tbuckley/cabot-search huggingface dataset:
Sex Differences in Procedural Outcomes Among Patients Undergoing Left Atrial Appendage Occlusion
Authors: Douglas Darden, Thao Duong, Chengan Du, Muhammad Bilal Munir, Frederick T. Han, Ryan Reeves, Jacqueline Saw, Emily P. Zeitler, Sana M. Al-Khatib, Andrea M. Russo, Karl E. Minges, Jeptha P. Curtis, James V. Freeman, Jonathan C. Hsu
Journal: JAMA Cardiology (2021)

Left atrial appendage occlusion (LAAO) has emerged as an alternative to anticoagulation for select patients with atrial fibrillation; however, women have been underrepresented in clinical trials of LAAO, and sex-specific subanalyses are limited.To evaluate the sex differences in the baseline characteristics of patients undergoing LAAO implant and in the in-hospital outcomes after LAAO implant.A total of 49 357 patients in the National Cardiovascular Data Registry LAAO Registry undergoing LAAO with the Watchman device between January 1, 2016, and June 30, 2019, were included in this study.Female or male sex.The primary outcomes were aborted or canceled procedure, major adverse event, any adverse event, prolonged hospital stay longer than 1 day, and death. Unadjusted and multivariable adjusted logistic regression analyses were performed to assess sex differences in in-hospital adverse events.In this cohort study of 49 357 patients (mean [SD] age, 76.1 [8.0] years), 20 388 women (41.3%) and 28 969 (58.7%) men underwent LAAO. Compared with men, women were older and had a higher prevalence of paroxysmal atrial fibrillation, prior stroke, and uncontrolled hypertension but a lower prevalence of congestive heart failure, diabetes, and coronary artery disease. After multivariable adjustment, there were no differences in aborted or canceled procedures between women and men (613 [3.0%] vs 851 [2.9%]; odds ratio [OR] 1.01, 95% CI, 0.90-1.13). Women were more likely than men to experience any adverse event (1284 [6.3%] vs 1144 [3.9%]; P < .001; OR, 1.63; 95% CI, 1.49-1.77; P < .001) or major adverse event (827 [4.1%] vs 567 [2.0%]; P < .001; OR, 2.06; 95% CI, 1.82-2.34; P < .001) owing to pericardial effusion requiring drainage (241 [1.2%] vs 144 [0.5%]) or major bleeding (349 [1.7%] vs 244 [0.8%]). Women were also more likely than men to experience a hospital stay longer than 1 day (3272 [16.0%] vs 3355 [11.6%]; P < .001; adjusted OR, 1.46; 95% CI, 1.38-1.54; P < .001) or death (adjusted OR, 2.01; 95% CI, 1.31-3.09; P = .001), although death was rare and absolute differences were minimal (58 [0.3%] vs 37 [0.1%]; P < .001).This study suggests that, compared with men, women have a significantly higher risk of in-hospital adverse events after LAAO. Further research aimed at risk reduction, particularly strategies to reduce the risk of pericardial effusion and major bleeding, in women undergoing LAAO is warranted.
KRAS Inhibitor Resistance in <i>MET</i>-Amplified <i>KRAS</i>G12C Non–Small Cell Lung Cancer Induced By RAS- and Non–RAS-Mediated Cell Signaling Mechanisms
Authors: Shinichiro Suzuki, Kimio Yonesaka, Takeshi Teramura, Toshiyuki Takehara, Ryoji Kato, Hitomi Sakai, Koji Haratani, Junko Tanizaki, Hisato Kawakami, Hidetoshi Hayashi, Kazuko Sakai, Kazuto Nishio, Kazuhiko Nakagawa
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Treatment with KRASG12C inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non–small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear. The purpose of this study was to identify the mechanisms underlying acquired sotorasib resistance, and to explore potential treatments for rescuing patients with sotorasib-resistant KRASG12C NSCLC cells. Experimental Design: Clones of sotorasib-sensitive KRASG12C NSCLC H23 cells exposed to different concentrations of sotorasib were examined using whole-genomic transcriptome analysis, multiple receptor kinase phosphorylation analysis, and gene copy-number evaluation. The underlying mechanisms of resistance were investigated using immunologic examination, and a treatment aimed at overcoming resistance was tested in vitro and in vivo. Results: Unbiased screening detected subclonal evolution of MET amplification in KRASG12C NSCLC cells that had developed resistance to sotorasib in vitro. MET knockdown using small interfering RNA (siRNA) restored susceptibility to sotorasib in these resistant cells. MET activation by its amplification reinforced RAS cycling from its inactive form to its active form. In addition to RAS-mediated MEK–ERK induction, MET induced AKT activation independently of RAS. Crizotinib, a MET inhibitor, restored sensitivity to sotorasib by eliminating RAS–MEK–ERK as well as AKT signaling. MET/KRASG12C dual inhibition led to tumor shrinkage in sotorasib-resistant xenograft mice. Conclusions: MET amplification leads to the development of resistance to KRASG12C inhibitors in NSCLC. Dual blockade of MET and KRASG12C could be a treatment option for MET-amplified, KRASG12C-mutated NSCLC.
Pretreatment serum bile acid parameters and predictability of response to odevixibat, an ileal bile acid transport inhibitor, in children with progressive familial intrahepatic cholestasis
Authors: Henkjan Verkade, Folkert Kuipers, Quanhong Ni, Velichka Valcheva, Patrick Horn, Jan Mattsson, Per-Goran Gillberg, Lise Kjems
Journal: Journal of Hepatology (2021)
This Week in the Journal
Authors: Data Missing
Journal: New England Journal of Medicine (2021)

There was no significant difference between the two groups in the composite primary outcome of in-hospital death from any cause or cardiovascular or renal events. see Original Article, N Engl J Med 2021;385:516-525 Decompression versus Fusion for Lumbar Spondylolisthesis In a randomized trial conducted in Norway, decompression surgery alone was noninferior to decompression with instrumented fusion with respect to the percentage of patients who had a 30% reduction on a scale of pain and disability over a period of 2 years, with a noninferiority margin of −15 percentage points. see Original Article, N Engl J Med 2021;385:526-538 Age-Related Macular Degeneration Age-related macular degeneration is the leading cause of vision loss in older persons in industrialized nations. A biopsy was performed, and a diagnosis of neutrophilic eccrine hidradenitis was made. see Images in Clinical Medicine, N Engl J Med 2021;385:e19 Turning Purple with Pain A 32-year-old woman presented with a 10-year history of intermittent episodes of severe diffuse abdominal pain, occurring every month or two and usually lasting several days, with no apparent precipitant. see Clinical Problem-Solving, N Engl J Med 2021;385:549-554 SARS-CoV-2 and Immunosuppression In this article, the authors discuss the challenges of SARS-CoV-2 infection in patients with a weakened immune system, including the potential implications regarding viral evolution and transmission. see Sounding Board, N Engl J Med 2021;385:562-566 Fundamentals of Public Health: The Complementarity of Public Health and Medicine The approaches and achievements of public health and clinical medicine are often framed as dichotomies — “prevention versus cure” or “individual versus population health.” A bill in the Massachusetts legislature would provide such a right. see Perspective, N Engl J Med 2021;385:490-491 CAR T Cells for Refractory Systemic Lupus Erythematosus A 20-year-old woman with refractory SLE with active lupus nephritis (WHO class IIIA), nephrotic syndrome, pericarditis, pleurisy, rash, arthritis, and a history of Libman–Sacks endocarditis refractory to conventional immunosuppression had a complete response to CD19-specific chimeric antigen receptor T cells. see Correspondence, N Engl J Med 2021;385:567-569 Rare Thromboembolic Events among Vaccinated South Africans Among 288,368 South African health care workers who received the Ad26.COV2.S vaccine, no cases of vaccine-induced immune thrombotic thrombocytopenia have been observed, and the small number of thromboembolic events that have been noted occurred in persons with risk factors for thromboses other than vaccination. see Correspondence, N Engl J Med 2021;385:570-571
Immunophenotyping assessment in a COVID-19 cohort (IMPACC): A prospective longitudinal study
Authors: Nadine Rouphael, Holden Maecker, Ruth R. Montgomery, Joann Diray-Arce, Steven H. Kleinstein, Matthew C. Altman, Steven E. Bosinger, Walter Eckalbar, Leying Guan, Catherine L. Hough, Florian Krammer, Charles Langelier, Ofer Levy, Kerry McEnaney, Bjoern Peters, Adeeb Rahman, Jayant V. Rajan, Steven Sigelman, Hanno Steen, Harm van Bakel, Alyssa Ward, Michael R. Wilson, Prescott Woodruff, Colin R. Zamecnik, Alison D. Augustine, Al Ozonoff, Elaine F. Reed, Patrice M. Becker, Nelson Agudelo Higuita, Matthew C. Altman, Mark A. Atkinson, Lindsey R. Baden, Patrice M. Becker, Christian Bime, Scott C. Brakenridge, Carolyn S. Calfee, Charles B. Cairns, David Corry, Mark M. Davis, Alison D. Augustine, Lauren I. R. Ehrlich, Elias K. Haddad, David J. Erle, Ana Fernandez-Sesma, David A. Hafler, Catherine L. Hough, Farrah Kheradmand, Steven H. Kleinstein, Monica Kraft, Ofer Levy, Grace A. McComsey, Esther Melamed, William Messer, Jordan Metcalf, Ruth R. Montgomery, Kari C. Nadeau, Al Ozonoff, Bjoern Peters, Bali Pulendran, Elaine F. Reed, Nadine Rouphael, Minnie Sarwal, Joanna Schaenman, Rafick Sekaly, Albert C. Shaw, Viviana Simon
Journal: Science Immunology (2021)

IMPACC is a multicenter longitudinal study assessing clinical and immunologic manifestations of COVID-19 in hospitalized patients.
Athlete mental health: future directions
Authors: Alan Currie, Cheri Blauwet, Abhinav Bindra, Richard Budgett, Niccolo Campriani, Brian Hainline, David McDuff, Margo Mountjoy, Rosemary Purcell, Margot Putukian, Claudia L Reardon, Vincent Gouttebarge
Journal: British Journal of Sports Medicine (2021)

The impact of mental health symptoms and disorders in elite athletes is increasingly recognised. This led the International Olympic Committee (IOC) to produce a consensus statement1 and establish a Mental Health Working Group. Members of this group have extensive experience in research and practice in the field of athlete mental health and have collectively ascertained gaps in current knowledge and practices. This editorial reflects the authors’ opinions and aims to provide researchers and practitioners with future directions relating to mental health symptoms and disorders in elite sport, focusing on prevalence/incidence, prevention, screening, assessment and treatment.

The prevalence studies that are currently available have significant limitations,2 including the lack of data distinguishing mental health symptoms from disorders . The latter require a clinical assessment accounting for the intense and unique demands athletes face, which influence how symptoms and disorders may manifest. An example is the presence of mental health symptoms in overtrained athletes, how these are understood from perspectives such as low energy availability or impaired immune function and where existing classification systems may be inadequate.

Studies are limited by the influence of stigma related to mental health symptoms and disorders both in and out of sporting contexts, which likely impact athletes’ responses and do not take account of additional barriers to reporting, specifically cultural barriers including sex, religion, …
CRISPR sabotage
Authors: John van der Oost, Stan J. J. Brouns
Journal: Genome biology (2015)

The biological arms race generally involves the rapid co-evolution of anti-virus systems in host organisms and of anti-anti-virus systems in their viral parasites. The CRISPR-Cas system is an example of a prokaryotic immune system in which such co-evolution occurs, as was recently demonstrated by the characterization of a set of viral anti-CRISPR proteins.
MAAPER: model-based analysis of alternative polyadenylation using 3′ end-linked reads
Authors: Wei Vivian Li, Dinghai Zheng, Ruijia Wang, Bin Tian
Journal: Genome biology (2021)

Abstract Most eukaryotic genes express alternative polyadenylation (APA) isoforms. A growing number of RNA sequencing methods, especially those used for single-cell transcriptome analysis, generate reads close to the polyadenylation site (PAS), termed nearSite reads, hence inherently containing information about APA isoform abundance. Here, we present a probabilistic model-based method named MAAPER to utilize nearSite reads for APA analysis. MAAPER predicts PASs with high accuracy and sensitivity and examines different types of APA events with robust statistics. We show MAAPER’s performance with both bulk and single-cell data and its applicability in unpaired or paired experimental designs.
Association of Thrombosis With Hypereosinophilic Syndrome in Patients With Genetic Alterations
Authors: Orly Leiva, Olesya Baker, Andrew Jenkins, Andrew M. Brunner, Hanny Al-Samkari, Rebecca Karp Leaf, Rachel P. Rosovsky, Amir T. Fathi, James Weitzman, Larissa Bornikova, Valentina Nardi, Gabriela S. Hobbs
Journal: JAMA Network Open (2021)

Hypereosinophilic syndromes (HESs) are a rare group of disorders that result in overproduction of eosinophils, leading to tissue damage. Thrombotic complications in HES and associated risk factors in this patient population have not been extensively studied.To investigate the rates of and risk factors associated with thrombotic events in patients with HES, including markers of clonal hematopoiesis as evidenced by molecular aberrations on next-generation sequencing.This retrospective cohort study evaluated patients seen at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, from January 1, 2015, to January 1, 2020. Patients who had hypereosinophilia with an absolute eosinophil count of 1500 cells/μL or greater on 2 separate occasions at least 1 month apart and who underwent genetic or molecular testing as part of their work-up were included. Patients with secondary eosinophilia were excluded.Symptomatic and asymptomatic arterial and venous thrombotic events after the diagnosis of HES and all-cause death.A total of 71 patients (median age, 58 years [interquartile range (IQR), 43-67 years]; 36 women [51%]; 57 White patients [80%]) were included. Patients had a median follow-up time of 29 months (IQR, 19-49 months). Seventeen patients (24%) had 1 or more thrombotic events, including 11 venous thromboembolic events and 11 arterial thrombotic events (8 patients had ≥1 event and 3 patients had recurrent events). Patients with 1 or more thrombotic events had a higher median Eastern Cooperative Oncology Group performance status (median, 1 [IQR, 1-2] vs 0 [IQR, 0-1]; P = .002), had more frequent cardiac involvement (7 of 17 events [41%] vs 6 of 54 events [11%]; P = .01), more frequently received treatment (17 of 17 events [100%] vs 40 of 54 events [74%]; P = .02), and had more molecular aberrations on next-generation sequencing (12 of 17 [71%] vs 12 of 54 [26%]; P = .003) vs patients without thrombosis. After multivariable analysis, the presence of molecular aberration was associated with increased odds of thrombosis (adjusted odds ratio, 5.4; 95% CI, 1.1-27.7). Death occurred more frequently in patients with thrombotic events compared with those without (6 of 17 [35%] vs 2 of 54 [4%]; P = .002) and in patients with molecular aberrations compared with those without (6 of 24 [25%] vs 1 of 40 [3%]; P = .009), although only thrombotic events were significantly associated with increased odds of death after multivariable analysis.In this cohort study, thrombosis was common in patients with HES and was significantly associated with increased risk of death.
When staging becomes screening: public education is the key
Authors: Murali Varma, Krishna Narahari
Journal: BMJ (2021)

Lessing’s experience with incidentalomas raises important questions around cancer staging, overdiagnosis, and informed patient consent.1

Cancer staging investigations can detect unrelated abnormalities in other organs, such as an incidental small renal mass being detected while staging colon cancer.2 Colon cancer staging could thus result in radiological screening for kidney cancer. Moreover, one incidentaloma could lead to detection of another. An incidental renal cell carcinoma might be detected on abdominal ultrasonography while screening for an abdominal aortic aneurysm. Computed tomography to stage the renal cancer may then detect …
Epidemiological data and genome sequencing reveals that nosocomial transmission of SARS-CoV-2 is underestimated and mostly mediated by a small number of highly infectious individuals
Authors: Sheila F Lumley, Bede Constantinides, Nicholas Sanderson, Gillian Rodger, Teresa L Street, Jeremy Swann, Kevin K Chau, Denise O'Donnell, Fiona Warren, Sarah Hoosdally, Anne-Marie O'Donnell, Timothy M Walker, Nicole E Stoesser, Lisa Butcher, Tim EA Peto, Derrick W Crook, Katie Jeffery, Philippa C Matthews, David W Eyre
Journal: Journal of Infection (2021)
Microsatellite Stable Colorectal Liver Metastases—Understanding the Mechanisms of Immune Resistance
Authors: Sepideh Gholami, Axel Grothey, Heinz-Josef Lenz
Journal: JAMA Network Open (2021)

Chongkai Wang, MD, MS; Jaideep Sandhu, MBBS, MPH; Ching Ouyang, PhD; Jian Ye, PhD; Peter P. Lee, MD; Marwan Fakih, MD
Abstract 18147: Role of Adenosine Receptor Engagement in Ectonucleotide Triphosphate Diphosphohydrolase-1 Mediated Resistance to Conduit Arterial Thrombosis in Mice
Authors: Zachary M Huttinger, Michael W Milks, Michael S Nickoli, Lawrence C Long, Debra G Wheeler, Karen M Dwyer, Anthony J d'Apice, Simon C Robson, Peter J Cowan, Richard J Gumina
Journal: Circulation (2011)

Background: Ectonucleoside Triphosphate Diphosphohydrolase-1 (ENTPD-1/CD39) plays a key role in regulating platelet reactivity; it converts prothrombotic ATP and ADP to AMP which is further degraded by ecto-5’-nucleotidase (CD73) to adenosine, an anti-thrombotic mediator. The objective was to determine role of adenosine receptor engagement in ENTPDase-1 mediated resistance to in vivo arterial thrombosis in mice. Methods: Transgenic mice expressing human ENTPD-1 and littermate controls (WT) were subjected to FeCl 3 -induced carotid artery thrombosis. Results: ENTPD-1 mice displayed marked resistance to thrombosis (WT: 13.7 ± 0.9 min vs. ENTPD-1: 281.5 ± 57.3 min; P &lt;0.001; n=6/group; Figure). Treatment of mice with α-β-methylene-ADP (APCP; 2 mg/kg 15 minute prior to injury), a specific ecto-5’-nucleotidase antagonist, completely abrogated the protection from thrombosis mediated by ENTPD-1 overexpression (APCP-treated WT: 11.9 ± 1.0min vs. APCP-treated ENTPD-1: 26.5 ± 11.1 min; n=6/group; Figure), suggesting that ecto-5’-nucleotidase-mediated generation of adenosine is required for ENTPD-1 mediated resistance to in vivo thrombosis. Furthermore, in mice treated with the non-selective adenosine receptor antagonist 8-(p-Sulfophenyl) theophylline (8-SPT; 20 mg /kg 15 minutes prior to injury) the resistance to thrombosis observed in ENTPDase-1 overexpresssing mice was abrogated (8-SPT Treated WT (n=8): 10.5 ± 1.4 min vs. 8-SPT Treated ENTPD-1 (n=9): 14.3 ± 1.6 min; Figure). Conclusions: Adenosine receptor engagement contributes to the resistance to thrombosis mediated by ENTPDase-1 overexpression.
Ward based management of behavioural and psychological symptoms of dementia
Authors: Jenny Nguyen, Ina Ko, Santiago Martinez-Sosa, Ruth Mizoguchi
Journal: BMJ (2021)

### What you need to know

An 81 year old woman with vascular dementia has been admitted to the hospital following a fall in the community and is currently an inpatient on the ward. You are the doctor on call and have been asked to review the patient as she appears more confused and is trying to leave the ward. 

Worldwide, dementia affects 50 million people, with a predicted increase to 82 million by 2030.1 Dementia is characteristically progressive and severely affects activities of daily living.

Behavioural and psychological symptoms of dementia (BPSD) refer to a cluster of symptoms of dementia relating to perception, mood, thought content, or behaviour.2 They are associated with increased care costs and are important prognosticators of admission to nursing homes. It is estimated that more than 80% of people with dementia will experience BPSD during the course of the disease.3

BPSD are challenging to manage for patients, carers, and healthcare workers, but effective management can substantially improve quality of life for both patients and carers.

As people with dementia make up a relatively high proportion of hospital inpatients, clinicians working in an acute setting are likely to encounter BPSD often.

This article aims to introduce clinicians to BPSD, their key triggers in an inpatient …
Host lipidome and tuberculosis treatment failure
Authors: Rupak Shivakoti, John W. Newman, Luke Elizabeth Hanna, Artur T.L. Queiroz, Kamil Borkowski, Akshay N. Gupte, Mandar Paradkar, Pattabiraman Satyamurthi, Vandana Kulkarni, Murugesh Selva, Neeta Pradhan, Shri Vijay Bala Yogendra Shivakumar, Saravanan Natarajan, Ramesh Karunaianantham, Nikhil Gupte, Kannan Thiruvengadam, Oliver Fiehn, Renu Bharadwaj, Anju Kagal, Sanjay Gaikwad, Shashikala Sangle, Jonathan E. Golub, Bruno B. Andrade, Vidya Mave, Amita Gupta, Chandrasekaran Padmapriyadarsini
Journal: European Respiratory Journal (2021)

Introduction Host lipids play important roles in tuberculosis (TB) pathogenesis. Whether host lipids at TB treatment initiation (baseline) affect subsequent treatment outcomes has not been well characterised. We used unbiased lipidomics to study the prospective association of host lipids with TB treatment failure. Methods A case–control study (n=192), nested within a prospective cohort study, was used to investigate the association of baseline plasma lipids with TB treatment failure among adults with pulmonary TB. Cases (n=46) were defined as TB treatment failure, while controls (n=146) were those without failure. Complex lipids and inflammatory lipid mediators were measured using liquid chromatography mass spectrometry techniques. Adjusted least-square regression was used to assess differences in groups. In addition, machine learning identified lipids with highest area under the curve (AUC) to classify cases and controls. Results Baseline levels of 32 lipids differed between controls and those with treatment failure after false discovery rate adjustment. Treatment failure was associated with lower baseline levels of cholesteryl esters and oxylipin, and higher baseline levels of ceramides and triglycerides compared to controls. Two cholesteryl ester lipids combined in a unique classifier model provided an AUC of 0.79 (95% CI 0.65–0.93) in the test dataset for prediction of TB treatment failure. Conclusions We identified lipids, some with known roles in TB pathogenesis, associated with TB treatment failure. In addition, a lipid signature with prognostic accuracy for TB treatment failure was identified. These lipids could be potential targets for risk-stratification, adjunct therapy and treatment monitoring.
Covid-19: Charity offers scholarships to bereaved children of healthcare staff
Authors: Zosia Kmietowicz
Journal: BMJ (2021)

Covid-19: Charity offers scholarships to bereaved children of healthcare staff Zosia KmietowiczA UK charity is offering education scholarships worth £5000 (€5600; $6900) a year to children of NHS health and care workers who died from covid and who are going on to higher education.