: Use of Trulicity may be associated with gastrointestinal adverse reactions, sometimes severe. Trulicity has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Trulicity or any other antidiabetic drug.

ADVERSE REACTIONS

INDICATIONS AND USAGE Trulicity™ is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Risk of Thyroid C-cell Tumors: In male and female rats, dulaglutide causes a doserelated and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. Glucagon-like peptide (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether Trulicity will cause thyroid C-cell tumors, including MTC, in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined. One case of MTC was reported in a patient treated with Trulicity. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. Trulicity is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of Trulicity and inform them of symptoms of thyroid tumors (eg, a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Trulicity. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated.

Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. Pancreatitis: In Phase 2 and Phase 3 clinical studies, 12 (3.4 cases per 1000 patient years) pancreatitis-related adverse reactions were reported in patients exposed to Trulicity versus 3 in non-incretin comparators (2.7 cases per 1000 patient years).

An analysis of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to Trulicity (1.4 cases per 1000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient years). After initiation of Trulicity, observe patients carefully for signs and symptoms of pancreatitis, including persistent severe abdominal pain. If pancreatitis is suspected, promptly discontinue Trulicity. If pancreatitis is confirmed, Trulicity should not be restarted. Trulicity has not been evaluated in patients with a prior history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: The risk of hypoglycemia is increased when Trulicity is used in combination with

Clinical Studies Experience: Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Pool of Placebo-controlled Trials: These data reflect exposure of 1670 patients to Trulicity and a mean duration of exposure to Trulicity of 23.8 weeks. Across the treatment arms, the mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population in these studies was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.0 years and had a mean HbA1c of 8.0%. At baseline, 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60mL/min/1.73 m2) in 96.0% of the pooled study populations.

Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of Trulicity-Treated Patients: Placebo (N=568), Trulicity 0.75mg (N=836), Trulicity 1.5 mg (N=834) (listed as placebo, 0.75 mg, 1.5 mg): nausea (5.3%, 12.4%, 21.1%), diarrheaa (6.7%, 8.9%, 12.6%), vomitingb (2.3%, 6.0%, 12.7%), abdominal painc (4.9%, 6.5%, 9.4%), decreased appetite (1.6%, 4.9%, 8.6%), dyspepsia (2.3%, 4.1%, 5.8%), fatigued (2.6%, 4.2%, 5.6%). (a Includes diarrhea, fecal volume increased, frequent bowel movements. b Includes retching, vomiting, vomiting projectile. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. d Includes fatigue, asthenia, malaise.) Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Gastrointestinal Adverse Reactions: In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving Trulicity than placebo (placebo 21.3%, 0.75 mg 31.6%, 1.5 mg 41.0%). More patients receiving Trulicity 0.75 mg (1.3%) and Trulicity 1.5 mg (3.5%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.2%). Investigators graded the severity of gastrointestinal adverse reactions occurring on 0.75 mg and 1.5 mg of Trulicity as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively. In addition to the adverse reactions ≥5% listed above, the following adverse reactions were reported more frequently in Trulicity-treated patients than placebo (frequencies listed, respectively, as: placebo; 0.75 mg; 1.5 mg): constipation (0.7%; 3.9%; 3.7%), flatulence (1.4%; 1.4%; 3.4%), abdominal distension (0.7%; 2.9%; 2.3%), gastroesophageal reflux disease (0.5%; 1.7%; 2.0%), and eructation (0.2%; 0.6%; 1.6%).

Pool of Placebo- and Active-Controlled Trials: The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 6 placebo- and active-controlled trials evaluating the use of Trulicity as monotherapy and add-on therapy to oral medications or insulin. In this pool, a total of 3342 patients with type 2 diabetes were treated with Trulicity for a mean duration 52 weeks. The mean age of patients was 56 years, 2% were 75 years or older and 51% were male. The population in these studies was 71% White, 7% Black or African American, 11% Asian; 32% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.2 years and had a mean HbA1c of 7.6-8.5%. At baseline, 5.2% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 ml/min/1.73 m2) in 95.7% of the Trulicity population. In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed as ≥5% above. Other Adverse Reactions: Hypoglycemia: Incidence (%) of Documented Symptomatic (≤70 mg/dL Glucose Threshold) and Severe Hypoglycemia in Placebo-Controlled Trials: Add-on to Metformin at 26 weeks, Placebo (N=177), Trulicity 0.75 mg (N=302), Trulicity 1.5 mg (N=304), Documented symptomatic: Placebo: 1.1%, 0.75 mg: 2.6%, 1.5 mg: 5.6%; Severe: all 0. Add-on to Metformin + Pioglitazone at 26 weeks, Placebo (N=141), Trulicity 0.75 mg (N=280), Trulicity 1.5 mg (N=279), Documented symptomatic: Placebo: 1.4%, 0.75 mg: 4.6%, 1.5 mg: 5.0%; Severe: all 0.

Hypoglycemia was more frequent when Trulicity was used in combination with a sulfonylurea or insulin. Documented symptomatic hypoglycemia occurred in 39% and 40% of patients when Trulicity 0.75 mg and 1.5 mg, respectively, was co-administered with a sulfonylurea. Severe hypoglycemia occurred in 0% and 0.7% of patients when Trulicity 0.75 mg and 1.5 mg, respectively, was co-administered with a sulfonylurea. Documented symptomatic hypoglycemia occurred in 85% and 80% of patients when Trulicity 0.75 mg

TrulicityTM (dulaglutide)

TrulicityTM (dulaglutide)

Limitations of Use: Not recommended as a first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans. Prescribe Trulicity only to patients for whom the potential benefits outweigh the potential risk. Has not been studied in patients with a history of pancreatitis.

Consider other antidiabetic therapies in patients with a history of pancreatitis. Should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

It is not a substitute for insulin. Has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. Not recommended in patients with pre-existing severe gastrointestinal disease. The concurrent use of Trulicity and basal insulin has not been studied.

CONTRAINDICATIONS Do not use in patients with a personal or family history of MTC or in patients with MEN 2.

Do not use in patients with a prior serious hypersensitivity reaction to dulaglutide or to any of the product components.

WARNINGS AND PRECAUTIONS

Trulicity DG HCP BS 20APR2015 Brief Summary 7 x 9.75

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FEBRUARY 2017 MINNESOTA PHYSICIAN

DG HCP BS 20APR2015

DG HCP BS 20APR2015

PRINTER VERSION 1 OF 2

and 1.5 mg, respectively, was co-administered with prandial insulin. Severe hypoglycemia occurred in 2.4% and 3.4% of patients when Trulicity 0.75 mg, and 1.5 mg, respectively, was co-administered with prandial insulin. Heart Rate Increase and Tachycardia Related Adverse Reactions: Trulicity 0.75 mg and 1.5 mg resulted in a mean increase in heart rate (HR) of 2-4 beats per minute (bpm). The long-term clinical effects of the increase in HR have not been established. Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to Trulicity. Sinus tachycardia was reported in 3.0%, 2.8%, and 5.6% of patients treated with placebo, Trulicity 0.75 mg, and Trulicity 1.5 mg, respectively.

Persistence of sinus tachycardia (reported at more than 2 visits) was reported in 0.2%, 0.4%, and 1.6% of patients treated with placebo, Trulicity 0.75 mg and Trulicity 1.5 mg, respectively. Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of ≥15 beats per minute, were reported in 0.7%, 1.3%, and 2.2% of patients treated with placebo, Trulicity 0.75 mg, and Trulicity 1.5 mg, respectively.

Immunogenicity : Across four Phase 2 and five Phase 3 clinical studies, 64 (1.6%) Trulicitytreated patients developed anti-drug antibodies (ADAs) to the active ingredient in Trulicity (ie, dulaglutide). Of the 64 dulaglutide-treated patients that developed dulaglutide ADAs, 34 patients (0.9% of the overall population) had dulaglutide-neutralizing antibodies, and 36 patients (0.9% of the overall population) developed antibodies against native GLP-1. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to dulaglutide cannot be directly compared with the incidence of antibodies of other products. Hypersensitivity : Systemic hypersensitivity adverse reactions sometimes severe (eg, severe urticaria, systemic rash, facial edema, lip swelling) occurred in 0.5% of patients on Trulicity in the four Phase 2 and Phase 3 studies. Injection-site Reactions: In the placebo-controlled studies, injection-site reactions (eg, injection-site rash, erythema) were reported in 0.5% of Trulicity-treated patients and in 0.0% of placebo-treated patients. PR Interval Prolongation and Adverse Reactions of First Degree Atrioventricular (AV) Block: A mean increase from baseline in PR interval of 2-3 milliseconds was observed in Trulicity-treated patients in contrast to a mean decrease of 0.9 millisecond in placebo-treated patients. The adverse reaction of first degree AV block occurred more frequently in patients treated with Trulicity than placebo (0.9%, 1.7%, and 2.3% for placebo, Trulicity 0.75 mg, and Trulicity 1.5 mg, respectively). On electrocardiograms, a PR interval increase to at least 220 milliseconds was observed in 0.7%, 2.5%, and 3.2% of patients treated with placebo, Trulicity 0.75 mg, and Trulicity 1.5 mg, respectively. Amylase and Lipase Increase: Patients exposed to Trulicity had mean increases from baseline in lipase and/or pancreatic amylase of 14% to 20%, while placebotreated patients had mean increases of up to 3%.

DRUG INTERACTIONS Trulicity slows gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with Trulicity. Drug levels of oral medications with a narrow therapeutic index should be adequately monitored when concomitantly administered with Trulicity. In clinical pharmacology studies, Trulicity did not affect the absorption of the tested, orally administered medications to any clinically relevant degree.

USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category C: There are no adequate and well-controlled studies of Trulicity in pregnant women. The risk of birth defects, loss, or other adverse outcomes is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes to maintain good metabolic control before conception and throughout pregnancy. Trulicity should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In rats and rabbits, dulaglutide administered during the major period of organogenesis produced fetal growth reductions and/or skeletal anomalies and ossification deficits in association with decreased maternal weight and food consumption attributed to the pharmacology of dulaglutide. Nursing Mothers: It is not known whether Trulicity is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for clinical adverse reactions from Trulicity in nursing infants, a decision should be made whether to discontinue nursing or to discontinue Trulicity, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of Trulicity have not been established in pediatric patients. Trulicity is not recommended for use in pediatric patients younger than 18 years. Geriatric Use: In the pool of placebo- and active-controlled trials, 620 (18.6%) Trulicity-treated patients were 65 years of age and over and 65 Trulicity-treated patients (1.9%) were 75 years of age and over. No overall differences in safety or efficacy were detected between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment: There is limited clinical experience in patients with mild, moderate, or severe hepatic impairment. Therefore, Trulicity should be used with caution in these patient populations. In a clinical pharmacology study in subjects with varying degrees of hepatic impairment, no clinically relevant change in dulaglutide pharmacokinetics (PK) was observed. Renal Impairment: In the four Phase 2 and five Phase 3 randomized clinical studies, at baseline, 50 (1.2%) Trulicity-treated patients had mild renal impairment (eGFR ≥60 but <90 mL/min/1.73 m2), 171 (4.3%) Trulicitytreated patients had moderate renal impairment (eGFR ≥30 but <60 mL/min/1.73 m2) and no Trulicity-treated patients had severe renal impairment (eGFR <30 mL/min/1.73 m2).

TrulicityTM (dulaglutide)

Trulicity DG HCP BS 20APR2015 Brief Summary 7 x 9.75

DG HCP BS 20APR2015

No overall differences in safety or effectiveness were observed relative to patients with normal renal function, though conclusions are limited due to small numbers. In a clinical pharmacology study in subjects with renal impairment including end-stage renal disease (ESRD), no clinically relevant change in dulaglutide PK was observed. There is limited clinical experience in patients with severe renal impairment or ESRD. Trulicity should be used with caution, and if these patients experience adverse gastrointestinal side effects, renal function should be closely monitored. Gastroparesis: Dulaglutide slows gastric emptying. Trulicity has not been studied in patients with pre-existing gastroparesis.

OVERDOSAGE Overdoses have been reported in clinical studies. Effects associated with these overdoses were primarily mild or moderate gastrointestinal events (eg, nausea, vomiting) and nonsevere hypoglycemia. In the event of overdose, appropriate supportive care (including frequent plasma glucose monitoring) should be initiated according to the patient’s clinical signs and symptoms.

PATIENT COUNSELING INFORMATION See FDA-approved Medication Guide • Inform patients that Trulicity causes benign and malignant thyroid C-cell tumors in rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (eg, a lump in the neck, persistent hoarseness, dysphagia, or dyspnea) to their physician. • Inform patients that persistent severe abdominal pain, that may radiate to the back and which may (or may not) be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue Trulicity promptly, and to contact their physician, if persistent severe abdominal pain occurs.

• The risk of hypoglycemia may be increased when Trulicity is used in combination with a medicine that can cause hypoglycemia, such as a sulfonylurea or insulin. Review and reinforce instructions for hypoglycemia management when initiating Trulicity therapy, particularly when concomitantly administered with a sulfonylurea or insulin. • Patients treated with Trulicity should be advised of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform patients treated with Trulicity of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs. • Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of GLP-1 receptor agonists. If symptoms of hypersensitivity reactions occur, patients must stop taking Trulicity and seek medical advice promptly. • Advise patients to inform their healthcare provider if they are pregnant or intend to become pregnant. • Prior to initiation of Trulicity, train patients on proper injection technique to ensure a full dose is delivered. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations. • Inform patients of the potential risks and benefits of Trulicity and of alternative modes of therapy.

Inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and advise patients to seek medical advice promptly. • Each weekly dose of Trulicity can be administered at any time of day, with or without food. The day of once-weekly administration can be changed if necessary, as long as the last dose was administered 3 or more days before. If a dose is missed and there are at least 3 days (72 hours) until the next scheduled dose, it should be administered as soon as possible. Thereafter, patients can resume their usual once-weekly dosing schedule. If a dose is missed and the next regularly scheduled dose is due in 1 or 2 days, the patient should not administer the missed dose and instead resume Trulicity with the next regularly scheduled dose. • Advise patients treated with Trulicity of the potential risk of gastrointestinal side effects. • Instruct patients to read the Medication Guide and the Instructions for Use before starting Trulicity therapy and review them each time the prescription is refilled. • Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens. • Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels towards the normal range. HbA1c is especially useful for evaluating long-term glycemic control.

Eli Lilly and Company, Indianapolis, IN 46285, USA US License Number 1891 Copyright © 2014, 2015, Eli Lilly and Company. All rights reserved.

Additional information can be found at www.trulicity.com DG HCP BS 20APR2015 TrulicityTM (dulaglutide)

DG HCP BS 20APR2015

PRINTER VERSION 2 OF 2 MINNESOTA PHYSICIAN FEBRUARY 2017

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CAPSULES

Rates of Infants Born with Opioid Withdrawal Rising A study from the University of Minnesota School of Public Health has shown a significant increase in cases of babies born with Neonatal Abstinence Syndrome, or opioid withdrawal, especially in rural areas.

“Every infant who is withdrawing has a mom who was exposed to opioids, and possibly, didn’t have access to the treatment she needed,” said Katy Kozhimannil, PhD, associate professor of health policy and management at the University of Minnesota’s School of Public Health and co-author of the study. “So many people are prescribed opioids for pain and become physically dependent on them. Some of these people become pregnant, but they can’t just stop taking opioids—both because of their dependence, but also because without opioids, a baby could withdraw in utero and possibly die.”

The researchers investigated the growth over time in opioid use during pregnancy and its effects on women and their babies. They discovered a

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seven-fold increase in the occurrence of Neonatal Abstinence Syndrome in rural areas and a four-fold increase in urban areas between 2004 and 2013.

More than 21 percent of all cases in the U.S. were in rural areas, where fewer than 15 percent of all births take place.

“These are huge increases and very concerning,” said Kozhimannil. “The trend is stronger in rural areas where the infrastructure for screening, treatment, and support services for maternal opioid dependence is much more limited compared to urban areas. Solutions need to be tailored to rural areas, because approaches designed for urban areas are less effective or work in different ways in rural communities.”

According to Kozhimannil, the best way to address the issue is a public health approach focusing on prevention. Recommendations include implementing policies and programs to reverse the rising trend of opioid-affected births in rural areas that focus on both prevention and treatment; treatment that consists of in-community support; and

FEBRUARY 2017 MINNESOTA PHYSICIAN

developing or enhancing rural health care infrastructure to include mental health, substance abuse, chronic pain, and obstetric services.

Grand Rapids Hospital Merges with Fairview Fairview Health Services has acquired Grand Itasca Clinic & Hospital in Grand Rapids as a wholly owned subsidiary, effective Jan. 1.

Fairview plans to make investments in areas such as oncology and cardiology in the community as part of the deal, according to James Hereford, Fairview president and CEO. In addition, Grand Itasca will be in a better position to negotiate payment rates with health insurers and contracts with vendors.

There will be no staffing changes at Grand Itasca. It will keep its name and local board of directors, with the addition of three Fairview representatives to the existing 12-member board.

The move continues a trend of community hospitals merging with larger hospital systems, as 38 of

Minnesota’s 147 hospitals are currently independent, according to the Minnesota Hospital Association.

CHI St. Gabriel’s Health to Integrate Dental Care The Minnesota Department of Health (MDH) has awarded a $100,000 grant to CHI St. Gabriel’s Health to better integrate their primary care and dental services.

CHI St. Gabriel’s Health’s Family Medical Center, a certified Health Care Home clinic in Little Falls, will expand its partnership with Apple Tree Dental to increase on-site access to dental care. They will also be partnering with South Country Health Alliance and Morrison County Social Services.

According to MDH, one in four adults in the U.S. have untreated cavities, which are the most common chronic disease among children. The grants are meant to address this issue, as research has linked poor oral health and gum disease to other chronic diseases including diabetes and heart disease.

In Morrison County, more than 11 percent of residents live in households with income below the federal poverty level. In addition, in this rural part of the state many people have to travel more than an hour for oral health services. CHI St. Gabriel’s Health and Apple Tree Dental are teaming up to expand patient access to integrated, on-site, and mobile dental care in the area.

CHI St. Gabriel’s will use the grant funds to develop a process for assessing medical patients’ oral health needs and training staff to make appropriate referrals to Apple Tree Dental. They will also hire a community care worker to conduct home visits to assess the dental needs of patients who have difficulty travelling to a clinic. Funds will also be used to expand electronic health record systems to better coordinate and track patients’ oral and medical health information.

Minnesota to Pilot Certified Behavioral Health Clinics Minnesota has been selected as one of eight states to pilot a new model of mental and chemical health care through the U.S. Department of Health & Human Services. The pilot, called Certified Community Behavioral Health Clinics, is a model designed to bring together behavioral, chemical, and physical health care for people with mental and substance use disorders. They are meant to serve as a “one-stop-shop” for those who have trouble getting the services they need.

The model addresses the issue of how a person with mental illness typically has to navigate a complex system to receive care, including contacting several agencies to obtain various services. And those seeking treatment for mental and substance use disorders are rarely able to receive care for both through the same agency. Through the model, clinics will offer services including primary care screening, cognitive behavioral therapy, motivational interviewing, and trauma-focused therapy for children.

Six Minnesota clinics began preparing last spring, and DHS certified the clinics as pilot sites in the fall—Northern Pines Mental Health Center in north-central Minnesota;

Northwestern Mental Health Center, serving seven northwest counties; Wilder Children and Family Services in the metro area; People Incorporated in the metro area; Ramsey County Mental Health Center in the metro area; and Zumbro Valley Mental Health Center in Olmsted and Fillmore counties in southeast Minnesota.

The other seven states that were selected are Missouri, New York, New Jersey, Nevada, Oklahoma, Oregon, and Pennsylvania. States have until July 1 to begin their two-year demonstration programs and funding continues through Dec. 31, 2018.

St. Luke’s Acquires Duluth ENT Clinic Northland Ear, Nose & Throat Associates, PA, in Duluth has joined the St. Luke’s health system. It will now be known as St. Luke’s Ear, Nose & Throat Associates. The clinic’s doctors will remain and it will stay at its current location, where it has been for more than 25 years.

“We’re looking forward to continuing our working relationship with the specialists and other members of the ENT staff for years to come,” said John Strange, St. Luke’s president and CEO. “Welcoming the group to the St. Luke’s family is the right fit for our patients. It’s another way we can give them the best possible care.”

Fairview to Study Treatment for Hypertension Fairview Health Services is launching a one-year, 800-person prospective research study involving gene-specific treatment protocols for high blood pressure. The condition affects 1 in 3 adults in the U.S. and causes 1,000 deaths each year.

“We believe we can dramatically cut the time, cost, and side effects involved in managing high blood pressure through the use of gene-specific treatment protocols,” said Dang Tran, MD, vice president of medical practice at Fairview Medical Group and principal investigator of the study.

Qualified patients at eight Fairview clinics may be able to enroll in the randomized controlled clinical research trial. Fairview entered a clinical research agreement with MINNESOTA PHYSICIAN FEBRUARY 2017

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CAPSULES

Geneticure, a Minnetonka-based pharmacogenetics testing company, to conduct the study. Early research of Geneticure’s patented genetic test has shown that it can help clinicians personalize hypertension treatment for each patient for better, more effective results.

“The implications for the nation’s health are staggering,” said Bob Beacher, RPh, president of shared clinical services at Fairview. “Uncontrolled hypertension contributes to strokes, coronary heart disease, and cardiovascular disease. The findings from this research could transform the health of an entire population.”

CentraCare Expands Telestroke Program CentraCare Health’s Telestroke/ Vacsular Neurology Clinic is continuing to expand in its second year, through a $540,000, three-year grant from the Department of Health and Human Services’ Rural Health Care Services Outreach Grant Program.

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It launched in late 2015, allowing post-stroke and transient ischemic attack (TIA) patients receiving follow-up care at CentraCare Health– Long Prairie to participate in a telehealth patient navigator program.

The goal is to improve access to care and health outcomes among these patients in Chippewa, Pope, Swift, Todd, Wadena, and parts of Stearns counties.

The program is based out of Long Prairie, with three other locations that launched at the same time in Paynesville, Melrose, and Sauk Centre. Glacial Ridge Health System in Glenwood implemented the program in December, and Tri-County Health’s program in Wadena will launch in January. This spring, the program will expand to Swift County–Benson Health Services in Benson and Lakewood Health System in Staples.

Patients are enrolled in the program within five to seven days after they are discharged. The patient navigator then works with the patient and their health care providers and family to manage their care, which

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can be done face-to-face, via telephone, or by video conferencing using telemedicine equipment.

Pilot Projects Aim to Treat Psychosis Earlier Two new mental health pilot projects are launching in the metro area with the goal of reducing how long it takes for a person experiencing psychosis to get treatment. The pilot projects, called Coordinated Specialty Care, will service Minnesotans ages 15 through 40 who have early signs of psychosis. Studies have shown that early treatment increases the chance of a successful recovery.

The projects are the result of a 2008 research project from the National Institute of Mental Health that shows this care model is more effective than usual treatment approaches for psychosis, that treatment is most effective when received earlier, and that treatment for psychosis can be delivered successfully in the community.

Three organizations will receive up to $2.97 million in federal funds through the State of Minnesota.

Hennepin County Medical Center will have one team and the University of Minnesota Psychiatry Clinic in St. Louis Park will have two teams, each serving up to 30 people. The Minnesota Center for Chemical and Mental Health is the third organization that will receive funding, to be used for providing technical support including training, consultation, and community information sessions.

“The need for treatment for first episode psychosis is great,” said Piper Meyer-Kalos, principal investigator and executive director for the Minnesota Center for Chemical and Mental Health. “Currently, people experiencing psychosis for the first time are typically waiting well over a year to get treatment.”

The pilots will use teams of specialists who offer psychotherapy, medication management, family education, coping skills, training, and education, and possibly case management and peer support.

MEDICUS

Fergus Couch, PhD, chair of the division of experimental pathology in the department of laboratory medicine and pathology at Mayo Clinic, has received the Outstanding Investigator Award for Breast Cancer Research from the American Association for Cancer Research. The award recognizes an investigator of no more than 50 years of age whose work has had or may have a far-reaching impact on the etiology, detection, diagnosis, treatment, or prevention of breast cancer. Couch was honored for his seminal work in identifying the inherited genes and mutations that predispose individuals to breast cancer.

In his most recent work, he has been working to estimate risks of breast cancer associated with pathogenic variants identified by clinical genetic testing using multigene panels, and is leading an effort to identify genetic factors that account for the missing heritability of breast cancer. Couch earned his PhD in biochemistry at the University College Cork, Ireland.

Joel Boyd, MD, orthopedic surgeon at TRIA Orthopaedic Center, has been selected by Gov. Mark Dayton to serve on the board of directors of the Minnesota State High School League (MSHSL), an organization with the goal of improving the health and safety for high school athletes in Minnesota. Boyd represents the public in his role on the board—other members represent a specific school or district. He has more than 25 years of experience in orthopedics and sports medicine, including nine years as a team physician for the Minnesota Vikings. He currently serves as head team physician for the Minnesota Wild and the University of Minnesota Golden Gophers men’s football team. Boyd earned his medical degree at Temple University School of Medicine in Philadelphia, Penn.

Patricia Walker, MD, has received the Shotwell Award from the Twin Cities Medical Foundation for her work as a nationally recognized expert on refugee and immigrant health. Walker serves as professor in the division of infectious disease and international health at the University of Minnesota and an adjunct professor in the School of Public Health. Previously, Walker served for 23 years as medical director of HealthPartners Center for International Health, a refugee and immigrant health clinic. Now, she is pursuing further research while she continues to care for patients at the Center for International Health. Walker earned her medical degree at Mayo Medical School and a diploma in tropical medicine and hygiene from the London School of Tropical Medicine and Hygiene.

Marc Gorelick, MD, has been named the new president and chief operating officer of Children’s Minnesota. He currently serves as chief operating officer and executive vice president of Children’s Hospital of Wisconsin and will step into his role at Children’s Minnesota on March 20. Gorelick has more than 20 years of experience in pediatric emergency medicine, education, and research, as well as hospital operations and health care leadership. Previously, he served as executive vice president of Children’s Hospital and Health System and professor of pediatrics (emergency medicine) at the Medical College of Wisconsin. He earned his medical degree from Duke University and a master’s degree in clinical epidemiology from the University of Pennsylvania.

MINNESOTA PHYSICIAN FEBRUARY 2017

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INTERVIEW

Bouncing back from burnout Corey Martin, MD, Buffalo Hospital Physician burnout has become an epidemic. How did this happen? ultiple studies show that physician burnout continues to rise. These studies reveal more than emotionally exhausted doctors. Dissatisfied patients, unhappy families, compromised care quality, risky prescribing patterns, and hospital-associated infections accompany this climate of caregiver fatigue. A recent Minnesota Hospital Association study of 13,000 physicians showed that over 50 percent experienced some level of burnout related to their jobs. Forty-two percent reported loss of control over their work load, while 51 percent indicated burnout due to lack of sufficient time for documentation. These and nationwide numbers confirm a systemic problem in need of intervention.

M

Multiple factors contribute to this phenomenon.

Increased paperwork and electronic medical record keeping add hours of data entry tasks, while decreasing time spent with patients. Expanding government regulations and heightened emphasis on measurements leave physicians scrambling to keep up with quality metrics. Physician training and culture also contribute to the crisis by failing to support doctors’ emotional capacity to sustain themselves and build beneficial relationships with others.

What are the symptoms of physician burnout?

Symptoms of caregiver burnout affect both our professional and personal lives. Emotionally exhausted physicians report depression, withdrawal from relationships, and feelings of professional inadequacy. These symptoms are often fueled by a sense of loss or compromise of our unique, daily contributions as doctors. We lose track of how to have conversations with patients and run the risk of treating patients as objects. A waning enthusiasm for work and a low sense of personal accomplishment further impact marriages and family relationships.

Symptoms of burnout often find their roots in medical training. Most of us enter medical school with a strong desire to help people. Then we learn to be stoic, wear a white coat, and keep emotions securely locked inside. Throughout medical school and our residencies, we work unrealistically long hours. We rarely take time to process personal

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experiences of patient deaths or difficult diagnoses. It should come as no surprise that new doctors exiting their residencies show comparable burnout symptoms to those who have practiced medicine for 20 years.

Please tell us about the Bounce Back Project and how it got started.

The Bounce Back Project emerged from the loss of two highly regarded Buffalo Hospital physicians who died in 2014—one in an accident and the other by

collaboration of physicians, nurses, and hospital leaders dedicated to improving the health and well-being of health care professionals and the communities they serve. The project launched in the fall of 2015. Bryan Sexton, PhD, associate professor at Duke University’s School of Medicine, shared a simple strategy with hundreds of individuals from the Buffalo and Monticello area: At bedtime, write down three good things in your life every day for two weeks. Dr. Sexton’s studies have shown that this practice produces results as powerful as prescribed anti-depressants and can last for six months.

What is resilience?

Resilience refers to our ability to bounce back from the stresses of life. It’s not about avoiding stress, but about learning to thrive while co-existing within the stress. Learning to live a more resilient life comes with numerous benefits such as decreased depressive symptoms and increased emotional well-being. Resilience also improves working memory, sleep, immune system function, relationships, and our capacity to cope.

[Resilience “...”is] not about avoiding stress, but about learning to thrive while co-existing within the stress. suicide. Their untimely deaths prompted the hospital community to pause and ask important questions about the fragility of life. It also brought to light a need to attend to our own well-being and that of our colleagues.

This led a group of Buffalo physicians and hospital leaders to attend a resilience conference hosted by the Minnesota Hospital Association (MHA). Here they encountered disturbing burnout statistics along with powerful tools for developing resiliency. Our physicians recognized that this work held the potential for healing their own personal and professional lives. They also saw that it could improve the health of their patients and the health of a much larger community beyond the hospital.

Today the Bounce Back Project consists of a

What are the Five Pillars of Resilience?

The Five Pillars of Resilience help reframe our thinking so that we can see ourselves, and the world around us, in new more positive ways. The five pillars include: self-awareness, mindfulness, self-care, positive relationships, and purpose. By helping people strengthen and apply these pillars, we see them become more resilient.

How can we go from surviving to thriving? “...”

The Bounce Back Project helps physicians regain a sense of joy and purpose in their medical practices. Complete success at this will require broadbased changes, from improving medical training to optimizing technology, enhancing the physician/ patient experience, and restoring humanity to health care. It will also require a change in caregivers’ attitudes.

Bounce Back contributes to this positive enterprise with tools, interventions, and proven methods to reduce burnout and improve caregivers’ quality of life.

The Bounce Back Project involves broad-based community support.

What can you tell us about the partnerships you have developed?

We currently partner with 48 organizations ranging from churches and coffee shops to police

departments, schools, counseling services, and hospice organizations that have made a commitment to support Bounce Back. Additionally, we developed a research collaboration with Brené Brown, PhD, of the University of Houston. Teachers, educators, and administrative leaders in Buffalo are using Brown’s books and teaching materials and will integrate and share what they’ve learned with their students.

Bounce Back will offer the first in a series of mindfulness programs for physicians beginning March 20, 2017. The long-lasting benefits of mindfulness include significant reductions in physician burnout nine months after initial training.

Mindfulness also promotes performance and improves one’s ability to bounce back after challenges.

What plans does the Bounce Back Project have for the future?

Our first CME conference hosted 300 health care professionals eager to learn more and identify their own experiences with burnout. Conference evaluations made it clear we accurately identified multiple causes and results of emotional exhaustion.

We now plan to offer ongoing CME conferences.

Our connections with the medical community provide a foundation from which we expect to grow our Mentorship Program for physicians and managers, as well as an Adaptive Leadership Education Series offered to our own leaders and front-line staff. The coming months will also find Bounce Back reaching out throughout our region, collaborating with colleagues, and creating safe spaces in which physicians and other care providers can have conversations about both the problems and solutions.

We know that burnout fosters personal isolation and withdrawal from important social connections.

The coming months will see expanded Bounce Back tools and teaching opportunities designed to improve social connections. Opportunities will also include building resilience, positive emotion, generosity, gratitude, and mindfulness. Historically these approaches to well-being have been considered nice but not necessary. We now know the opposite is true.

Please share some examples of how your work has helped physicians rediscover the joy of practicing medicine.

Personally, the Bounce Back Project has helped me define what brings meaning and purpose to my life. This work has shown me that I don’t have to be everything to everyone. I can set boundaries and choose to spend time in a manner that’s important to my personal and professional well-being. I can

begin my patient visits by asking them what is going well in their lives rather than always approaching them from a negative posture of what’s wrong.

Due to Bounce Back, several of my colleagues have reshaped their work schedules and even left certain aspects of their work behind. Others have introduced meditation and exercise to their daily schedules and identified what matters most to them.

How can physicians become involved with the Bounce Back Project?

The problem of burnout in health care must be addressed through a variety of initiatives that care for the caregivers. The Bounce Back Project (www. bouncebackproject.org) raises this truth to a practical yet inspired level. We link people and organizations to resources that have proven to bring better health and quality of life to our entire community.

Corey Martin, MD, is director of Medical Affairs for Buffalo Hospital and leads Allina Health System’s approach to address burnout in caregivers.

He is one of the creators of the award-winning Bounce Back Project. Dr. Martin is a practicing family physician and a graduate of Yale School of Medicine. He is a recovering perfectionist and aspiring “good enoughist.”

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3Precision medicine from cover

Molecular and digital information The emergence of the concept of P4 medicine began concurrently with the completion of the Human Genome Sequencing project in 2004. The ability to determine the specific sequence of genes for individual humans suggested the possibility of identifying variations that were unique to a specific person and defining their basis in health and disease. As specific sequences of DNA were associated with specific phenotypic expressions, variants in given genes could be associated with specific pathology and clinical disorders. Genomic medicine began to emerge. These developments suggested that each person was molecularly unique and indeed most humans differ from each other by only 6 million nucleotide base pairs out of a total of 3.5 billion DNA nucleotides in the entire human genome. Therefore, intra-individual variation Genes can only function constitutes about 0.02 percent of our DNA. This as parts of networks. type of molecular specificity made P4 medicine a potential reality allowing enhanced diagnostic specificity, more detailed understanding of causality and progression of disease, the development of highly targeted therapeutics, and the insight to understand both health and wellness.

information technologies, high throughput biomolecular analytic devices, complex computational algorithms and biomathematics, molecular biology, the social realities of medical infrastructure, and economics.

P4 medicine is predicated on four key principles: • Predictive elements are essential to proactive intervention, which can drive disease mechanisms prior to the appearance of symptoms.

• Preventive approaches follow directly from the predictive. Defining disease pathogenesis allows early intervention, delineation of risk factors, and reducing the chances for a pathology to manifest.

• Personalized transcends the traditional approach to health care, which doesn’t often include the understanding or appreciation of the complexities of biology and the environment.

• Participatory recognizes that the individual must be an active part in the preventive and predictive aspects of medicine. The flow of information between individuals and health care professionals is critical at all stages of biomedical assessment and throughout all aspects of health-related interventions, which results in truly individual-based personalized medicine.

Over the past two decades, major advancements have been made in genomic DNA analysis. Today at least 150 targeted disease-related tests are commercially available for clinical use, with an average of approximately 30 variants for each gene as single nucleotide polymorphisms (SNPs), copy number variations (CNV), frank mutations, and sequence deletions. This provides roughly 4,500 genomic changes to guide diagnostic decisions and targeted therapeutics. However, this represents less than 0.5 percent of genomic DNA. The number of accessible sites can be increased by whole exon gene sequencing, which identifies the roughly 22,000 transcribable human genes. This is accomplished by utilizing high throughput sequencing technologies, which provide rapid parallel analysis and are referred to as next generation sequencing (NGS). Emerging third generation DNA sequencing instruments utilize a nanopore technology, which facilitates the passage of long strands of DNA through the pores and allows electronic analysis with extensive parallel sequencing. This instrumentation has the potential to run a complete whole genome sequence (3.5 billion nucleotide base pairs), in less than an hour.

The conversion of this genomic data into useful information required the development of sophisticated analytics, advanced mathematical modeling, and genome specific algorithms. These in turn require rapid, high-capacity computer systems that segregate the excessive biologic signal-to-noise problems associated with large data systems and convert this staggering amount of genomic-based information into clinically useful knowledge.

The genome in context Genomic analysis alone does not provide a sufficient basis for molecularbased personalized precision medicine, or optimal clinical application commensurate with significant biologic expression. All sequencing technologies provide only structural genomics, whereas functional genomics is needed. Genes by themselves are only digital information storage systems, albeit of remarkable capacity; but genes can only function as parts of networks. This allows the downstream transfer of a gene’s digital information via discrete signaling pathways that modify, amplify, process, transfer, enhance, combine, replicate, transcribe, and translate

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the genomic data into biologic effects and the expression of a phenotype.

Systems biology based assessment of multi-omic factors is the foundation of effective individualized and precision-based medicine.

the genomic information of the human genome. How much of this information is actually transcribed to the host is variable, but biologically relevant.

The role of proteomics as a personal biomarker database will be facilitated The Pioneer 100 Project by the adoption of SWATH-mass spectrometry, which can analyze the Perhaps the most effective and impressive demonstration of the systems complex mixture of the proteome from single cells to whole individuals, medicine approach utilizing multi-omics with high-dimensional perform digitalized peptide measurements, and quantify the unique protein diagnostics and data analytics to create a clinically relevant model of profile more rapidly and precisely, providing enormous amounts of data precision medicine, is the Pioneer 100 Project, on quantitatively small samples. Mass spectrometry which was carried out by Leroy Hood and provides proteomics with the power of precise global colleagues at the Institute for Systems Biology in measurements with an equivalence to what next Seattle. generation sequencing has brought to genomics. The The Pioneer 100 Project subjected 108 Sequencing technologies information content of proteins is greater than the volunteers to whole genome sequencing, lab tests genome. The proteome is both digital on the basis provide only structural (blood, urine, and saliva for 150 assays, metabolic of amino acids and sequences and analog as a result genomics, whereas functional biomarkers and unique proteins), gut microbiome of changes in their 3D structure. This approach is genomics is needed. analysis, and continuous lifestyle monitoring. multi-omic as opposed to an exclusively genomeThe result created dynamic personal data centric based precision medicine, and encompasses clouds in which the actionable database increases the concepts of systems biology. over time. This resulted in a multi-omic correlation Processing genomic digital information is data network, that when analyzed identified achieved by using cellular machinery, beginning with the â&#x20AC;&#x153;communitiesâ&#x20AC;? that were more connected with each other than with the transcription of the digital DNA code into a single stranded messenger rest of the network. This allowed the identification of more than 4,000 RNA (mRNA). Further processing at the ribosome generates a series of previously unrecognized statistically significant correlations between data smaller, signaling interferences RNAs, many of which can attach to DNA sequences and serve as regulatory transcription factors. The ribosome, Precision medicine to page 424 which is the most complicated nanomachine in nature, further translates the mRNA information into peptides and larger structural and functional proteins, many of which are enzymes that facilitate an extensive range of metabolic processes. Other peptides also interact with genomic DNA as regulators of transcription.

Genome information is digital, and its translation into proteins is configurational information as these molecules fold and rotate into a variety of three-dimensional structures and expose their surfaces in a dance of unlimited variation. As a human translates this DNA information into greater than 1 million proteins, the amplification of information is staggering and contributes significantly to the multiplicity of biologic expression as health or disease. Further bio-modification occurs as the consequence of intracellular and extracellular environmental effects, many of which are the results of epigenomic factors expressed by methylation of nucleoproteins.

The clinical relevance of this molecular modification is that each of these processes results in the production of chemical biomarkers that are cellular for specific tissues or organs. These biomarkers are the signatures of bio-modification, biologic information processing, and gene expression.

These molecules provide the functional complement to the structural gene sequences in DNA and are the basis for functional genomics. Therefore, genes are relevant only in context and are defined on the basis of the networks in which they are biologically expressed. This provides the molecular basis for precision medicine.

The microbiome The microbiome constitutes a biomass of 5 to 7 kilograms per person, inhabiting our GI tract and external body surfaces. Each human microbial composition is unique and each microbiome contains 500 to 1,000 times

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3Reforming health care reform from cover

the ACA. The Executive Order is more of a policy statement than an immediate, implementable change for the health care system, since the ACA cannot be repealed via executive order. Since Trump oversees the executive typical bill. However, reconciliation has a much narrower scope to affect agencies that implement the ACA, he and his agency leadership are able to policy, since it can only be used for legislation that changes spending, choose how to implement those provisions. For example, the Department of revenues, and the federal debt limit (Reich and Kogan, Introduction to Health and Human Services (HHS) and the Internal Budget “Reconciliation,” 2016).

Revenue Service (IRS) could modify the process for Consequently, reconciliation likely cannot be used claiming a hardship for purchasing health insurance to support a complete repeal of the ACA. Consumer to be easier or more lenient, perhaps by removing protection measures of the ACA, including the legal the requirement that the hardship documentation framework for insurance exchanges, are expected to include either proof of recent bankruptcy filing or remain in place. For example, the provision allowing Health care laws and eviction. Administrative regulations like these can young adults to stay on their parents’ insurance regulations will receive be changed, but do require a specific legal process plans until age 26 doesn’t affect the federal budget, significant attention in 2017. of “notice and comment” under the Administrative and could not be scrapped. Reconciliation could be Procedure Act, which the order does acknowledge. used to modify entitlement spending for programs This process takes anywhere from a couple of like Medicare and Medicaid, putting states that months to a couple of years. On the other hand, expanded their Medicaid programs at significant risk Trump’s administration could decide to cease for major changes and budget cuts. enforcing various provisions of the ACA; Trump Furthermore, a reconciliation bill won’t address ACA advisors have stated publicly that Trump is considering ceasing to enforce replacement proposals, because the process is limited in its authority and the individual mandate tax penalty altogether. While this would likely result scope. The timing and content of a replacement is contentious among in significant litigation for violating a key tenant of the ACA, it is a route Republican legislators; some are pushing for a replacement immediately, Trump’s administration could pursue. while others advocate for implementing the repeal over a period of two to three years to alleviate stress on the health care system.

What is likely to change under ACA repeal?

Executive powers can also impact ACA reform to a certain extent. On his first day in office, President Trump released an executive order regarding

Many proposals to modify or replace the ACA have been introduced by various Republican legislators since its implementation. The most prominent proposals are examined as follows.

Tom Price’s ACA reforms Congress passed a bill in January 2016 (H.R. 3762, 114th Congress) known as the Empowering Patients First Act (EPFA). It provides a preview of what’s possible via the reconciliation process. The key tenants of this bill include discontinuing the individual mandate, repealing tax credits to purchase insurance coverage, and ending Medicaid expansion. This bill was ultimately vetoed by President Obama, but it would have shut down the Federal government’s capability to run health insurance exchanges, cut insurance subsidies, eliminate the individual mandate penalty, and reverse Medicaid expansion efforts, at minimum. EPFA was introduced by current House Budget Chair Rep. Tom Price, who was nominated for Secretary of HHS by Trump. Upon his nomination, Price promised that the impending health care reform would bear significant resemblance to EPFA. Between EPFA and other legislation sponsored by Price, he has demonstrated his desire to overhaul health care coverage in every sector, including ending mandatory purchase of insurance, modifying Medicaid eligibility and funding, and revisiting quality and payment measures for Medicare.

1. There would be no requirement to have health insurance.

EPFA would remove the individual mandate. However, like the ACA, EPFA still requires insurers to cover all individuals who purchase insurance, regardless of health status, often referred to as “guaranteed issue.”

Additionally, EPFA allows insurers to charge higher premiums by rating an individual on his or her health status if that individual does not maintain “continuous coverage.” Under EPFA, a lapse in coverage would allow an insurer to charge a consumer up to 150 percent higher premiums. This is a significant deviation from the ACA, where only age, geographic area, and smoking status are allowable rating factors for calculating premiums. Many argue that the concept of guaranteed issue without the individual mandate

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will cause many healthy and young people to be unwilling to pay the price of the rising health insurance premiums in the individual market if they don’t have to. The resulting increase in uninsured individuals may adversely affect health care systems and providers, as they are likely to see an increase in emergency and charity care as a result.

Block grants give the government more control over how much it will spend overall, since the grants are determined up-front and don’t vary based on enrollment. They also give states more control over how to spend federal funding within the program, and proponents of block grants claim that this increased control would result in greater efficiency.

2. Medicaid expansion would be repealed Likely, switching to a block-grant mechanism without replacement. EPFA significantly cuts would cut overall federal spending on Medicaid. eligibility for Medicaid by repealing the ACA’s The Congressional Budget Office (CBO) estimates Medicaid expansion efforts in its entirety. EPFA that the block grant in Price’s 2017 Fiscal Year doesn’t offer any replacement mechanism to find Budget (FYB) would cut Medicaid spending by $1 Reconciliation likely cannot a landing spot for the over 15 million people who trillion over a decade. The CBO also estimates that enrolled in Medicaid. Those who would no longer block grants would lead to a $7 billion reduction be used to support a be eligible for Medicaid if the expansion is repealed in spending in 2017, but a $169 billion reduction complete repeal of the ACA. could revert to purchasing coverage in the individual by 2026, equivalent to cutting one third of the market. However, the high premiums in the program’s budget (Edwin Park, Mar. 15, 2016). It’s individual market may be too substantial for many difficult to predict how many fewer people would be citizens to afford. This is likely, given EPFA’s tax able to receive Medicaid as a result of that cut. For credit reform; while the ACA determines tax-credit reference, House Speaker Paul Ryan’s 2012 Medicaid eligibility by income, EPFA determines eligibility by block-grant proposal estimated that between 14 and 20 age, giving someone more tax credits the older they become, regardless of million fewer people would be receiving Medicaid by 2022 (John Holahan income. Therefore, the uninsured rate is likely to increase. et al., Oct. 2012). While no concrete calculations have been similarly conducted for Price’s 2017 FYB plan, it’s safe to assume that an overall cut 3. Medicaid would be funded as a block grant. Price has proposed in Medicaid funding would result in many fewer people on the program funding Medicaid via a block-grant structure. Block grants give each state who would need to seek health insurance coverage via the individual market a set annual amount of federal funding. This deviates from the current or forgo coverage altogether. funding structure, whereby the federal government pays a certain percentage of each Medicaid enrollee’s bill, regardless of how many people are enrolled.

Reforming health care reform to page 404

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SPECIAL FOCUS: MEDICAL DEVICES

Treating patients who have medical devices What to keep in mind

BY STUART STEICHEN, DO

T

he world of medicine has changed dramatically with the introduction of medical devices, such as pacemakers, artificial joints, targeted drug delivery systems, and eye lenses. Family medicine physicians are often the first providers to recognize the need for such devices. But more important, once patients start feeling better, they often don’t follow up with their specialists, instead choosing to see their family physician for ongoing medical care. Here are some things we need to keep in mind when treating patients who have medical devices.

Cardiovascular devices The heart is a prime location for implanted medical devices. From pacemakers and stents to implantable cardioverter defibrillators, cardiac resynchronization therapy devices, mechanical heart valves, and even left ventricular assist devices (LVADs), these medical therapies have become more prevalent, especially in older patients. We should be especially vigilant with patients who have cardiovascular disease, helping them learn to listen to

their bodies and watch for signs of difficulty breathing, fainting or dizziness, weight gain, edema in the legs and ankles, and any heart rate changes.

Joint replacement Total joint replacement is one of the most common, and most successful, orthopedic surgeries. Today, many younger, active patients receive new joints and may need to have them replaced during the course of their lifetime. Watch for obvious signs that a joint replacement might be failing, such as increased pain or reduced range of motion. Also, watch for signs of deep vein thrombosis (DVT) in patients with joint replacements. Pain in the leg or arm, accompanied by redness or warmth, could signal a DVT.

Imaging and procedure safety Before scheduling imaging studies, make sure the patient’s device is MRIsafe. Today, more devices are MRI-friendly than before. Even patients with some pacemakers can have an MRI safely, but it’s important to check on the model of device before suggesting an MRI study or check with a radiologist.

Radiologists are a good source of information about what imaging is safe for patients with medical devices. They typically err on the side of safety if they can’t find specific information, especially when it comes to spinal implants.

While some pacemakers and defibrillators today are MRI-safe, patients with metal implants, including pacemakers, defibrillators, insulin pumps, spinal implants, pain management systems, or deep brain stimulation devices, generally should not receive the following medical procedures: • Catheter microwave ablation • Diathermy treatment (high frequency, short wave, or microwave) • MRI (magnetic resonance imaging)—unless specifically noted to be safe • MRA (magnetic resonance angiography) scan • Transurethral needle ablation (TUNA) Procedures such as CT scans, ultrasound, electrocautery, high-energy radiation therapy, radiofrequency ablation, and transcutaneous electrical nerve stimulation (TENS) usually can be performed safely, if the proper precautions are taken to avoid direct interference with the device itself.

New medications Many patients are on new prescriptions for medications after a device implant. Some will remember to tell you. Some will wait for you to ask.

It is an important question. Patients who have received a mechanical heart valve, for example, will most likely be on blood thinners that need to be monitored regularly. We have a special anticoagulation clinic that monitors a patient’s INR and provides immediate results. Remember that patients on blood thinners are more susceptible to injury if they fall, and blood thinners may need to be stopped prior to a patient’s surgical procedure.

Opioid addiction Don’t let chronic pain relief lead to narcotic addiction for your patients.

Devices that control pain, either through spinal cord stimulation that blocks pain signals to the brain or targeted drug delivery that delivers pain

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medication through a catheter to the spinal area, are wonderful devices to help patients suffering from chronic pain. Sometimes, however, the devices lessen the pain but don’t take it away completely. Patients may request narcotic pain medications to bridge the gap. Be cautious of patients who “doctor shop” to receive multiple prescriptions for painkillers. The most common requests are for hydrocodone, oxycodone, morphine, and codeine.

Also, be wary of prescribing painkillers that might heighten the dosage or interfere with medications patients are already receiving.

Due to the increased issue with opioid dependence and the drug’s addictive potential, alternatives such as Gabapentin and Lyrica have been shown to help with neuropathic pain. Also, the NSAID Meloxicam has continued to gain popularity for appropriate patients. Alternatives to opioid medications also include holistic therapies, meditation, physical therapy, drug patches, and acupuncture. Medical cannabis has also been gaining in popularity. This is a controversial issue that will continue to be in the news and have a political undertone.

Infection Infections aren’t as frequent as one might think, but they can be deadly, and we need to be vigilant. Medical devices implanted under the skin, even intraocular eye lenses, can create pockets of infection. If not caught early, they can lead to systemic infections, including sepsis. Patients may not know an infection is starting, so make a point to check the implant site during regular office visits to look for redness, inflammation, seepage at the incision site, or fever. A patient with a serious infection also might present with clammy or sweaty skin, confusion, shortness of breath, or a high heart rate.

Before scheduling imaging studies, make sure the patient’s device is MRI-safe.

The Centers for Disease Control and Prevention suggests that physicians use prescription drug monitoring programs to identify patients who might be at higher risk for overdose or those with substance abuse problems. Try to avoid combinations of prescription painkillers and sedatives, unless medically indicated, and always prescribe the lowest effective dose and quantity needed.

It also is important to know when a patient needs to take antibiotics before a dental appointment to prevent an infection. Those with artificial knees and hips usually don’t need to, but other device implants may require them. Be wary of the dangers of overuse. Dentists can prescribe an antibiotic if they feel it is necessary, as well.

Depression Depression may be more prevalent after a medical device implant. Watch for signs of depression in patients with medical devices, especially cardiovascular devices, deep brain stimulators, or new joints. While studies have not shown any direct cause and effect relationship, physicians have reported an increase in patients exhibiting Treating patients with medical devices to page 254

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SPECIAL FOCUS: MEDICAL DEVICES

New assistive devices Meeting the patient’s needs

BY GARY GOLDISH, MD; ERIC NICKEL, MS; AND ANDREW HANSEN, PHD

T

he VA Minneapolis Adaptive Design and Engineering (MADE) Program is a multidisciplinary group of innovators, including bio-medical engineers and health care researchers who design, build, and test adaptive devices. We don’t typically try to develop super high-tech assistive devices. Instead we strive to develop assistive devices with just the right amount of tech to meet our patients’ needs. Sometimes the simplest devices are the most reliable and efficient. A recent example of a simple but effective device developed by our program is a head extension assist for people with amyotrophic lateral sclerosis (ALS), who have trouble holding their head up. People with neck muscle weakness often complain that traditional devices that work by resting the chin on collars or braces are uncomfortable and interfere with speaking, eating, and turning their head. Our simple device consists of a Velcro elastic strap that attaches to the back of a baseball cap and then, like suspenders, connects to the back of a patient’s pants or belt. Chin or head movement is not restricted.

For people who experience varying degrees of weakness throughout the day,

the elastic strap is adjustable by changing the tension on the head support.

When we develop new devices, we keep simplicity in mind because high tech is not always the solution.

Manual wheelchair improvements The VA MADE Program is working on new prototypes for manual wheelchair users. Census data from 2010 indicate there were approximately 3.6 million wheelchair users in the U.S. While power wheelchairs seem to be an attractive option for some, 70 to 84 percent of wheelchair users still prefer manual models because of reduced cost and maintenance, and relative ease of vehicle transport. Unfortunately, repetitive strain from wheeling and excessive upper extremity loading during transfers results in shoulder pain in 60 to 70 percent of wheelchair users, and is a common cause for eventual abandonment of manual chairs. In a 2013 article in Clinical Biomechanics, Slowik and Neptune used mechanical modeling to determine that optimal shoulder wheeling efficiency occurs when the center of the hand rim is about 10 degrees in front of the shoulders. However, if the tires are placed forward of the wheelchair user’s center of mass, the wheelchair will tip backwards.

In addition, with the hand rim moved that far forward, the tire creates a barrier to a lateral transfer in and out of the wheelchair.

Ergonomic wheelchair Although manual wheelchair propulsion mechanics have not changed significantly over the past century, our goal was to develop an alternative manual wheelchair with ergonomically positioned hand rims without sacrificing stability. We achieved this by uncoupling the hand rim from the drive wheel with a chain-driven system, similar to a bicycle (see Figure 1).

This allowed us to place the hand rim in the preferred forward position, while a quick release of the hand rim allows the occupant to easily perform an unobstructed lateral transfer (see Figure 2). Since we use gears, we can

Chain drive allows separation of the hand rim.

Hand Rim Drive Wheel

Figure 1. The ergonomic wheelchair with a chain drive and decoupling hand rim from the drive wheel.

Source: VA image by April Eilers and used with permission.

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customize the gear ratio between the hand rims and drive wheels to ease the effort of propulsion. By removing both hand rims, the wheelchair is easily converted to a transport wheelchair for accessing tighter spaces.

Another frequent complaint of manual wheelchair users is that rain and snow splashes on their hands, which reduces their grip on the hand rims and poses a problem with maintaining hand hygiene. Because our device keeps the tire separate from the hand rim, wheel debris is less of an issue.

While some people with paraplegia opt for power wheelchairs to gain full mobility in the standing position, these devices are usually not covered by third-party payers if the insured has the upper extremity strength to propel a manual chair. Obviously, switching from manual wheelchair propulsion to power mobility also eliminates an important opportunity for exercise.

In addition, these power wheelchairs have the added disadvantage of being quite expensive and prone to mechanical failure. They are also bulky and heavy, which makes them even more difficult to transport than regular power wheelchairs.

A more mobile standing wheelchair The second wheelchair the VA MADE Program is developing is an improved standing wheelchair for Another relatively recent breakthrough in people with leg paralysis. The most obvious benefits standing technology has been the development of of standing for a paralyzed person are improved robotic controlled leg braces that assist a paralyzed High tech is not always sense of well-being and the ability to reach things person to stand and walk. However, due to the risk the solution. in a traditional environment where standing is the of being stranded or falling, the FDA released these norm. Another benefit of standing periodically is the devices only under the condition that the user is relief of seated pressure on the buttocks, which helps accompanied at all times by an attendant who has lessen the incidence of pressure sores. In 2010 in the been trained to assist the user in case of a malfunction Journal of Spinal Cord Medicine, Sprigle showed or fall. These robotic devices also require the use that standing significantly relieved both sacral and of crutches to provide counterbalance at all times, ischial pressure, whereas wheelchairs that recline or tilt back were not as effectively restricting the use of the upper extremities for other tasks while effective at relieving pressure at both of these pressure points. Each time a standing or walking. paralyzed person stands to reach for something off a high shelf or shakes Despite the perceived health and psychological benefits of standing, someoneâ&#x20AC;&#x2122;s hand while standing at eye level, they are effectively relieving it is estimated that only 0.4 percent of manual wheelchair users use a pressure without the need for further prompting. There are other theoretical health benefits of standing for paralyzed people including reduced spasticity, New assistive devices to page 244 improved bone density, as well as improved bladder and bowel function, although each of these benefits require additional validation.

Currently there are a number of commercially available manual wheelchairs and power wheelchairs on the market that assist the paralyzed person to a standing position. Manual standing wheelchairs typically utilize lever arms and lightweight gas springs to assist the user to a standing position, but once upright, the hand rims are no longer within reach, rendering the wheelchair user immobile. Power standing wheelchairs have a battery-powered electronic motor that propels the wheel and provides the power to shift the paralyzed person to a standing position. The patient controls these wheelchair functions with a joystick. Since the joystick moves with the patient into the standing position, the patient is still able to propel the wheelchair while standing. These wheelchairs therefore allow the user to move more freely in a world where walking is considered the norm (e.g., move freely between tasks at kitchen counters, in the garage, or at a workbench).

Figure 2. (Left) Hand rims can be removed without sacrificing wheelchair stability.

(Right) Allows closer positioning and no obstacle to direct lateral transfers.

Source: VA image by April Eilers (used with permission by Eilers and the subject in the photo).

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3New assistive devices from page 23

Gary Goldish, MD, is a physiatrist at the Minneapolis VA Health Care System where he has subspecialized in spinal cord injury medicine and is the medical

manual wheelchair with the standing feature. We believe that adding the director of the VA MADE Program. functionality of standing mobility to a manual wheelchair may encourage more wheelchair users to adapt to standing as part of their normal routine.

Eric Nickel, MS, is a design engineer at the VA MADE Program.

This motivated us to develop a standing wheelchair that retained the advantages of a manual wheelchair, but included the functional advantages of allowing mobility once in the standing position.

Andrew Hansen, PhD, is a research biomedical We achieved this by installing a chain-drive system engineer at the Minneapolis VA Health Care System, on a commercially existing standing wheelchair director of the VA MADE Program, and an associate called the LEVO LAE from Dane Technologies, professor of rehabilitation medicine at the University Inc., in Brooklyn Park (see Figure 3). The addition There [are] approximately of Minnesota. of the chain drive lets the hand rims move with 3.6 million wheelchair users the user to a standing position allowing the user to in the U.S. Note: The views and opinions expressed in this report push the hand rims from the standing position (see are those of the authors and not necessarily those of Figure 4). Rear casters assure stability while seated the Department of Veterans Affairs or the University of and deployable front casters ensure stability while standing. Mid-wheel positioning of the drive wheel Minnesota. allows the occupantsâ&#x20AC;&#x2122; center of mass to remain over the drive wheel while seated or standing (see Figure 5).

Acknowledgements: The current Ergonomic Wheelchair prototype was We are currently making improvements to both of our wheelchair designs and plan to begin the testing necessary before transitioning our devices to industry for production. Videos of our wheelchairs can be seen at the following links:

4 http://bit.ly/StandingWheelchair 4 http://bit.ly/ErgonomicWheelchair

developed with an award from the Mike Utley Foundation. The current Mobile Manual Standing Wheelchair prototype was developed with an award from the Paralyzed Veterans of America and an award from the Department of Veterans Affairs Rehabilitation Research and Development Service is supporting our continued development.

Figure 3. The commercially available LEVO LAE allows standing, but hand rims and tire remain out of reach.

Source: Dane Technologies, Inc., and used with permission.

Figure 4. The new drive system was added to allow hand rims to rise up with the wheelchair user.

Source: Dane Technologies, Inc., and used with permission.

Figure 5. Allows wheeling in both the seated and standing position.

Source: VA image by April Eilers (used with permission by Eilers and the subject in the photo).

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3Treating patients with medical devices from page 21 signs of depression after these kinds of implants. It may be a short-term reaction to a new medical condition, or it may be something else. Screen your patient for depression if you sense a change.

Exercise

lookout for other conditions, such as high blood pressure, diabetes, and congestive heart failure. The patient may not recognize the symptoms of these comorbidities, as they are often subtle at first, but taking time to check for them will help to avoid serious problems down the road.

Today, many patients wear an implantable insulin pump to help manage their diabetes. Patients with diabetes are at a higher risk for cardiovascular diseases, kidney disease, blindness, neuropathy, retinopathy, obesity, high blood pressure, obstructive sleep apnea, fatty liver disease, cancer, and fractures. We need to make sure that we are taking all the necessary steps to prevent the onset of these comorbidities in our patients with diabetes.

Exercise is still important. Regardless of which medical device a patient has had implanted, exercise is still important.

Individuals with joint replacements usually leave the hospital with a regimen for physical and occupational therapy. Helping them keep up with their therapy is important. Likewise, individuals Watch for signs of Conclusion with cardiovascular devices need to keep their Medical devices are becoming more prevalent. depression in patients with hearts working strongly, but they should stay away Technological advances are increasing rapidly, medical devices. from heavy lifting or anything that puts a strain making it likely that we will see more and more on the heart. Thereâ&#x20AC;&#x2122;s no excuse for not exercising, patients with implanted medical devices. While but you may need to help your patients find new this article didnâ&#x20AC;&#x2122;t address all of the medical devices ways to stay in shape. I tell my patients to try for 30 we see in our patients, it is meant to be a reminder minutes of exercise at least five times a week, if they that while a patient may come to us for a sore can. Walking and water aerobics can wear off calories, but make sure any throat, we need to be mindful of the whole patient, including any implanted implanted medical device is water-safe. medical device, in order to provide a high standard of care.

Comorbidities As people age and need medical devices, they frequently have comorbidities.

Physicians with patients who have cardiovascular devices should be on the

Stuart Steichen, DO, is a family medicine physician at the Apple Valley Medical Center.

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SPECIAL FOCUS: MEDICAL DEVICES

The hybrid closed loop therapy system A step closer to an artificial pancreas

BY AMY B. CRIEGO, MD; ANDERS L. CARLSON, MD; AND RICHARD M. BERGENSTAL, MD

L

iving with type 1 diabetes (T1D) requires constant real-time attention and forward thinking to manage blood glucose variability.

Improving blood glucose control with more time spent in range, while minimizing both low and high blood glucose variations, is very time consuming and often very frustrating. Improvements in insulin pump therapy and continuous glucose monitoring technology have been beneficial, but device use still remains quite low. According to data from the T1D Exchange Clinic Registry (77 clinics in 35 states collecting common data on children and adults with T1D), about 60 percent of people with type 1 diabetes use insulin pump therapy and only 10 to 15 percent use continuous glucose monitoring. Many people with type 1 diabetes test their blood glucose up to 10 times or more daily. Parents of children with T1D are often fearful of blood glucose variability overnight and end up waking their child every two to three hours for glucose monitoring. For these reasons, the term “artificial pancreas” carries an expectation of the device truly acting like the pancreas in managing glucose variability with minimal

to no need for human oversight or intervention. The recent FDA approval of the world’s first hybrid closed loop therapy system is a step toward this goal, but the device management and requirements for interaction must also be kept in mind.

The Medtronic 670G Hybrid Closed Loop system was approved by the FDA for people with T1D age 14 years and older with expected availability of the device in the spring of 2017. The 670G system incorporates a new, more accurate version of the Medtronic Guardian glucose sensor than previously available that attaches to the body under the skin and an insulin infusion site catheter under the skin that is taped down and connected via tubing to the insulin pump. The insulin pump contains the algorithm software that automates insulin delivery changes based on the glucose sensor data. The device automatically makes changes in insulin delivery between meals and overnight, but users still need to manually administer an insulin bolus before eating based on meal content. The system is dependent on appropriate battery life for devices, accurate glucose sensor data, and consistent insulin infusion. Calibration of the device using finger-stick glucose values is necessary at a minimum every 12 hours.

The pivotal study Both the pediatric and adult endocrinology research teams at the International Diabetes Center (IDC) in Minneapolis (part of Park Nicollet/ HealthPartners Clinic and HealthPartners Institute), were involved in the pivotal trial of the 670G Hybrid Closed Loop system. The trial results were published in JAMA online Sep. 15, 2016 (Bergenstal et al.), and FDA approval of the 670G system followed shortly thereafter on Sep. 28, 2016.

The study was conducted across 10 sites (nine in the United States and one in Israel) and included 124 patients with type 1 diabetes, 15 at the IDC. Subjects had a mean age of 37.8 years, a mean duration of diabetes of 21.7 years, and a mean baseline HbA1c that was 7.4 percent (P < .001). Baseline measurements were established during a two-week run-in period followed by a three-month study phase of the hybrid closed loop system at home. The study included a five-night study in a supervised hotel setting once over the three month study phase.

Results showed a mean decrease in HbA1c of 0.5 percent. Time spent with glucose below 70 mg/dL decreased from a mean of 5.9 percent at baseline to 3.3 percent during system use, and time spent with glucose below 50 mg/dL decreased from 1 percent at baseline to 0.4 percent during system use. The amount of time spent in the target range of 71 mg/dL to 180 mg/ dL increased from 66.7 percent at baseline to 72.2 percent. Additionally, participants had better overnight control with the hybrid closed loop system with time in range averaging 75.3 percent compared with 66.8 percent at baseline (P < .001).

No diabetic ketoacidosis, severe hypoglycemia, or serious device-related adverse events were observed during the study, a total of 12,389 patientdays. Follow up continues with these study subjects to obtain more longterm data. Studies are also ongoing regarding use of the device in children ages 7 to 13 years.

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Patient experiences

Challenges for the clinician

At the completion of the aforementioned pivotal trial, 99 participants The hybrid closed loop technology also presents new challenges for the worldwide, 12 at the IDC, opted to continue using the system through clinician and diabetes team. For 50 years, IDC has used a patient-centered, the FDA’s continued-access program. The establishment of the continuedteam-based approach to diabetes management, and the advent of new access program was both interesting and revealing since it was the 670G technologies is no different. However the hybrid closed loop device may study research volunteers who successfully lobbied the FDA to approve require endocrinologists, diabetes educators, and patients to think about a continuation phase of the study due to their insulin delivery differently. For example, some of the enthusiasm during the study. Overall, patients were “clinical pearls” to pump management used in the very pleased with the device. Parents of a 14-year-old past may no longer apply or may need adjustment. with T1D who used the 670G device said it was the How patients’ glucose responds to things like stress first time they had slept through the night in over 10 or exercise may be different than they are used to.

The term “artificial pancreas” years. Another patient was thrilled that her fasting For example, we had previously advised patients carries an expectation of the blood glucose was more reliably stable, and she was to reduce their insulin delivery rate during or after device truly acting like the not waking up one to two times per night just to exercise (temporary basal rate) or eat additional pancreas. check blood glucose and take a correction dose of carbohydrates to avoid hypoglycemia. Now with the 670G system, a higher glucose target range of insulin (or eat glucose if she was low). In the study, 150 mg/dL (versus the usual preset glucose target volunteers at the IDC had a consistently safe night range of 120 mg/dL) can be temporarily set by the of sleep with less worry. Waking up in the morning patient to avoid hypoglycemia around exercise. The with an in-range blood glucose was probably the algorithm in the pump continues to change the amount of insulin delivered biggest benefit expressed. While clinicians are frequently focused on HbA1c as it senses the direction the glucose is moving. Further, how we display, and glucose values, the reduction in the daily burden of living with T1D share, and interpret blood glucose and insulin delivery data also changes. by letting the hybrid closed loop system do a portion of the work was a There are many more clinical pearls in using the 670G system and the IDC substantial benefit. This was especially beneficial overnight when insulin looks forward to working with clinicians and diabetes educators to help needs can vary significantly and blood glucose variability is worrisome and can be potentially catastrophic. For those not choosing to continue using the The hybrid closed loop therapy system to page 314 hybrid closed loop system after the initial three-month study, reasons varied but some subjects did express a sense of burnout from device management.

Managing patient expectations Patients changing to hybrid closed loop therapy do not need to be insulin pump experts. They do, however, need to demonstrate safe and competent use of an insulin pump. They should be able to safely follow management recommendations for hyperglycemia and hypoglycemia. They should also be able to accurately count carbohydrates. Many aspects of the hybrid closed loop technology are similar to traditional pumps, and patients should be trained and comfortable with using bolus calculation features as well as with continuous glucose monitoring. Patients will still need to change the insulin reservoir and infusion set, insert and calibrate sensors, and navigate the menu features and settings on the device. It is important to manage patients’ expectations that this device does not eliminate the need for diabetes selfmanagement but rather is an advanced tool that can help them achieve better diabetes goals.

Glucose sensor Infusion site

Transmitter Insulin pump with closed-loop algorithm software

Figure 2.

The 670G Hybrid Closed Loop system: insulin pump (with closed loop software and insulin infusion site) and glucose sensor with transmitter to send glucose values to the insulin pump every five minutes.

Source: Medtronic

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PROFESSIONAL UPDATE: GENOMICS

CFTR modulator therapy New hope for treating cystic fibrosis

BY TERRI LAGUNA, MD, MSCS

“Y

our baby has a disease called cystic fibrosis (CF). There is no cure for CF; however, the University of Minnesota Cystic Fibrosis Center will work with your family to provide the best in clinical care to allow your child to live as long and healthy a life as possible.” This was a typical conversation held with families at the time of initial CF diagnosis

by Minnesota state newborn screening just five years ago. Today, this conversation has a more optimistic focus: hope for the future. Thanks to remarkable research progress by the CF community in the search to cure CF, personalized medications are now available that are tailored to the genetic mutations that cause the disease, allowing for an individualized treatment approach never thought to be possible before.

Cystic fibrosis remains the most common autosomal recessive lifelimiting illness in the Caucasian population, with approximately 35,000 adults and children in the U.S. living with CF. Secondary to significant advances in medical care and therapies, the life expectancy in CF has dramatically increased from less than a year of age in 1940 to almost 41

years old today. Although the biggest cause of morbidity and mortality in CF is damage to the lungs, the disease affects almost every organ including the sinuses, liver, pancreas, GI tract, sweat glands, and reproductive organs.

CF is caused by a genetic mutation in the protein that makes a chloride channel called the cystic fibrosis transmembrane conductance regulator (CFTR). This chloride channel is responsible for regulating salt and fluid homeostasis throughout the body. The phenotype seen in CF is the direct result of genetic mutations that alter either the presence or function of CFTR at the apical surface of epithelial cells in exocrine organs. Well over 2,000 different CFTR mutations have been identified to date, and these have been categorized into five functional classifications that provide a framework with which to consider personalized therapeutic approaches. Class I, II, and III mutations are considered severe, as minimal chloride transport is observed, which results in the classic “pancreatic insufficient” CF phenotype. Class IV and V mutations allow for some residual chloride channel function, with these patients often having preserved pancreatic function (i.e., pancreatic sufficiency) and a milder CF phenotype. Gaining an understanding of the relationship between mutation class and CF phenotype has paved the way for the discovery of mutation-targeted therapeutics.

Current treatment Although the CFTR gene was discovered in 1989, successful gene therapy and an ultimate cure have proven to be elusive. Therefore, treatment of CF has traditionally been focused on alleviating the complications of absent or reduced chloride function. Secondary to impacted mucus in the airways, impaired mucociliary clearance, infection and inflammation are treated using a combination of nebulized mucolytic medications, inhaled antibiotics, and high-frequency chest wall oscillation therapy. This aggressive regimen of airway clearance is a twice daily cornerstone of therapy for all patients living with CF. Damage from blocked pancreatic ducts necessitates the use of exogenous pancreatic enzymes, vitamins, and salt to combat the malabsorptive symptoms that are characteristic of CF. Multidisciplinary health care teams provide a comprehensive approach to the care of patients with CF and their families, and this therapeutic approach has resulted in a steady increase in life expectancy. However, the disease has always been one step ahead of our medications and treatments—until now.

New drug development The Cystic Fibrosis Foundation (CFF) was founded in 1955 by a group of parents with the goals to understand the disease, create new treatments, and ultimately find a cure. In the late 1990s, the CFF expanded its research program and partnered with biotech and pharmaceutical companies to utilize high-throughput screening (HTS) approaches to identify compounds that could restore CFTR function in vitro. HTS involves the robotic drug screening of millions of compounds in cell-based fluorescence assays of CFTR activity.

It was through this HTS approach that two types of CFTR modulators (or “hits”) were discovered: potentiators and correctors. Potentiators are capable of augmenting the function of CFTR that is already present on the epithelial cell surface and therefore helping to restore chloride conductance. Correctors serve to improve the processing and chaperoning of CFTR in the cell, allowing it to reach the epithelial cell surface where it could now participate in chloride flux.

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The identification of potentiators and correctors via HTS was only the first step in the process of new drug development. The function of these compounds has to be validated using in vitro cell models of human bronchial epithelial cells. Then, following successful drug development in animal models, these potential therapeutic agents need to be put to the test in human clinical trials with the goal of identifying drugs that successfully treat the underlying issue of chloride channel dysfunction in CF. The path to approval by the U.S. Food and Drug Administration (FDA) is a long one; however, CFTR modulator therapy represents a treatment for CF unlike any medication we have had in our drug arsenal against this life-shortening disease.

significantly improved lung function, decreased the number of CF pulmonary exacerbations, and improved weight gain in people with CF. This was the first time a drug had been identified that directly impacted chloride channel function in CF resulting in clinical improvement and FDA approval for use in people with CF ≥ 6 years of age with at least one copy of the G551D CFTR mutation in 2012.

Following the successful completion of additional clinical trials using Ivacaftor in people with CF harboring other gating mutations similar to G551D, the FDA has now extended its use in people with CF ≥ 2 years of age with one of 10 specific CFTR mutations, covering approximately 10 percent of the entire CF population.

Help for some

Although the approval of Ivacaftor was a significant accomplishment by the CF scientific community, there was still work to be done to identify a therapy for the remaining 90 percent of the CF population.

The most common CFTR mutation, Phe508del, was the next target given that nearly 50 percent of the CF population is homozygous for this mutation and close to 80 percent harbors at least one copy of the Phe508del mutation. Phe508del is a Class II CFTR mutation, meaning the CFTR protein is degraded in the cell during trafficking and processing steps, preventing it from making it intact to the epithelial cell surface and, therefore, making an unsuitable candidate for Ivacaftor use. Through the use of HTS, a second class of CFTR modulator therapy was identified—a corrector called Lumacaftor. The

The disease has always been one step ahead of our medications and treatments.

Ivacaftor (or Kalydeco) was the first potentiator drug identified through the process of HTS to be evaluated in clinical trials. In order for a potentiator compound to augment chloride conductance, it requires the presence of CFTR on the epithelial cell surface, a characteristic of CFTR genetic mutations belonging only to Class III or IV. These “gating mutations” have very limited or absent CFTR function, with Gly551Asp-CFTR (G551D) being the most prevalent of these mutations and present in 4–5 percent of the CF population. As Dr. Frank Accurso and Dr. Bonnie Ramsey reported in the New England Journal of Medicine, in clinical trials in people with CF with at least one copy of G551D, Ivacaftor was found to significantly improve chloride channel function as measured by surrogate markers of CFTR activity: sweat testing and nasal potential difference measurements.

When tested longitudinally using meaningful clinical endpoints, Ivacaftor

Focusing on the Phe508del mutation

CFTR modulator therapy to page 304

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3CFTR modulator therapy from page 29

on their genotype, the epitome of personalized medicine. For maximum benefit, this medication should be initiated prior to the onset of either pancreatic or lung disease—perhaps even in utero! Clinical trials of the above-mentioned FDAfunction of a corrector compound is to improve cellular processing of CFTR, approved medications continues in younger age groups, hopefully resulting therefore allowing it to reach the cell surface. Unfortunately, clinical trials of in eventual approval for newborns. Unfortunately, these drugs do not reverse Lumacaftor alone in people with CF homozygous for the Phe508del mutation disease already acquired secondary to chloride channel dysfunction. And much failed to show clinical benefit. However, as Dr. Claire Wainwright reported to their disappointment, patients with CF are not yet able to stop their daily in the New England Journal of Medicine, clinical trials evaluating the effect airway clearance treatments or nutritional support of the combination of Lumacaftor in combination once they start taking these new medications. CFTR with Ivacaftor (Orkambi) in people homozygous for modulators are not yet the “cure,” although they will Phe508del did show significant clinical benefit— significantly extend longevity and improve quality of with improved lung function, a decreased rate of The goal of the CFF is to life. As a result of these advances in treatment for CF, CF pulmonary exacerbations, and a higher body identify a CFTR modulator the conversation that is had upon diagnosis by state mass index. This effect was not seen in people with therapy for its entire population, newborn screening programs has changed significantly.

CF heterozygous for Phe508del. Following extensive regardless of genotype.

“Yes, your baby has CF; however, research advances evaluation in clinical trials, Lumacaftor/Ivacaftor was over the last few years have led to the discovery of FDA-approved for use in people with CF ≥ 6 years of new medications that correct the underlying chloride age who are homozygous for the Phe508del mutation transport defect in CF. Based on the genetic mutations in 2015, with ongoing trials in younger children. that your baby has, there either is or shortly will be a medication available to Finding a therapy for the rest of the CF population help increase the longevity of your child’s life.” We are now able to give parents The goal of the CFF is to identify a CFTR modulator therapy for its entire the hope that their children born with CF have the potential for a normal life population, regardless of genotype. The approval of Kalydeco and Orkambi has expectancy—encouraging words we were never able to provide before. provided a therapy for approximately 60 percent of the CF population; however, the search for other medications is ongoing. HTS and drug development Terri Laguna, MD, MSCS, is an assistant professor of pediatrics, co-director of the continues for CFTR mutations in other classes, in addition to searching for Minnesota Cystic Fibrosis Center, and director of the Pediatric Cystic Fibrosis Program CFTR modulators with more robust clinical effects and fewer potential side at the University of Minnesota. She is board-certified in pediatric pulmonology. effects. Ideally, a CFTR modulator will be available for every CF patient based

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3The hybrid closed loop therapy system from page 27 them get up and running successfully if they choose to use the system and have an appropriate support team available. Medtronic may have the first hybrid closed loop system approved by the FDA, but there are several other institutions and companies with their own “artificial pancreas” technologies who are also actively working in the field, and over the next few years each of these new systems will have their own unique features.

Continued advancements The notion of an “artificial pancreas” has been around for over 30 years, with advancements in its development seemingly right around the corner.

While this first-generation hybrid closed loop technology is very exciting— like with cell phones or computers—the future of these devices is even more promising. The current hybrid closed loop systems deliver only insulin to help control the blood glucose levels. It is likely we will develop more sophisticated algorithms to fine-tune the delivery of the insulin or faster acting insulins to better control blood glucose levels after meals. There is also work going on with automated insulin delivery systems that deliver not only insulin, to keep the blood glucose levels down, but also deliver glucagon if needed, to try and prevent the glucose from going too low.

Cost and insurance reimbursement will be major factors in how widely and quickly these technologies are adopted. It will be important for the entire diabetes community to work closely with health care systems, device manufactures, payers, and charitable foundations to ensure that people with T1D who may benefit from hybrid closed loop therapy and wish to pursue

its use have affordable access to this technology. Appropriate device training and follow up will be essential for safe and effective implementation. Many new systems are currently under development, and there will be a need for patients to step forward to be on the frontier of new diabetes technology.

We rely on volunteer research participants to push this field forward, and with their continued dedication to improving diabetes, we hope progress will continue to ease the burden of type 1 diabetes.

Amy B. Criego, MD, is chair of the Department of Pediatric Endocrinology at Park Nicollet and is a medical director at the International Diabetes Center in Minneapolis. She is a T1D Exchange Clinic Registry Investigator and an investigator on JDRF and NIH/NIDDK grants to study new artificial pancreas systems.

Anders L. Carlson, MD, is a medical director at the International Diabetes Center in Minneapolis, and an adult endocrinologist and director of the Diabetes Program at HealthPartners, based in St. Paul. He is also an investigator on JDRF and NIH/NIDDK grants to study new artificial pancreas systems.

Richard M. Bergenstal, MD, is the executive director of the International Diabetes Center at Park Nicollet in Minneapolis and an adult endocrinologist.

He is past-president of the American Diabetes Association and was the ADA’s Outstanding Physician Clinician in 2007. He serves on the T1D Exchange Clinic Registry Steering Committee and is the PI on an NIH/NIDDK grant to study the next generation of artificial pancreas systems.

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CHRONIC DISEASE

Treating obesity A multidisciplinary approach

BY CHARLES J. BILLINGTON, MD, AND DANIEL B. LESLIE, MD

found between patient and individual medications. Four new medications are on the market.

O

besity is now recognized as a disease, and can be Qsymia provides probably the most potent effect on body weight, and effectively considered a chronic disease. Obesity creates is a combination of low doses of phentermine and topiramate. Phentermine morbidity and mortality in as an individual agent has been around since 1959, itself, particularly in its most and relating to that long history is approved only severe forms. Obesity also drives for short-term use. Topiramate is an anti-epileptic the development of other chronic illnesses. As such, and migraine preventive that is known to have effective medical management is urgently needed, considerable body weight loss potential. When particularly among those most severely affected.

Obesity is now recognized these two drugs are combined, clinical trials

New medications

as a disease.

There is an obesity treatment gap created by limitations in the effectiveness of lifestyle interventions alone combined with recognition that not all severely obese patients can or should get bariatric surgery. The use of medications is crucial treatment that can fill this gap, improve adherence to lifestyle change, and provide effective relief of illness for a substantial fraction of patients.

Fortunately, pharmaceutical science has provided a number of recent treatment options, enhancing the likelihood that an appropriate fit can be

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indicate that body weight loss in the range of 10 to 15 percent can be achieved, a magnitude of weight loss similar to lap-band surgery. The most common side effects with the Qsymia drug combination are dry mouth and tingling in the extremities and face (paraesthesias).

Lorcaserin (also known as Belviq) is a highly selective serotonin agonist shown to be safe and effective for obesity treatment. The selective nature of this serotonin medication alleviates concerns about heart valve problems associated with nonselective serotonin weight loss medications. Extensive

clinical trials indicated no heart problems associated with this medication, and overall safety for the medication is relatively good. The principal side effects tend to be headaches. Overall weight loss effectiveness is in the 8 percent body weight range, but there are some individuals who respond better.

Contrave combines low doses of two medications with a long history as the individual drugs, bupropion and naltrexone. This combination medication is effective in the 8 to 10 percent body weight range in clinical trials, but again there are individuals who respond better. The principal side effects with this medication tend to be nausea and dysphoria.

Liraglutide (also known as Saxenda) has been recently approved as medical treatment for obesity at a higher dose than already used in treatment of diabetes. Liraglutide has a several year history as effective treatment for type 2 diabetes, and is known to be associated with weight loss in that setting. This higher dose of liraglutide produces weight loss in the range of 10 percent. This medication requires a daily subcutaneous injection, and has the most common side effect of nausea.

Tackling hunger and cravings Overall, these medications, as well as off-label use of some of the key components of these medications, can relieve two of the most important biological barriers preventing patients from losing weight, hunger and cravings. Medications like phentermine and lorcaserin can provide relief from hunger. Craving can be managed with drugs like topiramate, naltrexone, and bupropion. Liraglutide appears to provide some benefit for both hunger and cravings.

Use of these medications can provide clinically meaningful weight loss, and alleviate illness and suffering. The principal barrier limiting these medications is the combination of significant cost and infrequent coverage by payers. When we are able to overcome these barriers, the medications can contribute significant benefit to our patients suffering from obesity.

Surgery In regards to bariatric surgery the trend in procedure type has changed dramatically over the last five years and at the University of Minnesota.

Ninety-five percent of primary bariatric surgeries performed at the University of Minnesota Medical Center in 2015 and 2016 were vertical sleeve gastrectomies. In this procedure, a large volume of stomach is removed completely and unlike with gastric bypass, there is no rerouting of the intestines while with vertical sleeve gastrectomy, patients are able to lose 50 to 60 percent of their excess weight (about 20 to 25 percent of initial body weight). In comparison to gastric bypass, previously the most common procedure, the sleeve offers reduction in long-term complications such as iron deficiency anemia, nutritional deficiencies, internal hernias, marginal ulcers, and hypoglycemia.

A multidisciplinary approach In a combined medical and surgical weight management program, lifestyle changes as well as medications can be used in many different ways.

Preoperatively, medical weight management can assist with weight loss before surgery therefore lowering the risk of complications during and after surgery and give patients a head start on their weight loss journey.

and helps with long-term weight maintenance. Over time, the role of revision surgery has become less common and therefore medications can also be of benefit to patients who may have regained some weight after bariatric surgery.

Close collaboration between medical and surgical weight management programs is also key for patients who do not want weight loss surgery or patients who are not candidates for weight loss surgery for other medical or psychological reasons. Although weight loss results with lifestyle and medications is modest in comparison with surgery, research has shown that weight loss as low as Treating obesity to page 344

QUALIFICATIONS FOR BARIATRIC SURGERY at the University of Minnesota Medical Center 14 BMI ≥ 40, or more than 100 pounds overweight.

24 BMI ≥35 and at least two obesity-related comorbidities such as type II diabetes (T2DM), hypertension, sleep apnea and other respiratory disorders, non-alcoholic fatty liver disease, osteoarthritis, lipid abnormalities, gastrointestinal disorders, or heart disease.

34 I nability to achieve a healthy weight loss sustained for a period of time with prior weight loss efforts.

44 Patient must be psychologically stable.

54 Smoking cessation required prior to surgery.

eight loss requirement three to six months prior 64 W to surgery.

For example, a person who is 5’ 5” tall, weighs 250 pounds, and has a BMI of 41 may be eligible for bariatric surgery.

It is not a requirement for all bariatric programs, but at the University of Minnesota any person who smokes needs to stop smoking prior to surgery. Patients also have a weight loss goal to meet prior to surgery. This reduces the risk of complications during the surgery and it also empowers the patient toward a successful weight loss journey.

After surgery, patients can expect to lose weight during the first six to 18 months. Surgery is only a tool and in order for that tool to continue to work, lifestyle changes are necessary.

This includes eating healthy foods, limiting the amount of calories and carbohydrate intake, and incorporating exercise into their daily lives. Life-long follow up is also recommended for all patients who have weight loss surgery in our program.

Following surgery, continued support from a medical weight management program and possibly weight loss medications typically improves outcomes for bariatric surgery patients and optimizes weight loss

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3Treating obesity from page 33 5 percent of initial body weight can lead to favorable improvements in blood pressure, cholesterol, glucose levels, and insulin sensitivity.

The best weight-loss and overall health results are achieved with a comprehensive program involving weight management providers, surgeons, dietitians, and behavioral specialists providing individualized treatment.

Charles J. Billington, MD, is professor of medicine at the University of A multidisciplinary approach to the treatment of obesity is needed to Minnesota and associate director of the Minnesota Obesity Center. He created optimize the patient’s success. This approach may consist of behavioral therapy regarding diet and exercise with an individualized plan prescribed and directs the medical weight management programs at the Minneapolis by dietitians, exercise physiologists, health coaches, VA Medical Center and the University of Minnesota. or weight management providers. Sometimes a preHis research has focused on the brain mechanisms packaged meal replacement plan may play a role in of obesity, originally the role of Neuropeptide Y in medically supervised diet changes. Psychological appetite and energy metabolism, and subsequently evaluations and continued therapy are also A multidisciplinary approach on brain mechanisms regulating food intake, physical treatments that are key to assisting with behavior to the treatment of obesity activity and energy metabolism. His clinical research changes and stress management. Providers should is needed to optimize has focused on obesity treatment and energetics of also evaluate a patient’s current and past medical the patient’s success. activity, and more recently on the effects of bariatric history and identify any medications that are considered “weight gainers.” These may include surgery on diabetes. steroids, psychiatric medications, and insulin.

Weight loss medications may help with appetite reduction, cravings and/or to change the patient’s thoughts and interest in food. There are medications approved for the treatment of obesity such as phentermine, Contrave, Qsymia, Belviq, and Saxenda as well as others commonly used off label for weight loss such as topiramate and naltrexone.

Insurance coverage continues to be a barrier to the use of many of these medications but hopefully with the growing awareness of obesity as a chronic disease, these medications may be more widely available in the future.

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Daniel B. Leslie, MD, is assistant professor in the Department of Surgery at the University of Minnesota, the system-wide director of Bariatric Surgery for University of Minnesota Health and Fairview, and the medical director for CentraCare Weight Management. He is board-certified in surgery (ABS) and obesity medicine (ABOM). He has an active interest in diabetes and cardiovascular risk reduction after bariatric procedures as well as novel interventions to treat bariatric patients.

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RESEARCH

Autism and genetic discoveries The search for clinical biomarkers

BY MADHUMATHI RAO, MD, MS, AND SUMA JACOB, MD, PHD

A

utism spectrum disorder (ASD) is a neuropsychiatric disorder that is present in all racial, ethnic, and socioeconomic groups, and is five times more common in boys than in girls. The prevalence in the United States has increased from 1/166 children in the year 2000 to about 1/68 in 2012, a total approaching 3 million people in the U.S. alone. It is unclear if the increase in prevalence is due to more awareness of the symptoms of autism in the general public leading to an increase in its diagnosis or, if it is from increased incidence of the disease itself. According to the CDC, the total cost per year for children with ASD in the U.S. was estimated to be between $11.5 billionâ&#x20AC;&#x201C;$60.9 billion (2011 U.S. dollars). This significant economic burden represents a variety of direct and indirect costs, from medical care to special education to lost parental productivity. In addition to medical costs, intensive behavioral interventions for children with ASD cost $40,000 to $60,000 per child per year.

What we know According to DSM-5, autism spectrum disorder (ASD) is a range of neurodevelopmental disorders encompassing the previously defined

DSM-IV independent diagnoses of autism, Asperger syndrome, pervasive developmental disorder (PDD-NOS), and childhood disintegrative disorder.

ASD (henceforth autism) is a heritable and highly heterogeneous disorder, caused by familial genetic risks in addition to possible gene/environment interactions during early development. Cardinal features of autism include impairments in social behavior and communication as well as restricted and repetitive interests. In addition to the wide variability in the presentation of core deficits (see Figure 1), it is seen with a broad range of intellectual abilities, and sensory and motor impairments. Often, patients suffer from anxiety disorders, aggression, epilepsy, and gastrointestinal disorders that bring them to initial clinical attention.

The heterogeneity inherent to autism makes each individual unique, requiring personalized educational, social, occupational, and medical care for which, unfortunately, options to date remain limited. Autism continues to be a clinical diagnosis delivered by trained clinicians using standardized assessments with no confirmatory biomarkers. Neither current interventions (that predominantly target behaviors), nor medications are approved to treat the core symptoms and cognitive deficits of autism. This characterizes the complexity of the molecular pathways and pathogenesis of autism that has challenged researchers for the past two decades.

The central goal of genetic research in autism as with other neuropsychiatric disorders is to identify molecular pathways for further investigation that would result in associating biological mechanisms with behavior. Based on experience with other fields of medicine, the resulting knowledge should enable the discovery of new treatments.

Figure 1. The variability of symptoms in autism.

Source: Madhu Rao, MD, MS, University of Minnesota.

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Early twin studies demonstrated significant heritability of autism, What may seem like large strides made in autism genetics research is still not enough to translate to clinical practice. The initial findings have leading to large-scale genetic studies that further confirmed that autism underscored the need for far larger sample sizes if we are to successfully elucidate is highly familial. In the U.S., the siblings of children with autism are the genetic framework of autism. In order to identify unknown genetic estimated to be at more than a tenfold increase in risk for an autism mutations, make accurate genotype-phenotype associations with statistical diagnosis themselves, moreover, family members of children with autism significance, a lot of data needs to be collected and analyzed. Integration of are also more likely to have a history of psychiatric diseases, including genetic knowledge with clinical information will ultimately drive creation schizophrenia, bipolar disorder, and depression. Such familial presentation of effective prevention strategies, diagnostic tools, of psychiatric illnesses is consistent with a complex, and personalized treatment programs. To this end, inherited genetic risk. It was soon recognized that several efforts are underway, to leverage advanced the study of the human genome in its entirety technologies to implement the â&#x20AC;&#x153;Big Dataâ&#x20AC;? approach The total cost per year for was at the heart of investigating the complexity in autism research and management. of autism. Technological advances over the past children with ASD in the U.S. decade have made whole genome sequencing faster was estimated to be between The three Vs of Big Data and more affordable. Genome-wide association $11.5 billionâ&#x20AC;&#x201C;$60.9 billion.

Big Data is commonly defined with three Vs: data studies (GWAS) have made it possible to identify that arrives in increasing volumes, with ever higher some common variants (heritable) contributing to velocity, and containing great variety as opposed to such polygenic risk as well as de-novo mutations traditional low volume static database systems. It uses (spontaneous). Susceptibilities to environmental advanced technologies such as cloud-based storage, real-time computing, factors were identified such as advanced parental age, intrauterine exposures and business intelligence to analyze data and draw correlations. Big Data including infections, immunologic effects and toxins, fetal cerebral has been successfully implemented in the industry to evaluate market trends hypoxemia, prematurity, and environmental toxins. Some gene variants and drive business strategy. For example, Google analyzes the clicks, links, were found to be common with diseases such as fragile X syndrome, schizophrenia, and intellectual disabilities. As such, several global research and content on 1.5 trillion page views per day and delivers search results initiatives involving subjects from different ethnicities and geographies plus personalized advertising in milliseconds. Big Data technology has been have identified genes that are convincingly associated with autism and have resulted in some early biological insights.

Autism and genetic discoveries to page 384

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3Autism and genetic discoveries from page 37 successfully used in biomedical research and the health care industry to study prevalence and trends, risk factors, genotype/phenotype associations, health care costs, and optimization. A well-known example in clinical

STRUCTURED

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Several large research projects are already underway in autism research.

These initiatives are supported by the government and private sectors, as well as academic institutions across the world.

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HIPAA SECURITY REAL-TIME PROCESSING

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CLINICAL CARE 3 PREVENTION 3 DIAGNOSIS 3 TREATMENT

Figure 2. Big Data–Autism research.

Source: Madhu Rao, MD, MS, University of Minnesota.

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The vision for utilizing Big Data technology in autism research is to create a secure, central repository of data with real-time processing capabilities that can extract accurate patterns to inform clinical care (see Figure 2).

The sources of data are varied and the data itself can be structured and unstructured. Structured data sets include predefined entities such as labs, imaging, medications, genome maps, scientific literature, IEPs (individual educational plans), and financial reports. Unstructured data sets include data feeds from social media such as email, texts, tweets, video, and audio files that would inform the needs and trends of the autism community. With a global unique identifier for each subject, data is designed to be compliant with HIPAA guidelines to protect anonymity and confidentiality. Cloudbased technology and artificial intelligence tools are used to store, process, analyze, and report on the Big Data. The overarching goal of this initiative is to build a large sample size that ensures the statistical power needed to translate genetic research into the clinical practice of autism.

Current Big Data studies in autism

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medicine is the Framingham Heart Study that collected and analyzed data starting in 1948 with 5,209 patients and added to the repository, several generations since then. This study has proven crucial to our understanding of heart disease including its risk factors and pharmacological management.

The National Database for Autism Research (NDAR) is a U.S. National Institutes of Health (NIH)-funded research data repository created by integrating heterogeneous data sets through data sharing agreements between autism researchers and the NIH. To date, NDAR houses one of the largest repositories of neuroscience and genomic research data as well as clinical data, behavioral assessments, and outcomes from novel interventions (800 different variables).

Another initiative that integrates genomic data is MSSNG, a collaboration between Google and Autism Speaks. (Pronounced “missing” the vowels are left out “to represent the missing pieces of the autism puzzle.”)

MSSNG completed its first phase by collecting and making available data from the whole genome sequencing of blood DNA of 10,000 subjects diagnosed with autism as well as their families. The goal is to continually add whole genome sequences and their annotations and phenotype data with different levels and portals of access to researchers to empower their studies.

EU-AIMS is a large autism study based in Europe that involves collaboration across organizations represented by affected individuals and their families, academia, and the biotech industry. EU-AIMS Longitudinal European Autism Project (LEAP) combines genetics, neuroimaging, cognitive testing, and clinical assessments to identify biomarkers for autism that act as population stratifiers and potentially as endpoints in clinical trials.

Simons Foundation Powering Autism Research for Knowledge (SPARK) is a research initiative that aims to recruit, engage, and retain a community of 50,000 individuals with autism and their family members living in the U.S. SPARK is unique because this first-of-its-kind study can be done entirely from home with DNA collection taken from saliva collected in “spit-kits” shipped to each home. Moreover, anyone with a professional diagnosis of autism can participate, making this study accessible to a large group of individuals. This research project is centrally coordinated by

the Simons Foundation Autism Research Initiative (SFARI) and includes collaboration with 21 university-affiliated research clinics in 18 states across the U.S., including the University of Minnesota. The SPARK study recently reached the milestone of reaching 10,000 participants. More information can be obtained from University of Minnesota SPARK team at SPARK-MN@ umn.edu or visit http://cnbd.umn.edu/research/suma-jacobs-lab/spark.

Conclusion As with all neuropsychiatric disorders, genomics research has enormous potential to point to the biological underpinnings of autism, and aid in the discovery of biological markers and development of personalized treatments. Particularly with continued aggregation of samples from all consortium studies and clinical information located with providers and data from social media contributed by families, Big Data-based genomics research will greatly improve our understanding of autism in the coming years, leading to much needed new treatments.

The Focus in NeuroDevelopment (FIND) Network is a voluntary registry that is used to connect individuals in the neurodevelopmental disorder community with research opportunities, educational resources, Genomics research has and events. Members of the FIND Network have the opportunity to hear about research being enormous potential to done on neurodevelopmental disorders and are Madhumathi Rao, MD, MS, is a second year point to the biological periodically contacted if they are eligible to take resident at the University of Minnesota Medical School underpinnings of autism. part in research. They are also invited to educational in the Department of Psychiatry. Dr. Raoâ&#x20AC;&#x2122;s interests events, and receive information about resources are in leveraging technology innovations towards in the Minnesota region. Members of the FIND management of neurodevelopmental disorders.

Network are under no obligation to take part in research studies that they are contacted about. The FIND Network is a valuable tool for improving understanding, enhancing treatment, and Suma Jacob, MD, PhD, is an associate professor at the University of extending resources for neurodevelopmental disorders in Minnesota. The Minnesota Medical School in the Department of Psychiatry and the Center for FIND Network is a collaborative effort made possible by the University of Neurobehavioral Development. She is board-certified in general adult as well Minnesota Autism Initiative, organizations serving individuals with and as child and adolescent psychiatry. Her research focuses on biomarkers and without neurodevelopmental disorders. Please visit http://cnbd.umn.edu/ research/suma-jacob-lab/find-network. treatment targets for autism spectrum disorder.

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3Reforming health care reform from page 19 Price’s block-grant proposal in his 2017 FYB does not detail if any groups of people will still automatically qualify for Medicaid (e.g., pregnant women) or what required benefits must remain (e.g., primary care). Therefore, it’s currently difficult to predict how this change would affect health system and health provider reimbursement. However, providers should expect a continued emphasis on efficiency in delivering care, especially if overall funding for Medicaid programs is cut, since states will have less money to cover certain benefits and inevitably reduce the amount of individuals covered.

4. Medicare quality and payment measures would be updated.

EPFA requires the Secretary of HHS to submit a proposal to Congress detailing a formalized process for the development of performance-based quality measures that could be applied to physicians’ services for Medicare.

While EPFA gives no details regarding the proposal’s specific requirements, it does state that the proposal must be in agreement with the Physician Consortium for Performance Improvement and must utilize measures agreed upon by each specialty organization. Additionally, Price voted in favor of the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA), which put Medicare payment for physician services on the value-based track.

However, Price has recently criticized the law’s reporting requirements as too burdensome for physicians and stated the process should be streamlined.

Price is likely to continue to delay MACRA’s implementation to give physicians enough time to prepare for the new requirements.

Paul Ryan’s Better Way for Health Care Plan House Speaker Paul Ryan has also introduced an ACA replacement,

Better Way for Health Care (BWHC). Ryan has been heavily involved in Trump’s transition team and is often portrayed as a major orchestrator of health reform. There are many similarities between Price’s EPFA and Ryan’s BWHC, including maintaining the ban on denying insurance for preexisting conditions with the continuous coverage caveat, changing Medicaid to a block grant, and providing tax credits in the individual market based on age rather than income.

BWHC suggests transforming Medicare into a premium support or voucher program. Under this model, those eligible for Medicare would receive a fixed stipend or voucher from the federal government to purchase health care from either traditional Medicare plans or private health insurance plans. To further lower costs, this type of program would move away from a defined benefit set and toward a narrower provider network.

However, it’s uncertain how Medicare reform efforts would align with Medicare Advantage business already existing in our current health benefits coverage model. This lucrative business line, often referred to as privatized Medicare, is often touted as a solution to entitlement reform for health benefits by Republicans. It’s unclear if a cap on premium support under a Medicare voucher program could align with what makes Medicare Advantage so popular: robust provider and benefits choice for its beneficiaries at affordable, in-network rates.

The Patient CARE Act Senator Orrin Hatch proposed a health care reform measure with Sen. Richard Burr and Rep. Fred Upton called the Patient CARE Act. Like EPFA and BWHC, the Patient CARE Act allows health insurers to charge people more if they don’t maintain continuous coverage. However, the Patient CARE Act goes a step further by allowing the government to select a default plan for those who don’t pick anything. These default plans would have premiums equal to the value of the tax credit, so enrollees would not be forced to spend additional money; in order to keep premiums low enough to equate to the tax credit, the coverage will likely be very minimal, akin to catastrophic coverage.

The Patient CARE Act also seeks to increase transparency of health care costs. For example, insurers would be required to disclose the cost of health care services. Another measure would incentivize states to publish hospital charges to increase their Medicaid grants.

Conclusion While health care reform efforts could come via a variety of proposals and policy leaders, one thing is certain: health care laws and regulations will receive significant attention in 2017. The timing of the reform efforts is unclear, but Republican lawmakers are indicating a need for a simultaneous “repeal and replace” measure. Regardless of the process or timing, health care providers and systems should expect to face changes early on under the new administration.

Stephen Warch, JD, is a Shareholder in the health care practice group of Nilan Johnson Lewis, PA, and also serves as President of the firm. Steve is a former Deputy General Counsel with UnitedHealthcare, and a former Assistant Attorney General with the State of Minnesota.

Lindsay McLaughlin, JD, MPH, is a health care attorney with Nilan Johnson Lewis, PA. Her practice—rooted in her background as the Health Policy Advisor for the Minnesota Department of Commerce—focuses on regulatory and compliance work for a variety of health care entities, including health care systems and health insurers.

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3Precision medicine from page 17 sources. This inter-omic community analysis demonstrated the power of this approach to create a basis for individualized, and precise evaluations with the following observations: • The majority of pathologies identified, were not clinically evident through history, physical examination, visualization studies, or standard clinical laboratory tests.

• The majority of these diagnoses were in the limited categories of pathology (diabetes, abnormal cholesterol, early dementia).

• Preclinical intervention with lifestyle and dietary changes with or without pharmacologic therapy were able to reverse, or significantly impact the progression of these disorders.

• This approach evaluated health as well as disease and provided a molecular basis for defining wellness.

Genome editing as a model for precision medicine The development of genome editing technologies in the last five years has allowed modification of specific sites in DNA with surgical precision such as the insertion of a single nucleotide, single gene, or multiple gene sequences. These methods offer the potential to modify or correct structural abnormalities within the human genome and to alleviate genetic disorders attributable to specific DNA sequence variations. These technologies are the ultimate application of precision medicine. Genomic editing is a three-step procedure involving: 1. Identification of the desired target gene sequence.

2. A sequence-specific endonuclease, which acts as a molecular scissors to cut both strands of the DNA to stimulate DNA repair at the target site.

3. A homologous DNA template that is used by the cellular DNA repair factors that specifies the desired edit to the target sequence.

Site-specific nuclease technologies include CRISPR /Cas-9 (clustered regularly interspaced short palindromic repeats) and TALENs (transcription activator-like effector nuclease). Both methodologies offer the possibility of gene corrective therapies, and have other exciting applications. St. Paul-based Recombinetics, Inc., and its biomedicine subsidiary, Surrogen, utilize these techniques to replicate human disease DNA sequences into animals and create model precision models. Pigs are used because they have great physiologic and genetic homology with humans and are our closest non-primate relatives. These surrogate animals are avatars that allow the expression of human disease phenotypes and are ideal for pharmacologic, therapeutic, and medical device development. The Surrogen research team can utilize a systems biology approach to these animals by accessing multiple cell and organ specific biomarkers and provide a multi-omic assessment of the genomic mediated biologic expression that defines the animal’s disease phenotype. These humanized swine models are the ideal complement to establishing the scientific basis for personalized precision medicine, bringing the future of health care closer to the present.

Conclusion Precision medicine is integrative and multifactorial. It recognizes the complexities of human biology and the interactive role with physical and social environments. It acknowledges the primacy of information and provides the tools for its acquisition, manipulation, storage, and conversion to applicable health care knowledge. P4 medicine is transformational and cross-disciplinary and will contribute to addressing many of society’s challenges and complex issues.

David R. Brown, MD, FACE, is vice president of Biomedicine at Recombinetics, Inc., a staff physician at Children’s Hospitals and Clinics, Minnesota Pediatric Endocrinology and Genomics and on the Executive Board of the Newborn Foundation.

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ANNOUNCEMENT

I CAN DO ADVENTURE The approaching holiday season is about hope, magic and miracles. So too, is Diveheart. The Downers Grove-based not for profit organization provides hope, magic, and even miracles, to individuals with disabilities.

Diveheart offers children, veterans and others with disabilities the opportunity to escape gravity through Scuba Therapy. Diveheart participants include individuals with virtually any type of disability including Down syndrome, autism, cerebral palsy, paraplegia, blindness, deafness, spinal cord injuries, traumatic brain injury, post-traumatic stress disorder and more.

HOPE The Diveheart vision is to unleash the unrealized human potential that often exists in individuals with disabilities. The confidence, independence and self-esteem realized by Diveheart participants is tremendous.

Diveheart helps individuals focus on what they can do, rather than what they can’t do.

MAGIC Diveheart Scuba Therapy helps participants focus on their abilities, rather than their disabilities. This helps them to take on challenges that they may never have taken on before. Furthermore the forgiving, weightless environment of underwater offers buoyancy and balance to individuals who might struggle on land. They’re often able to move in ways that are impossible before joining a Diveheart program. Zero gravity is the great equalizer.

MIRACLES Diveheart participants have experienced improved range of motion, ability to focus, pain relief and more. The aspect of pressure while diving provides benefits for people with autism and chronic pain due to spinal cord injuries. Some tell us that after diving, they’re pain free for up to three weeks, often for the first time since their injury.

Every one is able to help perpetuate hope, magic and miracles during the holiday season. Your donation helps to make it possible for individuals with disabilities to experience Scuba Therapy, and the resulting benefits so that they might “Imagine the Possibilities” in their lives. Please visit www.diveheart.org/donate/ to learn more about how you can help promote the hope, magic and miracles of Diveheart. Diveheart donations are also accepted at 900 Ogden Ave #274 Downers Grove, Illinois 60515.

Jim Elliott Founder & President Diveheart

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