Naomi Fisher

A pilot study conducted by Brigham investigators found that an innovative care-delivery program helped participants reduce their blood pressure in just seven weeks.

Hypertension, or high blood pressure, affects nearly half of U.S. adults, according to the American Heart Association. Despite the serious consequences that can result from hypertension—which puts patients at an increased risk for heart attacks, strokes and other cardiovascular events—elevated blood pressure often remains untreated or undertreated for years.

Seeing opportunities for improvement, a team of innovators and clinicians at the Brigham developed a new care-delivery program for home use that aims to improve hypertension control rates quickly and at a significantly lower cost than traditional, clinic-based blood pressure programs.

The new approach, piloted with 130 participants, helped 81 percent of patients achieve blood pressure control in, on average, less than two months. The results of the pilot study were published recently in Clinical Cardiology. Patients who enrolled had uncontrolled blood pressure (greater than 140/90) and were recruited from Brigham and Women’s Primary Care Associates, Longwood, and the Watkins Cardiovascular Clinic.

“This is a striking result, especially given the very short time frame in which control was reached,” said Naomi Fisher, MD, director of the Brigham’s Hypertension Service and Hypertension Specialty Clinic. “There are a few notable health care systems that have matched or exceeded this control rate, but most clinical practices do not approach this rate of success.”

Incorporating Technology

To overcome some of the challenges that clinical practices face, Fisher and colleagues combined several innovative strategies to create their program. Participants each received a Bluetooth-enabled blood pressure device that automatically transmits blood pressure measurements—taken by patients at home—into electronic medical records.

In addition, patients had access to “patient navigators”—non-physicians trained to use a clinical algorithm developed by hypertension specialists. The program enabled rapid assessment and medication dosage adjustments for patients. Medication adjustments were made every two weeks until home blood pressure was under 135/85.

The next step will be to test the program’s effectiveness with a larger population. With this approach, the team anticipates significant cost effectiveness and cost savings, in addition to the prevention of cardiovascular events and death from treating hypertension more intensively in men and women.

“The time-honored model of treating hypertension via traditional visits to the doctor is neither effective nor sustainable,” said Fisher. “Organizations can and should develop and adopt innovative technologies to create sustainable solutions for hypertension control.”

This work was supported by an institutional Brigham Care Redesign Incubator and Startup Program (BCRISP) award.

A homeless individual is defined as someone who lacks fixed and reliable housing, and it is estimated that more than half a million people fit that description daily in the U.S. Looking at data across three states, investigators from the Brigham and Beth Israel Deaconess Medical Center (BIDMC) recently found that a growing proportion of homeless patients are being hospitalized and for very different health concerns than the broader American population.

Rishi Wadhera

The retrospective cohort study examined patterns, causes and outcomes of acute hospitalizations for homeless and non-homeless patients in three populous and diverse U.S. states: California, Florida and Massachusetts. They observed a rise in acute hospital use among homeless individuals, primarily driven by mental illness and substance use disorder. The results were published in the journal Medical Care last month.

“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 Division of Cardiovascular Medicine 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.”

To examine these trends, hospital discharge data was acquired from Massachusetts and Florida between 2007 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 federal Agency for Healthcare Research and Quality. This dataset includes information such as homeless status, billing, demographics and diagnoses.

Overall, the researchers analyzed over 185,000 hospitalizations for homeless individuals and more than 32 million hospitalizations for non-homeless individuals. Over the periods studied, acute hospitalizations for homeless individuals increased in all three states (see infographic at left). Homeless patients were more often white (62 percent), male (76 percent), around 46 years old and either uninsured (42 percent) or insured by Medicaid (32 percent).

The researchers found that reasons for hospitalization among homeless and non-homeless individuals differed starkly, even after accounting for differences in demographics.

More than 50 percent of hospitalizations among homeless individuals were for mental illness and substance use disorder, while these conditions accounted for less than 20 percent of hospitalizations among demographically comparable non-homeless individuals.

Homeless adults also had a longer mean length of stay, averaging 6.5 days vs. 5.9 days among non-homeless patients. 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,” he added. “It is also possible that these patterns suggest inadequate longitudinal care for homeless individuals, and that, from a policy perspective, we need to do a better job of providing more consistent, reliable outpatient care to this population.”

A prototype of the ovulation-testing tool

Capitalizing on the latest technological advancements, a team of Brigham investigators has built a low-cost smartphone tool that can predict a woman’s ovulation and aid in family planning.

Powered by microfluidic technology (in which fluids flow through microscopic channels), artificial intelligence (AI) and the ubiquity of smartphones, the tool automatically detects fern-like patterns—a marker of ovulation—in a saliva sample. The team evaluated the performance of the device using artificial saliva in the lab and validated results in human saliva samples from six subjects, observing greater than 99 percent accuracy in effectively predicting ovulation. The results are published in Lab on a Chip.

“Before we started this project, we weren’t aware that such a need existed,” said corresponding author and principal investigator Hadi Shafiee, PhD, of the Division of Engineering in Medicine and Division of Renal Medicine.

“When we published last year on a technology for analyzing sperm to detect male infertility, we were approached by those who had read about our work and were wondering if we could develop a smartphone-based system to provide ovulation testing at home. Our study indicates that an accurate, automated and low-cost test is indeed possible.”

Those three elements are key, as current methods for monitoring fertility are often costly or subjective. These methods include ovulation detection by determining a woman’s luteinizing hormone (LH) level (a clinical blood test or at-home urine “dipstick” test), rectal or basal body temperature analysis, cervical mucus characterization and salivary ferning analysis. Salivary ferning refers to the unique appearance of dried saliva from a woman who is ovulating; when collected on a glass slide, saliva takes on a crystallized structure that resembles fern leaves. While relatively inexpensive and simple, this analysis is highly subjective. When performed by a layperson, it is prone to misinterpretation.

A diagram of the tool’s various components

To overcome this challenge, Shafiee and colleagues developed an automated process for detecting ferning in a saliva sample. Their AI algorithm was pre-trained with 1.4 million images from a broad visual database and then, more precisely, retrained with more than 1,500 salivary ferning images to classify saliva images into two categories: ovulating and nonovulating samples.

he team then evaluated the system’s ability to differentiate ovulating and nonovulating human saliva samples from six subjects. The women collected and tested their samples using the smartphone tool during both ovulating and nonovulating phases of their menstrual cycle (results were confirmed using a urine test).

To perform the test, saliva was collected on a microfluidic device, smeared and left to air-dry. The sample was inserted into a 3D-printed attachment affixed to a smartphone. The software then analyzed the fern patterns, correctly identifying ovulation in 99 percent of samples and nonovulation in 100 percent of them.

“One of the biggest advantages to this method is cost—whereas nonreusable urine stick tests can add up to $210 to $240 over the course of six months, our device represents the possibility of a one-time purchase,” said co-author Manoj Kumar Kanakasabapathy, a senior research assistant in the Shafiee laboratory. “Beyond human ovulation, there are applications here as well for animal breeding and even for dry-eye disease, which can also produce fern-like patterns in samples from eye mucosa.”

Prudhvi Thirumalaraju, another co-author and a senior research assistant in Shafiee’s lab, added: “One of the biggest problems with saliva-based tests, we realized, was that users find it difficult to interpret the fern patterns. We figured that advances in AI can be put to good use here to help people get objective results on their smartphones.”

The new system is constrained by some of the same limitations as traditional ovulation tests, and it cannot detect ovulation in women with estrogen imbalance, cysts in the ovaries and those who take fertility medications. Smoking or alcohol consumption may also interfere with accurate detection. The device will require additional testing in a larger population and approval by the U.S. Federal Drug Administration before it can be brought to market.

Anthony D’Amico

What’s the best way to prevent aggressive prostate cancer from coming back? A new multinational study of more than 600 men with an advanced form of the disease confirms surgery alone does not offer the highest chance of survival and examines outcomes for men following a new combination treatment plan.

The study, conducted by Brigham researchers, investigated how treatment with surgery plus the appropriate use of postoperative low-dose radiation and hormone therapy fared as an option for these men before cancer recurrence. The current standard of care involves a slightly different treatment combination: high-dose radiation and hormone therapy. Researchers found that less than 10 percent of men who underwent either combination therapy died within five years, compared to 22 percent of men who underwent surgery alone.

Published earlier this month in JAMA Oncology, the findings position postoperative radiation and hormone therapy, administered before cancer recurrence, as a new prostate cancer treatment option for men with a Gleason Score of 9 or 10 electing to undergo surgery. The Gleason Score is the grading system used to assess the aggressiveness of prostate cancer and determine appropriate treatment. The higher the Gleason Score, the more likely the cancer will grow and spread quickly.

“In many cases when cancer recurs, radiation and hormone therapy are recommended, but our findings indicate that the best survival outcomes may be achieved by implementing these therapies directly after surgery and not waiting for the cancer to recur,” said Anthony D’Amico, MD, PhD, chief of Genitourinary Radiation Oncology. “While more than 75 percent of men in this study had risk factors for recurrence following surgery for which radiation and hormone therapy could have been recommended, only one-third received those treatments.”

A prior study showed that the risk of death is much higher when surgery alone is performed, compared to following the current standard of care. D’Amico said clinicians are often reluctant to use radiation and hormone therapy following surgery for patients with aggressive prostate cancer due to concerns about overtreatment.

“However, overtreatment in this population with aggressive and advanced prostate cancer is very unlikely, given that prostate cancer will recur in at least 80 percent of these men within five years of surgery and require radiation or hormone therapy at that time,” he said.

Avik Chatterjee

Opioid-related overdoses and deaths remain a major public health concern in Massachusetts, yet adolescents who experience opioid-related nonfatal overdose 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 (DPH), the analysis examined data on Massachusetts adolescents, 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 just under 200 adolescents versus more than 22,000 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 Opportunity to Intervene’

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. “Individuals 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 rates in Massachusetts, researchers analyzed DPH data pooled from the entire state. This dataset represents 98 percent of Massachusetts residents and includes nonidentifiable medical information from hospitals, ambulance systems, substance-use systems, health insurance companies and homeless shelters.

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

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.

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 study demonstrates that the opioid epidemic is different in adolescents,” Chatterjee said. “This new knowledge will shape how we intervene and prevent opioid overdoses in adolescents.”

If you or someone you know would like to seek support for substance use disorder, contact the Addiction Recovery Program, an outpatient service in the Department of Psychiatry that helps patients with substance use disorder, at 617-983-7060, option 2.

During a medical emergency, the last thing anyone wants to worry about is their ability to pay for care. But according to a recent study by Brigham researchers, flawed insurance policies can result in denied coverage for patients visiting an emergency department (ED) based on their discharge diagnosis.

Brigham investigators analyzed a national sample of ED visits between 2011 and 2015 to determine the proportion that could be denied coverage if commercial insurers across the U.S. adopted the coverage-denial criteria of a large national insurer, Anthem, Inc., based on ED discharge diagnoses.

Shih-Chuan (Andrew) Chou

Researchers studied ED visits of more than 28,000 commercially insured adults, ages 15 to 64, and found that the insurer’s list of nonemergent diagnoses would classify coverage denial for nearly 16 percent of the visits examined. On a larger scale, that could translate to 4.6 million ED visits annually. Their findings were published this month in JAMA Network Open.

“Up to one-sixth of adult emergency department patients with private health insurance would qualify for further review and may be denied coverage under this policy,” said lead study author Shih-Chuan (Andrew) Chou, MD, MPH, of the Department of Emergency Medicine.

Researchers noted that in almost 90 percent of ED visits, the primary presenting symptoms that brought patients to the emergency department were the same presenting symptoms as those with diagnoses at risk of denial. Yet, among these patients, more than 65 percent received emergency-level services, such as imaging or multiple blood tests.

Jeremiah Schuur

Researchers concluded that it is problematic for insurance companies to retrospectively determine coverage for a visit based on diagnosis because patients decide to go to the ED based on their symptoms – a decision that may be very reasonable at that time.

“Nearly 90 percent of adult ED patients will have symptoms that could lead to a nonemergency diagnosis – and review for possible coverage denial – including symptoms such as chest pain, which is one of the most common reasons patients are hospitalized from the ED,” Chou said.

Senior author Jeremiah Schuur, MD, MHS, of Emergency Medicine, said the onus should not be on patients to determine if such symptoms warrant coverage for emergency care.

“Patients come to the ED with symptoms and not diagnoses,” he said. “After-the-fact policies that use final diagnoses to judge the appropriateness of an ED visit and further apply a financial penalty will put patients in a difficult spot where they are expected to self-determine whether there is a concerning illness. A better solution is to make it easier for patients to receive care for acute illnesses when they want to go outside the ED and access, for example, urgent care centers.”

The weight loss drug lorcaserin shows promise for reducing the risk of diabetes and aiding patients with the disease, according to a recent study by Brigham researchers.

Approved by the U.S. Food and Drug Administration in 2012 for adults with obesity – and those who are overweight and have weight-related medical problems – lorcaserin controls a patient’s appetite by triggering feelings of fullness. Investigators from the Thrombolysis in Myocardial Infarction (TIMI) Study Group led a clinical trial to test the effects of lorcaserin, manufactured by the trial’s sponsor, Eisai Inc., in 12,000 overweight or obese patients at risk for a heart attack or stroke. At the start of the trial, more than half of participants had diabetes and another third had prediabetes.

Erin Bohula

During this year’s European Association for the Study of Diabetes and in a simultaneous publication in The Lancet, the research team reported that taking lorcaserin decreased risk for diabetes, induced diabetes remission and reduced risk of diabetes complications in obese and overweight patients.

These latest findings build on a related discovery the same team of Brigham investigators reported earlier this year on the cardiovascular safety and weight loss effectiveness of lorcaserin.

“We recently presented findings showing that use of lorcaserin resulted in modest but sustained weight loss among obese and overweight patients without increasing risk of heart attack and stroke,” said co-lead author Erin Bohula, MD, DPhil, a cardiovascular medicine and critical care specialist in the Division of Cardiovascular Medicine and a staff investigator for the TIMI Study Group. “Now we report that, when added to lifestyle interventions, lorcaserin significantly reduced incidence of diabetes, increased rates of diabetes remission and reduced the risk of diabetic microvascular complications.”

Benjamin Scirica

Researchers found that lorcaserin reduced risk of diabetes by 19 percent in prediabetic participants. Among those with diabetes, 21 percent saw a reduced risk of diabetic microvascular complications, which affect small blood vessels and lead to issues in the kidney (persistent microalbuminuria), eyes (diabetic retinopathy) or nerves (diabetic neuropathy).

“Lorcaserin provides another tool, beyond diet and exercise, for patients hoping to achieve and maintain weight loss. And, happily, even relatively modest weight loss can improve the diabetes control in those with diabetes and reduce the development of diabetes in those at risk,” said co-lead author Benjamin Scirica, MD, also of Cardiovascular Medicine and a senior investigator for the TIMI Study Group.

Hypoglycemia, or dangerously low levels of blood sugar, could be a negative side effect of taking lorcaserin for patients already on medications to lower blood sugar. For example, among participants taking insulin or a sulfonylurea (a medication to treat Type 2 diabetes), researchers reported more events of severe hypoglycemia requiring hospitalization or considered to be life-threatening – recording 12 events with lorcaserin versus four events with a placebo. The authors note that this finding highlights the importance of carefully adjusting agents known to increase risk of hypoglycemia, especially while a patient is working to lose weight.

“Given the global prevalence of obesity and its association with Type 2 diabetes and complications that can cause death or greatly diminish quality of life, we need therapeutic strategies that can be added to lifestyle modification to prevent and control diabetes,” said Scirica. “This rigorous and large-scale randomized study demonstrates the potential for improving glycemic control when adding a weight loss agent to a treatment plan.”

From left: Edwin Silverman, Fran Grodstein, Scott Weiss, Yukari Perrella and Meir Stampfer

When Fran Grodstein, ScD, associate director of the Channing Division of Network Medicine and director of its Chronic Disease Epidemiology Unit, reflects on the many seminal discoveries made by Channing investigators over the past 50 years, there is no shortage of groundbreaking research that comes to mind.

Underpinning all of those accomplishments – from findings about the risks associated with consuming foods containing trans fats to the role of aspirin in preventing colorectal cancer – is not just academic excellence. Equally essential has been the Channing’s longstanding culture of professional and personal support that inspires dedication to its mission, Grodstein told an audience of investigators, clinicians and staff during a recent event celebrating the Channing’s 50th anniversary.  

“It’s a true culture of kindness, generosity and support that I have absolutely no doubt is the only reason we’ve remained as successful as we have been,” said Grodstein, one of several speakers at the ceremony and symposium commemorating the Channing’s anniversary milestone in Bornstein Amphitheater on Sept. 20.

In 1968, the Channing Laboratory became an independent research entity at Boston City Hospital with its own building on Albany Street. The Channing moved to Longwood Avenue in 1977 and joined what is now the BWH Department of Medicine. In 2012, it became the Channing Division of Network Medicine. 

Now comprising 96 faculty, 39 trainees and 145 staff members, the Channing Division of Network Medicine uses an integrated, network-based, systems biology-driven approach to better understand complex diseases and to develop new treatments and preventive strategies for them. 

Edwin Silverman, MD, PhD, chief of the division, chronicled his own history with the Channing and reflected on the many opportunities it has given him to learn and grow. Joining the lab as a postdoctoral fellow in 1994, he established the Boston Early-Onset Chronic Obstructive Pulmonary Disease (COPD) Study, which sought to identify genetic factors associated with the disease in young people. 

Silverman recalled driving 40,000 miles over four years to administer questionnaires, perform breathing tests and collect blood samples in participants’ homes. A map illustrating those travels still hangs in his office as a reminder of those early days. 

Over the years, he said, it has been exciting to witness the extraordinary research contributions made by Channing scientists and staff. Numerous studies transformed the perception of COPD from a purely smoking-related to disease to one defined by both genetic and environmental risk factors. 

Silverman also highlighted several discoveries that led directly to U.S. policy changes to improve public health, including the labeling and removal of trans fats in foods after Channing researchers in the Nurses Health Study found a link between trans fats and increased risk of coronary heart disease and overall mortality. In another example, Channing-led research resulted in changes to federal environmental regulations after investigators showed that fine-particulate air pollution levels were associated with increased mortality. 

“A key principle in all of this has been the willingness and ability to integrate population-based research, laboratory research and innovative data analysis,” Silverman said. 

Looking ahead, the division will continue its multidisciplinary research studies of many diseases, while working to intensively develop research programs in three major areas of study: healthy aging, the microbiome and the study of multiple “omics” (a term referring to the group of sciences ending in the suffix “-omics,” such as genomics and metabolomics) to better understand what causes complex diseases to emerge and progress.

“I am very proud of what Channing investigators have accomplished, both historically and in the current era,” said Joseph Loscalzo, MD, PhD, chair of Medicine and physician-in-chief at BWH. “But I’m even more excited about what Channing investigators will contribute in the future as their approach to big data, systems analysis, systems dynamics and network medicine come to full fruition.”

Brigham Health President Betsy Nabel, MD, applauded the division for its remarkable work and commitment to improving public health over the past five decades.

“I want to congratulate and thank all of you, the entire Channing team – including investigators, staff and trainees – for your valuable contributions to the Brigham, to our knowledge of medicine and all that you’ve done for our patients and families,” Nabel said. 

Dayna Johnson

Sleep apnea is a common sleep disorder associated with an increased prevalence of cardiovascular disease, hypertension, diabetes and other chronic health disorders. About 80 to 90 percent of individuals with sleep apnea are undiagnosed, and a large number of them are African Americans, according to a new BWH study.

Brigham investigators determined the prevalence of sleep apnea among 852 African-American adult men and women living in Jackson, Miss., and participating in the Jackson Heart Sleep Study. Researchers explored sleep apnea predictors and estimated the proportion of undiagnosed cases. They found a high prevalence of sleep apnea among this large sample of African-American men and women, and the majority – 95 percent – were undiagnosed and untreated. Their results were published this month in the journal SLEEP.

“We discovered that only 5 percent of individuals with moderate or severe sleep apnea had been diagnosed. In other words, over 95 percent of this sample experience nightly stresses associated with periods when breathing stops and oxygen levels fall. Untreated sleep apnea can increase risk for hypertension-related diseases such as stroke, a condition disproportionately common in African Americans,” said Dayna Johnson, PhD, associate epidemiologist in the Division of Sleep and Circadian Disorders and lead author on the study. “We also learned that asking about habitual snoring and measuring neck size (a risk factor for sleep apnea) can help identify individuals at risk.”

Researchers found that 24 percent of participants had moderate or severe sleep apnea, but only 5 percent had been diagnosed by a doctor. Men had a 12-15 percent higher prevalence of the disorder compared to women. The average age of the study sample was 63 years old; 66 percent of participants were female. In addition to habitual snoring and larger neck size, higher body-mass was identified as another important marker of sleep apnea. This is the first-known study of its size to conduct objective testing for sleep apnea and administer validated questionnaires in a sample of African Americans.

Susan Redline

“There is a large burden of untreated sleep apnea in the population. Our results point to the opportunity to improve sleep apnea screening and diagnosis in the population as a means for reducing health disparities,” said Susan Redline, MD, MPH, senior author of the study.

Michael Twery, PhD, director of the National Center on Sleep Disorders Research at National Heart, Lung and Blood Institute, added: “These findings in the Jackson Heart Study reveal that sleep apnea is underdiagnosed and a potential threat to the health and safety of African Americans. Further studies are needed to develop the tools and systems required to facilitate diagnosis and treatment of sleep apnea in African Americans and other communities.”

Mandeep Mehra posits that several details in the Mona Lisa suggest the iconic portrait’s subject suffered from a chronic medical condition.

The source of the Mona Lisa’s mystery has been a topic of scrutiny for centuries, and one Brigham physician-scientist maintains that her captivating expression reveals important medical clues about Lisa Gherardini, the subject of Leonardo da Vinci’s iconic painting.

Previously, researchers hypothesized that Gherardini suffered from familial heart disease and a lipid disorder. This diagnosis was made by rheumatologists and endocrinologists in 2004 and is primarily based on the skin lesions visible in the portrait.

In an article in Mayo Clinic Proceedings, Mandeep R. Mehra, MD, medical director of the BWH Heart & Vascular Center, detailed a new medical interpretation of the famous portrait. He suggested that the Mona Lisa’s thinning hair, missing eyebrows, skin lesions and yellowed eye and skin color point to a different condition: hypothyroidism.

The diagnosis is based on a careful analysis of Gherardini’s face and body as well as epidemiological information about 16th-century Italy. After studying the painting, Mehra concluded that while some visual clues are consistent with a lipid disorder, the era in which Gherardini lived weakens the feasibility of premature heart disease. In the 16th century, inaccurate understandings of the human body and rudimentary medical care meant that someone with heart disease in their 20s was unlikely to live to age 63, as Gherardini reportedly did.

Iodine is critical for the function of the thyroid, but because the body does not produce this mineral, it must be consumed through food sources or supplements. Without enough iodine, the thyroid cannot produce certain hormones, resulting in hypothyroidism. This condition is associated with a variety of symptoms, including fatigue, facial swelling, hair loss and weight gain. Prior to the invention of iodized salt, hypothyroidism was common among people whose diet did not naturally contain iodine.

While the Italian Renaissance was a period of great artistic development, it was also a time in which poor nutrition and insufficient medical care were common, even among the wealthy. The diets of 16th-century Italians were lacking in iodine. Gherardini lived in Florence, a city whose inland location prevented easy access to the seafood or meat that could have prevented hypothyroidism.

Gherardini is depicted with suggestion of a swollen thyroid gland, also known as a goiter, which supports the diagnosis of hypothyroidism, Mehra said. Additionally, historical records indicate that Gherardini gave birth to her son Andrea shortly before sitting for the portrait. She likely developed peripartum hypothyroidism – a form of the disease that emerges during pregnancy – that continued to affect her as a chronic condition.

Mehra noted it is also possible that she may have had hypothyroidism with primary biliary cirrhosis, a disease that destroys the bile ducts in the liver, although living for 40 years with that condition untreated would have been unlikely.

“The enigma of the Mona Lisa can be resolved by a simple medical diagnosis of a hypothyroidism-related illness,” he said. “In many ways, it is the allure of the imperfections of disease that give this masterpiece its mysterious reality and charm.”

Don’t trade bread for bacon just yet. According to a recent study by Brigham researchers, low-carbohydrate diets may not be as healthy as popularly believed.

Upon examining the relationship between carbohydrate intake and lifespan, investigators discovered that while higher carbohydrate intake was related to greater risk of mortality, so was lower carbohydrate intake.

The team, whose findings have been published online in The Lancet Public Health, concluded that the longest life expectancy was seen among individuals whose regular consumption of carbohydrates was in the midrange – about half of total caloric intake.

Prior randomized trials of low-carbohydrate diets have suggested short-term benefits, including weight loss and cardiovascular risk factor control, but longer-term data on trial outcomes has been unavailable. Meanwhile, data from observational studies on the long-term health effects of low-carbohydrate diets had been conflicting, largely due to differences in dietary patterns between different populations in the study groups.

To get a more accurate picture, the BWH researchers, working with collaborators at Harvard T. H. Chan School of Public Health, examined data from more than 430,000 adults enrolled across eight studies and three continents.

Sara Seidelmann

“It was important to combine data from North American, European and Asian countries in order to fully understand and appreciate the relationship between carbohydrate intake and risk of earlier death that exists across the global spectrum of eating patterns,” said Sara Seidelmann, MD, PhD, a fellow in the Division of Cardiovascular Medicine.

Plant- vs. Meat-based Diets

After looking at what types of foods participants regularly ate, Seidelmann and her colleagues noted that people with low-carbohydrate diets more frequently consumed meat and other animal-based foods, compared to individuals with different levels of carbohydrate intake.

They subsequently observed that diets largely based on animal-derived protein and fat sources – from foods like lamb, beef, pork and chicken – were associated with higher mortality. Those that favored plant-derived protein and fat intake – from foods like vegetables, nuts, peanut butter and whole-grain breads – had a lower mortality rate.

“Our data suggest that animal-based low carbohydrate diets, which are more prevalent in North American and European populations, shorten life span in the long term,” Seidelmann said.

“Alternatively, if one chooses to restrict carbohydrate intake as an approach for weight loss or to improve heart health, replacement of carbohydrates with predominately plant-based fats and proteins should be strongly considered as an alternative.”

Senior author Scott Solomon, MD, of Cardiovascular Medicine and Edward D. Frohlich Distinguished Chair at BWH added: “These results help us better understand the relationship between the specific components of diet and cardiovascular health. While a randomized trial has not been performed to compare different types of diets, these data suggest that shifting towards a more plant-based diet should help attenuate cardiovascular disease.”

Nasal polyps – soft, round outgrowths that can appear in the nasal passages and sinuses – can be chronic and relentless. Although noncancerous, these outgrowths can grow large enough to block the nose and sinuses, leading to discomfort, breathing problems and infections. And while they can be surgically removed, they may grow back, sometimes in a matter of days.

Although most patients are happy to be rid of their polyps, for researchers, that tissue is precious: It may hold critical clues about intense, allergic inflammation. Brigham investigators, along with collaborators from the Broad Institute and Massachusetts Institute of Technology, have used some of the most advanced sequencing technology to peer into nasal polyps – gleaning new insights into this condition and the severe form of inflammation that may lead to disorders such as asthma, allergic rhinitis and allergic eczema. Their findings were recently published online in Nature.

“For our patients, one of the most frustrating things about chronic, allergic conditions is that we have no cure. Surgery can relieve discomfort for those with nasal polyps, but in many cases the effect is only temporary,” said co-corresponding author Nora Barrett, MD, of the Division of Rheumatology, Immunology and Allergy. “My group’s goal is to understand why the inflammatory process persists once it begins and to uncover the cause of these conditions.”

Barrett and colleagues obtained samples from 12 patients with nasal polyps or other sinus conditions, collecting a total of 18,036 cells. They compared these to nasal scrapings from healthy individuals. To better understand what genes might be involved in nasal polyps, the team then used a technique called massively parallel, single-cell RNA sequencing, which allows investigators to determine which genes are “turned on” in each cell. Rather than focusing on just one kind of suspected cell, they used this approach to look at every cell type – such as blood cells, skin tissue cells and so forth – found in harvested samples.

What they found surprised them. One of the most striking discoveries the researchers reported was that epithelial progenitor cells – which produce the cells that line the airways – had been permanently altered in the polyp samples. In fact, even when removed from the tissue and grown in the lab, the resulting cells showed marked genetic differences.

“To a dramatic extent, inflammation had changed the basic tissue architecture at the genetic level,” Barrett said. “These lasting changes may be driving the recurrence and persistence of chronic, allergic inflammation for nasal polyps and other allergic conditions.”

The Nature publication offers a global, cellular map of inflamed tissue for what is known as type 2 inflammation – a severe form of inflammation that involves immune cells that have gone rogue, triggering a cascade of immune action. The map points to many pathways that have been altered, and Barrett and colleagues are working through these to identify which ones may be driving inflammation and which ones may be resulting from the inflammatory process.

The research team also tested an antibody that helped restore normal genetic activity – suggesting that it may be possible to develop therapies to prevent nasal polyps from returning by restoring a normal balance to cells that have been altered by inflammation.

The team also hopes to use the new information to develop a genetic signature that would allow clinicians to take a swab of nasal mucosa to test for lung conditions.

Andrea Pusic

When women decide to undergo breast reconstruction after a mastectomy, they’re typically presented with two options for the procedure: an implant-based reconstruction or an autologous, or “flap,” reconstruction, which uses skin, fat or muscle from elsewhere in the body to rebuild the breast.

While demand for breast reconstruction surgery is rising, there has been limited evidence-based, patient-centered data about satisfaction and quality-of-life measures after the procedure.

In a new study, Brigham researchers evaluated patient-reported satisfaction and well-being outcomes for more than 2,000 women nationwide prior to their initial reconstruction surgery and two years afterward. They found that patients who underwent flap reconstruction had greater satisfaction with their breasts, as well as greater psychosocial and sexual well-being two years after surgery, compared to those who underwent implant reconstruction.

The findings, shared last month in JAMA Surgery, built on the one-year, patient-reported outcomes of the Mastectomy Reconstruction Outcomes Consortium (MROC).

“Patient-centered data can best inform patients and clinicians about the potential risks and expected outcomes of breast reconstruction when making a decision between implant-based or autologous breast reconstruction,” said Andrea Pusic, MD, MHS, FACS, FRCSC, chief of the Division of Plastic and Reconstructive Surgery and senior author of the study. “Given the personal and intimate nature of breast reconstruction, patient-centered data are arguably the best measures of outcomes. Understanding the expectations and quality-of-life outcomes for previous patients may help new patients and their care providers in the decision-making process.”

A Closer Look: Flap vs. Implant

The study looked at patients from 11 centers, including the Brigham. Patient satisfaction with breasts, psychosocial well-being, physical well-being and sexual well-being were measured in scores on the BREAST-Q, a validated breast-surgery, patient-reported outcome questionnaire, calibrated to detect differences between specific procedure groups and patients over time.

In addition to their overall findings, Pusic and her team discovered that the differences in patient satisfaction with their breasts and their sexual well-being became greater at the two-year mark. For patients who underwent implant-based reconstruction, satisfaction rates declined over time, likely due to symmetry issues and the inability of the implant to age naturally.

After one year, no difference in the physical well-being of the chest was reported. At two years, patients who received flap reconstruction reported favorable outcomes for physical well-being of the chest compared with implant reconstruction, but the difference remained small.

Importantly, although patients reported overall high satisfaction with flap reconstruction, physical well-being of the abdomen was not fully restored, even though approximately two-thirds of the autologous patients had muscle-sparing or perforator flap procedures. The authors note that additional research and innovation is required to further minimize the negative effect of flap harvest on abdominal wall function.

Researchers said additional studies with even longer-term follow-up are warranted to determine the association of the type of reconstruction with patient-reported outcomes when radiation is required.

Jennifer Stuart

Even though women who develop preeclampsia or gestational hypertension during pregnancy see their high blood pressure return to normal after delivery, a new study indicates they are considerably more likely to develop cardiovascular disease risk factors, such as high cholesterol and Type 2 diabetes, later in life.

Previous research has shown that women with high blood pressure during pregnancy are more likely to have a heart attack or stroke compared to women who had normal blood pressure during pregnancy. What has been less clear until now is their likelihood of developing cardiovascular disease risk factors and when such conditions begin to emerge – knowledge that is critical to developing effective screening guidelines.

To help close this gap, researchers from BWH and the Harvard T.H. Chan School of Public Health measured how often and when women with preeclampsia or gestational hypertension during their first pregnancy developed high blood pressure, diabetes and high cholesterol after pregnancy.

In addition to revealing an increased risk for all three cardiovascular risk factors, the data showed that they emerged shortly after pregnancy and persisted for decades. The findings were published in Annals of Internal Medicine earlier this month.

“Many researchers believe that pregnancy acts a cardiometabolic ‘stress test’ and that pregnancy complications may help identify women who are predisposed to develop cardiovascular disease risk factors and events later in life,” said Jennifer Stuart, ScD, associate epidemiologist in the Division of Women’s Health. “Women who have had complications, such as preeclampsia or gestational hypertension, and their doctors can use this ‘early warning signal’ to improve their cardiovascular health by modifying their diet or physical activity before those risk factors emerge.”

This study was conducted among almost 60,000 women enrolled in the Nurses’ Health Study II who had given birth at least once. Participants were studied for approximately 25 to 32 years after the first pregnancy, depending on the risk factor.

Women with preeclampsia or gestational hypertension were two to three times more likely to develop high blood pressure. They also had a 70 percent higher rate of Type 2 diabetes and a 30 percent higher rate of high cholesterol, compared to women with normal blood pressure in pregnancy.

The risk factors studied also developed at younger ages and sooner after pregnancy in women who had preeclampsia or gestational hypertension. The relative risk of developing high blood pressure was strongest within five years after the first birth, and the increased risk persisted for several decades.

Women with high blood pressure during more than one pregnancy were even more likely to later develop high blood pressure, diabetes and high cholesterol.

These findings were not explained by shared risk factors such as pre-pregnancy body mass index, smoking or family history.

“As recommended by the American Heart Association, doctors should obtain a detailed history of pregnancy complications from their patients and screen women who had high blood pressure in pregnancy at regular intervals after pregnancy for cardiovascular disease risk factors,” Stuart said.

Tamarra James-Todd

Hormones have a significant influence on a woman’s health and well-being throughout her lifetime. While much is known about how hormones work, the exact ways they affect health and organ systems are far less understood.

This gap is problematic because women experience sex-specific conditions, diseases and health outcomes directly linked to their hormones, according to BWH researchers who explored these complex issues during the 13th annual Women’s Health Luncheon, a fundraiser benefitting the Mary Horrigan Connors Center for Women’s Health and Gender Biology, on May 11.

The concern is part of a broader one about the underrepresentation of female study participants in medical research and scarcity of sex-specific treatments, especially as many diseases affect women in different ways or disproportionately compared to men, said Hadine Joffe, MD, MSc, executive director of the Connors Center, vice chair of research in the Department of Psychiatry and director of the Women’s Hormone and Aging Research Program at BWH.

“When the health of women is understood, valued and protected, everyone benefits,” Joffe said. “That is why the Connors Center is working actively to advance women’s health by catalyzing research, informing and advocating across the community, and transforming education for the next generation of leaders in medicine.”

Event organizers also announced the Connors Center IGNITE Awards, which will support innovative research in women’s health by providing seed funding for early-stage projects related to the development and testing of new treatments in women. This year’s luncheon raised nearly $700,000; of that total, $100,000 will fuel two IGNITE Awards.

“We will be relentless in pushing ourselves and our peers to do everything possible to understand and advance women’s health,” said Brigham Health President Betsy Nabel, MD. “We will continue down this path not just because it’s the brave thing to do, but because it’s the right thing to do.”

This year’s program, “Hot and Heavy: A Woman’s Relationship with Her Hormones,” featured presentations from three leading female BWH investigators working to advance research and care in the areas of birth control, menopause and environmental sources of hormones.

‘A Critical Health Issue’

Renowned broadcast journalist and CBS 60 Minutes correspondent Lesley Stahl delivered the event’s keynote address, reflecting on recent interviews she conducted with researchers about the science behind a grandmother’s love and the mental health benefits of caring for grandchildren.

“I used to think there were four necessities for life: food, oxygen, love and friendship,” Stahl said. “Now I know there is a fifth – purpose.”

Lydia Pace, MD, MPH, director of the Women’s Health Policy and Advocacy Program at the Connors Center, highlighted the evolution of hormonal contraceptives. She noted that while the birth control pill has been revolutionary, long-lasting alternatives such as contraceptive implants and intrauterine devices (IUDs) are more effective. However, these options remain underutilized partly due to misconceptions about their expense among patients and providers and a lack of training among primary care physicians.

Expanding access to these devices is crucial, Pace said, noting that almost half of U.S. pregnancies are unintended.

“For many women with chronic medical conditions, like many women we care for at the Brigham, being able to prevent or carefully time a pregnancy is a critical health issue,” she said.

In the next presentation, Joffe explored the science behind hot flashes, the most common peri- and post-menopausal symptom, and disruption of sleep. These sudden, intense sensations of warmth and sweating are linked to hormonal changes in these periods of a woman’s life, but their exact cause is still a mystery, Joffe said.

Still, several treatments have shown to be successful in managing these symptoms, she noted. For women who have trouble sleeping due to hot flashes, options include hormonal therapy and selective serotonin-reuptake inhibitors, a class of drugs most commonly used to treat depression. Practicing good sleep hygiene – such as avoiding the use of electronic devices in bed – is also critical to achieve good sleep, Joffe said.

Hidden Hormones

Tamarra James-Todd, PhD, MPH, an epidemiologist in the Division of Women’s Health, discussed the issue of women’s exposure to “hidden hormones” in countless consumer products. Also known as endocrine-disrupting chemicals (EDCs), these substances are found in everything from food packaging to beauty products to furniture and electronic equipment, James-Todd explained.

Women are disproportionately exposed to these chemicals, with the average American woman being exposed to 168 EDCs each day, compared to 80 for men, James-Todd said. Exposure to high concentrations of EDCs has been associated with early onset of puberty, infertility, pregnancy loss, preterm birth and gestational diabetes, among other adverse outcomes.

Hope is on the horizon, however. Two female legislators, Sens. Dianne Feinstein of California and Susan Collins of Maine, are leading efforts to strengthen the U.S. Food and Drug Administration’s authority to regulate ingredients used in personal care products. Until then, James-Todd noted there are several lifestyle changes that can reduce broader exposure to EDCs. These include using glass containers for storing and reheating food, adopting fragrance-free products and purchasing home products made from natural materials like bamboo.

Thomas Kupper

Two patients with mycosis fungoides (MF), a rare type of lymphoma that affects the skin, can appear to have identical diseases upon first diagnosis, but they might develop radically different outcomes. Many patients have a very slow-growing form of the disease, which first appears as a rash, and often have normal life expectancies. But a subset will develop an aggressive, deadly form of it that can spread throughout the skin and beyond, becoming untreatable.

If identified early, patients with this aggressive form of MF may be eligible for a stem cell transplant to cure the disease. But once MF progresses and becomes treatment-resistant, it is nearly impossible to achieve the complete remission required for a successful stem cell transplant. 

A tool to accurately determine which early-stage patients are at risk of dying from MF – the most common form of cutaneous T cell lymphoma – and which patients are likely to only require conventional therapy is desperately needed. BWH investigators are now one step closer to bringing such a tool to the clinic.

A research team led by Thomas Kupper, MD, chair of the Department of Dermatology, has found that genetic sequencing can accurately predict which early-stage patients have the aggressive form of MF. Specifically, they discovered that performing high-throughput sequencing of a gene called T-cell receptor beta (TCRB) better predicts which patients will develop the deadly form of MF than any other established factor. Their results were published this month in Science Translational Medicine.

“We are excited to bring precision medicine to the management of MF patients,” said Kupper, the paper’s senior author. “While more work needs to be done, we think this approach has the potential to prospectively identify a subgroup of patients who are destined to develop aggressive, life-threatening disease, and treat them in a more aggressive fashion with the intent to better manage, and ideally cure, their cancer.”  

More than 80 percent of early-stage patients with MF will have a non-aggressive form of the disease and will live for decades after diagnosis and will often die of unrelated causes. But patients with advanced forms of MF have a dismal prognosis, with life expectancies ranging from one and a half to four years, even with current therapies. Kupper and colleagues founded the Cutaneous Lymphoma Clinic at Dana-Farber Cancer Institute in 1999 to develop better diagnostic and prognostic tools for MF and other forms of cutaneous T cell lymphoma. Since 2002, thousands of patients have been seen, and almost 900 patients have participated in a longitudinal study to follow their disease progression through biopsies and blood samples. 

New Insights

In the current study, researchers sequenced T cell receptor genes from biopsied skin tissue at the site of lesions from more than 300 patients with cutaneous T cell lymphoma, most of whom had MF. By sequencing massive amounts of DNA at once, BWH researchers could produce a snapshot of the TCRB genes from many cells at the site of the lesion. 

The team used this technique to measure the percentage of total T cells that are clones of the mutated MF lymphoma T cells – a metric called tumor clone frequency (TCF). An elevated TCF predicted, with high sensitivity and specificity, the likelihood of disease progression and overall survival of patients with early stage MF.

“Under the microscope, benign T cell and MF T cells are hard to distinguish,” said Kupper. “However, every T cell has a unique DNA sequence of its T cell receptor, which we can detect by high-throughput DNA sequencing. High-throughput DNA sequencing and calculations of TCF allow us to make predictions that would never have been possible before. As a physician who has treated patients with this disease for decades, I am excited to be involved with work that so directly and profoundly affects the care and management of these patients.”

Krista Huybrechts

Women who are prescribed antipsychotic medications to treat bipolar disorder, schizophrenia and other severe mental health disorders face several unknowns about potential side effects when deciding whether to remain on these therapies during pregnancy.

New research from BWH investigators sheds light on one of these previously unanswered questions, finding that pregnant women taking certain antipsychotics are at an increased risk for developing gestational diabetes.

Several antipsychotic medications are known to cause metabolic side effects, including weight gain and diabetes, in the general population. Whether their continued use during pregnancy leads to an increased risk of gestational diabetes was not previously known.

Gestational diabetes, which causes high blood-sugar levels during pregnancy, can lead to complications such as preeclampsia, cesarean delivery and high birth weights, among other conditions. Additionally, about 50 percent of women who have gestational diabetes will develop Type 2 diabetes years after giving birth – making it all the more important that clinicians and patients understand the risk associated with antipsychotics during pregnancy. The BWH research team quantified this risk, and their results were recently published in American Journal of Psychiatry.

“Different antipsychotics have different levels of risk of metabolic side effects,” said senior author Krista Huybrechts, PhD, MS, an epidemiologist in the Division of Pharmacoepidemiology and Pharmacoeconomics. “Clinicians must weigh the benefits of staying on a stable regimen against the risks of continuing treatment with a higher-risk antipsychotic during pregnancy to make an informed decision about the best course of treatment for the patient.”

The researchers focused on five antipsychotics used to treat severe mental health disorders: aripiprazole, ziprasidone, quetiapine, risperidone and olanzapine. The study compared women who had stopped taking antipsychotics during pregnancy and women who had continued to take them during the first 20 weeks of pregnancy. None of the women in the study had pre-existing diabetes, and the study controlled for confounding factors, such as obesity, that may lead to greater risk of gestational diabetes.

Researchers found that continued use of three medications – aripiprazole, ziprasidone and risperidone – during pregnancy was not associated with an increased risk of gestational diabetes. However, the continued use of quetiapine led to a 28 percent increased risk. The likelihood of developing gestational diabetes was higher for those who took olanzapine, with a 61 percent increased risk.

Researchers noted these outcomes are similar to those seen in the general population among patients who take these medications and develop metabolic side effects. In particular, quetiapine is associated with a moderate risk of metabolic side effects, and olanzapine has been shown to carry the highest risk of them.

While this study looked at the risks associated with remaining on certain antipsychotics during pregnancy, researchers did not examine the outcomes associated with switching pregnant patients from these high-risk antipsychotics to lower-risk alternatives. Huybrechts and her team hope to address this question in future work.

Tracy Young-Pearse

Using human stem cells, Brigham researchers have created a miniature 3-D model of the brain to study a gene mutation tied to major mental illnesses, such as schizophrenia, bipolar disorder and depression. 

Previously, it had been difficult to find the right tools to study how this mutation alters brain development in humans. However, advancements in engineering human stem cells now enable researchers to grow “mini-organs” – visible to the naked eye – and use gene-editing tools in the lab to insert specific mutations into these cells. Researchers from the Brigham are using these new technologies to study the effects of a specific genetic mutation in these miniature brain models, also known as cerebral organoids, which are cultured from human stem cells. The team’s results were recently published in Translational Psychiatry.

“Mini-brains can help us model brain development,” said senior author Tracy Young-Pearse, PhD, head of the Young-Pearse Lab in the Ann Romney Center for Neurologic Diseases at BWH. “Compared to traditional methods that have allowed us to investigate human cells in culture in two dimensions, these cultures let us investigate the three-dimensional structure and function of the cells as they are developing, giving us more information than we would get with a traditional cell culture.”

To create the mini-brains for the study, researchers cultured human-induced pluripotent stem cells (iPSCs), which are generated from patient blood samples and can be “directed” to become any type of cell in the body. Using a gene-editing tool, they disrupted a specific gene linked to mental illness, DISC1. This allowed them to model the mutation seen in studies of families suffering from these diseases. The team compared mini-brains grown from stem cells with and without this mutation.

Those with the genetic mutation showed significant structural disruptions compared to models in which the DISC1 gene was intact. Specifically, the fluid-filled spaces between brain cells, known as ventricles, were more numerous and smaller than in the modified mini-brains. This showed researchers that while the typical cells are present in mini-brain models containing the mutation, they are not in their expected locations.

The modified mini-brains also showed increased signaling in a neural pathway known to be important for giving the brain the correct shape and organization, and one that is disrupted in bipolar disorder. By blocking this pathway in the modified mini-brains, researchers were able to “rescue” them. That is, the mutant models developed a structure similar to that of the mini-brains grown from normal stem cells. This suggests that the pathway studied, known as the WNT pathway, could be a potential target for future therapies.

“By producing cerebral organoids from iPSCs, we can carefully control these experiments. We know that any differences we are seeing are because of the mutation that we introduced,” said Young-Pearse. “By looking at how DISC1-mutations disrupt brain morphology and gene expression, we are strengthening the link between DISC1-mutation and major mental illness, and providing new avenues for investigation of this relationship.”

James Philip uses a simulation to demonstrate anesthesia’s effects the body.

BWH staff joined local families, students and community members in the Hale Building for Transformative Medicine to experience science in an interactive way on April 19. As part of this year’s Cambridge Science Festival, the Brigham Research Institute (BRI) hosted a “science fair,” providing attendees an up-close look at cutting-edge projects at the Brigham.  

“This science fair was a great success, drawing in an impressive crowd of all ages and interests and giving our remarkable researchers a chance to showcase their incredible work,” said Jackie Slavik, PhD, executive director of the BRI.

An attendee tries out a virtual reality headset.

The event featured hands-on demonstrations to make science interesting and accessible for everyone from scientists to young children. The Pediatric/Newborn Medicine Research table combined education and entertainment with various brain science activities, including an arts-and-crafts station.

Another exhibit, Gas Man, used a computer simulation to show attendees the path of anesthesia uptake and distribution throughout the body. The Zebrafish Core Facility hosted a table where guests could learn about how these miniscule water-dwellers are used in laboratories to study behavior, diabetes, heart disease, regeneration, stem cell biology and cancer.

Visitors crowded around the Tactical Neurosurgical Team’s interactive demonstration of the head-mounted mixed reality navigation system. An augmented and virtual reality display also drew in a mass of people, all vying for the chance to try out the medical imaging device, which is used to view and annotate imaging scans.

Sat Bir Singh Khalsa, PhD, of the Division of Sleep Medicine, led several meditative yoga sessions based in science, teaching participants how to find inner peace within their everyday routines. Finally, the Drinker Iron Lung, whose roots trace back to the Peter Bent Brigham Hospital, stood as a notable piece of history in medicine and science. Even as it was wheeled down the halls of the hospital in advance of the fair, it was a showstopper. Jeffrey Drazen, MD, chief of the Division of Medical Communications, presented the device’s history as people gathered to see – and even climb inside – a machine that saved the lives of countless polio victims, starting in 1929.

The Department of Pathology held its 12th annual Research Celebration in the Hale Building for Transformative Medicine on April 6. A poster session showcased basic, clinical and translational research conducted in Pathology and in collaboration with other departments. 

The event also honored this year’s winners of the Thomas J. Gill III, MD, and Simon Simonian, MD, ScD, Prize for Research Excellence, which recognizes the accomplishments of young investigators and how their relationships with mentors have influenced their success. Previously awarded to one pair of recipients, this year the prize was given to four: Nikki Kong, PhD, and mentor Li Chai, MD; Michael Mina, MD, PhD, and mentor Stephen Elledge, PhD; David Papke Jr., PhD, and mentor George Mutter, MD; and Pascal Yazbeck, PhD, and mentor Tanya Mayadas, PhD.

Stefan Tullius

Men and women who receive donated organs can have different rates of transplant rejection – an outcome that, in some cases, is influenced by the sex of the donor.

A recent study by BWH investigators assesses what is currently known about the effects of biological sex differences, possible mechanisms that may explain discrepancies between rejection rates for male and female recipients and what questions remain to be explored in future studies. Their analysis is published in Trends in Immunology.

“In solid organ transplantation, the importance and implications of the sex of both the donor and the recipient have long been underappreciated,” said Stefan Tullius, MD, PhD, chief of the Division of Transplant Surgery. “The differences may be subtle, but I think they are very relevant, particularly as we move toward individualizing immunosuppression and try to find ways to be more specific in our treatment. I think understanding the relevance of sex differences will play a significant role in this.”

Transplant rejection is a complicated phenomenon with many contributing factors, and the researchers note that mismatched sex of a donor should not be cause for concern for transplant recipients. However, data on transplant rejection rates have been correlated with specific patterns of donor and recipient sex in several types of transplanted organs, including kidneys and hearts.

Kidneys transplanted from female donors are more likely to be rejected, especially among male recipients. Hearts from female donors also had lower rates of success when transplanted into male recipients.

The authors also note the importance of age. Female recipients age 45 and older were less likely to experience transplant rejection, especially when they received the organ from a female donor.

Tullius and his colleagues describe two important categories of biological sex differences that may influence immune response and help account for these different rates: genetics and hormones.

Approximately 50 genes on the X chromosome play a role in immune function, and they may influence whether the body accepts or rejects an organ. Additionally, encoded on the Y chromosome are male histocompatibility antigens – which tell the immune system whether a tissue belongs in the body or should be treated as a foreign object – that are known to cause transplant rejection of skin grafts in women. Different hormonal environments between men and women may also influence the immune system’s response to transplanted organs.

The team also notes that certain therapies that target hormone receptors – such as selective estrogen receptor modulators – could be used in the future to influence male and female immune responses. Further analysis in experimental and clinical models will be needed to determine if this kind of therapeutic approach may be helpful for organ transplantation.

Erika Rangel

Women constitute more than half of today’s medical school graduates, yet they remain underrepresented in general surgery, making up 40 percent of residents and only 18 percent of faculty members in the U.S. This discrepancy has been attributed to lack of female role models, gender discrimination, as well as pregnancy and child care concerns. Following a national survey of general surgery residents who had at least one pregnancy during residency, BWH investigators at the Center for Surgery and Public Health discovered these challenges have led to striking consequences.

Their findings, published in JAMA Surgery, reveal significant cultural challenges and infrastructure shortcomings that led 39 percent of respondents to seriously consider leaving residency and 30 percent to report they would advise a female medical student against pursuing a career in surgery.

“Overall, women were very excited to have this issue studied formally. There have been publications reporting a growing number of female surgeons having children during residency, but this is the first national study to look at the actual perspectives of general surgery residents who were pregnant,” said Erika Rangel, MD, MS, lead study author and a surgeon and researcher in the Division of Trauma, Burn and Surgical Critical Care.

Battling Stigma

The survey assessed perceptions of working while pregnant, maternity leave policies, breastfeeding and lactation, child care and motherhood, job satisfaction, perceptions of stigma, attitudes of colleagues and satisfaction with training program support.

The results of the survey reveal a lingering negative stigma surrounding pregnancy, with 75 percent of respondents having witnessed faculty members or other residents making negative comments about pregnant trainees or childbearing during training. Sixty percent of participants reported that there was a negative stigma associated with being pregnant as a surgical resident, and just over half perceived pressure to plan pregnancies during nonclinical time.

The majority of participants – 86 percent – worked an unmodified schedule until delivery, with similar numbers reporting that requesting accommodations for less-demanding rotations during pregnancy would have been perceived negatively by their peers and supervising faculty.  Two-thirds were concerned their work schedule or duties adversely affected their health or the health of their unborn child.

Inadequate workplace infrastructure, including lactation support and child care options, also posed challenges for participants in addition to a lack of mentorship on balancing career with pregnancy and motherhood.

Fostering a Supportive Environment

At BWH, the Department of Surgery is actively working to create an equitable work environment for its surgical trainees. Douglas Smink, MD, surgical residency program director and co-author of the manuscript, has organized discussions on gender issues and disparities within residency for trainees, facilitated by female faculty.

“There is no good reason why the goals of training in surgery and starting a family should feel mutually exclusive,” said Gerard Doherty, MD, chair of the Department of Surgery and surgeon-in-chief of Brigham Health and Dana-Farber Cancer Institute. “Understanding what that experience has been like for recent trainees is a next step in the continual improvement of surgical training. Developing effective, progressive employment practices for our surgical residents will help us to recruit, to retain and to deliver the most prepared surgeons to society.”

Paul Nguyen

Despite the fact that black men face higher rates of prostate cancer and are more at risk of dying from the disease, they are underrepresented in clinical trials. BWH investigators recently identified a potential barrier that may be disproportionately preventing black patients from enrolling in these trials: lab test results.

Clinical trials can offer patients access to cutting-edge treatments with the potential to extend their survival and shape the future standard of care. As of last year, more than 400 prostate cancer clinical trials were being conducted to find interventions for patients. BWH investigators found that nearly half of these studies used laboratory values that varied by race, disproportionately excluding black men. Their results are published in JAMA Oncology.

“Something as simple as a lab-value exclusion criteria may serve as yet another barrier to allowing African-American patients to take part in randomized trials,” said corresponding author Paul Nguyen, MD, of the Department of Radiation Oncology. “We hope that this message will reach researchers who are designing clinical trials and setting entry criteria: We need to be cognizant that the criteria we choose may inadvertently make it harder for African-American patients to participate.”

Lead author Marie Vastola, a research assistant in Radiation Oncology, and her colleagues examined prostate cancer trials collected from clinicaltrials.gov. Specifically, they investigated the use of two components measured in blood tests – serum creatinine (sCr) and absolute neutrophil count (ANC) – to determine a patient’s eligibility for the trial.

Marie Vastola

sCr is used as a measurement of kidney function, but average levels vary by race. Black patients tend to have higher sCr concentrations than white patients or patients of other races or ethnicities. ANC is measured to determine the health of a patient’s immune system. However, up to 8 percent of black patients may have benign ethnic neutropenia, a condition that decreases ANC levels but does not affect the immune system. Without adjusting for race, both measurements may disproportionately disqualify black patients from a clinical trial.

The team found that 47.9 percent of clinical trials used either sCr alone and/or required an ANC level that would exclude patients with benign ethnic neutropenia – two criteria that resulted in disproportionately excluding black patients from prostate cancer trials.

“Adjusting for race-based differences in clinical trial eligibility criteria may add slight logistical challenges, but these adjustments could prevent qualifying individuals from being excluded from trials solely because of laboratory differences caused by their race,” said Vastola.

Paul Anderson, MD, PhD, chief academic officer and senior vice president for Research and Education, gave a brief overview of the state of the Brigham’s academic mission, which includes research and education, during the President’s Leadership Forum on Jan. 17.

C. Giovanni TraversoIn the fight against human immunodeficiency virus (HIV), one of the biggest challenges is ensuring patients take their medication as prescribed. Studies have found only about 30 percent of HIV patients stick to their dosage plans, which can include multiple drugs that must be taken daily.

Researchers from BWH and Massachusetts Institute of Technology (MIT) recently developed a potential solution: an ingestible, slow-release pill that stays in the stomach to deliver a once-weekly, long-lasting dose of HIV medications. If successful, the innovative approach could prevent thousands of new HIV cases.

C. Giovanni Traverso, MB, BChir, PhD, gastroenterologist and biomedical engineer in the Division of Gastroenterology, and members of his lab collaborated with the Langer Lab at MIT to design the system. The pill’s effectiveness in delivering HIV treatment in preclinical models once per week was equal to – or better than – daily doses, Traverso said.

In the study detailing the team’s findings, published in Nature Communications on Jan. 9, researchers describe the medication as a “mini pill box” because it can hold multiple medications at once. Traverso, a principal investigator and co-corresponding author of the paper, and his team tested how well the system worked for the delivery of three HIV drugs over the course of a week.

Upon entering the stomach, the capsule (right) unfolds into a star-shaped structure (left), allowing food to pass as it releases medication.

Using a large-animal model, researchers measured the presence of each HIV medication in the bloodstream in the week following ingestion. Additionally, the team collaborated with groups at Harvard Medical School and the Institute for Disease Modeling to apply mathematical modeling to predict what happens with these extended-release systems when a patient misses a dose, and what can be done to improve prevention strategy.

Simulations showed that this new system could not only reduce therapeutic failures, but it could also prevent thousands of new HIV cases when used prior to exposure. Researchers found that moving from a daily to weekly dose could improve the efficacy of pre-exposure prevention strategies by up to 20 percent. Predictive models of populations in South Africa showed that implementing the new dosage form had the potential to prevent 200,000 to 800,000 new infections over the next 20 years.

The team built the “mini pill box” based on a design it had developed in 2016 of a capsule that, once inside the stomach, unfolds into a star-shaped structure. It is too large to exit the stomach, yet designed to allow food to continue passing through the digestive system as it continues releasing medication. The pill eventually breaks down in the stomach and passes through the digestive tract.

Researchers are working to validate results from the preclinical models to translate their latest findings into a potential therapy for HIV patients.

Reisa Sperling

A BWH researcher is one of three physician-scientists working to launch the Alzheimer’s Clinical Trials Consortium (ACTC), which will create a network of 35 Alzheimer’s disease trial sites across the country to find new ways to treat or prevent the disease.

The novel project, funded by the National Institutes of Health (NIH), is expected to be awarded up to $70 million in grants over five years.

Reisa Sperling, MD, director of the Center for Alzheimer Research and Treatment in the Department of Neurology, will collaborate with colleagues at Mayo Clinic in Rochester, Minn., and the Keck School of Medicine at the University of Southern California (USC) in San Diego, Calif., to accelerate clinical trials for Alzheimer’s disease and related dementias.

“We must overhaul our current recruitment strategies for clinical trials, particularly to improve the diversity of our study participants and to reach people who do not yet have symptoms of Alzheimer’s disease for inclusion in future prevention trials,” said Sperling, who serves as the principal investigator of the ACTC at both BWH and Massachusetts General Hospital (MGH). “The new ACTC presents a terrific opportunity to innovate in recruitment, cognitive assessments and neuroimaging for the next generation of Alzheimer’s trials.”

The ACTC will be led jointly by the selected research teams, with scientific input from the NIH’s National Institute on Aging.

The consortium’s diverse team and improved infrastructure will alleviate some of the challenges involved in conducting clinical trials, including the expense of recruitment and site activation. Several other leading researchers at BWH, including Dennis Selkoe, MD, Gad Marshall, MD, Dominic Walsh, PhD, and Dorene Rentz, PsyD, will work on ACTC efforts to implement more sensitive biomarkers and cognitive tests in early intervention trials.

The consortium will offer shared support services, enabling researchers to design better clinical trials, manage and analyze large amounts of data, and recruit participants from diverse backgrounds. The group will also share data, software, instruments and biologic samples such as blood, tissue and cerebrospinal fluid.

The ACTC will also help researchers engage in new collaborations to test promising therapies and prevention strategies. Researchers at the Brigham and their colleagues are leading efforts to find ways to intervene as early as possible, before the first signs and symptoms of Alzheimer’s appear when some treatments are expected to be most effective. But prevention trials – such as the A4 Study led by Sperling and her collaborators – can require screening thousands of volunteers to identify eligible participants, which can be time-consuming and resource-intensive. The ACTC aims to offer the infrastructure, shared resources and expertise to help surmount these hurdles.

Radiology images can reveal critical clues not only about a patient’s current injuries, but also about patterns of violence a person may be experiencing. A recent study by BWH investigators reveals new ways that radiologists can be involved in the care of victims of intimate-partner violence.

Presenting their findings during the annual meeting of the Radiological Society of North America, the team found common clinical and radiologic patterns that could alert radiologists about potential intimate-partner violence. This knowledge can spark conversations with referring physicians and multidisciplinary care teams to get patients the help they need.

“We are recognizing new ways for radiologists to be involved in the care of victims of intimate-partner violence and that there might be more information available in the radiology images, which is evident only when we are cognizant of the subtle patterns of injury,” said Radiology resident Elizabeth George, MD. “We, as radiologists, should work closely with referring physicians and can often put the pieces together as an unbiased witness.”

The case that inspired the principal investigator Bharti Khurana, MD, involved a young woman who arrived at BWH’s Emergency Department (ED) with a nasal fracture that appeared to be next to another old, healed fracture. While going through prior studies of the patient on the hospital’s picture archiving and communication system, Khurana also came across a recent wrist fracture. This pattern of recurrent injury raised suspicion for intimate-partner violence, a finding the referring physician initially had not considered.

“This also led us to connect with Hanni Stoklosa, MD, and Annie Lewis-O’Connor, PhD, MPH, NP, who were already working on the clinical and social aspects of this issue,” said Khurana, program director of the Emergency Radiology Fellowship at BWH. “We then went on to design this research study to objectively assess the clinical and radiologic findings in this population.”

The study analyzed information from 185 patients who were seen in the Brigham’s ED and referred to the hospital’s Intimate Partner Violence support program. The research team evaluated information about the patients’ demographics, clinical presentation and history and imaging findings over the past five years.

The team found that 81.6 percent of patients had a prior history of abuse, including physical, emotional or sexual abuse. Most had received radiologic examinations in the past.

Common patterns of injury emerged. These included facial fractures, soft tissue injuries (swelling, hematoma or contusion) and extremity fractures, often involving the upper body, suggesting patients were injured while trying to defend themselves during an assault.

The team also identified that patients often presented with physical or psychologic symptoms that were not directly related to the abuse. Patients in the study were more likely to be homeless, while the sexual assault victims often suffered from illicit drug use.

“Images do not lie and can sometimes tell us more than the patient in this situation,” said Khurana. “In the emergency room setting, the priority is to identify acute issues, so old fractures or fracture-related deformities may not be given sufficient importance in that moment. But these may be pivotal in making the diagnosis of intimate-partner violence. We need further research to establish the accuracy of imaging patterns in these victims; however, I am hopeful that we, as radiologists, are going to make invisible visible.”

Ellen Bubrick

Investigators from across the Brigham were honored with several awards from the Brigham Research Institute (BRI).

Ellen Bubrick, MD, of the Department of Neurology, was selected by a public vote as the winner of the 6th annual BRIght Futures Prize, a $100,000 award, for her project, “Break the Shake: Ultrasound Treatment for Epilepsy.”

Having an opportunity during the voting period to raise awareness about epilepsy – a disorder of recurrent seizures with few effective treatment options– was as rewarding as the prize itself, Bubrick said. In addition to the disorder’s effect on the body, epilepsy often causes patients to suffer from depression and anxiety. 

Inspired by the resilience of those living with epilepsy, Bubrick dedicated the prize to patients: “This award is for you,” she said.

This year marked the first that two winners were selected to split the BRI Director’s Transformative Award, conferring a $250,000 grant to each recipient. Principal investigators for the award-winning projects are:

• Michael Brenner, MD, chief of the Division of Rheumatology, Allergy and Immunity, for “Disease Deconstruction by Single Cell Transcriptomics: Onsite Single Cell RNA-seq Core”
• Terrie Inder, MD, MBChB, chair of the Department of Pediatric Newborn Medicine, for “Healthy Starts to Life”

Other honors announced during the ceremony included the Research Excellence Awards, a $1,000 prize given to 10 investigators for their outstanding contributions to research.

Tanuja Chitnis

A first-of-its-kind clinical trial at the Brigham has shown that administering an oral multiple sclerosis (MS) drug to patients younger than 18 years of age is safe and 82 percent more effective than an injectable treatment that is the current standard of care.

Although multiple sclerosis is a disease that primarily affects adults, it’s estimated that up to 5 percent of patients with MS have a history of symptoms before age 18. Although some medications for adults are used “off-label” to treat these young patients, there are currently no drugs approved by the U.S. Food and Drug Administration (FDA) for treating MS in children.

Tanuja Chitnis, MD, a neurologist in the Ann Romney Center for Neurologic Diseases, led the international consortium of researchers who studied the MS drug fingolimod. The team found that the drug was even more effective at preventing relapse than the current standard of care, and prevented relapse better in this young patient population than it did in adults. Pediatric patients with MS are more likely to experience relapse than adults and can have cognitive issues, walking disabilities and other impairments.

“I’ve been working in this field for 15 years, and I believe this is going to change the treatment of this disease,” said Chitnis, who is also the medical director of the CLIMB Natural History study at the Partners MS Center and founding director of the Partners Pediatric MS Center at MassGeneral Hospital for Children. “There’s a growing awareness that children can have MS. We need clinical data on the relative efficacy, safety and tolerability of drugs that we use to treat adults in our pediatric population.”

The Trial

The trial is the first randomized, clinical trial in pediatric MS. Known as the PARADIGMS trial, the two-year study included patients between ages 10 and 18 who had experienced a relapse of MS in the last year.

The team found that fingolimod reduced the annual relapse rate by 82 percent compared to those who received the current standard of care, an injection called interferon beta-1a. Additionally, the safety profile of the drug was like that seen in adults. As of now, fingolimod has not received FDA approval for pediatric use.

Chitnis also sees broader implications for early detection and treatment of MS. “Pediatric MS represents one of the earliest forms of the disease, or MS in its onset, and the high efficacy of this drug shows it may target an important mechanism for the initiation of MS,” said Chitnis.