Faculty Bibliography

Our genome is not made of naked DNA but a fiber (chromatin) composed of DNA and proteins packaged into our chromosomes. The basic building block of chromatin is the nucleosome, which has two copies of each of the proteins called histones (H2A, H2B, H3, and H4) wrapped by 146 base pairs of DNA. Regions of our genetic material are found between the more open (euchromatin) and more compact (heterochromatin) regions of the genome that can be variably accessible to the underlying genes. Furthermore, post-translational modifications (PTMs) on histones, such as on H3, are critical for regulating chromatin accessibility and gene expression. While site-specific antibodies were the tool of choice for histone PTM analysis in the early days (pre-2000s), enter Don Hunt changing the histone PTM field forever. Don's clever thinking brought new innovative mass spectrometry-based approaches to the epigenetics field. His lab's effort led to the discovery of many new histone modifications and methods to facilitate the detection and quantification of histone PTMs, which are still considered state of the art in the proteomics field today. Due to Don's pioneering work in this area, many labs have been able to jump into the epigenetics field and "Hunt" down their own histone targets. A walkthrough of those early histone years in the Hunt Lab is described by three of us who were fortunate enough to be at the right place, at the right time.

Despite the rise in chronic, untreated opioid use among pregnant women, their rate of receiving medications for opioid use disorder (MOUD) has remained stagnant since the mid-1990s. Using retrospective cross-sectional substance use treatment admissions data from 2015 to 2019, we examined access to treatment for opioid use by pregnant adults across 48 U.S. states. We found that younger adults, Black women, those referred to treatment by a criminal justice agency (e.g., judge, probation officer), those reporting polysubstance use, and those receiving treatment in residential settings were far less likely to receive MOUD (i.e., methadone, buprenorphine, naltrexone). We used multilevel analysis to examine the structural influence of state-level reproductive rights policies on pregnant women's access to MOUD. Adjusted counterfactual predictions reveal being admitted to treatment in a severely restrictive state context results in a significant decline in the likelihood of receiving MOUD, from 67% to 29%. We estimate 12,609 additional pregnant women seeking treatment for opioid use would have accessed first-line opioid pharmacotherapy if individuals in restrictive states had accessed medication at the same rate as those in more supportive states. Taken together, these findings offer insights into how reproductive rights serve as a structural determinant of health and safeguard for opioid medication treatment. We discuss the consequences of reversing reproductive rights policies amidst rising rates of drug overdose deaths among pregnant women along with the growing availability of illegally manufactured opioid analogs, as well as psychostimulant co-use, re-shaping overdose risk patterns in the U.S.

Hard-to-heal wounds represent a global and growing medical and economic burden. Skin autografting is a useful treatment option but is often limited by donor site morbidity, logistical considerations, and grafting success in compromised wound beds. Combining autologous skin cell suspension (ASCS) technology with minced dermal grafts can allow for dermal elements and epithelial healing as well as closed donor sites. This study explores the combination of minced autografting with ASCS in healing recalcitrant wounds. Two patients with diabetic foot ulcers (DFUs) whose previous skin grafting had failed were included. Under local anesthesia, donor skin was harvested as a full-thickness ellipse and divided into a superficial split-thickness graft (STSG) and a dermal autograft. ASCS was prepared from the STSG, and the dermal component was finely minced using a scalpel. Prepared wound beds were directly dressed with Telfa clear and compression dressings. Patients included a 62-year-old man with a DFU (15 cm²) on the left plantar heel present for 2 years, and a 53-year-old man with a DFU (10 cm²) on the plantar surface of the first metatarsal head present for 2 years. After combination treatment, complete closure was achieved by days 27 and 24, respectively. There was evidence of continued remodeling and skin thickening for the following 4 months. Combining dermal mincing with ASCS promotes healing of both dermal and epidermal layers while enabling primary closure of donor sites. These initial cases are encouraging, and ongoing studies are validating outcomes in more patients with various hard-to heal wounds.

INTRODUCTION/BACKGROUND:Opioid withdrawal is a regular occurrence for many people who use illicit opioids (PWUIO) involving acute physical and psychological pain. Yet, there is very little data on the withdrawal experience of people in methadone maintenance treatment (MMT) and almost none from the patients' experience. Learning more about patients' withdrawal experiences can help to inform policies and practices that are better suited to address withdrawal and may improve patient satisfaction as well as uptake and retention. METHODS:This article is based on 29 semi-structured interviews with people who use illicit opioids who reported recent withdrawal experience. The study conducted interviews remotely via Zoom between April and August 2022 and later transcribed them professionally. The study team then coded data thematically using Atlas.ti, based on a combination of inductive and deductive coding strategies and informed by the literature and study aims. RESULTS:Participants described withdrawal as a significant issue that negatively impacts their treatment experience and increases the likelihood of treatment cessation. Their accounts of withdrawal were complex and often involved multiple factors; however, feeling underdosed and missing clinic dosing hours were seen as important vectors that led to their withdrawal experiences. Importantly, participants framed feeling underdosed and missing clinic dosing hours as institutional problems, resulting primarily from clinic policies, practices, and culture rather than from patients' decisions or individual behavior. Specifically, they cited restricted access to take-home doses, limited hours of operation, and a punitive focus on complete abstinence as factors that made withdrawal difficult to avoid. CONCLUSIONS:Patients' accounts demonstrate a disconnect between providers' focus on promoting complete abstinence and patients, who were often using MMT for more pragmatic reasons that did not include complete abstinence from all drugs. These findings support growing calls for the integration of MMT into the mainstream healthcare system by making it available via prescription from office-based medical settings and dispensed through pharmacies.

INTRODUCTION/BACKGROUND:We investigated the feasibility and validity of the remotely-administered neuropsychological battery from the National Alzheimer's Coordinating Center Uniform Data Set (UDS T-Cog). METHODS:Two hundred twenty Penn Alzheimer's Disease Research Center participants with unimpaired cognition, mild cognitive impairment, and dementia completed the T-Cog during their annual UDS evaluation. We assessed administration feasibility and diagnostic group differences cross-sectionally across telephone versus videoconference modalities, and compared T-Cog to prior in-person UDS scores longitudinally. RESULTS:Administration time averaged 54 min and 79% of participants who initiated a T-Cog completed all 12 subtests; completion time and rates differed by diagnostic group but not by modality. Performance varied expectedly across groups with moderate to strong associations between most T-Cog measures and in-person correlates, although select subtests demonstrated lower comparability. DISCUSSION/CONCLUSIONS:The T-Cog is feasibly administered and shows preliminary validity in a cognitively heterogeneous cohort. Normative data from this cohort should be expanded to more diverse populations to enhance utility and generalizability. HIGHLIGHTS/UNASSIGNED:This study examined the feasibility and validity of the remote Uniform Data Set (also known as the T-Cog) and contributes key normative data for widespread use.A remote neuropsychological battery was feasibly administered with high overall engagement and completion rates, adequate reliability compared to in-person testing, and evidence of validity across diagnostic groups.Typical barriers to administration included hearing impairment, technology issues, and distractions; hearing difficulties were particularly common among cognitively impaired groups.Certain tests were less closely related to their in-person correlates and should be used with caution.

INTRODUCTION/BACKGROUND:Maternal undernutrition and inflammation in utero may significantly impact the neurodevelopmental potential of offspring. However, few studies have investigated the effects of pregnancy interventions on long-term child growth and development. This study will examine the effects of prenatal nutrition and infection management interventions on long-term growth and neurodevelopmental outcomes of offspring. METHODS:The Enhancing Nutrition and Antenatal Infection Treatment ('ENAT') study (ISRCTN15116516) was a pragmatic, open-label, 2×2 factorial, randomised clinical effectiveness study implemented in 12 rural health centres in Amhara, Ethiopia. The study enrolled 2399 pregnant women who were randomised to receive routine care, an enhanced nutrition package (iron and folic acid, monthly household supply of iodised salt, and micronutrient-fortified balanced energy protein supplement for undernourished women), an enhanced infection management package (genitourinary tract infection screening and treatment, and enhanced deworming), or both packages. In the present Longitudinal Infant Development and Growth study, a subset of 480 children of mothers from ENAT will be recruited equally from each of the four study arms and visited at 12, 18, and 24 months of postnatal age. We will evaluate a range of domains and deploy multiple measures to assess child neurodevelopment, including resting electroencephalography and visual evoked potentials, Hammersmith Infant Neurological Examination, eye-tracking, Bayley Scales of Infant and Toddler Development (Bayley-III), and Magnetic Resonance Imaging (MRI). DISCUSSION/CONCLUSIONS:This study will advance understanding of the impact of nutrition and inflammation in pregnancy on long-term offspring neurodevelopment. This study aims to fill a critical knowledge gap on the benefits of prenatal interventions to promote the health of mothers and their offspring. ETHICS AND DISSEMINATION/BACKGROUND:This study was approved by the Institutional Review Boards of Addis Continental Institute of Public Health (ACIPH/IRB/002/2022) and Mass General Brigham (2023P000461). Results will be disseminated to local and international stakeholders. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT06296238.

BACKGROUND:Clinical guidelines have concluded that there are insufficient data to provide recommendations for the hemoglobin threshold for the use of red cell transfusion in patients with acute myocardial infarction (MI) and anemia. After the recent publication of the Myocardial Infarction and Transfusion (MINT) trial, we performed an individual patient-level data meta-analysis to evaluate the effect of restrictive versus liberal blood transfusion strategies. METHODS:We conducted searches in major databases. Eligible trials randomly assigned patients with MI and anemia to either a restrictive (i.e., transfusion threshold of 7-8 g/dl) or liberal (i.e., transfusion threshold of 10 g/dl) red cell transfusion strategy. We used individual patient data from each trial. The primary outcome was a composite of 30-day mortality or MI. RESULTS:We included 4311 patients from four trials. The primary outcome occurred in 334 patients (15.4%) in the restrictive strategy and 296 patients (13.8%) in the liberal strategy (relative risk [RR] 1.13, 95% confidence interval [CI], 0.97 to 1.30). Death at 30 days occurred in 9.3% of patients in the restrictive strategy and in 8.1% of patients in the liberal strategy (RR 1.15, 95% CI, 0.95 to 1.39). Cardiac death at 30 days occurred in 5.5% of patients in the restrictive strategy and in 3.7% of patients in the liberal strategy (RR 1.47, 95% CI, 1.11 to 1.94). Heart failure (RR 0.89, 95% CI, 0.70 to 1.13) was similar in the transfusion strategies. All-cause mortality at 6 months occurred in 20.5% of patients in the restrictive strategy compared with 19.1% of patients in the liberal strategy (hazard ratio 1.08, 95% CI, 1.05 to 1.11). CONCLUSIONS:Pooling individual patient data from four trials did not find a definitive difference in our primary composite outcome of MI or death at 30 days. At 6 months, a restrictive transfusion strategy was associated with increased all-cause mortality. (Partially funded by a grant from the U.S. National Heart, Lung, and Blood Institute [R01HL171977].).

Circadian rhythms are intrinsic, 24 h cycles that regulate key physiological, mental, and behavioral processes, including sleep-wake cycles, hormone secretion, and metabolism. These rhythms are controlled by the brain's suprachiasmatic nucleus, which synchronizes with environmental signals, such as light and temperature, and consequently maintains alignment with the day-night cycle. Molecular feedback loops, driven by core circadian "clock genes", such as Clock, Bmal1, Per, and Cry, are essential for rhythmic gene expression; disruptions in these feedback loops are associated with various health issues. Dysregulated lipid metabolism in the brain has been implicated in the pathogenesis of neurological disorders by contributing to oxidative stress, neuroinflammation, and synaptic dysfunction, as observed in conditions such as Alzheimer's and Parkinson's diseases. Disruptions in circadian gene expression have been shown to perturb lipid regulatory mechanisms in the brain, thereby triggering neuroinflammatory responses and oxidative damage. This review synthesizes current insights into the interconnections between circadian rhythms and lipid metabolism, with a focus on their roles in neurological health and disease. It further examines how the desynchronization of circadian genes affects lipid metabolism and explores the potential mechanisms through which disrupted circadian signaling might contribute to the pathophysiology of neurodegenerative disorders.

UNLABELLED: TRIAL REGISTRATION/UNASSIGNED:clinicaltrials.gov Identifier: NCT01179568.