Check out “What’s New in Research” to find out about discoveries and advancements from Brigham researchers. This month, we feature new research from Brigham researchers on a diagnostic for sleep apnea, Alzheimer’s dementia and the cost of delirium, consistent benefits for women and men from a heart failure treatment, a liquid metal for dissolving biomedical devices, a novel therapy to reduce lipoprotein(a), immune factors and predisposition to HIV and HSV, the prevalence of a rectal adenocarcinoma mutation, DNA biomarkers for oropharynx cancers, a new bioink for printing blood vessels, obstructive sleep apnea, choosing between hospice care and dialysis, a comparison of treatments for pulmonary embolism, electronic health record use and quality outcomes and more.
Individual Patterns in Sleep Apnea Provide a Better Approach to Diagnosis and Treatment
One in ten Americans suffer from obstructive sleep apnea (OSA), where breathing is repeatedly disrupted during sleep. OSA has been linked to increased risk of cardiac issues, dementia, and many other health problems. While sleep apnea is a complex process, constantly changing with many factors during the night, doctors diagnose and categorize sleep apnea patients with a single number—the apnea-hypopnea index (AHI), which is the average apnea event rate across the night. Consequently, the AHI has been shown to be a poor predictor of health outcomes, as it ignores the timing and patterns of events. To improve patient care, a team of researchers from Brigham and Women’s Hospital and Boston University have pioneered an “instantaneous AHI”, which evolves moment-to-moment based on data from sleep stage and body position and patterns of past apnea activity. Their improved model allowed researchers to accurately predict when events will occur, which could help sleep clinicians develop individualized treatments for their sleep apnea patients.
“The AHI has prevented us from seeing major differences between patients who are currently seen as clinically identical,” said corresponding author Michael Prerau, PhD, of the Brigham Division of Sleep and Circadian Disorders. “By using this new approach, we see that people with the exact same AHI have very different patterns of activity, which can help us to develop better, more individualized treatments for sleep apnea.”
Read more in Sleep.
Patients with Alzheimer’s Dementia and Related Disorders Who Also Have Delirium Incur Greater Healthcare Costs that Increase Over Time
Alzheimer’s Dementia and Related Disorders (ADRD) affects upwards of 5 million people in the United States, with no known treatments to stop or prevent its progression. Associated with these diagnoses are costly healthcare bills, which are especially costly for ADRD patients that additionally experience delirium: a preventable mental deterioration. The exact yearly healthcare costs associated with delirium in older hospitalized patients with ADRD had not been examined prior to a study by researchers at the Brigham and the Marcus Institute, Hebrew SeniorLife. The team conducted a health economics analysis of Medicare costs at 30-, 90-, and 365-days for 311 patients with and without ADRD, some of whom developed delirium during their hospital stay. The team found the average additional cost for one delirium ADRD patient’s year of care to be $34,828 more than non-delirium ADRD counterparts; this gap between delirium ADRD patients’ and non-delirium ADRD patients’ price tags was also found to increase throughout the year. Furthermore, the study showed that delirium ADRD patients’ increased costs occurred later in the 365-day period, while non-delirium ADRD patients’ costs remained consistent over time and non-ADRD delirium patients’ costs remained consistently increased over time.
“The cost for delirium and severe delirium in ADRD patients is not upfront but rather long term — like costs for care and supports at home after hospitalization and delirium,” said lead author Tammy Hshieh, MD, MPH, of the Brigham’s Division of Aging and the Aging Brain Center, Hebrew SeniorLife. “Because delirium is preventable, patients and their families can advocate for nonpharmacologic interventions and general vigilance with clinical care during hospitalization to try to prevent the costly downstream cascade.”
Study Shows Heart Failure Treatment with Dapagliflozin Consistently Benefited both Men and Women
When it comes to heart failure (HF), sex differences are known to impact everything from risk factors to clinical presentation to response to treatment, making sex a key factor to consider in studies of emerging pharmacotherapies. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as dapagliflozin, have become an important pharmacotherapy solution for patients with HF, yet more data are needed to assess their effect and safety between sexes. Investigators from the Brigham conducted a study to rectify this gap in knowledge, using a pre-specified patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure). Clinical outcomes for 11,007 randomized patients, 35-percent of whom were women, were compared by sex across the spectrum of left ventricular ejection fraction. In both DAPA-HF and DELIVER, men and women responded similarly and positively to dapagliflozin when it came to primary outcomes of worsening HF or cardiovascular death, and secondary outcomes of general health status.
“Given the consistency of our trial with other SGLT2 inhibitor trials like EMPEROR, sex-specific indications may not be needed for this class of HF therapies in the future,” said lead author Xiaowen (Wendy) Wang, MD, of the Division of Cardiovascular Medicine. “We are pleased dapagliflozin was safe and well-tolerated in both sexes, with improvement in clinical outcomes and health status.”
Read more in Circulation.
Researchers Identify Biocompatible Liquid Metal for Better Control of Biomedical Devices
Medical devices that robustly serve a purpose then slowly break down over time are highly sought after for applications ranging from drug delivery to sensor-integrated health monitoring. Researchers at the Brigham, in search of a tough and durable material that can also be triggered to break down after use, turned to something new: biocompatible liquid metals. The research team identified eutectic gallium indium (EGaIn) as an ideal metal for biomedical application and tested whether it could be formulated for targeted breakdown of aluminum in the body. The team investigated EGaIn in four parts: initiating embrittlement, controlling breakdown behavior, demonstrations of potential biomedical uses, and biocompatibility. Using these four investigative angles, they found a functional formulation of EGaIn, realizing the potential of an actively-triggerable metal to provide functional properties and a controllable end-of-life.
“We can now take advantage of the excellent mechanical properties of metals to make highly durable biomedical devices, and still be able to break them down on demand without requiring invasive retrieval procedures like surgery,” said lead author Vivian Feig, PhD, of the Division of Gastroenterology, Hepatology and Endoscopy. “This capability could improve the translational potential of technologies like long-term ingestible drug delivery systems, metal stents, and metal tissue staples. Moving forward, we are excited to explore whether we can extend this active triggering mechanism to other metals that are more commonly used in the clinic, such as titanium.”
Read more in Advanced Materials.
Clinical Trial Finds Novel Therapy Markedly Reduced Lipoprotein(a) Levels in People with Cardiovascular Disease
Lipoprotein(a) is a special type of bad cholesterol that is believed to contribute to heart disease, but there are no approved pharmacological therapies to decrease its concentration in the bloodstream. Olpasiran is an investigational drug that reduces lipoprotein(a) concentration by degrading the RNA that codes for a protein that is an essential part of the molecule. Researchers at Brigham and Women’s Hospital conducted a phase 2, randomized, placebo-controlled clinical trial of olpasiran in patients with established cardiovascular disease to evaluate its safety and tolerability and to identify an optimal dose of olpasiran for reducing lipoprotein(a) levels. The trial included 227 patients who received one of four doses of olpasiran and 54 who received a placebo. They found that patients who received higher doses of olpasiran had more than a 95% drop in lipoprotein(a) over 36 weeks compared to placebo. The treatment was not associated with serious side effects apart from occasional injection site swelling and related mild reactions.
“These study results show that marked and sustained reduction of lipoprotein(a) is possible through RNA interference using olpasiran,” said lead author Michelle O’Donoghue, MD, MPH, Cardiovascular Division, Brigham and Women’s Hospital. “These findings set the stage for a much larger phase 3 trial to definitively evaluate if lowering lipoprotein(a) translates into better outcomes. Olpasiran is a very promising therapy for individuals with high lipoprotein(a) levels who currently don’t have any effective therapies to lower its concentration.”
Read more in the New England Journal of Medicine.
Study Highlights Converging and Diverging Immune Factors that May Predispose People to HIV and HSV
Genital herpes, caused by the herpes simplex virus-2 (HSV-2), is a known risk factor for HIV acquisition: people infected with HSV are three times more likely to acquire HIV. But do HIV predictors and other risk factors in the immune system and cervical mucosa predispose people to acquiring HSV-2? To answer this question, investigators at the Brigham analyzed longitudinal samples of cervical and serum biomarker levels for immune activation, before and after subjects acquired HSV-2. They found that altered levels of specific biomarkers in the mucosa and serum were associated with HSV-2 acquisition only, while others overlapped with biomarkers and combinations predictive of HIV-1 acquisition. This study helps highlight the converging and diverging factors predisposing one to both viral diseases.
“HSV-2 infections, which cause genital herpes, have a high global prevalence especially in regions of Sub-Saharan Africa that are at the center of the HIV pandemic, where as much as 80 percent of women are infected with HSV-2,” said corresponding author Raina Fichorova, MD, PhD, of the Department of Obstetrics and Gynecology. “By identifying molecular predictors of HSV-2 risk, we help provide targets for future development of preventive treatments.”
Read more in Sexually Transmitted Infections.
Pinpointing the Prevalence of Mismatch Repair (MMR)-Deficient Rectal Adenocarcinomas
A widely-circulated clinical trial published earlier this year in the New England Journal of Medicine described a new treatment that eradicated cancer in all 12 of its patients with locally advanced mismatch repair (MMR)-deficient rectal adenocarcinomas. Clinicians say the finding will spark a paradigm shift in the treatment of MMR-deficient rectal cancer, but there remains uncertainty about how many patients have that specific condition. Researchers at the Brigham have analyzed a collection of 16,083 colorectal adenocarcinoma biopsies to determine how many patients would benefit from the promising new treatment. In a letter published in NEJM, they write that whereas the earlier clinical trial estimated that 5–10% of rectal cancer patients have the MMR-deficient subtype, their data suggest that 2.65% do. They also observed that while younger patients appear to be at higher risk of developing MMR-deficient adenocarcinoma — a previously described phenomenon — an unexpectedly high number of older patients also had the condition, highlighting the importance of screening at all ages. The letter suggests that analysis of biopsy material is sufficient for MMR testing in 99.9% of cases.
“We have leveraged the volume of the largest gastrointestinal pathology group in the U.S. to study the prevalence of mismatch repair deficiency in colorectal adenocarcinoma,” said lead author David J. Papke, Jr., MD, PhD, of the Pathology Department. “We used our study cohort to determine the prevalence of mismatch repair deficiency in rectal adenocarcinoma, thereby defining the population likely to benefit from this novel therapeutic approach.”
Read more in The New England Journal of Medicine.
Use of DNA Biomarkers for Detecting Early-Stage HPV-Positive Oropharynx Cancers Has Limitations
Oropharynx cancers caused by human papillomavirus (HPV) have risen dramatically over the years, superseding tobacco use and heavy drinking as the primary driver of new cases. Fortunately, HPV-positive oropharynx cancers have an improved survival rate compared to other head and neck cancers, allowing for less intensive treatment options, especially if diagnosed at early stages. One promising biomarker for early diagnosis and predicting reoccurrence, circulating tumor HPV DNA (ctHPV DNA), is found in the blood of almost 90% of patients with HPV-positive oropharynx cancer and can be detected using commercially available blood assays measuring HPV DNA from tumor cells (TTMV-HPV DNA). However, in a study of 110 HPV-positive oropharynx cancer patients, Brigham investigators found that TTMV-HPV DNA levels are linked to the presence of cancer in the lymph nodes and are often indetectable in patients without neck masses. This has a tremendous impact on how the test is interpreted and applied for early-stage disease and may mean it is not as effective for screening and early diagnosis of this increasingly common disease.
“ctHPV DNA testing is emerging as a powerful tool in the diagnosis, treatment, and post-treatment surveillance of HPV-positive oropharynx cancer,” said first author Eleni M. Rettig, MD, of Brigham and Women’s Hospital Division of Otolaryngology-Head and Neck Surgery and Dana-Farber Cancer Institute. Rettig is also an affiliated faculty member in the Center for Surgery and Public Health. “It’s increasingly critical to understand both the strengths and limitations of this test.”
Read more in JAMA-Otolaryngology Head and Neck Surgery.
Novel Bioink Capable of Constructing Physiological Blood Vessels
Cardiovascular diseases (CVDs) remain among the leading causes of global morbidity and mortality. In patients with CVD, blood vessels―which transport blood, oxygen, and nutrients―can become constricted or obstructed, leading to numerous complications. While revascularization and grafting are common procedures carried out during surgeries, biofabricated grafts used during these operations can have many drawbacks, for example, weak mechanical strength. To overcome these issues, researchers at the Brigham used bioengineering advancements to improve 3D bioprinting of vascular tissues with functional and mechanical hallmarks. The team used crosslinking properties of natural polymers to develop a double-network hydrogel bioink capable for bioprinting conduits. These conduits had key physiological characteristics of blood vessels including strong vasoconstriction, vasodilation, perfusability, and barrier performance comparable to native vessels. In line with the ongoing COVID-19 pandemic, the researchers also showed the possibility of using these vessels for SARS-CoV-2 pseudoviral testing.
“The vessels we have printed truly mimic a lot of the mechanics of native vessels,” said senior corresponding author, Y. Shrike Zhang, PhD, of the Division of Engineering in Medicine. “This research demonstrates the potential for such conduits to serve as vascular models for grafts in vascular surgeries, other disease studies, and broad biomedical applications.” The other co-corresponding authors included Xuanhe Zhao, PhD, of the Department of Mechanical Engineering at MIT, and C. Keith Ozaki, MD, of the Division of Vascular and Endovascular Surgery at the Brigham.
Read more in Science Advances.
Correlation Between Obstructive Sleep Apnea and Other Phenotypes Has Implications for Patients with Insomnia, Diabetes
A new study from researchers at the Brigham examines the relationship between obstructive sleep apnea (OSA) and cardiometabolic and pulmonary diseases. Using a sample of 11,155 Hispanic participants, of which 31 percent have OSA, the team looked for genetic correlations between respiratory events and 54 anthropometric, glycemic, cardiometabolic, pulmonary, and sleep phenotypes, including insomnia, which was self-reported based on a questionnaire. The team composed Polygenic Risk Scores (PRS) representing the genetic basis of each phenotype. The team determined that OSA has shared genetic basis with anthropometric (specifically body fat) distribution, blood pressure, glycemic phenotypes, and insomnia. Using Mendelian randomization analysis, the team was able to infer which phenotypes had a causal relationship.
“We see strong evidence that body fat distribution measures play a causal role in OSA as well as glycemic phenotypes,” said Tamar Sofer, PhD, of the Brigham’s Division of Sleep and Circadian Disorders. “This implies that individuals with type 2 diabetes may wind up developing OSA. PRS of insomnia predicted OSA suggesting that people who have insomnia may have it because they have OSA, which disturbs their sleep.”
Researchers Examine What Happens When Patients Can Choose Concurrent Dialysis and Hospice Care
Today, patients utilizing their Medicare Hospice Benefits with end-stage kidney disease (ESKD) are forced to make the traumatic choice between continuing dialysis or enrolling in hospice. The Veterans Health Administration (VA), when compared to Medicare, has far more liberal criteria for hospice eligibility; whether such criteria improve access to concurrent dialysis and hospice care for ESKD patients was unknown prior to a recent study by Brigham and Women’s researchers. The team set out to compare how the frequency of concurrent hospice and dialysis among veterans with ESKD varied based on hospice payer: Medicare, VA inpatient hospice, or VA-financed community hospice. A retrospective cross-sectional study of all 70,577 VA enrollees in the US Renal Data System registry was used. Based on their analysis, the team concluded that patients who received VA-financed hospice services were more likely to receive concurrent dialysis than patients who received Medicare-financed hospice. Additionally, the researchers found that, on average, patients who stopped dialysis before entering hospice died within four days, whereas those who continued in a concurrent care model lived about 43 days.
“Because patients who are on dialysis for kidney failure die within days to weeks of stopping dialysis, they are particularly vulnerable to Medicare’s ‘terrible choice’ – if they want to receive hospice services, they can expect to live only a very short time after hospice enrollment,” said lead author Melissa Wachterman, MD, MPH. “Our study will provide critical perspective as Medicare is currently considering whether it should change the Medicare Hospice Benefit to allow for concurrent care.”
Read more in JAMA Health Forum.
Study Compares Therapies for Intermediate-High Risk Pulmonary Embolism Patients
While relatively common and associated with high mortality rates, intermediate-high-risk pulmonary embolism (PE) has no known optimal treatment. To rectify this gap in knowledge, researchers at Brigham and Women’s, with collaborators at other centers, conducted a randomized clinical trial with 94 adult intermediate-high-risk PE patients. Patients were randomly assigned to receive either conventional catheter-directed thrombolysis (cCDT) plus anticoagulation, or anticoagulation monotherapy. As their primary outcome, researchers looked at differences between the two groups in improvement of 3-month echocardiographic measures of right ventricle (RV) to left ventricle (LV) ratio greater than 0.9. The team also measured several secondary outcomes at 72-hour and 3-month marks, as well as major bleeding events. The collected data indicated no significant decrease in the 3-month RV/LV ratio in cCDT versus anticoagulation monotherapy groups. The team observed noteworthy favorable numerical differences in cCDT patients over their anticoagulation monotherapy counterparts in several imaging indices at the 3-month follow-ups. Additionally, major bleeding events — verified in pooled analyses paired with prior smaller trials of cCDT — were rare. These results suggest the potential for cCDT to have a more favorable, durable effect on several 3-month imaging indices — an observation that warrants further clinical trials.
“Although our study was cut short due to the COVID-19 pandemic and is not fully definitive, it is the largest completed randomized trial of these patients to-date and provides support for a definitive clinical outcomes trial in the future,” said senior and co-corresponding author of the article Behnood Bikdeli, MD, MS, of the Division of Cardiovascular Medicine. “Patients, clinicians, and investigators should be excited about these results and look for definitive outcomes trials.”
Read more in JAMA Cardiology.
Increased Electronic Health Record Time Associated with Enhanced Quality Outcomes in Primary Care
In the United States, the electronic health record (EHR) has become increasingly prevalent in the day-to-day practice of physicians, with primary care physicians (PCPs) spending the most time in the EHR. Yet, the association between time spent in the EHR and quality of ambulatory care was unclear before Brigham researchers investigated this critical intersection. In their cross-sectional study of 291 primary care physicians, the team tracked ambulatory quality measures (year-end, PCP panel-level achievement of targets for hemoglobin A1C level control, lipid management, hypertension control, diabetes screening, and breast cancer screening) and found a significant, positive relationship between EHR time and some of these measures — panel-wide hemoglobin A1C level control, hypertension control, and breast cancer screening. These associations suggest that extra time spent in the EHR may benefit certain care outcomes, particularly for doctors who spend less than half their time seeing patients.
“Although increased EHR time is associated with burnout, it may represent a level of thoroughness or communication that enhances certain outcomes,” said lead author Lisa Rotenstein, MD, MBA, of the Primary Care Center of Excellence at the Brigham. “It may be useful for future studies to characterize payment models, workflows, and technologies that enable high-quality ambulatory care delivery while minimizing EHR burden.”
Read more in JAMA Network Open.