University of Massachusetts Chan Medical School

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    Cell-Type-Specific Circadian Bioluminescence Rhythms in Dbp Reporter Mice

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    Circadian rhythms are endogenously generated physiological and molecular rhythms with a cycle length of about 24 h. Bioluminescent reporters have been exceptionally useful for studying circadian rhythms in numerous species. Here, we report development of a reporter mouse generated by modification of a widely expressed and highly rhythmic gene encoding D-site albumin promoter binding protein (Dbp). In this line of mice, firefly luciferase is expressed from the Dbp locus in a Cre recombinase-dependent manner, allowing assessment of bioluminescence rhythms in specific cellular populations. A mouse line in which luciferase expression was Cre-independent was also generated. The Dbp reporter alleles do not alter Dbp gene expression rhythms in liver or circadian locomotor activity rhythms. In vivo and ex vivo studies show the utility of the reporter alleles for monitoring rhythmicity. Our studies reveal cell-type-specific characteristics of rhythms among neuronal populations within the suprachiasmatic nuclei ex vivo. In vivo studies show Dbp-driven bioluminescence rhythms in the liver of Albumin-Cre;DbpKI/+ liver reporter mice. After a shift of the lighting schedule, locomotor activity achieved the proper phase relationship with the new lighting cycle more rapidly than hepatic bioluminescence did. As previously shown, restricting food access to the daytime altered the phase of hepatic rhythmicity. Our model allowed assessment of the rate of recovery from misalignment once animals were provided with food ad libitum. These studies confirm the previously demonstrated circadian misalignment following environmental perturbations and reveal the utility of this model for minimally invasive, longitudinal monitoring of rhythmicity from specific mouse tissues

    The Role of the Nucleosomal Acidic Patch in Histone Dimer Exchange

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    Eukaryotes organize their genomes by wrapping DNA around positively charged proteins called histones to form a structure known as chromatin. This structure is ideal for keeping the genome safe from damage, but also becomes an obstacle for the transcriptional machinery to access information stored in the DNA. To facilitate a balance between storage and accessibility, eukaryotes utilize a family of enzymes known as ATP-dependent chromatin remodelers to directly manipulate chromatin structure. The diverse activities of these chromatin remodeling enzymes range from simply sliding nucleosomes to reveal transcription start sites, to editing the composition of a nucleosome by exchanging canonical histones for histone variants. Chromatin remodeling enzymes recognize features of the nucleosome that activate their ATPase domains and enable proper remodeling function. One nuclear epitope that has been extensively studied is the nucleosomal acidic patch. This negatively charged region on the face of the nucleosome has been shown to be essential for remodeling enzymes like Chd1, ISWI, and INO80C. The chromatin remodeler SWR1C edits nucleosomes by removing the canonical histone H2A from nucleosomes and exchanges it for the histone variant H2A.Z, but the role of the acidic patch in this process has not been investigated. In this work, I showed that SWR1C has normal binding affinity to acidic patch mutant nucleosomes and retains ATPase stimulation but can no longer exchange dimers on this substrate. This work also identified a novel arginine anchor on the essential SWR1C subunit, Swc5, that binds specifically to the nucleosomal acidic patch. The data in this work suggest a mechanism where SWR1C engages nucleosomes and uses the Swc5 subunit to recognize the nucleosomal acidic patch to couple ATPase activity to histone dimer exchange

    Bringing All the Stakeholders to the Table: A Collaborative Approach to Data Sharing

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    Objective: This paper examines a unique data set disclosure process at a medium sized, land grant, research university and the campus collaboration that led to its creation. Methods: The authors utilized a single case study methodology, reviewing relevant documents and workflows. As first-hand participants in the collaboration and disclosure process development, their own accounts and experiences also were utilized. Results: A collaborative approach to enhancing research data sharing is essential, considering the wide array of stakeholders involved across the life cycle of research data. A transparent, inclusive data set disclosure process is a viable route to ensuring research data can be appropriately shared. Conclusions: Successful sharing of research data impacts a range of university units and individuals. The establishment of productive working relationships and trust between these stakeholders is critical to expanding the sharing of research data and to establishing shared workflows

    Factorbook: an updated catalog of transcription factor motifs and candidate regulatory motif sites

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    The human genome contains approximately 2000 transcriptional regulatory proteins, including approximately 1600 DNA-binding transcription factors (TFs) recognizing characteristic sequence motifs to exert regulatory effects on gene expression. The binding specificities of these factors have been profiled both in vitro, using techniques such as HT-SELEX, and in vivo, using techniques including ChIP-seq. We previously developed Factorbook, a TF-centric database of annotations, motifs, and integrative analyses based on ChIP-seq data from Phase II of the ENCODE Project. Here we present an update to Factorbook which significantly expands the breadth of cell type and TF coverage. The update includes an expanded motif catalog derived from thousands of ENCODE Phase II and III ChIP-seq experiments and HT-SELEX experiments; this motif catalog is integrated with the ENCODE registry of candidate cis-regulatory elements to annotate a comprehensive collection of genome-wide candidate TF binding sites. The database also offers novel tools for applying the motif models within machine learning frameworks and using these models for integrative analysis, including annotation of variants and disease and trait heritability. Factorbook is publicly available at; we will continue to expand the resource as ENCODE Phase IV data are released

    Presence of Geriatric Conditions Is Prognostic of Major Bleeding in Older Patients with Atrial Fibrillation: a Cohort Study

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    BACKGROUND: In older patients with atrial fibrillation (AF), physical, cognitive, and psychosocial limitations are prevalent. The prognostic value of these conditions for major bleeding is unclear. OBJECTIVE: To determine whether geriatric conditions are prospectively associated with major bleeding in older patients with AF on anticoagulation. DESIGN: Multicenter cohort study with 2-year follow-up from 2016 to 2020 in Massachusetts and Georgia from cardiology, electrophysiology, and primary care clinics. PARTICIPANTS: Diagnosed with AF, age 65 years or older, CHA2DS2-VASc score of 2 or higher, and taking oral anticoagulant (n=1,064). A total of 6507 individuals were screened. MAIN MEASURES: A six-component geriatric assessment of frailty, cognitive function, social support, depressive symptoms, vision, and hearing. Main outcome was major bleeding adjudicated by a physician panel. KEY RESULTS: At baseline, participants were, on average, 75.5 years old and 49% were women. Mean CHA2DS2-VASc score was 4.5 and the mean HAS-BLED score was 3.3. During 2.0 (+/- 0.4) years of follow-up, 95 (8.9%) participants developed an episode of major bleeding. After adjusting for key covariates and accounting for competing risk from death, cognitive impairment (hazard ratio [HR] 1.62, 95% confidence interval [CI]: 1.02-2.56) and frailty (HR 2.77, 95% CI 1.38-5.58) were significantly associated with the development of major bleeding. CONCLUSIONS: In older patients with AF taking anticoagulants, cognitive impairment and frailty were independently associated with major bleeding

    Comparison of Abdominopelvic CT Diagnoses at Academic Teaching Hospitals in Rwanda and the United States

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    Purpose: The purpose of this study was to compare the disease processes encountered on abdominal and pelvic CT examinations at academic teaching hospitals in Rwanda and the United States and to highlight how these differences may impact a global radiology collaboration. Materials and Methods: In this retrospective study, we included 130 patients (mean 59 +/-17 years, range 20-91, F:M 74:56) who underwent abdominal/pelvic CT examinations between April 1st-12th, 2019. CT examinations were prospectively encountered in clinical work at the Centre Hospitalier Universitaire de Kigali or University Teaching Hospital of Kigali (CHUK) in Kigali, Rwanda, where the radiology report impression, patient age, gender, study indication, CT protocol, and clinical diagnosis were recorded when available. Abdominal/pelvic CT examinations at the Massachusetts General Hospital (MGH) in Boston, Massachusetts, United States were then retrospectively reviewed for the same information. Patient age and gender were compared using Student’s t-test and Chi-square statistic. Frequency of formal recommendations in radiology reports, available comparison of CT examinations, presence of known diagnoses, and intravenous and oral contrast media use were compared using Fisher’s exact test. Diagnostic categories were qualitatively compared. Results: A wide variety of pathology was encountered by abdominal/pelvic CT at both sites of imaging, with qualitative differences observed in cancer types, infectious agents, and how imaging guides care. Patients in Rwanda were older (p=0.0017), more likely to receive intravenous (p \u3c 0.05) and positive oral contrast (p \u3c 0.05) media and less likely to receive a formal recommendation in their radiology report (p \u3c 0.05). Patients in the United States were more likely to have an available prior abdominal/pelvic CT (p \u3c 0.05), to present for follow-up of a known diagnosis (p \u3c 0.05), and to receive a formal recommendation in their radiology report (p \u3c 0.05). Conclusion: Participation in global radiology collaborations is beneficial for radiologists by broadening exposure to pathologies and practice different from their own institution and region

    Prior histories of posttraumatic stress disorder and major depression and their onset and course in the three months after a motor vehicle collision in the AURORA study

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    BACKGROUND: A better understanding of the extent to which prior occurrences of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) predict psychopathological reactions to subsequent traumas might be useful in targeting posttraumatic preventive interventions. METHODS: Data come from 1306 patients presenting to 29 U.S. emergency departments (EDs) after a motor vehicle collision (MVC) in the advancing understanding of recovery after trauma study. Patients completed self-reports in the ED and 2-weeks, 8-weeks, and 3-months post-MVC. Associations of pre-MVC probable PTSD and probable MDE histories with subsequent 3-months post-MVC probable PTSD and probable MDE were examined along with mediation through intervening peritraumatic, 2-, and 8-week disorders. RESULTS: 27.6% of patients had 3-month post-MVC probable PTSD and/or MDE. Pre-MVC lifetime histories of these disorders were not only significant (relative risk = 2.6-7.4) but were dominant (63.1% population attributable risk proportion [PARP]) predictors of this 3-month outcome, with 46.6% prevalence of the outcome among patients with pre-MVC disorder histories versus 9.9% among those without such histories. The associations of pre-MVC lifetime disorders with the 3-month outcome were mediated largely by 2- and 8-week probable PTSD and MDE (PARP decreasing to 22.8% with controls for these intervening disorders). Decomposition showed that pre-MVC lifetime histories predicted both onset and persistence of these intervening disorders as well as the higher conditional prevalence of the 3-month outcome in the presence of these intervening disorders. CONCLUSIONS: Assessments of pre-MVC PTSD and MDE histories and follow-ups at 2 and 8 weeks could help target early interventions for psychopathological reactions to MVCs

    Nontraumatic brain parenchymal hemorrhage: The usual suspects and more

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    Brain parenchymal hemorrhage is a common neuroimaging finding in an emergency room. It is considered primary in the absence of an underlying lesion or coagulopathy. Secondary hemorrhages are caused by various structural causes and pathologies. The goals of imaging are to identify the hematoma, assess factors that have prognostic significance, assess associated complications, identify an underlying etiology whenever possible, and guide therapeutic decisions. The review provides an illustrative review of various etiologies of non-traumatic brain parenchymal hemorrhage and their imaging evaluation

    Characteristics, Outcomes, and Severity Risk Factors Associated With SARS-CoV-2 Infection Among Children in the US National COVID Cohort Collaborative

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    Importance: Understanding of SARS-CoV-2 infection in US children has been limited by the lack of large, multicenter studies with granular data. Objective: To examine the characteristics, changes over time, outcomes, and severity risk factors of children with SARS-CoV-2 within the National COVID Cohort Collaborative (N3C). Design, Setting, and Participants: A prospective cohort study of encounters with end dates before September 24, 2021, was conducted at 56 N3C facilities throughout the US. Participants included children younger than 19 years at initial SARS-CoV-2 testing. Main Outcomes and Measures: Case incidence and severity over time, demographic and comorbidity severity risk factors, vital sign and laboratory trajectories, clinical outcomes, and acute COVID-19 vs multisystem inflammatory syndrome in children (MIS-C), and Delta vs pre-Delta variant differences for children with SARS-CoV-2. Results: A total of 1068410 children were tested for SARS-CoV-2 and 167262 test results (15.6%) were positive (82882 [49.6%] girls; median age, 11.9 [IQR, 6.0-16.1] years). Among the 10245 children (6.1%) who were hospitalized, 1423 (13.9%) met the criteria for severe disease: mechanical ventilation (796 [7.8%]), vasopressor-inotropic support (868 [8.5%]), extracorporeal membrane oxygenation (42 [0.4%]), or death (131 [1.3%]). Male sex (odds ratio [OR], 1.37; 95% CI, 1.21-1.56), Black/African American race (OR, 1.25; 95% CI, 1.06-1.47), obesity (OR, 1.19; 95% CI, 1.01-1.41), and several pediatric complex chronic condition (PCCC) subcategories were associated with higher severity disease. Vital signs and many laboratory test values from the day of admission were predictive of peak disease severity. Variables associated with increased odds for MIS-C vs acute COVID-19 included male sex (OR, 1.59; 95% CI, 1.33-1.90), Black/African American race (OR, 1.44; 95% CI, 1.17-1.77), younger than 12 years (OR, 1.81; 95% CI, 1.51-2.18), obesity (OR, 1.76; 95% CI, 1.40-2.22), and not having a pediatric complex chronic condition (OR, 0.72; 95% CI, 0.65-0.80). The children with MIS-C had a more inflammatory laboratory profile and severe clinical phenotype, with higher rates of invasive ventilation (117 of 707 [16.5%] vs 514 of 8241 [6.2%]; P \u3c .001) and need for vasoactive-inotropic support (191 of 707 [27.0%] vs 426 of 8241 [5.2%]; P \u3c .001) compared with those who had acute COVID-19. Comparing children during the Delta vs pre-Delta eras, there was no significant change in hospitalization rate (1738 [6.0%] vs 8507 [6.2%]; P = .18) and lower odds for severe disease (179 [10.3%] vs 1242 [14.6%]) (decreased by a factor of 0.67; 95% CI, 0.57-0.79; P \u3c .001). Conclusions and Relevance: In this cohort study of US children with SARS-CoV-2, there were observed differences in demographic characteristics, preexisting comorbidities, and initial vital sign and laboratory values between severity subgroups. Taken together, these results suggest that early identification of children likely to progress to severe disease could be achieved using readily available data elements from the day of admission. Further work is needed to translate this knowledge into improved outcomes

    Healthcare Utilization in Youth with Mental Health Conditions

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    Background Youth and young adults represent a critical time for early detection and intervention of serious mental health conditions (SMHCs); however, of all age groups, health care use is lowest in young adults. Continued access to health services such as outpatient primary care and specialized mental health care, especially during the transition from pediatric to adult care, is important to improving outcomes in those with serious mental health conditions. Methods Stakeholder engagement and a mixed-method design were used. Quantitative Aims 1 and 2 used the IBM MarketScanCommercial Database. Qualitative Aim 3 used semi-structured interviews with a purposive sample of pediatricians and child/adolescent psychiatrists. Stakeholders were engaged throughout all Aims to ensure relevance of goals, real-world interpretation of results, and dissemination of key findings. Aim 1 described patterns of outpatient (e.g., primary, reproductive, mental health care) and acute (e.g., emergency room use, inpatient hospitalization) health care use by age, and serious mental health condition for youth and young adults. Aim 2 used logistic models with generalized estimating equations to identify factors associated with mental health follow-up after hospitalization and emergency room use for a serious mental health condition. Aim 3 explored pediatrician and child/adolescent psychiatrist perspectives on coordinated care for youth and young adults with serious mental health conditions, particularly as they transition to adult care. Main Results The prevalence of outpatient mental health care and primary care decreased with age, with a larger drop in primary care utilization. While 74.0-78.4% of those aged 12-17 years used both outpatient mental health care and primary care, 53.1-59.7% of those aged 18-27 years did. Differences were observed by mental health condition; those with schizophrenia and other psychotic disorders had the lowest rates of outpatient primary care use and the highest rates of acute care use. Of those hospitalized, 42.7% received follow-up within 7 days and 64.7% within 30 days. Of those with emergency room use not resulting in a hospitalization, 28.6% received follow-up within 7 days and 46.4% within 30 days. Having established mental health care strongly predicted follow-up, and more so than having established primary care. Providers described poor communication systems, no organized process for the transition from pediatric to adult care, a lack of time and reimbursement, and inadequate connection to community supports as key barriers to continuous, coordinated care for youth with serious mental health conditions. Conclusion Findings provide foundational knowledge to inform efforts to provide a comprehensive continuum of care for people with serious mental health conditions, potentially through increased access to primary care and specialized mental health care via enhanced care coordination of providers


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