tbuckley/cabot-search huggingface dataset:
Impact of lifetime body mass index trajectories on the incidence and persistence of adult asthma
Authors: Gulshan Bano Ali, Adrian J. Lowe, Jennifer L. Perret, E. Haydn Walters, Caroline J. Lodge, David Johns, Alan James, Bircan Erbas, Garun S. Hamilton, Gayan Bowatte, Richard Wood-Baker, Michael J. Abramson, Dinh S. Bui, Shyamali C. Dharmage
Journal: European Respiratory Journal (2022)

High body mass index (BMI) trajectories from childhood to adulthood are associated with the development of some chronic diseases, but whether such trajectories influence adult asthma has not been investigated to date. Therefore, we investigated associations between BMI trajectories from childhood to middle age (5-43 years) and incidence, persistence and relapse of asthma from ages 43 to 53 years.In the Tasmanian Longitudinal Health Study (n=4194), weight and height were recorded at eight time-points between 5 and 43 years of age. BMI trajectories were developed using group-based trajectory modelling. Associations between BMI trajectories and asthma incidence, persistence and relapse from age 43 to 53 years, bronchial hyperresponsiveness (BHR) at age 50 years, and bronchodilator responsiveness at age 53 years were modelled using multiple logistic and linear regression.Five distinct BMI trajectories were identified: average, low, child high-decreasing, child average-increasing and high. Compared with the average trajectory, child average-increasing and high trajectories were associated with increased risk of incident asthma (OR 2.6, 95% CI 1.1-6.6 and OR 4.4, 95% CI 1.7-11.4, respectively) and BHR in middle age (OR 2.9, 95% CI 1.1-7.5 and OR 3.5, 95% CI 1.1-11.4, respectively). No associations were observed for asthma persistence or relapse.Participants with child average-increasing and high BMI trajectories from childhood to middle age were at higher risk of incident adult asthma. Thus, encouraging individuals to maintain a normal BMI over the life course may help reduce the burden of adult asthma.
Successfully Implementing Digital Health to Ensure Future Global Health Security During Pandemics
Authors: Bandar Al Knawy, Mollie Marian McKillop, Joud Abduljawad, Sasu Tarkoma, Mahmood Adil, Louise Schaper, Adam Chee, David W. Bates, Michael Klag, Uichin Lee, Zisis Kozlakidis, George Crooks, Kyu Rhee
Journal: JAMA Network Open (2022)

<h3>Importance</h3> COVID-19 has highlighted widespread chronic underinvestment in digital health that hampered public health responses to the pandemic. Recognizing this, the Riyadh Declaration on Digital Health, formulated by an international interdisciplinary team of medical, academic, and industry experts at the Riyadh Global Digital Health Summit in August 2020, provided a set of digital health recommendations for the global health community to address the challenges of current and future pandemics. However, guidance is needed on how to implement these recommendations in practice. <h3>Objective</h3> To develop guidance for stakeholders on how best to deploy digital health and data and support public health in an integrated manner to overcome the COVID-19 pandemic and future pandemics. <h3>Evidence Review</h3> Themes were determined by first reviewing the literature and Riyadh Global Digital Health Summit conference proceedings, with experts independently contributing ideas. Then, 2 rounds of review were conducted until all experts agreed on the themes and main issues arising using a nominal group technique to reach consensus. Prioritization was based on how useful the consensus recommendation might be to a policy maker. <h3>Findings</h3> A diverse stakeholder group of 13 leaders in the fields of public health, digital health, and health care were engaged to reach a consensus on how to implement digital health recommendations to address the challenges of current and future pandemics. Participants reached a consensus on high-priority issues identified within 5 themes: team, transparency and trust, technology, techquity (the strategic development and deployment of technology in health care and health to achieve health equity), and transformation. Each theme contains concrete points of consensus to guide the local, national, and international adoption of digital health to address challenges of current and future pandemics. <h3>Conclusions and Relevance</h3> The consensus points described for these themes provide a roadmap for the implementation of digital health policy by all stakeholders, including governments. Implementation of these recommendations could have a significant impact by reducing fatalities and uniting countries on current and future battles against pandemics.
Risk of Opioid Overdose Associated With Concomitant Use of Oxycodone and Selective Serotonin Reuptake Inhibitors
Authors: Ismaeel Yunusa, Joshua J. Gagne, Kazuki Yoshida, Katsiaryna Bykov
Journal: JAMA Network Open (2022)

Some selective serotonin reuptake inhibitors (SSRIs) inhibit the enzymes responsible for the metabolism of oxycodone, a potent prescription opioid. The clinical consequences of this interaction on the risk of opioid overdose have not been elucidated.
Insufficiency of compound immune checkpoint blockade to overcome engineered T cell exhaustion in pancreatic cancer
Authors: Ingunn M Stromnes, Ayaka Hulbert, Meagan R Rollins, Ryan S Basom, Jeffrey Delrow, Patrick Bonson, Adam L Burrack, Sunil R Hingorani, Philip D Greenberg
Journal: Journal for ImmunoTherapy of Cancer (2022)

Achieving robust responses with adoptive cell therapy for the treatment of the highly lethal pancreatic ductal adenocarcinoma (PDA) has been elusive. We previously showed that T cells engineered to express a mesothelin-specific T cell receptor (TCRMsln) accumulate in autochthonous PDA, mediate therapeutic antitumor activity, but fail to eradicate tumors in part due to acquisition of a dysfunctional exhausted T cell state. Here, we investigated the role of immune checkpoints in mediating TCR engineered T cell dysfunction in a genetically engineered PDA mouse model. The fate of engineered T cells that were either deficient in PD-1, or transferred concurrent with antibodies blocking PD-L1 and/or additional immune checkpoints, were tracked to evaluate persistence, functionality, and antitumor activity at day 8 and day 28 post infusion. We performed RNAseq on engineered T cells isolated from tumors and compared differentially expressed genes to prototypical endogenous exhausted T cells. PD-L1 pathway blockade and/or simultaneous blockade of multiple coinhibitory receptors during adoptive cell therapy was insufficient to prevent engineered T cell dysfunction in autochthonous PDA yet resulted in subclinical activity in the lung, without enhancing anti-tumor immunity. Gene expression analysis revealed that ex vivo TCR engineered T cells markedly differed from in vivo primed endogenous effector T cells which can respond to immune checkpoint inhibitors. Early after transfer, intratumoral TCR engineered T cells acquired a similar molecular program to prototypical exhausted T cells that arise during chronic viral infection, but the molecular programs later diverged. Intratumoral engineered T cells exhibited decreased effector and cell cycle genes and were refractory to TCR signaling. Abrogation of PD-1 signaling is not sufficient to overcome TCR engineered T cell dysfunction in PDA. Our study suggests that contributions by both the differentiation pathways induced during the ex vivo T cell engineering process and intratumoral suppressive mechanisms render engineered T cells dysfunctional and resistant to rescue by blockade of immune checkpoints.
Perceptions on Burnout and the Medical School Learning Environment of Medical Students Who Are Underrepresented in Medicine
Authors: Jamieson M. O’Marr, Shin Mei Chan, Lake Crawford, Ambrose H. Wong, Elizabeth Samuels, Dowin Boatright
Journal: JAMA Network Open (2022)

Burnout is a highly prevalent issue among medical trainees, but there has been limited research characterizing burnout specifically among medical students from groups who are underrepresented in medicine (URIM). To assess the association between components of the medical school learning environment and burnout among medical students who are URIM vs those who are not. This retrospective cross-sectional survey study evaluated responses of allopathic medical students graduating from all US allopathic medical schools in 2016 and 2017 to the American Medical Colleges Graduation Questionnaire. Analysis was completed between December 1, 2019, and July 1, 2020. Self-identification as a medical student who is URIM. Self-reported measures of medical student overall, disengagement, and exhaustion-related burnout using the Oldenburg Burnout Inventory for Medical Students. The American Medical Colleges Graduation Questionnaire had an 81% response rate, yielding 26 567 complete participant responses that were included the analysis. A total of 13 645 individuals (51.4%) were male, and 3947 (14.9%) identified as URIM (ie, Alaska Native, Black, Hispanic/Latinx, Native American, and/or Pacific Islander). Medical students who are URIM reported modestly higher levels of exhaustion-related burnout (mean [SD], 11.84 [3.62] vs 11.48 [3.61]; P < .001) and modestly lower mean burnout scores associated with disengagement (mean [SD], 9.24 [3.56] vs 9.36 [3.58]; P = .047). Medical students who are URIM also reported marginally less favorable student-faculty interactions in the learning environment (mean [SD], 14.09 [3.45] vs 14.29 [3.35]; P < .001). Medical students who are URIM were more likely to be in the top quartile of those who experienced exhaustion-related burnout (odds ratio, 1.19 [95% CI, 1.09-1.29]) but less likely to be in the top quartile for disengagement (odds ratio, 0.87 [95% CI, 0.80-0.94]). Regardless of URIM status, those who reported learning environment scores in the bottom quartile were more likely to experience higher rates of burnout as were those who experienced at least 1 episode of discrimination. This survey study found that medical students who are URIM had a higher risk for exhaustion-related burnout. This burnout is likely multifactorial and could represent a resiliency or survival bias, the burden of increased responsibility, and/or recurrent discrimination. The learning environment can play a key role in mitigating burnout in both medical students who are URIM and those who are not and is deserving of further research.
The gut–meningeal immune axis: Priming brain defense against the most likely invaders
Authors: Rafael Di Marco Barros, Zachary Fitzpatrick, Menna R. Clatworthy
Journal: The Journal of Experimental Medicine (2022)

The gastrointestinal tract contains trillions of microorganisms that exist symbiotically with the host due to a tolerant, regulatory cell–rich intestinal immune system. However, this intimate relationship with the microbiome inevitably comes with risks, with intestinal organisms being the most common cause of bacteremia. The vasculature of the brain-lining meninges contains fenestrated endothelium, conferring vulnerability to invasion by circulating microbes. We propose that this has evolutionarily led to close links between gut and meningeal immunity, to prime the central nervous system defense against the most likely invaders. This paradigm is exemplified by the dural venous sinus IgA defense system, where the antibody repertoire mirrors that of the gut.
遗传性肺圆柱瘤
Authors: S.M. Brown, M. Arefi, R. Stones, P.S. Loo, S. Barnard, C. Bloxham, N. Stefanos, J.A.A. Langtry, S. Worthy, E. Calonje, A. Husain, N. Rajan
Journal: British Journal of Dermatology (2018)
Results from a Test-to-Release from Isolation Strategy Among Fully Vaccinated National Football League Players and Staff Members with COVID-19 — United States, December 14–19, 2021
Authors: Christina D. Mack, Erin B. Wasserman, Marie E. Killerby, Rieza H. Soelaeman, Aron J. Hall, Adam MacNeil, Deverick J. Anderson, Patti Walton, Saamir Pasha, Emily Myers, Catherine S. O’Neal, Christopher J. Hostler, Navdeep Singh, Thom Mayer, Allen Sills
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

During December 2021, the United States experienced a surge in COVID-19 cases, coinciding with predominance of the SARS-CoV-2 B.1.1.529 (Omicron) variant (1). During this surge, the National Football League (NFL) and NFL Players Association (NFLPA) adjusted their protocols for test-to-release from COVID-19 isolation on December 16, 2021, based on analytic assessments of their 2021 test-to-release data. Fully vaccinated* persons with COVID-19 were permitted to return to work once they were asymptomatic or fever-free and experiencing improving symptoms for ≥24 hours, and after two negative or high cycle-threshold (Ct) results (Ct≥35) from either of two reverse transcription-polymerase chain reaction (RT-PCR) tests† (2). This report describes data from NFL's SARS-CoV-2 testing program (3) and time to first negative or Ct≥35 result based on serial COVID-19 patient testing during isolation. Among this occupational cohort of 173 fully vaccinated adults with confirmed COVID-19 during December 14-19, 2021, a period of Omicron variant predominance, 46% received negative test results or had a subsequent RT-PCR test result with a Ct≥35 by day 6 postdiagnosis (i.e., concluding 5 days of isolation) and 84% before day 10. The proportion of persons with positive test results decreased with time, with approximately one half receiving positive RT-PCR test results after postdiagnosis day 5. Although this test result does not necessarily mean these persons are infectious (RT-PCR tests might continue to return positive results long after an initial positive result) (4), these findings indicate that persons with COVID-19 should continue taking precautions, including correct and consistent mask use, for a full 10 days after symptom onset or initial positive test result if they are asymptomatic.
Detection of tumor-specific DNA methylation markers in the blood of patients with pituitary neuroendocrine tumors
Authors: Grayson A Herrgott, Karam P Asmaro, Michael Wells, Thais S Sabedot, Tathiane M Malta, Maritza S Mosella, Kevin Nelson, Lisa Scarpace, Jill S Barnholtz-Sloan, Andrew E Sloan, Warren R Selman, Ana C deCarvalho, Laila M Poisson, Abir Mukherjee, Adam M Robin, Ian Y Lee, James Snyder, Tobias Walbert, Mark Rosenblum, Tom Mikkelsen, Arti Bhan, John Craig, Steven Kalkanis, Jack Rock, Houtan Noushmehr, Ana Valeria Castro
Journal: Neuro-Oncology (2022)

Abstract Background DNA methylation abnormalities are pervasive in pituitary neuroendocrine tumors (PitNETs). The feasibility to detect methylome alterations in circulating cell-free DNA (cfDNA) has been reported for several central nervous system (CNS) tumors but not across PitNETs. The aim of the study was to use the liquid biopsy (LB) approach to detect PitNET-specific methylation signatures to differentiate these tumors from other sellar diseases. Methods We profiled the cfDNA methylome (EPIC array) of 59 serum and 41 plasma LB specimens from patients with PitNETs and other CNS diseases (sellar tumors and other pituitary non-neoplastic diseases, lower-grade gliomas, and skull-base meningiomas) or nontumor conditions, grouped as non-PitNET. Results Our results indicated that despite quantitative and qualitative differences between serum and plasma cfDNA composition, both sources of LB showed that patients with PitNETs presented a distinct methylome landscape compared to non-PitNETs. In addition, LB methylomes captured epigenetic features reported in PitNET tissue and provided information about cell-type composition. Using LB-derived PitNETs-specific signatures as input to develop machine-learning predictive models, we generated scores that distinguished PitNETs from non-PitNETs conditions, including sellar tumor and non-neoplastic pituitary diseases, with accuracies above ~93% in independent cohort sets. Conclusions Our results underpin the potential application of methylation-based LB profiling as a noninvasive approach to identify clinically relevant epigenetic markers to diagnose and potentially impact the prognostication and management of patients with PitNETs.
Genetic susceptibility to viral disease in humans
Authors: Trine H. Mogensen
Journal: Clinical Microbiology and Infection (2022)

BackgroundDuring the past decades, studies on patients with severe viral infections have revealed rare inborn errors of immunity (IEIs) underlying these diseases. This has led to important new insights into the molecular genetics and immunological mechanisms governing susceptibility to viral infection in humans.ObjectivesHerein, the current knowledge on major IEIs predisposing to severe or chronic viral infections are described and discussed, and the clinical implications of these findings for individualized prophylaxis and treatment are outlined.SourcesThe review is based on a broad literature search, including relevant studies primarily based on patients, supported by experimental molecular models in vitro or in mice, to characterize the pathophysiological mechanism governing these disease conditions.ContentCurrent concepts and principles of genetic predisposition to viral infections in humans are described with a major focus on defects related to innate immune responses and new concepts of constitutive immune mechanisms. The topic therefore spans from seminal studies on the human genetics of herpesvirus infections in the central nervous system, severe influenza, and disease after vaccination with live attenuated viral vaccines, to genetic resistance to viral infection.ImplicationsPast and present studies of patients with IEIs conferring vulnerability to viral infections have taught us important lessons on protective innate and adaptive antiviral immunity in humans. Such knowledge also has important clinical implications, allowing development of prophylactic and therapeutic solutions to prevent or dampen the clinical consequences of insufficient or dysregulated antiviral immunity in patients. Collectively, such measures are likely to improve patient management at an individualized level and help societies reduce the disease burden from viral infections.
Interpretation of the Efficacy of Multidisciplinary Geriatric Assessment Intervention on Chemotherapy-Related Toxic Effects in Older Adults With Cancer
Authors: Ayumu Matsuoka, Maiko Fujimori
Journal: JAMA Oncology (2022)

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Corrigendum to: ‘Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target’ [J Hepatol 2021 (74) 1155-1166]
Authors: Massih Ningarhari, Stefano Caruso, Théo Z. Hirsch, Quentin Bayard, Andrea Franconi, Anne-Laure Védie, Bénédicte Noblet, Jean-Frédéric Blanc, Giuliana Amaddeo, Nathalie Ganne, Marianne Ziol, Valérie Paradis, Catherine Guettier, Julien Calderaro, Guillaume Morcrette, Youngsoo Kim, A. Robert MacLeod, Jean-Charles Nault, Sandra Rebouissou, Jessica Zucman-Rossi
Journal: Journal of Hepatology (2022)
Diastolic Blood Pressure Alleles Improve Congenital Heart Defect Repair Outcomes
Authors: Joseph H. Breeyear, Jacob M. Keaton, Eric S. Torstenson, Andrew H. Smith, Derek Klarin, Scott M. Damrauer, Pradeep Natarajan, Sara L. Van Driest, Jeffrey G. Weiner, Prince J. Kannankeril, Todd L. Edwards
Journal: Circulation Research (2022)

Background: Congenital heart defects (CHDs) affect 40 000 US births per year, half of which require surgical intervention. Individual differences in surgical outcomes including mortality and complications are not well understood but may be due to genetic variability. We hypothesized that polygenic risk scores (PRSs) for blood pressure in adults are associated with treatments and postsurgical outcomes in children with CHD, as CHD survivors are at higher risk of negative cardiometabolic disease. Methods: We used imputed genotype data from pediatric participants requiring surgery for CHD (median age at surgery, 201 days; n max =2498). Base data for the systolic and diastolic blood pressure PRSs (n max =760 226) came from published genome-wide association study. The blood pressure PRSs were tested for association with postsurgical outcomes. All effects presented are per SD increase in PRS and adjusted for age, sex, body mass index, surgical complexity score, and first 10 principal components of ancestry. Results: A higher diastolic blood pressure PRS was associated with decreased in-hospital mortality risk (odds ratio, 0.57 [0.39–0.82]; P =0.0022). Additional analyses suggest an interaction between diastolic blood pressure PRS and vasopressor dose. Those with a diastolic blood pressure PRS 1 SD above the mean, receiving a vasopressor dose in the top tertile, were estimated to have 52% (32%–66%) lower risk of in-hospital mortality compared with those with a vasopressor dose in the bottom tertile. Conclusions: These results suggest a genetically determined postsurgical survival advantage for CHD patients with blood pressure increasing alleles. Further study may reveal novel mechanisms contributing to postoperative morbidity and mortality, and this approach may assist in early identification of children at risk for adverse postoperative outcomes.
Eligibility for pharmacological therapies in heart failure with reduced ejection fraction: implications of the new Chronic Kidney Disease Epidemiology Collaboration creatinine equation for estimating glomerular filtration rate
Authors: Jawad H. Butt, Carly Adamson, Kieran F. Docherty, Muthiah Vaduganathan, Scott D. Solomon, Inder S. Anand, Faiez Zannad, Lars Køber, Pardeep S. Jhund, John J.V. McMurray
Journal: European Journal of Heart Failure (2022)

The new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimating glomerular filtration rate (eGFR), based on serum creatinine, that does not incorporate race may reclassify individuals, irrespective of race, from one eGFR category to another, with implications for eligibility for treatments in patients with heart failure and reduced ejection fraction (HFrEF).