tbuckley/cabot-search huggingface dataset:
Mutations disrupting neuritogenesis genes confer risk for cerebral palsy
Authors: Sheng Chih Jin, Sara A. Lewis, Somayeh Bakhtiari, Xue Zeng, Michael C. Sierant, Sheetal Shetty, Sandra M. Nordlie, Aureliane Elie, Mark A. Corbett, Bethany Y. Norton, Clare L. van Eyk, Shozeb Haider, Brandon S. Guida, Helen Magee, James Liu, Stephen Pastore, John B. Vincent, Janice Brunstrom-Hernandez, Antigone Papavasileiou, Michael C. Fahey, Jesia G. Berry, Kelly Harper, Chongchen Zhou, Junhui Zhang, Boyang Li, Hongyu Zhao, Jennifer Heim, Dani L. Webber, Mahalia S. B. Frank, Lei Xia, Yiran Xu, Dengna Zhu, Bohao Zhang, Amar H. Sheth, James R. Knight, Christopher Castaldi, Irina R. Tikhonova, Francesc López-Giráldez, Boris Keren, Sandra Whalen, Julien Buratti, Diane Doummar, Megan Cho, Kyle Retterer, Francisca Millan, Yangong Wang, Jeff L. Waugh, Lance Rodan, Julie S. Cohen, Ali Fatemi, Angela E. Lin, John P. Phillips, Timothy Feyma, Suzanna C. MacLennan, Spencer Vaughan, Kylie E. Crompton, Susan M. Reid, Dinah S. Reddihough, Qing Shang, Chao Gao, Iona Novak, Nadia Badawi, Yana A. Wilson, Sarah J. McIntyre, Shrikant M. Mane, Xiaoyang Wang, David J. Amor, Daniela C. Zarnescu, Qiongshi Lu, Qinghe Xing, Changlian Zhu, Kaya Bilguvar, Sergio Padilla-Lopez, Richard P. Lifton, Jozef Gecz, Alastair H. MacLennan, Michael C. Kruer
Journal: Nature Genetics (2020)
Association Between Lipoprotein Particles and Atherosclerotic Events in Nonalcoholic Fatty Liver Disease
Authors: Samarth Patel, Mohammad Bilal Siddiqui, Jose Hernandez Roman, Emily Zhang, Emily Lee, Steve Shen, Masoud Faridnia, Robert J. Mintini, Sherry Boyett, Michael O. Idowu, Arun J. Sanyal, Velimir A. Luketic, Mohammad Shadab Siddiqui
Journal: Clinical Gastroenterology and Hepatology (2020)
Toll-like receptors revisited; a possible role for TLR1 in lupus nephritis
Authors: Sule Yavuz, Matteo Bianchi, Sergey Kozyrev, Karin Bolin, Dag Leonard, Pascal Pucholt, Johanna K Sandling, Anders Bengtsson, Andreas Jönsen, Solbritt Rantapää-Dahlqvist, Christopher Sjöwall, Elisabet Svenungsson, Iva Gunnarsson, Kerstin Lindblad-Toh, Lars Rönnblom
Journal: Annals of the Rheumatic Diseases (2020)

Toll-like receptors revisited; a possible role for TLR1 in lupus nephritisSeveral studies in systemic lupus erythematosus (SLE) have shown a possible role of endosomal toll-like receptors (TLRs) in lupus nephritis (LN), but the role of those interacting with ligands in the plasma membrane remains unclear. 1 Herein, we revisit the genetic contribution of TLRs in SLE inspired by a patient with LN who carries a rare TLR1 variant.We analysed coding and regulatory regions of the TLR1-10 genes in 855 patients with SLE (online supplemental data 1).Six variants (rs142003616, rs76600635, rs72493538, rs41305843, rs113706342, rs41311400) within TLR1, one (rs10006364) within TLR2, one (rs79088436) within TLR5 and two (rs55695972, rs117985012) within TLR6 were significantly enriched in LN but only rs142003616 (TLR1) remained significant after Bonferroni correction (p<0.039,online supplemental table 1).To assess its biological significance, we employed in-silico functional annotation.The calculated deleteriousness score, CADD PHRED, for rs142003616 (5.56) points at the variant's potential functional importance.The rare risk allele is predicted to create a strong binding site for the core binding factor (CBF). 2 CBF, also known as runt-related transcription factors (RUNX), are also associated with SLE, psoriasis and rheumatoid arthritis. 3To evaluate rs142003616 functional potential, we lastly performed a reporter assay that demonstrated a significantly higher expression of the reporter with the G allele in Jurkat (p<0.0001) and Daudi cells (p<0.001), and a strong enhancer potential without allelic difference in THP-1 (figure 1).Of interest, despite the higher prevalence of proliferative LN overall (215 of 292 LN, 75%), it was less associated with rs142003616 in comparison to membranous LN (p=0.047,Fisher's exact test).Table 1 summarises the characteristics of patients with LN carrying the minor allele of rs142003616.One of them was a 39-year-old woman (#6 table 1) admitted on July 17, 2023 by guest.
European Respiratory Society statement on sleep apnoea, sleepiness and driving risk
Authors: Maria R. Bonsignore, Winfried Randerath, Sofia Schiza, Johan Verbraecken, Mark W. Elliott, Renata Riha, Ferran Barbe, Izolde Bouloukaki, Alessandra Castrogiovanni, Oana Deleanu, Marta Goncalves, Damien Leger, Oreste Marrone, Thomas Penzel, Silke Ryan, Dan Smyth, Joaquin Teran-Santos, Cecilia Turino, Walter T. McNicholas
Journal: European Respiratory Journal (2020)

Obstructive sleep apnoea (OSA) is highly prevalent and is a recognised risk factor for motor vehicle accidents (MVA). Effective treatment with continuous positive airway pressure has been associated with a normalisation of this increased accident risk. Thus, many jurisdictions have introduced regulations restricting the ability of OSA patients from driving until effectively treated. However, uncertainty prevails regarding the relative importance of OSA severity determined by the apnoea–hypopnoea frequency per hour and the degree of sleepiness in determining accident risk. Furthermore, the identification of subjects at risk of OSA and/or accident risk remains elusive. The introduction of official European regulations regarding fitness to drive prompted the European Respiratory Society to establish a task force to address the topic of sleep apnoea, sleepiness and driving with a view to providing an overview to clinicians involved in treating patients with the disorder. The present report evaluates the epidemiology of MVA in patients with OSA; the mechanisms involved in this association; the role of screening questionnaires, driving simulators and other techniques to evaluate sleepiness and/or impaired vigilance; the impact of treatment on MVA risk in affected drivers; and highlights the evidence gaps regarding the identification of OSA patients at risk of MVA.
Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors
Authors: Lulu Wang, Lin Yang, Chen Wang, Wei Zhao, Zhenlin Ju, Wei Zhang, Jianfeng Shen, Yang Peng, Clemens An, Yen T. Luu, Shumei Song, Timothy A. Yap, Jaffer A. Ajani, Gordon B. Mills, Xuetong Shen, Guang Peng
Journal: Journal of Clinical Investigation (2020)

ARID1A, a component of the chromatin-remodeling complex SWI/SNF, is one of the most frequently mutated genes in human cancer. We sought to develop rational combination therapy to potentiate the efficacy of immune checkpoint blockade in ARID1A-deficient tumors. In a proteomic analysis of a data set from The Cancer Genomic Atlas, we found enhanced expression of Chk2, a DNA damage checkpoint kinase, in ARID1A-mutated/deficient tumors. Surprisingly, we found that ARID1A targets the nonchromatin substrate Chk2 for ubiquitination. Loss of ARID1A increased the Chk2 level through modulating autoubiquitination of the E3-ligase RNF8 and thereby reducing RNF8-mediated Chk2 degradation. Inhibition of the ATM/Chk2 DNA damage checkpoint axis led to replication stress and accumulation of cytosolic DNA, which subsequently activated the DNA sensor STING-mediated innate immune response in ARID1A-deficient tumors. As expected, tumors with mutation or low expression of both ARID1A and ATM/Chk2 exhibited increased tumor-infiltrating lymphocytes and were associated with longer patient survival. Notably, an ATM inhibitor selectively potentiated the efficacy of immune checkpoint blockade in ARID1A-depleted tumors but not in WT tumors. Together, these results suggest that ARID1A’s targeting of the nonchromatin substrate Chk2 for ubiquitination makes it possible to selectively modulate cancer cell–intrinsic innate immunity to enhance the antitumor activity of immune checkpoint blockade.
Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority trial
Authors: Willem D F Venter, Simiso Sokhela, Bryony Simmons, Michelle Moorhouse, Lee Fairlie, Nkuli Mashabane, Celicia Serenata, Godspower Akpomiemie, Masebole Masenya, Ambar Qavi, Nomathemba Chandiwana, Kaitlyn McCann, Shane Norris, Matthew Chersich, Gary Maartens, Samanta Lalla-Edward, Alinda Vos, Polly Clayden, Elaine Abrams, Natasha Arulappan, Andrew Hill
Journal: The Lancet HIV (2020)
Sex Differences in Incident and Recurrent Coronary Events and All-Cause Mortality
Authors: Sanne A.E. Peters, Lisandro D. Colantonio, Ligong Chen, Vera Bittner, Michael E. Farkouh, Robert S. Rosenson, Elizabeth A. Jackson, Paul Dluzniewski, Bharat Poudel, Paul Muntner, Mark Woodward
Journal: Journal of the American College of Cardiology (2020)
SARS-CoV-2 samples may escape detection because of a single point mutation in the N gene
Authors: Katharina Ziegler, Philipp Steininger, Renate Ziegler, Jörg Steinmann, Klaus Korn, Armin Ensser
Journal: Eurosurveillance (2020)

We found that a single nucleotide polymorphism (SNP) in the nucleoprotein gene of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a patient interfered with detection in a widely used commercial assay. Some 0.2% of the isolates in the EpiCoV database contain this SNP. Although SARS-CoV-2 was still detected by the other probe in the assay, this underlines the necessity of targeting two independent essential regions of a pathogen for reliable detection.
Secular Changes in Mortality and Hospitalization over Time in People with Kidney Failure or Severe CKD as Compared with Other Noncommunicable Diseases
Authors: Marcello Tonelli, Natasha Wiebe, Matthew T. James, Scott W. Klarenbach, Braden J. Manns, Neesh Pannu, Pietro Ravani, Brenda R. Hemmelgarn
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement Unlike other noncommunicable diseases such as coronary disease and cancer, few new effective treatments have been developed for kidney failure or CKD in recent years. This retrospective cohort study included 548,609 people in Alberta, Canada with an incident noncommunicable disease, including those with kidney failure on renal replacement (KF-RRT) or severe CKD, who were diagnosed in 2004 through 2015. The authors found that patients with CKD and KF-RRT experienced secular reductions in mortality and mean annual days in the hospital at 1 and 5 years comparable with those experienced by patients with other common noncommunicable diseases, including myocardial infarction, diabetes, and certain malignancies. This contradicts the commonly held perception that outcomes associated with CKD or kidney failure have improved more slowly than those for other major noncommunicable diseases. Background Few new treatments have been developed for kidney failure or CKD in recent years, leading to perceptions of slower improvement in outcomes associated with CKD or kidney failure than for other major noncommunicable diseases. Methods Our retrospective cohort study included 548,609 people with an incident noncommunicable disease, including cardiovascular diseases, diabetes, various cancers, and severe CKD or kidney failure treated with renal replacement (KF-RRT), treated in Alberta, Canada, 2004–2015. For each disease, we assessed presence or absence of 8 comorbidities; we also compared secular trends in relative (compared to a referent year of 2004) and absolute risks of mortality and mean annual days in the hospital associated with each disease after 1 year and 5 years. Results Comorbidities increased significantly in number over time for all noncommunicable diseases except diabetes, and increased most rapidly for CKD and KF-RRT. Significant but relatively small reductions over time in the risk ratio of mortality at 1 year occurred for nearly all noncommunicable diseases. Secular trends in the absolute risk of mortality were similar; CKD and KF-RRT had a relatively favorable ranking at 1 year. Breast cancer, KF-RRT, diabetes, and colorectal cancer displayed the largest relative reductions in number of hospital days at 1 year. Significant absolute reductions in the number of hospital days were observed for both KF-RRT and CKD; the former had the highest absolute reduction among all noncommunicable diseases. Results were similar at 5 years. Conclusions We observed secular reductions in mortality and annual hospital days at 1 year and 5 years among incident patients with KF-RRT and severe CKD, as well as several other common noncommunicable diseases.
Discovery of mcr-3.1 gene carried by a prophage located in a conjugative IncA/C2 plasmid from a Salmonella Choleraesuis clinical isolate
Authors: Yuanlong Pan, Yuan Fang, Yuqing Feng, Na Lyu, Luping Chen, Jing Li, Xuebin Xu, Baoli Zhu, Yongfei Hu
Journal: Journal of Infection (2020)
Patient-reported outcome measures after COVID-19: a prospective cohort study
Authors: Alyson W. Wong, Aditi S. Shah, James C. Johnston, Christopher Carlsten, Christopher J. Ryerson
Journal: European Respiratory Journal (2020)

<b>Over 75% of patients admitted to hospital with COVID-19 have abnormal patient-reported outcome measures 3 months after symptom onset, with a third of patients reporting at least moderate impairment in major dimensions of quality of life</b>https://bit.ly/32QMMgw
Effectiveness of a Home- and School-Based Asthma Educational Program for Head Start Children With Asthma
Authors: Michelle N. Eakin, Sandra Zaeh, Thomas Eckmann, Elizabeth Ruvalcaba, Cynthia S. Rand, Marisa E. Hilliard, Kristin A. Riekert
Journal: JAMA Pediatrics (2020)

<h3>Importance</h3> Asthma is the most common chronic childhood disease, with Black children experiencing worse morbidity and mortality. It is important to evaluate the effectiveness of efficacious interventions in community settings that have the greatest likelihood of serving at-risk families. <h3>Objective</h3> To evaluate the effectiveness of a multilevel home- and school (Head Start)–based asthma educational program compared with a Head Start–based asthma educational program alone in improving asthma outcomes in children. <h3>Design, Setting, and Participant</h3> This randomized clinical trial included 398 children with asthma enrolled in Head Start preschool programs in Baltimore, Maryland, and their primary caregivers. Participants were recruited from April 1, 2011, to November 31, 2016, with final data collection ending December 31, 2017. Data were analyzed from March 18 to August 30, 2018. <h3>Interventions</h3> Asthma Basic Care (ABC) family education combined with Head Start asthma education compared with Head Start asthma education alone. <h3>Main Outcomes and Measures</h3> Asthma control as measured by the Test for Respiratory and Asthma Control in Kids (TRACK) score. <h3>Results</h3> Among the 398 children included in the analysis (247 boys [62.1%]; mean [SD] age, 4.2 [0.7] years), the ABC plus Head Start program improved asthma control (β = 6.26; 95% CI, 1.77 to 10.75;<i>P</i> &lt; .001), reduced courses of oral corticosteroids (β = −0.61; 95% CI, −1.13 to −0.09;<i>P</i> = .02), and reduced hospitalizations (odds ratio, 0.36; 95% CI, 0.21-0.61;<i>P</i> &lt; .001) during a 12-month period. <h3>Conclusion and Relevance</h3> In this randomized clinical trial, combined family and preschool asthma educational interventions improved asthma control and reduced courses of oral corticosteroids and hospitalizations. Multilevel interventions implemented in community settings that serve low-income minority families may be key to reducing disparities in asthma outcomes. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01519453
Functional CRISPR dissection of gene networks controlling human regulatory T cell identity
Authors: Kathrin Schumann, Siddharth S. Raju, Michael Lauber, Saskia Kolb, Eric Shifrut, Jessica T. Cortez, Nikolaos Skartsis, Vinh Q. Nguyen, Jonathan M. Woo, Theodore L. Roth, Ruby Yu, Michelle L. T. Nguyen, Dimitre R. Simeonov, David N. Nguyen, Sasha Targ, Rachel E. Gate, Qizhi Tang, Jeffrey A. Bluestone, Matthew H. Spitzer, Chun Jimmie Ye, Alexander Marson
Journal: Nature Immunology (2020)
A Randomized Placebo Controlled Phase II Trial Evaluating Exemestane with or without Enzalutamide in Patients with Hormone Receptor–Positive Breast Cancer
Authors: Ian Krop, Vandana Abramson, Marco Colleoni, Tiffany Traina, Frankie Holmes, Laura Garcia-Estevez, Lowell Hart, Ahmad Awada, Claudio Zamagni, Patrick G. Morris, Lee Schwartzberg, Stephen Chan, Ayca Gucalp, Laura Biganzoli, Joyce Steinberg, Lorenzo Sica, Maureen Trudeau, Denka Markova, Jamal Tarazi, Zhou Zhu, Thomas O'Brien, Catherine M. Kelly, Eric Winer, Denise A. Yardley
Journal: Clinical Cancer Research (2020)

To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor-positive (HR+) breast cancer.In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis.Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54-1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66-1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (Pinteraction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10-0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2.Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.
Association Between Exposure to Hurricane Irma and Mortality and Hospitalization in Florida Nursing Home Residents
Authors: David M. Dosa, Julianne Skarha, Lindsay J. Peterson, Dylan J. Jester, Nazmus Sakib, Jessica Ogarek, Kali S. Thomas, Ross Andel, Kathryn Hyer
Journal: JAMA Network Open (2020)

Nursing home residents are at heightened risk for morbidity and mortality following an exposure to a disaster such as a hurricane or the COVID19 pandemic. Previous research has shown that nursing home resident mortality related to disasters is frequently underreported. There is a need to better understand the consequences of disasters on nursing home residents and to differentiate vulnerability based on patient characteristics. To evaluate mortality and morbidity associated with exposure to Hurricane Irma, a Category 4 storm that made landfall on September 10, 2017, in Cudjoe Key, Florida, among short-stay (<90-day residence) and long-stay (≥90-day residence) residents of nursing homes. Cohort study of Florida nursing home residents comparing residents exposed to Hurricane Irma in September 2017 to a control group of residents residing at the same nursing homes over the same time period in calendar year 2015. Data were analyzed from August 28, 2019, to July 22, 2020. Residents who experienced Hurricane Irma were considered exposed; those who did not were considered unexposed. Outcome variables included 30-day and 90-day mortality and first hospitalizations after the storm in both the short term and the long term. A total of 61 564 residents who were present in 640 Florida nursing home facilities on September 7, 2017, were identified. A comparison cohort of 61 813 residents was evaluated in 2015. Both cohorts were mostly female (2015, 68%; 2017, 67%), mostly White (2015, 79%; 2017, 78%), and approximately 40% of the residents in each group were over the age of 85 years. Compared with the control group in 2015, an additional 262 more nursing home deaths were identified at 30 days and 433 more deaths at 90 days. The odds of a first hospitalization for those exposed (vs nonexposed) were 1.09 (95% CI, 1.05-1.13) within the first 30 days after the storm and 1.05 (95% CI, 1.02-1.08) at 90 days; the odds of mortality were 1.12 (95% CI, 1.05-1.18) at 30 days and 1.07 (95% CI, 1.03-1.11) at 90 days. Among long-stay residents, the odds of mortality for those exposed to Hurricane Irma were 1.18 (95% CI, 1.08-1.29) times those unexposed and the odds of hospitalization were 1.11 (95% CI, 1.04-1.18) times those unexposed in the post 30-day period. The findings of this study suggest that nursing home residents are at considerable risk to the consequences of disasters. These risks may be underreported by state and federal agencies. Long-stay residents, those who have resided in a nursing home for 90 days or more, may be most vulnerable to the consequences of hurricane disasters.
Clinical Screening for COVID-19 in Asymptomatic Patients With Cancer
Authors: Manish A. Shah, Sebastian Mayer, Francie Emlen, Evan Sholle, Paul Christos, Melissa Cushing, Manuel Hidalgo
Journal: JAMA Network Open (2020)

Division of Hematology and Medical Oncology created separate units for patients with confirmed COVID-19, patients with symptomatic but unconfirmed COVID-19, and asymptomatic patients with no known high-risk COVID-19 exposures. 2Patients were contacted prior to their appointment and triaged based on their COVID-19 risk status.To understand the success of our clinical screening and triaging procedures, we implemented a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing protocol in asymptomatic patients who required cancer care across the Division of Hematology and Medical Oncology.Methods This quality improvement study, approved by Weill Cornell Medicine, follows the Standards for Quality Improvement Reporting Excellence (SQUIRE) reporting guideline.Informed consent was waived because data were deidentified, per institutional policy.Patients were considered asymptomatic if they had no recent fever (defined as body temperature Ն100.5 °F for Ն5 days); no COVID-19 symptoms, which included cough, headache, loss of taste, and shortness of breath 3 ; or high risk exposure (eg, contact with an individual with confirmed COVID-19, nursing home stay, or hospitalization) within 14 days.Diagnosis of COVID-19 was confirmed using SARS-CoV-2 nasal swab polymerase chain reaction (PCR) testing (Cobas 6800; Roche Diagnostics) and SARS-CoV-2 IgM and IgG serological tests (Pylon 3D; ET HealthCare). 4Patients were retested every 1 to 2 weeks.Rates of positive SARS-CoV-2 PCR and COVID-19 serological tests and 95% CIs are reported, using the 2-sided Clopper-Pearson (exact) 95% CI.Statistical analyses were conducted using Stata statistical software version 13.1 (StataCorp). ResultsFrom April 30 through June 2, 2020, we performed 621 SARS-CoV-2 PCR tests on 537 asymptomatic patients (272 [50.7%] men) with hematologic or solid tumor malignant neoplasms (Table 1).Our patients were geographically representative of New York, New York, and surrounding areas, and more than 90% of patients were receiving active cytotoxic or targeted therapy.The rate of SARS-CoV-2 positivity was 0.64% (95% CI, 0.18%-1.64%).This includes 84 patients who had repeated SARS-CoV-2 tests, all of which were negative.Only 4 asymptomatic patients had test results positive for COVID-19, 2 each for hematologic and solid tumor neoplasms.We also performed serological tests from May 18 to June 2, 2020, on 238 asymptomatic patients.The rate of COVID-19 prior exposure in our asymptomatic cancer population was 4.23% (95% CI, 2.05%-7.65%)(Table 2).Notably, during this period, the SARS-CoV-2 PCR positivity rate in New York City in early May was 20%.