tbuckley/cabot-search huggingface dataset:
Association of hepatitis delta virus infection and hepatocellular carcinoma, hepatic decompensation, all-cause and liver-related death in a national cohort
Authors: Binu V. John, Dustin Bastaich, Mahmoud Manouchehri Amoli, Robert J. Wong, Donna M. Evon, Shari S. Rogal, David B. Ross, Timothy R. Morgan, Seth A. Spector, Gabriel Villada, Hann-Hsiang Chao, Bassam Dahman
Journal: Hepatology (2024)

Background: Hepatitis Delta Virus (HDV) infection is the most severe form of chronic hepatitis. However, studies on outcomes and causes of death in a United States-born population, with primarily horizontal transmission of HDV, are lacking. The aim of this study was to conduct a national study of patients with hepatitis D to understand the natural history and outcomes compared to patients with hepatitis B virus (HBV). infection. Methods: In a national cohort of 4,817 HBV infected veterans tested for HDV (99.6% US-born, 3.3% HDV positive) over a 23-year period, we used multivariable models to identify the factors associated with a composite outcome of hepatocellular carcinoma (HCC), decompensation, and liver-related mortality (LRM), as well as all-cause mortality of patients with HDV compared to HBV mono-infection. Results: HDV coinfection (vs. HBV monoinfection) was associated with a significantly higher incidence of composite liver-related outcomes at both 5 (23.84 vs. 7.98, p &lt;0.001), and 10 years (19.14 vs. 10.18, p &lt;0.001) respectively. The most common cause of death was liver-related (33.8% for HDV vs. 24.7% for HBV), followed by non-hepatic malignancies, (15.6 vs. 14.8%),cardiac (11.7 vs. 15.2%), and lung disease (5.2 vs. 3.7%). In multivariable models, HDV was associated with an increased risk of composite liver outcomes (aHR 2.57, 95% CI 1.87-3.52, p &lt;0.001), and all-cause mortality (aHR 1.52, 95% CI 1.20-1.93, p &lt;0.001). Conclusion: In a predominantly U.S born cohort of Veterans, HDV co-infection was associated with an increased risk of liver-related outcomes and all-cause mortality. Our findings support widespread testing for early identification of HDV.
Once-weekly insulin efsitora alfa versus once-daily insulin degludec in adults with type 1 diabetes (QWINT-5): a phase 3 randomised non-inferiority trial
Authors: Richard M Bergenstal, Ruth S Weinstock, Chantal Mathieu, Yukiko Onishi, Vishali Vijayanagaram, Michelle L Katz, Molly C Carr, Annette M Chang
Journal: The Lancet (2024)
Antibiotic use during influenza infection augments lung eosinophils that impair immunity against secondary bacterial pneumonia
Authors: Marilia Sanches Santos Rizzo Zuttion, Tanyalak Parimon, Stephanie A Bora, Changfu Yao, Katherine Lagree, Catherine A Gao, Richard G Wunderink, Georgios D Kitsios, Alison Morris, Yingze Zhang, Bryan J McVerry, Matthew E Modes, Alberto M Marchevsky, Barry R Stripp, Christopher M Soto, Ying Wang, Kimberly Merene, Silvia Cho, Blandine L Victor, Ivan Vujkovic-Cvijin, Suman Gupta, Suzanne Cassel, Fayyaz S Sutterwala, Suzanne Devkota, David M Underhill, Peter Chen
Journal: Journal of Clinical Investigation (2024)

A leading cause of mortality after influenza infection is the development of a secondary bacterial pneumonia. In the absence of a bacterial superinfection, prescribing antibacterial therapies is not indicated but has become a common clinical practice for those presenting with a respiratory viral illness. In a murine model, we found that antibiotic use during influenza infection impaired the lung innate immunologic defenses toward a secondary challenge with methicillin-resistant Staphylococcus aureus (MRSA). Antibiotics augment lung eosinophils, which have inhibitory effects on macrophage function through the release of major basic protein. Moreover, we demonstrated antibiotic treatment during influenza infection causes a fungal dysbiosis that drive lung eosinophilia and impair MRSA clearance. Finally, we evaluated three cohorts of hospitalized patients and found eosinophils positively correlated with antibiotic use, systemic inflammation, and worsened outcomes. Altogether, our work demonstrates a detrimental effect of antibiotic treatment during influenza infection that has harmful immunologic consequences via recruitment of eosinophils to the lungs thereby increasing the risk of developing a secondary bacterial infection.
Longitudinal analysis of viral dynamics in HIV+ to HIV+ HOPE Act kidney-transplant recipients
Authors: Tatianna Travieso, Hannah Stadtler, Naseem Alavian, Feng Gao, Mary Klotman, Cameron R Wolfe, Maria Blasi
Journal: Journal of Clinical Investigation (2024)

The HIV Organ Policy Equity (HOPE) Act allows individuals living with HIV to accept organs from donors with HIV. This practice widens the pool of available organs, but also presents important virological questions, including the potential for HIV superinfection of the recipient, viral persistence in the kidney, and loss of virological control.
Metabolic rewiring during bone development underlies tRNA m7G-associated primordial dwarfism
Authors: Qiwen Li, Shuang Jiang, Kexin Lei, Hui Han, Yaqian Chen, Weimin Lin, Qiuchan Xiong, Xingying Qi, Xinyan Gan, Rui Sheng, Yuan Wang, Yarong Zhang, Jieyi Ma, Tao Li, Shuibin Lin, Chenchen Zhou, Demeng Chen, Quan Yuan
Journal: Journal of Clinical Investigation (2024)

Translation of mRNA to protein is tightly regulated by transfer RNAs (tRNAs), which are subject to various chemical modifications that maintain structure, stability, and function. Deficiency of tRNA N7-methylguanosine (m7G) modification in patients causes a type of primordial dwarfism, but the underlying mechanism remains unknown. Here we report that the loss of m7G rewires cellular metabolism, leading to the pathogenesis of primordial dwarfism. Conditional deletion of the catalytic enzyme Mettl1 or missense mutation of the scaffold protein Wdr4 severely impaired endochondral bone formation and bone mass accrual. Mechanistically, Mettl1 knockout decreased abundance of m7G-modified tRNAs and inhibited translation of mRNAs relating to cytoskeleton and Rho GTPase signaling. Meanwhile, Mettl1 knockout enhanced cellular energy metabolism despite incompetent proliferation and osteogenic commitment. Further exploration revealed that impairment of Rho GTPase signaling upregulated the level of branched-chain amino acid transaminase 1 (BCAT1) that rewired cell metabolism and restricted intracellular α-ketoglutarate (αKG). Supplementation of αKG ameliorated the skeletal defect of Mettl1-deficient mice. In addition to the selective translation of metabolism-related mRNAs, we further revealed that Mettl1 knockout globally regulated translation via integrated stress response (ISR) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Restoring translation by targeting either ISR or mTORC1 aggravated bone defects of Mettl1-deficient mice. Overall, our study unveils a critical role of m7G tRNA modification in bone development by regulation of cellular metabolism and indicates suspension of translation initiation as a quality control mechanism in response to tRNA dysregulation.
The use of Reflectance Confocal Microscopy to diagnose Malignant Melanoma and Lentigo Maligna in the United Kingdom: A Prospective Observational Trial at a Single Centre
Authors: Howard P Stevens, Giovanni Pellacani, Colin Angus, Joseph N El-Jabbour
Journal: British Journal of Dermatology (2024)

Abstract Background Previous work with Reflectance Confocal Microscopy (RCM) imaging has shown high sensitivity and specificity for Malignant Melanoma (MM), but to date there have been no studies on a UK cohort. Objectives The study hypothesised that RCM could be used prospectively to accurately diagnose MM and lentigo maligna (LM) in a private UK secondary care, single clinician setting. The study assessed the potential for RCM to be used as a routine screening procedure. Methods 597 patients were recruited consecutively where MM or LM featured in the differential diagnosis after clinical examination. A sequential record was made of the clinical, dermoscopic, and RCM findings by a single dermatologist [HS] prior to biopsy. Imaging used the arm-mounted confocal microscope unless access was restricted and required the handheld probe. The likelihood of MM was scored for each modality, each diagnosis building on the last. Histology was assessed by a single blinded histopathologist [JJ]. Results 734 lesions were included in the analysis, including 86 MM and LM with a median diameter of 7.0 mm. The benign to malignant ratio was 3 to 1 (non-melanocytic malignancies included) and 8.3 to 1 for MM and LM only. The sensitivity and specificity for MM and LM was 62.8% (95% CI 51.70% to 72.98%) and 63.2% (59.27% to 66.84%) for clinical examination; 91.9% (83.95% to 96.66%) and 42.1% (38.14% to 45.88%) for dermoscopy; 94.2% (86.95% to 98.09%) and 83.2% (79.91% to 85.84%) for RCM. For RCM, PPV was 42.4% (38.13% to 46.81%) and NPV was 99.1% (97.87% to 99.60%). Conclusion This study demonstrates that RCM can reliably diagnose MM and is fast enough to be integrated into UK pigmented lesion clinics by dermatologists trained in RCM. “Number needed to treat” dropped from 3.9 with clinical examination to 3.0 with dermoscopy to 1.3 with RCM.
Development and Preliminary Validation of a Screener for Digital Health Readiness
Authors: Kristin L. Rising, Amanda Guth, Alexzandra T. Gentsch, Karla Martin Gonzalez, Richard Hass, Lindsey Shughart, Serena Gelfer, Megan McVane, Brooke Worster, Amy E. Leader
Journal: JAMA Network Open (2024)

Importance While telehealth use has grown, patient uptake is variable, which has the potential to increase health disparities. Identifying and understanding individuals’ barriers to digital health readiness can help health systems efficiently deploy resources to provide personalized patient-centered support. Objective To develop and validate an instrument to evaluate digital health readiness to identify and quantify barriers to digital readiness. Design, Setting, and Participants In this qualitative mixed-methods study conducted from April 26, 2022, to June 8, 2023, the instrument was created in 4 phases. Patients and health care professionals were interviewed to explore barriers to telehealth use, scale items were developed for the screener, cognitive interviews were conducted to refine scale items, and psychometric properties of the screener were evaluated. The study was conducted in an urban, multisite academic health system and the surrounding community. Participants were older than 18 years, English-speaking, and able to provide informed consent. Professionals worked within the Jefferson Health system and were involved in telehealth services. Exposure Participants completed a semistructured interview (duration: 6-19 minutes), a cognitive interview (duration: 13-137 minutes), or the draft screener survey (duration: 5-10 minutes). Main Outcomes and Measures Development and validation of a screener for digital health readiness. Results Of 519 patients approached, 19 were ineligible, 122 declined, and 11 were excluded from analysis, resulting in inclusion of 367 participants (32 patient interviews, 16 professional interviews, 15 cognitive interviews, 304 psychometric survey testing). All 16 professionals who were approached participated. Most patient participants were Black (46.7%) or White (37.9%), male (56.4%), and had a high school degree or some college (49.6%); mean (SD) age was 45 (23) years for participants in cognitive interviews, 53 (18) years for survey respondents, and 57 (14) years for patient interviews. The structured interviews uncovered 21 concepts, leading to 48 items that were refined through cognitive interviews. Psychometric analyses of the 29 items that emerged from the cognitive interviews resulted in a final screener with 24 items across 2 factors: technical readiness (18 items; factor loading range, 0.488-0.968) and quality-of-care concerns (6 items; factor loading range, 0.619-0.942). Conclusions and Relevance In this qualitative study of digital health readiness, the findings suggest that the screener items may be valid to assess the complexity of factors influencing digital health uptake and highlight several areas for potential intervention.
Selection Bias in Reporting of Median Waiting Times in Organ Transplantation
Authors: Simon Schwab, Andreas Elmer, Daniel Sidler, Lisa Straumann, Ueli Stürzinger, Franz Immer
Journal: JAMA Network Open (2024)

Importance Median organ waiting times published by transplant organizations may be biased when not appropriately accounting for censoring, death, and competing events. This can lead to overly optimistic waiting times for all transplant programs and, consequently, may deceive patients on the waiting list, transplant physicians, and health care policymakers. Objective To apply competing-risk multistate models to calculate probabilities for transplantation and adverse outcomes on the Swiss national transplant waiting list. Design, Setting, and Participants The WAIT (Waitlist Analysis in Transplantation) study was a retrospective cohort study of all transplant candidates in Switzerland listed from January 1, 2018, or later and observed until December 31, 2023. Transplant candidates were listed in 1 of the 6 transplant centers (Basel, Bern, Geneva, Lausanne, St Gallen, and Zurich) for heart, liver, lungs, kidney, or pancreas and/or islet transplant. A total of 4352 candidates were listed during the study period, of whom 709 (16.3%) were excluded due to living-donor transplant (691 in the kidney program and 18 in the liver program). Exposure Waiting for organ transplant. Main Outcomes and Measures Time to transplantation, death, or delisting. Competing-risk multistate models were used to analyze time-to-event data from the national organ waiting list with the Aalen-Johansen estimator to compute probabilities for both transplant and adverse outcomes. Results were compared with the sample median among only those undergoing transplant and the Kaplan-Meier method with censoring of competing events. Results Data from 3643 transplant candidates (2428 [66.6%] male; median age, 56 [range, 0-79] years) were included in the analysis. The median time to transplantation (MTT) was 0.91 (95% CI, 0.83-1.07) years for heart, 3.10 (95% CI, 2.57-3.77) years for kidney, 1.32 (95% CI, 0.76-1.55) years for liver, 0.80 (95% CI, 0.37-1.12) years for lung, and 1.62 (95% CI, 0.91-2.17) years for pancreas and/or islet programs. Alternative estimation methods introduced bias to varying degrees: the sample median among only persons undergoing transplantation underestimated the waiting time by 38% to 61% and the Kaplan-Meier method by 2% to 12% compared with the MTT. Conclusions and Relevance In this cohort study of transplant candidates in Switzerland, the MTT, the duration at which the transplant probability is 0.50, was used as a measure of average waiting time. Suboptimal methods led to biased and overly optimistic waiting time estimations; thus, applying appropriate competing-risk methods to address censoring and competing events is crucial.
Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma
Authors: Divya Nagarajan, Rebeca T Parracho, David Corujo, Minglu Xie, Ginte Kutkaite, Thale K Olsen, Marta Rúbies Bedós, Maede Salehi, Ninib Baryawno, Michael P Menden, Xingqi Chen, Marcus Buschbeck, Yumeng Mao
Journal: Journal of Clinical Investigation (2024)

Childhood neuroblastoma with MYCN-amplification is classified as high-risk and often relapses after intensive treatments. Immune checkpoint blockade therapy against the PD-1/L1 axis shows limited efficacy in neuroblastoma patients and the cancer intrinsic immune regulatory network is poorly understood. Here, we leverage genome-wide CRISPR/Cas9 screens and identify H2AFY as a resistance gene to the clinically approved PD-1 blocking antibody, nivolumab. Analysis of single-cell RNA sequencing datasets reveals that H2AFY mRNA is enriched in adrenergic cancer cells and is associated with worse patient survival. Genetic deletion of H2afy in MYCN-driven neuroblastoma cells reverts in vivo resistance to PD-1 blockade by eliciting activation of the adaptive and innate immunity. Mapping of the epigenetic and translational landscape demonstrates that H2afy deletion promotes cell transition to a mesenchymal-like state. With a multi-omics approach, we uncover H2AFY-associated genes that are functionally relevant and prognostic in patients. Altogether, our study elucidates the role of H2AFY as an epigenetic gatekeeper for cell states and immunogenicity in high-risk neuroblastoma.
Homelessness and Risk of End-Stage Kidney Disease and Death in Veterans With Chronic Kidney Disease
Authors: Alain K. Koyama, Robert Nee, Wei Yu, Devasmita Choudhury, Fei Heng, Alfred K. Cheung, Monique E. Cho, Keith C. Norris, Guofen Yan
Journal: JAMA Network Open (2024)

Importance Adults experiencing homelessness in the US face numerous challenges, including the management of chronic kidney disease (CKD). The extent of a potentially greater risk of adverse health outcomes in the population with CKD experiencing homelessness has not been adequately explored. Objective To evaluate the association between a history of homelessness and the risk of end-stage kidney disease (ESKD) and death among veterans with incident CKD. Design, Setting, and Participants This retrospective cohort study was conducted between January 1, 2005, and December 31, 2017. Participants included veterans aged 18 years and older with incident stage 3 to 5 CKD utilizing the Veterans Health Administration health care network in the US. Patients were followed-up through December 31, 2018, for the occurrence of ESKD and death. Analyses were performed from September 2022 to October 2023. Exposure History of homelessness, based on utilization of homeless services in the Veterans Health Administration or International Classification of Diseases, Ninth Revision or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. Homelessness was measured during the 2-year baseline period prior to the index date of incident CKD. Main Outcomes and Measures The primary outcomes were ESKD, based on initiation of kidney replacement therapy, and all-cause death. Adjusted hazard ratios (HRs) were calculated to compare veterans with a history of homelessness with those without a history of homelessness. Results Among 836 361 veterans, the largest proportion were aged 65 to 74 years (274 371 veterans [32.8%]) or 75 to 84 years (270 890 veterans [32.4%]), and 809 584 (96.8%) were male. A total of 26 037 veterans (3.1%) developed ESKD, and 359 991 (43.0%) died. Compared with veterans who had not experienced homelessness, those with a history of homelessness showed a significantly greater risk of ESKD (adjusted HR, 1.15; 95% CI, 1.10-1.20). A greater risk of all-cause death was also observed (HR, 1.48; 95% CI, 1.46-1.50). After further adjustment for body mass index, comorbidities, and medication use, results were attenuated for all-cause death (HR, 1.09; 95% CI, 1.07-1.11) and were no longer significant for ESKD (HR, 1.04; 95% CI, 0.99-1.09). Conclusions and Relevance In this cohort study of veterans with incident stage 3 to 5 CKD, a history of homelessness was significantly associated with a greater risk of ESKD and death, underscoring the role of housing as a social determinant of health.
Author Correction: Priming with FLO8-deficient Candida albicans induces Th1-biased protective immunity against lethal polymicrobial sepsis
Authors: Quan-Zhen Lv, De-Dong Li, Hua Han, Yi-Heng Yang, Jie-Lin Duan, Hui-Hui Ma, Yao Yu, Jiang-Ye Chen, Yuan-Ying Jiang, Xin-Ming Jia
Journal: Cellular and Molecular Immunology (2024)
High-intensity interval training for cardiometabolic health in adults with metabolic syndrome: a systematic review and meta-analysis of randomised controlled trials
Authors: Eric Tsz-Chun Poon, Waris Wongpipit, Hong-Yat Li, Stephen Heung-Sang Wong, Parco M Siu, Alice Pik-Shan Kong, Nathan A Johnson
Journal: British Journal of Sports Medicine (2024)

Objective To assess the effectiveness of high-intensity interval training (HIIT) compared with traditional moderate-intensity continuous training (MICT) and/or non-exercise control (CON) for modification of metabolic syndrome (MetS) components and other cardiometabolic health outcomes in individuals with MetS. Design Systematic review and meta-analysis Data sources Five databases were searched from inception to March 2024. Study appraisal and synthesis Meta-analyses of randomised controlled trials (RCTs) comparing HIIT with MICT/CON were performed for components of MetS (waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and fasting blood glucose (BG)) and clinically relevant cardiometabolic health parameters. Subgroup moderator analyses were conducted based on the intervention duration and HIIT volume. Results Out of 4819 studies, 23 RCTs involving 1374 participants were included (mean age: 46.2–67.0 years, 55% male). HIIT significantly improved WC (weighted mean difference (WMD) –4.12 cm, 95% CI –4.71 to –3.53), SBP (WMD –6.05 mm Hg, 95% CI –8.11 to –4.00), DBP (WMD –3.68 mm Hg, 95% CI –5.70 to –1.65), HDL-C (WMD 0.12 mmol/L, 95% CI 0.04 to 0.20), TG (WMD –0.34 mmol/L, 95% CI –0.41 to –0.27) and BG (WMD –0.35 mmol/L, 95% CI –0.54 to –0.16) compared with CON (all p&lt;0.01). HIIT approaches demonstrated comparable effects to MICT across all parameters. Subgroup analyses suggested that HIIT protocols with low volume (ie, &lt;15 min of high-intensity exercise per session) were not inferior to higher volume protocols for improving MetS components. Conclusion This review supports HIIT as an efficacious exercise strategy for improving cardiometabolic health in individuals with MetS. Low-volume HIIT appears to be a viable alternative to traditional forms of aerobic exercise.