The Brigham is home to nearly 5,000 researchers, including physician-investigators, biomedical scientists, and faculty, who publish new research papers on a range of scientific and medical subjects. Below are brief summaries of a selection of our community’s most recent work. If you have an upcoming Brigham publication, please contact bwhclinicalandresearchnews@partners.org.

Newborn Genomic Sequencing Detects Unanticipated Disease Risk Factors
BabySeq Project finds that genomic sequencing identified risk for childhood-onset disorders, including highly actionable conditions, in 9.4 percent of newborns

As genomic sequencing becomes increasingly commonplace in the clinic, questions remain about its use and role among newborns. Can sequencing provide actionable insights? How common is it to find something important to a child’s future health? What benefits or consequences will sequencing have for families? The BabySeq Project, a joint endeavor led by investigators at Brigham and Women’s Hospital and Boston Children’s Hospital, with collaborators at the Baylor College of Medicine, is revealing the answers to these questions and more. In a paper published in the American Journal of Human Genetics, the research team reports that genomic sequencing can identify risk for a wide range of disorders that may not be detected otherwise. Importantly, early knowledge about several of these conditions can lead to surveillance and interventions that could improve health outcomes for newborns and their families.

“The BabySeq Project is the first randomized trial of sequencing in newborns and the first study to fully examine the wealth of unanticipated genetic risk information in children,” said Robert Green, MD, MPH, co-director of the study at the Brigham and a professor at Harvard Medical School. “We were stunned by the number of babies with unanticipated genetic findings that could lead to disease prevention in the future.”

The BabySeq Project enrolled healthy newborns from the Brigham’s well baby nursery and ill newborns from BCH, the Brigham and Massachusetts General Hospital’s neonatal and pediatric intensive care units. Family histories were collected for all enrolled participants. Half of the families from each group were randomized to receive standard care, including “heel prick” newborn screening which tests for about 30 genetic conditions, and genetic counseling based on family history; the other half received whole exome sequencing in addition to standard care and genetic counseling. Sequencing results were disclosed to families during the genetic counseling session. The team monitored health outcomes and collected medical, behavioral and economic data at the time of disclosure, three months later and 10 months later to measure the impact of genomic sequencing on the infant’s clinical care, parent and clinician behaviors, and economic outcomes.

A total of 159 newborns (128 healthy newborns and 31 ill newborns) were randomized to receive genomic sequencing. Of those, 15 (9.4 percent) were found to have a genetic variant for which there was strong evidence of increased risk of a disorder that presents or is clinically manageable during childhood, or a variant in a gene for which there was moderate evidence of risk but for which an intervention during childhood might prevent devastating outcomes later in life.

The team found variants associated with several heart conditions, including six newborns with variants associated with dilated or hypertrophic cardiomyopathy and another newborn with a variant associated with supravalvular aortic stenosis. These conditions can be monitored over time, and families have been referred to cardiac specialists. Another newborn was found to have a risk variant for biotinidase deficiency. Further testing determined that the infant had partial biotinidase deficiency, a condition that can cause skin rash, hair loss and seizures. The child’s diet is now being supplemented with biotin, which is expected to prevent any disease manifestations.

“Sequencing results have potential to raise questions that may be upsetting for parents but could also lead to helpful or even lifesaving interventions,” said senior author and BabySeq co-director Alan Beggs, PhD, director of The Manton Center of Orphan Disease Research at Boston Children’s Hospital. “Only time will tell how the costs—both financial and in terms of extra medical testing and family stress—balance out against the benefits. That’s what we’re really trying to find out.”

The team also offered to provide information regarding their child’s risk for medically actionable, adult onset conditions. Three of 85 infants of parents who agreed to receive this information carried such variants. These variants were also identified in the mothers of the three children.

“Disclosing genetic risk for adult onset conditions in children has been discouraged in traditional genetics in order to protect the child’s ‘right not to know,’ but our results demonstrate that many parents want access to this information about their child,” said Green. “Our findings suggest that thoroughly sequencing newborns reveals potentially life-saving information in both infants and their parents far more commonly than was previously thought and should encourage our entire field to re-evaluate the value of comprehensively analyzing and disclosing genomic information at any age.”

Funding for this work was provided by the National Institutes of Health under award numbers U19HD077671, R01HD075802 and U41HG006834. Green is supported by grant funding from NIH, the Broad Institute and the DOD. He receives compensation for consultation from AIA, Helix, Ohana, Prudential, Verily and Veritas; and is co-founder, advisor and equity holder in Genome Medical, Inc.

Paper cited: Ceyhan-Birsoy, O et al. “Interpretation of genomic sequencing results in healthy and ill newborns: Results from the BabySeq Project” American Society for Human Genetics DOI: 10.1016/j.ajhg.2018.11.016
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Hospitalizations for Homeless Individuals Are on the Rise
Mental illness, substance use remain primary drivers of hospitalization among homeless adults

A homeless individual is one who lacks fixed and reliable housing, and it is estimated that 553,000 people fit that description on any given night in the United States. A new retrospective cohort study by investigators from Brigham and Women’s Hospital and Beth Israel Deaconess Medical Center examines patterns, causes and outcomes of acute hospitalizations between 2007 and 2013 for homeless individuals and non-homeless control groups in three populous and diverse U.S. states: Florida, California and Massachusetts. Data suggest a rise in acute hospital use among homeless individuals for mental illness and substance use disorder. The results were published in the journal Medical Care on Dec. 11.

“The homeless population is aging, and the rate of hospitalizations for homeless individuals is increasing,” said lead author Rishi Wadhera, MD, cardiology fellow in the Cardiovascular Division at the Brigham and health policy researcher at BIDMC. “Although there has been a recent push to establish better policy and public health measures to improve the health of homeless adults, few studies have examined the patterns and causes of hospitalizations in this population. We found that hospitalizations among homeless adults tend to be for a very different set of conditions than non-homeless adults, even after accounting for differences in demographics.”

To examine these trends, hospital discharge data was acquired from Massachusetts and Florida between 2001 and 2013 and from California between 2007 and 2011. This information came from the State Inpatient Databases (SIDs) of the Healthcare Cost and Utilization Project, created by the Agency for Healthcare Research and Quality. This dataset includes information such as homeless status, billing, demographics, and diagnoses. Hospitalization costs were determined by applying American Hospital Association cost-to-charge ratios to the total hospital charges provided in the SID.

Overall, the researchers analyzed 185,292 hospitalizations for homeless individuals and 32,322,569 hospitalizations for non-homeless individuals. Between 2007 to 2013 (2011 for Calif.), acute hospitalizations for homeless individuals increased in all three states. Massachusetts experienced an increase from 294 to 420 per 1000 homeless residents, Florida increased from 161 to 240/1,000, and California grew from 133 to 164/1,000. Homeless adults were more often white (62 percent), male (76.1 percent), around 46 years old, and either uninsured (41.9 percent) or insured by Medicaid (31.7 percent).

The researchers found that reasons for hospitalization among the two groups differed starkly. More than 50 fifty percent of hospitalizations among homeless individuals were for mental illness and substance use disorder, while these conditions explained less than 20 percent of hospitalizations among demographically comparable non-homeless individuals. Homeless adults also had a longer mean length of stay (6.5 vs. 5.9 days). However, homeless individuals had lower in-hospital mortality rates (0.9 percent vs. 1.2 percent) and lower mean costs per day ($1,535 vs. $1,834) than the comparable non-homeless control group.

“Some states, such as Massachusetts, have expanded Medicaid eligibility, which has increased rates of insurance among homeless individuals and improved access to care. This could have led to greater use of hospital services,” said Wadhera. “The increase in hospitalizations could also reflect more concerning trends. The opioid epidemic has disproportionately impacted the homeless population, and a repercussion of this may be an increase in acute hospitalizations. It is also possible that these patterns suggest inadequate outpatient care for homeless individuals, and that we need to do a better job of providing more consistent, reliable outpatient care to this population.”

“There is an urgent need to reduce financial and nonfinancial barriers to the use of ambulatory care, for behavioral health services in particular, to improve long-term management of physical and mental illness for homeless individuals,” said senior author Karen Joynt Maddox, MD, MPH, of Washington University in St. Louis. “We need better longitudinal data and further studies to understand how Medicaid expansion and other policy initiatives affect the health of this highly vulnerable population.”

Wadhera is supported by National Institutes of Health Training Grant T32HL007604-32, Brigham and Women’s Hospital, Division of Cardiovascular Medicine. Joynt Maddox receives research support from the National Heart, Lung, and Blood Institute (K23HL109177-03). Other co-authors have received research support from the National Heart, Lung and Blood Institute (R01HL136708) and the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology.

Paper cited: Wadhera, R et al. “Trends, Causes, and Outcomes of Hospitalizations for Homeless Individuals: A Retrospective Cohort Study” Medical Care DOI: 10.1097/MLR.0000000000001015
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Human TIM-3 with bound calcium

Researchers Image Atomic Structure of Important Immune Regulator
Understanding structure of human TIM-3 provides new insights for cancer and autoimmune drug development

A new study by investigators from Brigham and Women’s Hospital provides a biophysical and structural assessment of a critical immune regulating protein called human T-cell immunoglobulin and mucin domain containing protein-3 (hTIM-3). Understanding the atomic structure of hTIM-3 provides new insights for targeting this protein for numerous cancer and autoimmune therapeutics currently under clinical development. The findings of this study were published online in Scientific Reports on Nov. 30.

“The hTIM-3 protein is an important immune regulator, yet it has been difficult to target for drug development as high-resolution structure conformational details have been elusive,” said senior author Richard Blumberg, MD, chief of the Division of Gastroenterology, Hepatology and Endoscopy in the Department of Medicine at the Brigham. “We resolved the structure of hTIM-3 and established a novel biochemical assay to define its functionality, which will be useful for understanding the role of hTIM-3 in the immune system.”

The team captured a high-resolution X-ray crystal structure and nuclear magnetic resonance (NMR) image of the hTIM-3 IgV domain that is involved in functional interactions with CEACAM1, which is a crucial immune escape mechanism for many cancers. Importantly, the team determined the precise location of a calcium atom, an essential co-factor, bound to the hTIM-3 IgV domain.

“This is the first NMR analysis of any immune-related TIM molecule and the first high resolution structural report of the hTIM-3 IgV domain with association of critical co-factors such as calcium,” said author Amit Gandhi, PhD, a researcher in Blumberg’s laboratory in the Department of Medicine. “No one has been able to do this before. Hopefully this will help with the targeting of human hTIM-3 and the development of useful therapeutics.”

“This structure shown here represents a high resolution, physiologically relevant hTIM-3 molecule,” said author Walter Kim, MD, PhD, a researcher in Blumberg’s laboratory and associate physician in the Department of Medicine. “Now we can understand what specific regions of the protein are accessible for therapeutic drugs to bind.”

The NMR structural studies were led by Zhen-Yu Jim Sun, PhD, a researcher at Harvard Medical School. Funding for this work was supported by the NIH Grants 5R01DK051362-21 and the High Pointe Foundation to R.S.B. and 5P01AI073748-09 to V.K.K., and GM047467 and AI037581 to G.W.

Paper cited: Gandhi, A et al. “High resolution X-ray and NMR structural study of human T-cell immunoglobulin and mucin domain containing protein-3” Scientific Reports DOI: 10.1038/s41598-018-35754-0
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Researchers Explore What’s Behind Mediterranean Diet and Lower Cardiovascular Risk
Investigators identify, assess underlying mechanisms that may explain diet’s 25 percent reduction in cardiovascular risk for American women

A new study by investigators from Brigham and Women’s Hospital, Harvard Medical School, and the Harvard T.H. Chan School of Public Health offers insights from a cohort study of women in the U.S. who reported consuming a Mediterranean-type diet. Researchers found a 25 percent reduction in the risk of cardiovascular disease among study participants who consumed a diet rich in plants and olive oil and low in meats and sweets. The team also explored why and how a Mediterranean diet might mitigate risk of heart disease and stroke by examining a panel of 40 biomarkers, representing new and established biological contributors to heart disease. The team’s results are published in JAMA Network Open.

“Our study has a strong public health message that modest changes in known cardiovascular disease risk factors, particularly those relating to inflammation, glucose metabolism and insulin resistance, contribute to the long-term benefit of a Mediterranean diet on cardiovascular disease risk. This understanding may have important downstream consequences for the primary prevention of cardiovascular disease,” said lead author Shafqat Ahmad, PhD, a research fellow at the Brigham and at the Harvard Chan School.

Randomized trials in Mediterranean countries and observational studies have previously linked a Mediterranean diet to reductions in cardiovascular disease, but the underlying mechanisms have been unclear. The current research draws on data from more than 25,000 female health professionals who participated in the Women’s Health Study. Participants completed food intake questionnaires about diet, provided blood samples for measuring the biomarkers, and were followed for up to 12 years. The primary outcomes analyzed in the study were incidences of cardiovascular disease, defined as first events of heart attack, stroke, coronary arterial revascularization and cardiovascular death.

The team categorized study participants as having a low, middle or upper Mediterranean diet intake. They found that 428 (4.2 percent) of the women in the low group experienced a cardiovascular event compared to 356 (3.8 percent) in the middle group and 246 (3.8 percent) in the upper group, representing a relative risk reduction of 23 percent and 28 percent respectively, a benefit that is similar in magnitude to statins or other preventive medications

The team saw changes in signals of inflammation (accounting for 29 percent of the cardiovascular disease risk reduction), glucose metabolism and insulin resistance (27.9 percent), and body max index (27.3 percent). The team also found connections to blood pressure, various forms of cholesterol, branch-chain amino acids and other biomarkers, but found that these accounted for less of the association between Mediterranean diet and risk reduction.

“While prior studies have shown benefit for the Mediterranean diet on reducing cardiovascular events and improving cardiovascular risk factors, it has been a black box regarding the extent to which improvements in known and novel risk factors contribute to these effects,” said corresponding author Samia Mora, MD, MHS, a cardiovascular medicine specialist at the Brigham and Harvard Medical School. “In this large study, we found that modest differences in biomarkers contributed in a multi-factorial way to this cardiovascular benefit that was seen over the long term.”

The Women’s Health Study is supported by National Institutes of Health grants (CA047988, HL043851, HL080467, HL099355, and UM1 CA182913). Mora was supported by the research grants DK112940, HL134811 and HL136852, American Heart Association (0670007N) and the Molino Family Trust. LabCorp provided the LipoProfile IV results. Ahmad was supported through a fellowship and research support from Swedish Heart-Lung Foundation, Nutricia Research Foundation and Henning och Johan Throne-Holst stiftelse Fellowship Sweden. Other co-authors were supported by grants K01HL135342-02, HL60712, HL118264, and DK112940 from the National Institutes of Health.

Mora disclosed receiving institutional research grant support from Atherotech Diagnostics for research outside the current work, served as a consultant/scientific advisory board to Quest Diagnostics, and has a patent regarding the use of GlycA in relation to colorectal cancer risk. Another co-author received research grant support from AstraZeneca, Novartis, Amgen, Pfizer, and NHLBI, and is listed as a coinventor on patents held by the Brigham and Women’s Hospital related to the use of inflammatory biomarkers in CVD (licensed to AstraZeneca and Siemens). Another co-author reported receiving research support from the California Walnut Commission and honoraria for lectures from Metagenics and Standard Process and honoraria from Diet Quality Photo Navigation, outside the submitted work.

Paper cited: Ahmad, S et al. “Assessment of Risk Factors and Biomarkers Associated With Risk of Cardiovascular Disease Among Women Consuming a Mediterranean Diet” JAMA Network Open DOI: 10.1001/jamanetworkopen.2018.5708
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Lead author Dr. Saranna Fanning (top row, middle), senior authors Dr. Ulf Dettmer (bottom row, right) and Dr. Dennis Selkoe (bottom row, left) and colleagues have uncovered a potential therapeutic target for Parkinson’s disease. Increased lipid droplets (green fluorescence) in yeast (top row, left), rat (bottom row, middle) and human cortical neurons (top row, right) indicating activation of the neutral lipids pathway upon alpha-synuclein expression. Inhibition of SCD upstream of this pathway represents a novel PD therapeutic approach.

New Parkinson’s Disease Drug Target Revealed Through Study of Fatty Acids
From yeast to humans, signs point to a pivotal, neurotoxic role for fatty acid metabolism that’s gone awry  

The human brain is rich in lipids. Investigators studying Parkinson’s disease (PD) have become increasingly interested in lipids since both molecular and genetic studies have pointed to the disruption of the balance of the brain’s lipids as a potentially critical contributor to this disease. Beginning in yeast and moving through various model organisms and human cells, a new study led by investigators from Brigham and Women’s Hospital and Harvard Medical School has provided insights into the role of fatty acids and suggests that inhibiting a specific enzyme can protect against neurotoxicity. Their findings, which point to a novel therapeutic approach that could be developed to treat PD and some forms of Alzheimer’s disease, are published in Molecular Cell.

“People have been aware for many years of some connection between Parkinson’s disease and the brain’s lipids,” said lead author Saranna Fanning, PhD, of the Ann Romney Center for Neurologic Diseases at the Brigham and Harvard Medical School. “Through this collaborative effort, beginning with yeast models in the Lindquist lab and in the Selkoe and Dettmer labs leveraging rat cortical neurons and human cortical neurons, we’ve identified a pathway and a therapeutic target that no one has pursued before.”

Fanning’s work began in the lab of the Whitehead Institute’s Susan Lindquist, PhD, who passed away in 2016. She performed unbiased lipidomic profiling, measuring lipids and fatty acid changes in yeast that had been engineered to produce α-synuclein, a protein that forms the hallmark Lewy body clumps of PD. An increase was identified in the constituents of the neutral lipids pathway, including a monounsaturated fatty acid known as oleic acid. This finding was then replicated in rodent and human neuronal models, including patient cell lines, by Fanning and colleagues in the labs of co-senior authors Dennis Selkoe, MD, and Ulf Dettmer, PhD, at the Brigham. Additional experiments were carried out in the roundworm C. elegans, another classic model organism.

“It was fascinating to see how excess αS had such consistent effects on the neutral lipid pathway across model organisms, from simple baker’s yeast and cultured rodent neurons to cells derived from PD patients that carry extra copies of α-synuclein in their genome. All our models clearly pointed at oleic acid as a mediator of α-synuclein toxicity,” said Dettmer.

The team also measured signs of neurotoxicity in their models, looking for ways to target fatty acids or the pathways involved in their generation that would offer protection from PD. The researchers found that suppressing an enzyme known as stearoyl-CoA-desaturase (SCD), which helps generate oleic acid and other monounsaturated fatty acids, was protective, suggesting that SCD may be a promising therapeutic target.

While not currently used in the clinic, multiple inhibitors of SCD exist today and are used in research labs. Additional follow-up studies will be required to determine how well such testing begins in humans.

“The identification of SCD as an enzyme which contributes to α-synuclein-mediated lipid changes and neurotoxicity presents a unique opportunity for small-molecule therapies to inhibit the enzyme in models of PD and, ultimately, in human diseases,” said Selkoe.

Funding for this work was provided by the JPB Foundation, a fellowship from the Jane Coffin Childs Memorial Fund for medical research the National Institutes of Health (grants NS065743, GM102155, NS103123, NS099328, NS083845), the Austrian Science Fund FWF, and DK Molecular Enzymology Project W901 NAWI Graz.

Paper cited: Fanning, S et al. “Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment” Molecular Cell DOI: 10.1016/j.molcel.2018.11.028
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Blood Test for Tau, Alzheimer’s Disease Under Development
Investigators design, evaluate blood test for patients to detect tau, a hallmark of Alzheimer’s disease

Today, the only way to definitively diagnose Alzheimer’s disease in life is through brain scans and tests of cerebrospinal fluid that must be collected via lumbar puncture. Though cumbersome and expensive, such tests provide the most accurate diagnoses for patients. Investigators at Brigham and Women’s Hospital are working to develop a blood test that could replace these procedures to accurately diagnose or even predict Alzheimer’s disease before symptoms appear. The tau protein has long been implicated in Alzheimer’s, however, tau occurs as a family of related molecules which have subtly different properties. The Brigham team took advantage of the complexity of tau and built assays to measure different forms of tau and identified a subset of tau proteins which are specifically elevated in Alzheimer’s disease. The team’s new approach is detailed in Alzheimer’s & Dementia and featured in the journal’s December issue.

“A blood test for Alzheimer’s disease could be administered easily and repeatedly, with patients going to their primary care office rather than having to go into a hospital,” said corresponding author Dominic Walsh, PhD, of the Ann Romney Center for Neurologic Diseases at the Brigham. “Ultimately, a blood-based test could replace cerebrospinal fluid testing and/or brain imaging. Our new test has the potential to do just that. Our test will need further validation in many more people, but if it performs as in the initial two cohorts, it would be a transformative breakthrough.”

Walsh and colleagues developed tests capable of detecting different populations of tau fragments in cerebrospinal fluid and blood. They applied these tests to participants who had been recruited to the Harvard Aging Brain Study as well as research participants seen at the Institute of Neurology in London. Each participant donated both plasma and cerebrospinal fluid. They validated results in a second group of patients that had been recruited by the Shiley-Marcos Alzheimer’s Disease Research Center at the University of California, San Diego.

The team analyzed five different tests for tau fragments, finding that one, known as the NT1 assay, showed sufficient diagnostic sensitivity (the ability to predict AD cases) and specificity (the ability to exclude controls) to pursue its use as a potential screening tool for Alzheimer’s disease. This was confirmed in both sets of patients.

While performing the experiment twice—in two sets of patients with two different demographic backgrounds—provided important confirmation, the authors note that both groups of participants were small (65 participants and 86 participants, respectively). Larger groups of participants will need to be studied and the authors are also interested in studying patients over time to determine how tau levels in blood may change as the disease progresses and what those numbers may look like before the onset of symptoms.

“We’ve made our data and the tools needed to perform our test widely available because we want other research groups to put this to test,” said Walsh. “It’s important for others to validate our findings so that we can be certain this test will work across different populations.”

Funding for this work was provided by the Alzheimer’s Association Zenith Award, the Harvard Neuro-Discovery Center through a major gift from Rick and Nancy Moskovitz, a grant from Medimmune Plc, the Leonard Wolfson Experimental Neurology Center, the Weston Brain Institute and Wolfson Foundation, the National Institute for Health Research University College London Hospitals Biomedical Research Center, MRC Dementias Platform UK (MR/L023784/1), and Alzheimer’s Research UK.

Paper cited: Chen, Z et al. “Learnings about the complexity of extracellular tau aid development of a blood-based screen for Alzheimer’s disease” Alzheimer’s & Dementia DOI: 10.1016/j.jalz.2018.09.010
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Gut Protein Mutations Shield Against Spikes in Glucose
Study shines light on gene with potential to be new therapeutic target

Why is it that, despite consuming the same number of calories, sodium and sugar, some people face little risk of diabetes or obesity while others are at higher risk? A new study by investigators at Brigham and Women’s Hospital has uncovered mutations in a gene that appear to help drive this difference. Individuals with a specific variant in a gene known as SGLT1, which results in reduced uptake of sugars in the gut, had lower incidence of obesity, diabetes, death and heart failure, suggesting that SGLT1 may make a promising therapeutic target for metabolic disease. The team’s results were recently published in the Journal of the American College of Cardiology.

“These SGLT1 mutations have not been characterized in the general population before,” said first author Sara Seidelmann, MD, PhD, who performed this work as a clinical and research fellow in the Division of Cardiovascular Medicine at the Brigham working with senior author Scott Solomon, MD, professor of Medicine and The Edward D. Frohlich distinguished chair at the Brigham. “We were able to evaluate the association of genetic mutations in SGLT1 with the rise in blood sugar that occurs in response to dietary glucose in several large populations.”

Carbohydrates that enter the body are broken down in the small intestine into smaller pieces, such as glucose, and absorbed into bodily tissues. The sodium/glucose co-transporter-1 (SGLT1) protein plays a critical role in glucose transport into these tissues. Another SGLT family member—SGLT2—is the target of a class of diabetes drugs known as SGLT2 inhibitors. Researchers believe that while SGLT2 inhibitors stop glucose re-uptake in the kidneys, inhibiting SGLT1 could reduce glucose uptake at the source—the small intestine—which might reduce the carbohydrate load after a large meal.

Some SGLT1 mutations make the protein dysfunctional, which can cause nutrient malabsorption and even death in newborns, yet other mutations, such as the ones that the BWH researchers found, only slightly alter the protein’s function and do not have such devastating outcomes. To examine the effects of the latter kind of mutations, the research team used whole-exome sequencing to identify the unique genetic code of 5,687 participants in the ARIC (Atherosclerosis Risk in Communities) study, an on-going longitudinal analysis o­­f participants from four U.S. states. In addition to genetic analysis, these participants had also undergone an oral glucose tolerance test, in which they were provided with a sugary drink and then had their blood glucose levels tested two hours later. The results from the glucose test were then related to genetic variations in SGLT1.

An external validation analysis was performed to study the effect of SGLT1 variants on levels of sugar in the blood after the oral glucose challenge in a large European-Finnish population sample and a replication analysis was performed in African-American participants allowing for heterogenous representation. The researchers also performed a Mendelian randomization analysis to explore the long-term effects of lowering sugar absorption via these mutations on metabolic and cardiovascular disease. This type of analysis enables researchers to estimate the effect of a given variable—post-meal glucose in this case—without conducting an additional study.

Researchers found that 16 percent of European-American participants and 7.5 percent of African-American participants carried an SGLT1 mutation. Those with a mutation were protected from spikes in blood glucose levels after the ingestion of sugars, despite ingesting an equivalent number of calories as others. The Mendelian randomization analysis also showed that these people had a lower risk for obesity and less instances of diabetes mellitus, death and heart failure later in life.

“In addition to confirming the important role of SGLT1 in the digestion of dietary sugars, this work presents new potential opportunities for therapies,” said Solomon “The SGLT-1 receptor could be a potential therapeutic target for cardiometabolic disease and suggest that development of drugs that selectively inhibit SGLT-1 could be of benefit in certain high-risk individuals.” Nevertheless, Solomon and Seidelmann caution that developing such drugs takes many years and that clinical trials would be needed to determine their safety and efficacy.

Funding for this work was provided by the National Institutes of Health (NIH) (2T32HL094301-06, R01HL131532 and R01HL134168), NIH/National Institute of Diabetes and Digestive and Kidney Diseases (K24DK106414 and R01DK089174), National Heart, Lung, and Blood Institute (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN26820110000 9C, HHSN268201100010C, HHSN268201100011C, and HHSN26820 1100012C), the EU FP7 (313010 [BBMRI-LPC], nr. 305280, and HZ2020 633589 [Ageing with Elegans]), The Finnish Academy (269517), Finnish Foundation for Cardiovascular Research, the Yrjö Jahnsson Foundation and the Päivikki and Sakari Sohlberg Foundation. Co-authors of this study have received research grants or consulted with pharmaceutical companies—for a full list of disclosures, please see the paper in JACC.

Paper cited: Seidelmann, S et al. “Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk” Journal of the American College of Cardiology https://doi.org/10.1016/j.jacc.2018.07.061
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Researchers Examine Trends in Opioid Prescriptions in Children and Adolescents
Study suggests opioid prescriptions have steadily decreased since 2012

While the opioid crisis remains a major public health concern in the United States for people of all ages, relatively little research has been conducted in younger populations. A new study by investigators from Brigham and Women’s Hospital examined the trends in opioids prescribed for children and adolescents in an analysis of data between 2004 and 2017 from a large commercial insurance provider. The researchers observed a downward shift in opioid prescriptions in children and adolescents, which aligns with previously reported trends in adult populations. Their results are published in JAMA Pediatrics.

“Prior studies have shown that, between 1997 and 2012, the rate of hospitalizations due to opioid poisonings nearly doubled in U.S. children and adolescents. Understanding patterns of opioid use in children and adolescents is important because use in early life has been associated with a higher likelihood of opioid misuse in the future,” said first author Joshua Gagne, PharmD, ScD, of the Brigham Division of Pharmacoepidemiology and Pharmacoeconomics. “We sought to examine more recent opioid prescribing trends in younger populations as this age group has been consistently understudied.”

Outpatient opioid prescription rates and long-term (three or more consecutive months) opioid use were evaluated in individuals 18 years or younger from a large commercial insurance database, Optum Clinformatics Data Mart. The database included diverse populations from all 50 states with approximately 2.5 million individuals in this age range in each year. The analysis included all oral opioids used for pain, excluding cough suppressants. The researchers then calculated the monthly prevalence of opioid prescriptions per 1,000 individuals for each year between 2004 and 2017.

In 2004, an average of 3 of every 1,000 children and adolescents received an outpatient opioid prescription in a given month. Between 2009 and 2012, this number increased to 4 of every 1,000 before dropping to 2 per 1,000 children and adolescents in 2017. This trend was driven by a decrease in prescriptions of hydrocodone bitartrate, one of the most commonly dispensed opioids to children and adolescents. Dispensation of oxycodone remained stable over time and did not increase after the U.S. Food and Drug Administration (FDA) approved an extended-release version for children in 2015.

“These results show that prescription opioids dispensed to children and adolescents have been decreasing since 2012,” wrote the authors. “Despite the downward trends for opioid prescriptions, the frequency of opioid use remains high given the risks associated with these medications in younger populations.”

Funding for this work was provided by award K08HD075831 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health.

Paper cited: Gagne, J et al. “Trends in Opioid Prescription in Children and Adolescents in a Commercially Insured Population in the United States, 2004-2017” doi:10.1001/jamapediatrics.2018.3668
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Study Examines Opioid Use, Overdoses Among Massachusetts Adolescents
Adolescent females experience more non-fatal opioid overdoses than males; neither group receives adequate medication for follow-up treatment

Opioid-related overdoses and deaths remain a major public health concern in Massachusetts, yet adolescents who experience opioid-related nonfatal overdose (NFOD) have been rarely studied. Using public data, Brigham investigators recently unearthed several important ways in which the opioid crisis is playing out differently among young people versus adults.

Performed in collaboration with colleagues at the Boston University School of Medicine and Massachusetts Department of Public Health, the analysis examined data on adolescents in Massachusetts, ages 11 to 17, who experienced an opioid-related nonfatal overdose between 2012 and 2014. In addition to understanding how prevalent these events were in young people compared to adults, researchers also found differences in how adolescents receive medication to treat opioid use disorder after experiencing a nonfatal overdose. The team’s results were recently published in Drug and Alcohol Dependence.

Among the findings were that adolescent girls were more likely to experience an opioid-related nonfatal overdose—the opposite of what has been observed in adults —although the reasons for this remain unclear. Additionally, investigators discovered these events were, overall, far less common in young people in the period studied, occurring in 195 adolescents versus 22,311 adults.

“This evidence will help guide the conversation about adolescent opioid abuse. In a lot of ways, this study raises more questions than answers, such as why more adolescent girls are overdosing than boys,” said Avik Chatterjee, MD, MPH, first author and associate epidemiologist in the Division of Global Health Equity at the Brigham. “The ability to bring attention to a population that has been understudied with regard to the opioid epidemic will help researchers and physicians explore ways to treat this epidemic in adolescence.”

An opioid-related nonfatal overdose occurs when an individual uses an opioid, sometimes in conjunction with other drugs, and becomes mentally altered or sedated to the point that immediate, lifesaving treatment is necessary.

“A nonfatal overdose might be an opportunity to intervene,” said Chatterjee. “People are using opioids so much that they are at risk of dying, so this could be a time when health care professionals could step in and help the person obtain treatment before a fatal overdose occurs.”

To examine the adolescent and adult NFOD rates in Massachusetts, researchers analyzed data from 2012 to 2014, pooled from the entire state as part of Chapter 55 of the Acts of 2015. This dataset represents 98 percent of Massachusetts residents and includes non-identifiable medical information from hospitals, ambulance systems, substance-use systems, health insurance companies and homeless shelters.

Researchers were interested in examining whether adolescents received medication —methadone, buprenorphine or naltrexone—to treat an opioid use disorder within 12 months of experiencing a nonfatal overdose. They found that only 8 percent of adolescents were prescribed one of these medications within a year of the overdose.

“Adolescents have not received as much focus as adults in the opioid crisis,” said senior author Sarah Bagley, MD, an assistant professor and primary care physician at Boston Medical Center. “However, these data illustrate that in Massachusetts, adolescents have not been spared and that they are not receiving timely treatment.”

The authors note that these numbers may be low because many people now have access to opioid overdose reversal drugs outside of a health care setting.

“This analysis took advantage of a unique tool developed by the Massachusetts Department of Public Health (DPH) to enable us to access linked, multi-year data for analysis of fatal and non-fatal opioid overdoses, as well as for other health priorities and trends,” said Dana Bernson, DPH Assistant Director, Special Analytic Projects. “These results highlight the importance of our partnerships with researchers from academic, non-profit, private and government agencies in using data to respond to the opioid epidemic.”

Funding for this work was provided by the National Center for Advancing Translational Sciences (1K23 DA044324-01 and 1UL1TR001430), National Institute for Drug Abuse (K23 DA042168, K23 DA045085 and L40 DA042434) a Boston University School of Medicine Department of Medicine Career Investment Award, a Thrasher Research Fund Early Career Award and an Academic Pediatric Association Young Investigator Award.

Paper cited: Chatterjee, A et al. “Non-fatal opioid-related overdoses among adolescents in Massachusetts 2012-2014” Drug and Alcohol Dependence DOI: https://doi.org/10.1016/j.drugalcdep.2018.09.020

-BF