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Bigtools: a high-performance BigWig and BigBed library in Rust
Get PDFMotivation: The BigWig and BigBed file formats were originally designed for the visualization of next-generation sequencing data through a genome browser. Due to their versatility, these formats have long since become ubiquitous for the storage of processed sequencing data and regularly serve as the basis for downstream data analysis. As the number and size of sequencing experiments continues to accelerate, there is an increasing demand to efficiently generate and query BigWig and BigBed files in a scalable and robust manner, and to efficiently integrate these functionalities into data analysis environments and third-party applications.
Results: Here, we present Bigtools, a feature-complete, high-performance, and integrable software library for generating and querying both BigWig and BigBed files. Bigtools is written in the Rust programming language and includes a flexible suite of command line tools as well as bindings to Python.
Availability and implementation: Bigtools is cross-platform and released under the MIT license. It is distributed on Crates.io, Bioconda, and the Python Package Index, and the source code is available at https://github.com/jackh726/bigtools
Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis
Get PDFWhile neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression
UMCCTS Newsletter, March 2024
Get PDFThis is the March 2024 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.Supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grants UL1 TR001453, TL1 TR001454 and KL2 TR001455
Senescent-like microglia limit remyelination through the senescence associated secretory phenotype [preprint]
No full textThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.The capacity to regenerate myelin in the central nervous system (CNS) diminishes with age. This decline is particularly evident in multiple sclerosis (MS), which has been suggested to exhibit features of accelerated biological aging. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells (SCs) accumulate within demyelinated lesions after injury, and their elimination enhances remyelination in young mice but not in aged mice. In young mice, we observed the upregulation of senescence-associated transcripts primarily in microglia after demyelination, followed by their reduction during remyelination. However, in aged mice, senescence-associated factors persisted within lesions, correlating with inefficient remyelination. We found that SC elimination enhanced remyelination in young mice but was ineffective in aged mice. Proteomic analysis of senescence-associated secretory phenotype (SASP) revealed elevated levels of CCL11/Eotaxin-1 in lesions, which was found to inhibit efficient oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS
Training in eight low-and middle-income countries: lessons learned from a pilot study using the WHO-TDR dissemination and implementation massive open online course
Get PDFIntroduction: Non-communicable diseases (NCDs) are a leading cause of morbidity and mortality in low-and middle- income countries (LMICs). Despite this, a lack of funding, training and mentorship for NCD investigators in LMICs exists. In an effort to gain knowledge and skills to address these gaps, participants from the Global Research on Implementation and Translation Science (GRIT), a consortium of studies in eight LMICs and their networks, attended the dissemination and implementation (D&I) massive open online course (MOOC) developed by the Special Programme for Research and Training in Tropical Diseases at the World Health Organization to strengthen D&I capacity building. Here, we report on the pilot of this MOOC, which was implemented during the SARS COVID-19 pandemic from April- November 2020.
Methods: Participants completed pre-and post-training questionnaires to assess self-reported D&I competencies, general research skills, and research mentor access and quality. D&I competencies were measured by use of a scale developed for a US-based training program, with change in competency scores assessed by paired t test. We used univariate statistics to analyze the data for all other outcomes.
Results: Of the 247 participants enrolled, 32 (13%) completed all course requirements, 21 (9%) completed the pre-and post-surveys and are included in the analysis. D&I competency scores suggest improvement for those who had complete pre- and post-assessments. Trainee's average score on the full competency scale improved 1.45 points (0-5 scale) from pre- to post-test; all four subscales also showed evidence of improvements. There were small but not significant increases in competencies for grant writing, proposal/ manuscript writing and presentations from pre- to post-test assessment. 40% of trainees reported access to a research mentor and 12% reported access to a D&I specific mentor. Participants reported barriers (e.g., unstable internet access and challenges due to COVID-19) and facilitators (e.g., topical interests, collaboration with colleagues) to completing the MOOC.
Conclusions: Although COVID-19 affected program usage and completion, the MOOC was feasible. We also had signals of effectiveness, meaning among LMIC participants completing the course, there was improvement in self-report D&I competency scores. Recommendations for future D&I trainings in LMICs include (1) adding more topic specific modules (i.e., NCD research, general research skills) for scalability; (2) fostering more collaboration with participants across LMICs; and (3) establishing partnerships with D&I mentors for course participants
Preventing diabetes: What overweight and obese adults with prediabetes in the United States report about their providers' communication and attempted weight loss
Get PDFObjective: To investigate what overweight or obese adults with prediabetes in the United States report being told by providers about 1) having prediabetes, 2) diabetes risk, and 3) losing weight and the associations of these communications with attempted weight loss.
Methods: Data from 2015 to 2018 National Health and Nutrition Examination Surveys (NHANES) for adults with a body mass index in the overweight or obesity ranges and HbA1c in the prediabetes range were examined (n = 2085). Patient reported data on what providers told them about having prediabetes, being at risk for diabetes, and losing weight were compared with attempted weight loss.
Results: Most participants (66.4%) reported never being told they had prediabetes nor being at risk for diabetes, 13.0% reported being told they had prediabetes, 10.6% at risk for diabetes, and 8.0% both messages. 18.3% of participants reported being told to lose weight. Participants who reported being told they had prediabetes and at increased diabetes risk were more likely to report attempted weight loss (adjusted odds ratio (AOR) 1.8, 95% confidence interval (CI) 1.1-3.2). Reporting that they were told to lose weight was not significantly associated with an increase in reported weight loss attempts.
Conclusions: In this cohort of individuals with overweight/obesity and prediabetic HbA1c values, low rates communications with providers about prediabetes and diabetes risk were reported. When both were discussed, patients reported greater attempted weight loss. These findings draw attention to the potential impact that provider communications about prediabetes and diabetes risk may have on lifestyle behavior change
Pediatric Practices' Experiences with Massachusetts' Medicaid Accountable Care Organizations
No full textObjective: To examine the experience of Medicaid Accountable Care Organizations (ACOs) that include pediatric practices, including their motivations and experiences working together.
Methods: This mixed methods study is set within the first two years of the Massachusetts Medicaid ACO Program, which created 17 Medicaid ACOs across the Commonwealth in 2018. It combines qualitative interviews from organizational leaders across three Medicaid ACOs with pediatric representation (N=28; purposive sample; 2018) with a 44-item primary care practice leader survey (N=225 after 64% response rate; statewide stratified random sample of primary care practices; 2019). Interviews gathered information about organizational motivations and experiences with becoming a Medicaid ACO; the survey asked five domains of questions describing the experience of pediatric- and adult-focused primary care practices in joining Medicaid ACOs (e.g., how much practices solved problems jointly with the ACO). We used ordinary least squares regression to describe differences in experiences across pediatric vs. non-pediatric practices.
Results: Leaders of Medicaid ACO with pediatric representation expressed a desire to voice pediatric concerns regarding state Medicaid payment policy and to integrate social services as part of routine medical care. Relative to the experience of adult-focused primary care practice leaders, pediatric-focused practices reported less collaboration within the Medicaid ACO (95% confidence interval 0.81 to 0.05; p = 0.03) and less change toward standardization of policies such as physician compensation (95% confidence interval 0.61 to 0.02; p = 0.04).
Conclusions: Initial Medicaid ACO experiences can differ based on the degree to which organizations joining Medicaid ACO programs serve pediatric populations.
Article summary: Early in Massachusetts' implementation of Medicaid Accountable Care Organizations (ACO), pediatric-focused practices reported less collaboration and standardization within their Medicaid ACOs than adult-focused practices.No embarg
Epigenetic Enablers of Meningioma Growth
No full textMeningiomas are the most common primary intracranial brain tumor, often causing significant disability and sometimes even death. The most aggressive meningiomas commonly exhibit extensive genomic disruption that can lead to genotoxic and proteotoxic stress, but the mechanisms that enable these tumors to thrive are unknown. To date, meningiomas have no effective chemotherapy. This study used a high-throughput bioactive small molecule screen of established meningioma cell lines and RNA-sequencing of patient meningiomas to identify EHMT2/G9a inhibitors as potent cytotoxic agents in meningioma in vitro. Further, studies using the small molecule EHMT2/G9a inhibitor, UNC0631 demonstrated reduced tumor growth in an orthotopic xenograft mouse model of meningioma in vivo. We used CUT&Tag and transcriptomic analyses of established meningioma cell lines after EHMT2/G9a inhibition to identify the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress apoptotic signaling pathway as key factors in EHMT2/G9a-mediated meningioma cell death. After EHMT2/G9a inhibition, we observed a collapse of heat shock protein expression and hypothesized that downregulation of a deacetylase, Sirtuin 1 (SirT1), may be responsible. Consistent with decreased SirT1 activity, Heat Shock Factor 1 exhibited increased lysine acetylation and decreased DNA binding at the promoters of downregulated heat shock proteins. Overexpression of SirT1 or shRNA-mediated knockdown of the ER stress response mediators, ATF4 or CHOP/DDIT3, decreased meningioma cell death caused by EHMT2/G9a inhibition. The molecular chaperone and ER stress inhibitor, 4-phenylbutyric acid, abrogated meningioma cell death occurring after EHMT2/G9a inhibition. In conclusion, epigenetic maintenance of heat shock protein activity and suppression of the UPR/ER stress apoptotic signaling pathway by EHMT2/G9a and SirT1 are essential for aggressive meningioma growth.MD/PhD2026-04-2
Barriers and facilitators to pre-exposure prophylaxis (PrEP) uptake and adherence among men who have sex with men (MSM) in Thailand: a qualitative study
No full textYoung MSM (YMSM), aged 15-24, account for nearly half of new HIV infections in Thailand. Pre-exposure prophylaxis (PrEP) is an effective prevention medicine for populations at substantial HIV risk, yet YMSM frequently have suboptimal uptake of and adherence to PrEP. We conducted 35 in-depth interviews with YMSM to explore barriers and facilitators of both PrEP initiation and adherence. Interviews also elicited the perceptions and experiences of healthcare providers (HCPs) working with YMSM at three clinics in Bangkok. Primary barriers to PrEP initiation were limited accessibility, insufficient knowledge, and efficacy concerns; HCPs identified no-to-low self-perception of HIV risk, pre-existing health problems, fears of side effects, and living in distant provinces as barriers to PrEP initiation. YMSM primarily reported PrEP information and self-perceptions of elevated HIV risk as facilitators to PrEP initiation. Additionally, forgetfulness and low HIV risk awareness were common barriers to PrEP adherence. Reminders were a prominent facilitator of PrEP adherence alongside disclosure to close relationships, the routinization of regimens, and convenient facilities. HCPs regarded counseling as the leading facilitator of PrEP adherence. By understanding the barriers/facilitators of PrEP use, the current study seeks to help develop evidence-informed PrEP intervention programs among YMSM while considering cultural sensitivity
To treat or not to treat: a comparative effectiveness analysis of oral anticoagulant outcomes among U.S. nursing home residents with atrial fibrillation
No full textBackground: Nursing home residents with atrial fibrillation are at high risk for ischemic stroke, but most are not treated with anticoagulants. This study compared the effectiveness and safety between oral anticoagulant (OAC) users and non-users.
Methods: We conducted a new-user retrospective cohort study by using Minimum Data Set 3.0 assessments linked with Medicare claims. The participants were Medicare fee-for-service beneficiaries with atrial fibrillation residing in US nursing homes between 2011 and 2016, aged ≥ 65 years. The primary outcomes were occurrence of an ischemic stroke or systemic embolism (effectiveness), occurrence of intracranial or extracranial bleeding (safety) and net clinical outcome (effectiveness or safety outcomes). Secondary outcomes included total mortality and a net clinical and mortality outcome. Cox proportional hazards and Fine and Grey models estimated multivariable adjusted hazard ratios (aHRs) and sub-distribution hazard ratios (sHRs).
Results: Outcome rates were low (effectiveness: OAC: 0.86; non-users: 1.73; safety: OAC: 2.26; non-users: 1.75 (per 100 person-years)). OAC use was associated with a lower rate of the effectiveness outcome (sHR: 0.69; 95% Confidence Interval (CI): 0.61-0.77), higher rates of the safety (sHR: 1.70; 95% CI: 1.58-1.84) and net clinical outcomes (sHR: 1.20; 95% CI: 1.13-1.28) lower rate of all-cause mortality outcome (sHR: 0.60; 95% CI: 0.59-0.61), and lower rate of the net clinical and mortality outcome (sHR: 0.60; 95% CI: 0.59-0.61). Warfarin users, but not DOAC users, had a higher rate of the net clinical outcome versus OAC non-users.
Conclusions: Our results support the benefits of treatment with OACs to prevent ischemic strokes and increase longevity, while highlighting the need to weigh apparent benefits against elevated risk for bleeding. Results were consistent with net favorability of DOACs versus warfarin.Clinical and Population Health Researc