tbuckley/cabot-search huggingface dataset:
Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation
Authors: Nathalie Niyonzima, Jubayer Rahman, Natalia Kunz, Erin E. West, Tilo Freiwald, Jigar V. Desai, Nicolas S. Merle, Alexandre Gidon, Bjørnar Sporsheim, Michail S. Lionakis, Kristin Evensen, Beate Lindberg, Karolina Skagen, Mona Skjelland, Parul Singh, Markus Haug, Marieta M. Ruseva, Martin Kolev, Jack Bibby, Olivia Marshall, Brett O’Brien, Nigel Deeks, Behdad Afzali, Richard J. Clark, Trent M. Woodruff, Milton Pryor, Zhi-Hong Yang, Alan T. Remaley, Tom E. Mollnes, Stephen M. Hewitt, Bingyu Yan, Majid Kazemian, Máté G. Kiss, Christoph J. Binder, Bente Halvorsen, Terje Espevik, Claudia Kemper
Journal: Science Immunology (2021)

While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the “complosome,” functions as a vital orchestrator of cell-metabolic events underlying T cell effector responses. Whether intracellular complement is also nonredundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and generate autocrine C5a via formation of an intracellular C5 convertase. Cholesterol crystal sensing by macrophages induced C5aR1 signaling on mitochondrial membranes, which shifted ATP production via reverse electron chain flux toward reactive oxygen species generation and anaerobic glycolysis to favor IL-1β production, both at the transcriptional level and processing of pro–IL-1β. Consequently, atherosclerosis-prone mice lacking macrophage-specific C5ar1 had ameliorated cardiovascular disease on a high-cholesterol diet. Conversely, inflammatory gene signatures and IL-1β produced by cells in unstable atherosclerotic plaques of patients were normalized by a specific cell-permeable C5aR1 antagonist. Deficiency of the macrophage cell-autonomous C5 system also protected mice from crystal nephropathy mediated by folic acid. These data demonstrate the unexpected intracellular formation of a C5 convertase and identify C5aR1 as a direct modulator of mitochondrial function and inflammatory output from myeloid cells. Together, these findings suggest that the complosome is a contributor to the biologic processes underlying sterile inflammation and indicate that targeting this system could be beneficial in macrophage-dependent diseases, such as atherosclerosis.
Screen Use and Mental Health Symptoms in Canadian Children and Youth During the COVID-19 Pandemic
Authors: Xuedi Li, Leigh M. Vanderloo, Charles D. G. Keown-Stoneman, Katherine Tombeau Cost, Alice Charach, Jonathon L. Maguire, Suneeta Monga, Jennifer Crosbie, Christie Burton, Evdokia Anagnostou, Stelios Georgiades, Rob Nicolson, Elizabeth Kelley, Muhammad Ayub, Daphne J. Korczak, Catherine S. Birken
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Longitudinal research on specific forms of electronic screen use and mental health symptoms in children and youth during COVID-19 is minimal. Understanding the association may help develop policies and interventions targeting specific screen activities to promote healthful screen use and mental health in children and youth. <h3>Objective</h3> To determine whether specific forms of screen use (television [TV] or digital media, video games, electronic learning, and video-chatting time) were associated with symptoms of depression, anxiety, conduct problems, irritability, hyperactivity, and inattention in children and youth during COVID-19. <h3>Design, Setting, and Participants</h3> A longitudinal cohort study with repeated measures of exposures and outcomes was conducted in children and youth aged 2 to 18 years in Ontario, Canada, between May 2020 and April 2021 across 4 cohorts of children or youth: 2 community cohorts and 2 clinically referred cohorts. Parents were asked to complete repeated questionnaires about their children’s health behaviors and mental health symptoms during COVID-19. <h3>Main Outcomes and Measures</h3> The exposure variables were children’s daily TV or digital media time, video game time, electronic-learning time, and video-chatting time. The mental health outcomes were parent-reported symptoms of child depression, anxiety, conduct problems and irritability, and hyperactivity/inattention using validated standardized tools. <h3>Results</h3> This study included 2026 children with 6648 observations. In younger children (mean [SD] age, 5.9 [2.5] years; 275 male participants [51.7%]), higher TV or digital media time was associated with higher levels of conduct problems (age 2-4 years: β, 0.22 [95% CI, 0.10-0.35];<i>P</i> &lt; .001; age ≥4 years: β, 0.07 [95% CI, 0.02-0.11];<i>P</i> = .007) and hyperactivity/inattention (β, 0.07 [95% CI, 0.006-0.14];<i>P</i> = .04). In older children and youth (mean [SD] age, 11.3 [3.3] years; 844 male participants [56.5%]), higher levels of TV or digital media time were associated with higher levels of depression, anxiety, and inattention; higher levels of video game time were associated with higher levels of depression, irritability, inattention, and hyperactivity. Higher levels of electronic learning time were associated with higher levels of depression and anxiety. <h3>Conclusions and Relevance</h3> In this cohort study, higher levels of screen use were associated poor mental health of children and youth during the COVID-19 pandemic. These findings suggest that policy intervention as well as evidence-informed social supports are needed to promote healthful screen use and mental health in children and youth during the pandemic and beyond.
FOXO1 Dependent Transcription Network Is a Targetable Vulnerability of Mantle Cell Lymphoma
Authors: Ja-Young Jang, Inah Hwang, Heng Pan, Michael Kluk, Jun Yao, Xiangao Huang, Maurizio Di Liberto, Zhengming Chen, Karla V Ballman, Lewis C Cantley, Giorgio Inghirami, Olivier Elemento, Robert Baiocchi, Selina Chen-Kiang, Sandro Belvedere, Hongwu Zheng, Jihye Paik
Journal: Blood (2021)
Abstract 12127: The Effect of Daylight Savings Time Transitions on the Incidence of Out-of-Hospital Cardiac Arrest: An Interrupted Time Series Analysis
Authors: Jack Hook, Karen L Smith, Emily Andrew, Jocasta Ball, Ziad Nehme
Journal: Circulation (2021)

Introduction: Many studies have reported increases in the risk of acute cardiovascular events following daylight savings time (DST) transitions. We sought to investigate the effect of DST transitions on the incidence of out-of-hospital cardiac arrest (OHCA) in Victoria, Australia. Methods: Between January 2000 and December 2020, we performed an interrupted time series analysis of the daily number of OHCA cases of medical etiology from the Victorian Ambulance Cardiac Arrest Registry. The effect of DST transition on OHCA incidence was estimated using negative binomial models and reported as either ‘immediate’ or ‘cumulative’ effects. Immediate effects were the average effects observed on the day of DST transition or each of the 6 days after DST transition. Cumulative effects were the sum of the average effects up to 6 days after the day of DST transition. Models were adjusted for population growth, temporal trends, and public holidays. Results: A total of 89,409 adult OHCA of medical etiology were included. Following the spring DST transition (i.e. shorter day), there was an immediate 13% (IRR 1.13, 95% CI: 1.02, 1.25; p=0.02) increased risk of OHCA on the day of transition (Sunday) and the cumulative risk of OHCA remained higher over the first 2 days (IRR 1.17, 95% CI: 1.02, 1.34; p=0.03) compared to non-transitional days. Following the autumn (fall) DST transition (i.e. longer day), there was a significant lagged effect on the Tuesday following transition, with a 12% (IRR 0.88, 95% CI: 0.77, 0.99; p=0.04) reduced risk of OHCA. The autumn (fall) DST transition also showed a cumulative effect on OHCA incidence, with a 30% (IRR 0.70, 95% CI: 0.51, 0.96; p=0.03) reduction in the incidence of OHCA by the end of the transitional week. Subgroups aged &gt; 65 years and cases with initial non-shockable rhythms were most vulnerable to DST transitions. Conclusions: This study showed that there is a modest increased risk of OHCA in the 2 days following the spring DST transition and a decreased risk of OHCA in the week following the autumn DST transition. These findings should promote further research exploring strategies to reduce the risk of OHCA in vulnerable populations.
Role of cholangioscopy and therapeutic options in complex anastomotic strictures after liver transplantation
Authors: Mateus Pereira Funari, Bruno Salomão Hirsch, Tomazo Prince Franzini, Diogo Turiani Hourneaux de Moura, Antonio Afonso Miranda Neto, Thomas R. McCarty, Eduardo Guimarães Hourneaux de Moura
Journal: Endoscopy (2021)

Biliary strictures are among the most frequent complications following liver transplantation [1] [2]. Endoscopic treatment remains challenging; however, cholangioscopy may be an underutilized technique to improve outcomes for complex cases.
Association of Antiparietal Cell and Anti-Intrinsic Factor Antibodies With Risk of Gastric Cancer
Authors: Minkyo Song, M. Constanza Camargo, Hormuzd A. Katki, Stephanie J. Weinstein, Satu Männistö, Demetrius Albanes, Heljä-Marja Surcel, Charles S. Rabkin
Journal: JAMA Oncology (2021)

Autoimmune gastritis is an alternative cause of gastric carcinogenesis. This cause may be gaining importance with declining prevalence of chronic Helicobacter pylori infection.To determine the association of prediagnostic autoantibodies to gastric mucosa with gastric cancer (GC) risk.This cohort study used nested GC case-control analyses within separate Finnish cohorts of women of reproductive age (Finnish Maternity Cohort [FMC]; born 1938-1989) and older men (Alpha-Tocopherol, Beta-Carotene Cancer Prevention [ATBC] Study; born 1916-1939). There were 529 and 457 matched pairs from the FMC and ATBC Study, respectively, with mean participant ages of 30.5 and 57.5 years and medians of 17 and 11 years from baseline to cancer diagnosis. Data analyses were performed between August 2019 and November 2020.Antiparietal cell antibodies (APCAs), anti-intrinsic factor antibodies, and anti-H pylori antibodies were measured in baseline serum using immunoassays.Autoantibody associations were estimated by odds ratios (ORs) and 95% CIs.Of the 529 control participants in the FMC and 457 control participants in the ATBC Study, 53 (10%) women and 35 (7.7%) men were APCA seropositive, respectively, whereas 146 (28%) women and 329 (72%) men were H pylori seropositive. In the FMC, APCA seropositivity was statistically significantly associated with GC risk among H pylori-seronegative women (OR, 5.52; 95% CI, 3.16-9.64) but not H pylori-seropositive women (OR, 1.29; 95% CI, 0.64-2.60; P for interaction = .002). The APCA association with H pylori seronegativity was strongest for tumors in the fundus and corpus (OR, 24.84; 95% CI, 8.49-72.72). In the ATBC Study, APCA seropositivity was not associated with GC among either H pylori-seronegative men (OR, 0.99; 95% CI, 0.32-3.04) or H pylori-seropositive men (OR, 1.06; 95% CI, 0.60-1.88). In both cohorts, anti-intrinsic factor antibody seroprevalence was less than 2% among cases as well as controls and not statistically associated with GC risk.Results of this cohort study demonstrate that autoantibody positivity may reflect subclinical autoimmune gastritis in younger women. The findings among young females and corpus subsite align with increasing cancer incidence trends for these groups. Stronger autoimmune associations in H pylori-seronegative individuals support a model of autoimmune gastritis replacing H pylori as the driving factor.
Supplementing Dietary Fibers With a Low FODMAP Diet in Irritable Bowel Syndrome: A Randomized Controlled Crossover Trial
Authors: Daniel So, Chu K Yao, Zaid S Ardalan, Phoebe A Thwaites, Kourosh Kalantar-Zadeh, Peter R Gibson, Jane G Muir
Journal: Clinical Gastroenterology and Hepatology (2021)
Same-session salvage endoscopic submucosal dissection for an incompletely resected rectal neuroendocrine tumor
Authors: Vishal Garimella, Vinay Chandrasekhara
Journal: Endoscopy (2021)

A 61-year-old gentleman was referred for a rectal subepithelial lesion identified incidentally during screening colonoscopy. Lower endoscopic ultrasound demonstrated a 10-mm submucosal lesion 5 mm in thickness with well-defined borders not invading the muscularis propria ([Fig. 1]). Endoscopic mucosal resection (EMR) was performed with adequate submucosal lift ([Fig. 2]); however, hot snare resection transected the lesion with obvious residual yellow tissue within the submucosa ([Fig. 3]).
Tracking the Emergence of SARS-CoV-2 Alpha Variant in the United Kingdom
Authors: A Sarah Walker, Karina-Doris Vihta, Owen Gethings, Emma Pritchard, Joel Jones, Thomas House, Iain Bell, John I Bell, John N Newton, Jeremy Farrar, Ian Diamond, Ruth Studley, Emma Rourke, Jodie Hay, Susan Hopkins, Derrick Crook, Tim Peto, Philippa C Matthews, David W Eyre, Nicole Stoesser, Koen B Pouwels
Journal: New England Journal of Medicine (2021)
11. Chronic Kidney Disease and Risk Management: <i>Standards of Medical Care in Diabetes—2022</i>
Journal: Diabetes Care (2021)

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
SARS-CoV-2 B.1.1.529 (Omicron) Variant — United States, December 1–8, 2021
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

A new variant of SARS-CoV-2 (the virus that causes COVID-19), B.1.1.529 (Omicron) (1), was first reported to the World Health Organization (WHO) by South Africa on November 24, 2021. Omicron has numerous mutations with potential to increase transmissibility, confer resistance to therapeutics, or partially escape infection- or vaccine-induced immunity (2). On November 26, WHO designated B.1.1.529 as a variant of concern (3), as did the U.S. SARS-CoV-2 Interagency Group (SIG)* on November 30. On December 1, the first case of COVID-19 attributed to the Omicron variant was reported in the United States. As of December 8, a total of 22 states had identified at least one Omicron variant case, including some that indicate community transmission. Among 43 cases with initial follow-up, one hospitalization and no deaths were reported. This report summarizes U.S. surveillance for SARS-CoV-2 variants, characteristics of the initial persons investigated with COVID-19 attributed to the Omicron variant and public health measures implemented to slow the spread of Omicron in the United States. Implementation of concurrent prevention strategies, including vaccination, masking, increasing ventilation, testing, quarantine, and isolation, are recommended to slow transmission of SARS-CoV-2, including variants such as Omicron, and to protect against severe illness and death from COVID-19.
Outcomes Associated With Caustic Ingestion Among Adults in a National Prospective Database in France
Authors: Alexandre Challine, Léon Maggiori, Sandrine Katsahian, Hélène Corté, Diane Goere, Andrea Lazzati, Pierre Cattan, Mircea Chirica
Journal: JAMA Surgery (2021)

<h3>Importance</h3> Caustic ingestion in adults may result in death or severe digestive sequelae. The scarcity of nationwide epidemiological data leads to difficulties regarding the applicability of their analysis to less specialized centers, which are nevertheless largely involved in the emergency management of adverse outcomes following caustic ingestion. <h3>Objective</h3> To assess outcomes associated with caustic ingestion in adults across a nationwide prospective database. <h3>Design, Settings, and Participants</h3> Adult patients aged 16 to 96 admitted to the emergency department for caustic ingestion between January 2010 and December 2019 were identified from the French Medical Information System Database, which includes all patients admitted in an emergency setting in hospitals in France during this period. <h3>Exposure</h3> Esophageal caustic ingestion. <h3>Main Outcomes and Measures</h3> The primary end point was in-hospital patient outcomes following caustic ingestion. Multivariate analysis was performed to assess independent predictors of in-hospital morbidity and mortality. <h3>Results</h3> Among 22 657 226 patients admitted on an emergency outpatient basis, 3544 (0.016%) had ingested caustic agents and were included in this study. The median (IQR) age in this population was 49 (34-63) years, and 1685 patients (48%) were women. Digestive necrosis requiring resection was present during the primary hospital stay in 388 patients with caustic ingestion (11%). Nonsurgical management was undertaken in 3156 (89%). A total of 1198 (34%) experienced complications, and 294 (8%) died. Pulmonary complications were the most frequent adverse event, occurring in 869 patients (24%). On multivariate analysis, predictors of mortality included old age, high comorbidity score, suicidal ingestion, intensive care unit admission during management, emergency surgery for digestive necrosis, and treatment in low-volume centers. On multivariate analysis, predictors of morbidity included old age, higher comorbidity score, intensive care unit admission during management, and emergency surgery for digestive necrosis. <h3>Conclusions and Relevance</h3> In this study, referral to expert centers was associated with improved early survival after caustic ingestion. If feasible, low-volume hospitals should consider transferring patients to larger centers instead of attempting on-site management.
Characterizing and exploiting the many roles of aberrant H2B monoubiquitination in cancer pathogenesis
Authors: Lucile M. Jeusset, Kirk J. McManus
Journal: Seminars in Cancer Biology (2021)

Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is implicated in the control of multiple essential processes, including transcription, DNA damage repair and mitotic chromosome segregation. Accordingly, aberrant regulation of H2Bub1 can induce transcriptional reprogramming and genome instability that may promote oncogenesis. Remarkably, alterations of the ubiquitin ligases and deubiquitinating enzymes regulating H2Bub1 are emerging as ubiquitous features in cancer, further supporting the possibility that the misregulation of H2Bub1 is an underlying mechanism contributing to cancer pathogenesis. To date, aberrant H2Bub1 dynamics have been reported in multiple cancer types and are associated with transcriptional changes that promote oncogenesis in a cancer type-specific manner. Owing to the multi-functional nature of H2Bub1, misregulation of its writers and erasers may drive disease initiation and progression through additional synergistic processes. Accordingly, understanding the molecular determinants and pathogenic impacts associated with aberrant H2Bub1 regulation may reveal novel drug targets and therapeutic vulnerabilities that can be exploited to develop innovative precision medicine strategies that better combat cancer. In this review, we present the normal functions of H2Bub1 in the control of DNA-associated processes and describe the pathogenic implications associated with its misregulation in cancer. We further discuss the challenges coupled with the development of therapeutic strategies targeting H2Bub1 misregulation and expose the potential benefits of designing treatments that synergistically exploit the multiple functionalities of H2Bub1 to improve treatment selectivity and efficacy.
PET imaging to assess the impact of P-glycoprotein on pulmonary drug delivery in rats
Authors: Irene Hernández-Lozano, Severin Mairinger, Thomas Filip, Michael Sauberer, Thomas Wanek, Johann Stanek, Johannes A. Sake, Thomas Pekar, Carsten Ehrhardt, Oliver Langer
Journal: Journal of Controlled Release (2021)

Several drugs approved for inhalation for the treatment of pulmonary diseases are substrates of the adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (P-gp). P-gp is expressed in the apical membrane of pulmonary epithelial cells and could play a role in modulating the pulmonary absorption and distribution of inhaled drugs, thereby potentially contributing to variability in therapeutic response and/or systemic side effects. We developed a new in vivo experimental approach to assess the functional impact of P-gp on the pulmonary delivery of inhaled drugs in rats. By using positron emission tomography (PET) imaging, we measured the intrapulmonary pharmacokinetics of the model P-gp substrates (R)-[11C]verapamil ([11C]VPM) and [11C]-N-desmethyl-loperamide ([11C]dLOP) administered by intratracheal aerosolization in three rat groups: wild-type, Abcb1a/b(−/−) and wild-type treated with the P-gp inhibitor tariquidar. Lung exposure (AUClung_right) to [11C]VPM was 64% and 50% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b(−/−) rats, respectively, compared to untreated wild-type rats. For [11C]dLOP, AUClung_right was 59% and 34% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b(−/−) rats, respectively. Our results show that P-gp can affect the pulmonary disposition of inhaled P-gp substrates, whereby a decrease in P-gp activity may lead to lower lung exposure and potentially to a decrease in therapeutic efficacy. Our study highlights the potential of PET imaging with intratracheally aerosolized radiotracers to assess the impact of membrane transporters on pulmonary drug delivery, in rodents and potentially also in humans.