tbuckley/cabot-search huggingface dataset:
Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial
Authors: René Post, Menno R Germans, Maud A Tjerkstra, Mervyn D I Vergouwen, Korné Jellema, Radboud W Koot, Nyika D Kruyt, Peter W A Willems, Jasper F C Wolfs, Frits C de Beer, Hans Kieft, Dharmin Nanda, Bram van der Pol, Gerwin Roks, Frank de Beer, Patricia H A Halkes, Loes J A Reichman, Paul J A M Brouwers, Renske M van den Berg-Vos, Vincent I H Kwa, Taco C van der Ree, Irene Bronner, Janneke van de Vlekkert, Henri P Bienfait, Hieronymus D Boogaarts, Catharina J M Klijn, René van den Berg, Bert A Coert, Janneke Horn, Charles B L M Majoie, Gabriël J E Rinkel, Yvo B W E M Roos, W Peter Vandertop, Dagmar Verbaan, René Post, Menno R. Germans, Maud A. Tjerkstra, Mervyn D.I. Vergouwen, Korné Jellema, Radboud W. Koot, Nyika D. Kruyt, Peter W.A. Willems, Jasper F.C. Wolfs, Frits C. de Beer, Hans Kieft, Dharmin Nanda, Bram van der Pol, Gerwin Roks, Frank de Beer, Patricia H.A. Halkes, Loes J.A. Reichman, Paul J.A.M. Brouwers, Renske M. van den Berg-Vos, Vincent I.H. Kwa, Taco C. van der Ree, Irene Bronner, Henri P. Bienfait, Hieronymus D. Boogaarts, Catharina J.M. Klijn, Martine van Bilzen, H.J.G. Dieks, Koen de Gans, J.B.M. ten Holter, Jelle R. de Kruijk, Charlie T.J.M. Leijzer, Delmar Molenaar, Robbert J. van Oostenbrugge, Jeske van Pamelen, Fianne H.M. Spaander, Sarah E. Vermeer, Janneke van de Vlekkert, J. Manuela Voorend, René van den Berg, Bert A. Coert, Janneke Horn, Charles B.L.M. Majoie, Gabriël J.E. Rinkel, Yvo B.W.E.M. Roos, W. Peter Vandertop, Dagmar Verbaan
Journal: The Lancet (2020)
Therapeutic Potential of TLR8 Agonist GS‐9688 (Selgantolimod) in Chronic Hepatitis B: Remodeling of Antiviral and Regulatory Mediators
Authors: Oliver E. Amin, Emily J. Colbeck, Stephane Daffis, Shahzada Khan, Dhivya Ramakrishnan, Divya Pattabiraman, Ruth Chu, Holly Micolochick Steuer, Sophie Lehar, Leanne Peiser, Adam Palazzo, Christian Frey, Jessica Davies, Hassan Javanbakht, William M.C. Rosenberg, Simon P. Fletcher, Mala K. Maini, Laura J. Pallett
Journal: Hepatology (2020)

Background and Aims GS‐9688 (selgantolimod) is a toll‐like receptor 8 agonist in clinical development for the treatment of chronic hepatitis B (CHB). Antiviral activity of GS‐9688 has previously been evaluated in vitro in HBV‐infected hepatocytes and in vivo in the woodchuck model of CHB. Here we evaluated the potential of GS‐9688 to boost responses contributing to viral control and to modulate regulatory mediators. Approach and Results We characterized the effect of GS‐9688 on immune cell subsets in vitro in peripheral blood mononuclear cells of healthy controls and patients with CHB. GS‐9688 activated dendritic cells and mononuclear phagocytes to produce IL‐12 and other immunomodulatory mediators, inducing a comparable cytokine profile in healthy controls and patients with CHB. GS‐9688 increased the frequency of activated natural killer (NK) cells, mucosal‐associated invariant T cells, CD4 + follicular helper T cells, and, in about 50% of patients, HBV‐specific CD8 + T cells expressing interferon‐γ. Moreover, in vitro stimulation with GS‐9688 induced NK‐cell expression of interferon‐γ and TNF‐α, and promoted hepatocyte lysis. We also assessed whether GS‐9688 inhibited immunosuppressive cell subsets that might enhance antiviral efficacy. Stimulation with GS‐9688 reduced the frequency of CD4 + regulatory T cells and monocytic myeloid‐derived suppressor cells (MDSCs). Residual MDSCs expressed higher levels of negative immune regulators, galectin‐9 and programmed death‐ligand 1. Conversely, GS‐9688 induced an expansion of immunoregulatory TNF‐related apoptosis‐inducing ligand + NK cells and degranulation of arginase‐I + polymorphonuclear MDSCs. Conclusions GS‐9688 induces cytokines in human peripheral blood mononuclear cells that are able to activate antiviral effector function by multiple immune mediators (HBV‐specific CD8 + T cells, CD4 + follicular helper T cells, NK cells, and mucosal‐associated invariant T cells). Although reducing the frequency of some immunoregulatory subsets, it enhances the immunosuppressive potential of others, highlighting potential biomarkers and immunotherapeutic targets to optimize the antiviral efficacy of GS‐9688.
Cardiac Safety of Osimertinib: A Review of Data
Authors: Michael S. Ewer, Sri Harsha Tekumalla, Andrew Walding, Kwame N. Atuah
Journal: Journal of Clinical Oncology (2020)

Osimertinib is a third-generation, CNS-active, irreversible, oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits both EGFR-TKI-sensitizing and T790M resistance mutations. We assess the cardiac failure risk in patients receiving osimertinib by evaluating the available data.
Clinical Outcomes in Patients With Heart Failure Hospitalized With COVID-19
Authors: Ankeet S. Bhatt, Karola S. Jering, Muthiah Vaduganathan, Brian L. Claggett, Jonathan W. Cunningham, Ning Rosenthal, James Signorovitch, Jens J. Thune, Orly Vardeny, Scott D. Solomon
Journal: JACC Heart Failure (2020)

The purpose of this study was to evaluate in-hospital outcomes among patients with a history of heart failure (HF) hospitalized with coronavirus disease-2019 (COVID-19).
Consistency and Generalizability of Trials for Coronary Computed Tomography Angiography—Reply
Authors: Raymond J. Gibbons
Journal: JAMA Cardiology (2020)

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Bone Marrow Cell-Mediated Cardiac Regeneration: A Veritable Revolution**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Roberto Bolli, Hani Jneid, Buddhadeb Dawn
Journal: Journal of the American College of Cardiology (2005)
Methemoglobinemia and AKI in Patients with COVID-19: Don’t Forget G6PD Deficiency
Authors: Samraiz Nafees, Rouvick Gama, David Makanjuola, Virginia A. Quan
Journal: Journal of the American Society of Nephrology (2020)

Nafees, Samraiz; Gama, Rouvick; Makanjuola, David; Quan, Virginia A. Author Information
Clinical Evaluation of Kidney Function
Authors: Jerome P. Kassirer
Journal: New England Journal of Medicine (1971)

COMPARED to the use of inulin clearance as a measure of glomerular function, no single test of renal tubular function can be as specific since the renal tubules carry out many different functions. Studies of the maximal ability of the tubules to reabsorb glucose (TmG) or to secrete para-amino-hippurate (TmPAH) are, in fact, approximate indexes of functional tubular mass, but such studies are too complex for clinical purposes. As a substitute, tests of concentration and dilution and phenolsulfonphthalein (PSP) excretion have often been used to detect renal tubular damage early in its course and to follow . . .
Активность кишечной бактериальной гидролазы солей желчных кислот коррелирует с сердечно-сосудистым риском: исследование «случай — контроль»
Authors: A. Neverovskyi, V. Chernyavskyi, V. Shypulin, L. Gvozdecka, N. Mikhnova
Journal: GASTROENTEROLOGY (2020)

Актуальность. Уровень сывороточного холестерина частично регулируется благодаря метаболизму желчных кислот в кишечнике, зависящему от активности бактериальной гидролазы солей желчных кислот (ГСЖК). Существующие данные относительно четкого влияния ГСЖК на липидный обмен и сердечно-сосудистый риск недостаточны и противоречивы. Целью исследования было оценить взаимо­связь между относительной активностью (ОА) кишечной бактериальной ГСЖК и уровнями сывороточного холестерина и сердечно-сосудистым риском (ССР). Материалы и методы. Исследование проводилось по дизайну «случай — контроль» и включало 26 относительно здоровых участников (контрольная группа) и 77 пациентов с дислипидемией, без анамнеза тяжелых сердечно-сосудистых событий (основная группа). У участников были определены общая ОА кишечной бактериальной ГСЖК, показатели липидного профиля и уровни ССР по 5 шкалам риска. Результаты. ОА кишечной бактериальной ГСЖК была выше у здоровых участников по сравнению с участниками с дислипидемией (р &lt; 0,001). Была выявлена отрицательная корреляционная связь умеренной силы между ОА ГСЖК и общим холестерином (ОХ) (–0,38) и липопротеинами низкой плотности (ЛПНП) (–0,36) с линейным соотношением, которое определялось уравнением: ЛПНП = –5,33 • ОА ГСЖК + 4,479. Было обнаружено, что с увеличением ОА ГСЖК риск дислипидемии снижается (р &lt; 0,001), ОШ = 1,06 • 10–10 (95% ДИ; 2,5 • 10–15 – 4,5 • 10–6). Выявлена умеренная отрицательная корреляционная взаимосвязь между ОА ГСЖК и ССР, оцененным по шкалам Globorisk (–0,34), Framingham (–0,34), алгоритму ACC/AHA 2013 (–0,32), PROCAM (–0,35) и шкале ВОЗ (–0,34). Выводы. Общая ОА кишечной бактериальной ГСЖК негативно коррелировала с ОХ, ЛПНП, ССР, оцененным по 5 шкалам, и негативно ассоциировалась с риском дислипидемии.
Potentially adaptive SARS-CoV-2 mutations discovered with novel spatiotemporal and explainable AI models
Authors: Michael R. Garvin, Erica T. Prates, Mirko Pavicic, Piet Jones, B. Kirtley Amos, Armin Geiger, Manesh B. Shah, Jared Streich, Joao Gabriel Felipe Machado Gazolla, David Kainer, Ashley Cliff, Jonathon Romero, Nathan Keith, James B. Brown, Daniel Jacobson
Journal: Genome biology (2020)

Abstract Background A mechanistic understanding of the spread of SARS-CoV-2 and diligent tracking of ongoing mutagenesis are of key importance to plan robust strategies for confining its transmission. Large numbers of available sequences and their dates of transmission provide an unprecedented opportunity to analyze evolutionary adaptation in novel ways. Addition of high-resolution structural information can reveal the functional basis of these processes at the molecular level. Integrated systems biology-directed analyses of these data layers afford valuable insights to build a global understanding of the COVID-19 pandemic. Results Here we identify globally distributed haplotypes from 15,789 SARS-CoV-2 genomes and model their success based on their duration, dispersal, and frequency in the host population. Our models identify mutations that are likely compensatory adaptive changes that allowed for rapid expansion of the virus. Functional predictions from structural analyses indicate that, contrary to previous reports, the Asp 614 Gly mutation in the spike glycoprotein (S) likely reduced transmission and the subsequent Pro 323 Leu mutation in the RNA-dependent RNA polymerase led to the precipitous spread of the virus. Our model also suggests that two mutations in the nsp13 helicase allowed for the adaptation of the virus to the Pacific Northwest of the USA. Finally, our explainable artificial intelligence algorithm identified a mutational hotspot in the sequence of S that also displays a signature of positive selection and may have implications for tissue or cell-specific expression of the virus. Conclusions These results provide valuable insights for the development of drugs and surveillance strategies to combat the current and future pandemics.
Systemic Therapy for Estrogen Receptor–Positive, HER2-Negative Breast Cancer
Authors: Harold J. Burstein
Journal: New England Journal of Medicine (2020)

ER-positive, HER2-negative breast cancer, which accounts for about 70% of all breast cancers, is heterogeneous. Antiestrogen therapy is the cornerstone of systemic therapy, and its efficacy depends on such factors as grade, Ki-67 labeling, and progesterone receptor expression.
Targeting p300/CBP Attenuates Hepatocellular Carcinoma Progression through Epigenetic Regulation of Metabolism
Authors: Ling-Yan Cai, Shi-Jie Chen, Sen-Hao Xiao, Qin-Juan Sun, Chen-Hong Ding, Bai-Nan Zheng, Xin-Yan Zhu, Shu-Qing Liu, Feng Yang, Ya-Xi Yang, Bing Zhou, Cheng Luo, Xin Zhang, Wei-Fen Xie
Journal: Cancer Research (2020)

Abstract Targeting epigenetics in cancer has emerged as a promising anticancer strategy. p300/CBP is a central regulator of epigenetics and plays an important role in hepatocellular carcinoma (HCC) progression. Tumor-associated metabolic alterations contribute to the establishment and maintenance of the tumorigenic state. In this study, we used a novel p300 inhibitor, B029-2, to investigate the effect of targeting p300/CBP in HCC and tumor metabolism. p300/CBP–mediated acetylation of H3K18 and H3K27 increased in HCC tissues compared with surrounding noncancerous tissues. Conversely, treatment with B029-2 specifically decreased H3K18Ac and H3K27Ac and displayed significant antitumor effects in HCC cells in vitro and in vivo. Importantly, ATAC-seq and RNA-seq integrated analysis revealed that B029-2 disturbed metabolic reprogramming in HCC cells. Moreover, B029-2 decreased glycolytic function and nucleotide synthesis in Huh7 cells by reducing H3K18Ac and H3K27Ac levels at the promoter regions of amino acid metabolism and nucleotide synthesis enzyme genes, including PSPH, PSAT1, ALDH18A1, TALDO1, ATIC, and DTYMK. Overexpression of PSPH and DTYMK partially reversed the inhibitory effect of B029-2 on HCC cells. These findings suggested that p300/CBP epigenetically regulates the expression of glycolysis-related metabolic enzymes through modulation of histone acetylation in HCC and highlights the value of targeting the histone acetyltransferase activity of p300/CBP for HCC therapy. Significance: This study demonstrates p300/CBP as a critical epigenetic regulator of glycolysis-related metabolic enzymes in HCC and identifies the p300/CBP inhibitor B029-2 as a potential therapeutic strategy in this disease.
Mass population screening for SARS-CoV-2 and false positives—why Liverpool shows we have a problem
Authors: David Cook
Journal: BMJ (2020)

In The BMJ ’s Editor’s Choice article published on 19 November,1 Abbasi details some of the problems associated with the UK’s proposed mass testing regime. Despite many concerns, not least the ethical issues raised,2 mass testing is now planned for the UK.

As Abbasi says, “Although the false positive rate [of the screen] is small, it is still a problem in a low prevalence setting.” The mass screening trial in Liverpool showed that only …
The Impact of the COVID-19 Pandemic on the Mental Health of Health Workers Treating Patients with Kidney Diseases in Latin America (LA): Analysis from GlomCon Latin America Working Group (LGlomCon)
Authors: Sonia Rodriguez Ramirez, Franco H. Cabeza Rivera, Julio A. Gutierrez-Prieto, Javier Soto-Vargas, Blanca Martinez-Chagolla, Denisse Arellano-Mendez, Diana Aguirre, Desiree Garcia Anton, Carmen Avila-Casado
Journal: Journal of the American Society of Nephrology (2020)

Background: In Situation Report #13 by the World Health Organization and 39 days before declaring COVID-19 a pandemic, the WHO declared a 'COVID-19 infodemic'  The volume of coronavirus tweets was far too great for one to find accurate or reliable information  Healthcare workers were flooded with 'noise' which drowned the 'signal' of valuable COVID-19 information  To combat the infodemic, physicians created healthcare-specific micro-communities to share scientific information with other providers  Methods: We analyzed the content of six physician-created communities and categorized each message in one of five domains (Symptoms, Diagnostics, Therapeutics, Prevention, Pathophysiology)  We programmed 1) an application programming interface to download tweets and their metadata in JavaScript Object Notation beginning 11 March and 2) a reading algorithm using visual basic application in Excel to categorize the content  We superimposed the publication date of each tweet into a timeline of pandemic events  Finally, TD created a free repository of the dataset in the #NephTwitter Archives (https://bit ly/2M6HJQ2) to help healthcare workers find quality information when treating patients  Results: From 11 March to 27 April, 45% of the 19270 tweets in the dataset were categorized (signal)  Tweets about Therapeutics (34%) and Prevention (32%) were the most prevalent  Tweets about Therapeutics spiked six times;the first coming 4 days after the WHO declared COVID-19 a pandemic  The largest spike came on day 8: 5 days after the US President suggested hydroxychloroquine as a potential treatment  Tweets about antimalarial therapy comprised 15% of tweets in this category  Tweets about Prevention spiked five times;the largest coming 21 days after the pandemic declaration when 1 million global cases were reported  Protective equipment comprised 13% of tweets in this category  There were 2210 searches performed of the signal tweets in the #NephTwitter Archives  Evidence-based tweets comprised 1 in every 8 tweets in the categorized corpus  That ratio was better for tweets about antimalarials (1 in 3) and vaccines (2 in 3), the same for protective equipment, and worse for mechanical ventilation (1 in 31)  Conclusions: Algorithmic coding can 1) mitigate the COVID-19 infodemic and 2) identify & elevate illuminating evidence-based tweets  Both outcomes help healthcare workers find higher-quality information to combat the pandemic
Подвижник земской медицины на Екатеринославщине-Днепропетровщине (часть 1)
Authors: M. Chaban, Z. Shevtsova, V. Gaponov
Journal: GASTROENTEROLOGY (2020)

Представлен жизненный путь и профессиональная деятельность Петра Сочинского — земского врача, общественного деятеля, коллекционера, фольклориста, мецената, действительного члена Екатеринославской ученой архивной комиссии, который внес весомый вклад в развитие земской медицины и сохранение памятников истории и культуры на Приднепровье.
Vascular Tumor Recapitulated in Endothelial Cells from hiPSCs Engineered to Express the SERPINE1-FOSB Translocation
Authors: David G.P. van IJzendoorn, Daniela C.F. Salvatori, Xu Cao, Francijna van den Hil, Inge H. Briaire-de Bruijn, Danielle de Jong, Hailiang Mei, Christine L. Mummery, Karoly Szuhai, Judith V.M.G. Bovée, Valeria V. Orlova
Journal: Cell Reports Medicine (2020)

Chromosomal translocations are prevalent among soft tissue tumors, including those of the vasculature such as pseudomyogenic hemangioendothelioma (PHE). PHE shows endothelial cell (EC) features and has a tumor-specific t(7;19)(q22;q13) SERPINE1-FOSB translocation, but is difficult to study as no primary tumor cell lines have yet been derived. Here, we engineer the PHE chromosomal translocation into human induced pluripotent stem cells (hiPSCs) using CRISPR/Cas9 and differentiate these into ECs (hiPSC-ECs) to address this. Comparison of parental with PHE hiPSC-ECs shows (1) elevated expression of FOSB, (2) higher proliferation and more tube formation but lower endothelial barrier function, (3) invasive growth and abnormal vessel formation in mice after transplantation, and (4) specific transcriptome alterations reflecting PHE and indicating PI3K-Akt and MAPK signaling pathways as possible therapeutic targets. The modified hiPSC-ECs thus recapitulate functional features of PHE and demonstrate how these translocation models can be used to understand tumorigenic mechanisms and identify therapeutic targets.
Association of Stratification by Proportion of Patients Dually Enrolled in Medicare and Medicaid With Financial Penalties in the Hospital-Acquired Condition Reduction Program
Authors: Sukruth A. Shashikumar, R. J. Waken, Alina A. Luke, David R. Nerenz, Karen E. Joynt Maddox
Journal: JAMA Internal Medicine (2020)

The Hospital-Acquired Condition Reduction Program (HACRP) is a value-based payment program focused on safety events. Prior studies have found that the program disproportionately penalizes safety-net hospitals, which may perform more poorly because of unmeasured severity of illness rather than lower quality. A similar program, the Hospital Readmissions Reduction Program, stratifies hospitals into 5 peer groups for evaluation based on the proportion of their patients dually enrolled in Medicare and Medicaid, but the effect of stratification on the HACRP is unknown.
Performance of Breast Cancer Polygenic Risk Scores in 760 Female<i>CHEK2</i>Germline Mutation Carriers
Authors: Julika Borde, Corinna Ernst, Barbara Wappenschmidt, Dieter Niederacher, Konstantin Weber-Lassalle, Gunnar Schmidt, Jan Hauke, Anne S Quante, Nana Weber-Lassalle, Judit Horváth, Esther Pohl-Rescigno, Norbert Arnold, Andreas Rump, Andrea Gehrig, Julia Hentschel, Ulrike Faust, Véronique Dutrannoy, Alfons Meindl, Maria Kuzyakova, Shan Wang-Gohrke, Bernhard H. F Weber, Christian Sutter, Alexander E Volk, Olga Giannakopoulou, Andrew Lee, Christoph Engel, Marjanka K Schmidt, Antonis C Antoniou, Rita K Schmutzler, Karoline Kuchenbaecker, Eric Hahnen
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background Genome-wide association studies suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in genome-wide association studies–independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2. Methods A total of 760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, 2 SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were 2-sided. Results Both SNP sets provided concordant PRS results at the individual level (r = 0.91, P &amp;lt; 2.20 × 10−16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio of 1.71 per SD of the PRS was observed (95% confidence interval = 1.36 to 2.15, P = 3.87 × 10−6). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 hazard ratio = 1.23, 95% confidence interval = 0.86 to 1.78, P = .26). Conclusions PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition.