tbuckley/cabot-search huggingface dataset:
Pathogen diversity and antimicrobial resistance transmission of Salmonella enterica serovars Typhi and Paratyphi A in Bangladesh, Nepal, and Malawi: a genomic epidemiological study
Authors: Zoe A Dyson, Philip M Ashton, Farhana Khanam, Angeziwa Chunga Chirambo, Mila Shakya, James E Meiring, Susan Tonks, Abhilasha Karkey, Chisomo Msefula, John D Clemens, Sarah J Dunstan, Stephen Baker, Gordon Dougan, Virginia E Pitzer, Buddha Basnyat, Firdausi Qadri, Robert S Heyderman, Melita A Gordon, Andrew J Pollard, Kathryn E Holt, Happy C Banda, Prasanta K Biswas, Md A I Bhuiyan, Christoph Blohmke, Thomas C Darton, Christiane Dolecek, Sabina Dongol, Yama F Mujadidi, Jennifer Hill, Nhu T Hoang, Tikhala M Jere, Maurice Mbewe, Harrison Msuku, Tran V T Nga, Rose Nkhata, Sadia IA Rahman, Nazia Rahman, Neil J Saad, Trinh V Tan, Deus Thindwa, Merryn Voysey, Richard Wachepa
Journal: The Lancet Microbe (2024)
A prognostic and predictive computational pathology immune signature for ductal carcinoma in situ: retrospective results from a cohort within the UK/ANZ DCIS trial
Authors: Haojia Li, Arpit Aggarwal, Paula Toro, Pingfu Fu, Sunil S Badve, Jack Cuzick, Anant Madabhushi, Mangesh A Thorat
Journal: The Lancet Digital Health (2024)
Changing patterns of health risk in adolescence: implications for health policy
Authors: Oliver T Mytton, Liam Donaldson, Anne-Lise Goddings, Gabrielle Mathews, Joseph L Ward, Felix Greaves, Russell M Viner
Journal: The Lancet Public Health (2024)

Adolescence is a time of physical, cognitive, social, and emotional development. This period is a very sensitive developmental window; environmental exposures, the development of health behaviours (eg, smoking and physical activity), and illness during adolescence can have implications for lifelong health. In the UK and other high-income countries, the experience of adolescence has changed profoundly over the past 20 years. Smoking, drug use, and alcohol consumption have all been in long-term decline. At the same time, obesity and mental ill health have increased and are now common among adolescents, with new risks (ie, vaping, psychoactive substances, and online harms) emerging. In this Viewpoint, we describe these and related trends in England and the UK. Although previous work has explored these changes in isolation, in this Viewpoint we consider them collectively. We explore what might be driving the changes and consider the implications for practice, policy, and research.
Portal vein thrombosis: diagnosis, management, and endpoints for future clinical studies
Authors: Laure Elkrief, Virginia Hernandez-Gea, Marco Senzolo, Agustin Albillos, Anna Baiges, Annalisa Berzigotti, Christophe Bureau, Sarwa Darwish Murad, Andrea De Gottardi, François Durand, Juan-Carlos Garcia-Pagan, Ton Lisman, Mattias Mandorfer, Valérie McLin, Lucile Moga, Filipe Nery, Patrick Northup, Alexandre Nuzzo, Valérie Paradis, David Patch, Audrey Payancé, Vincent Plaforet, Aurélie Plessier, Johanne Poisson, Lara Roberts, Riad Salem, Shiv Sarin, Akash Shukla, Christian Toso, Dhiraj Tripathi, Dominique Valla, Maxime Ronot, Pierre-Emmanuel Rautou
Journal: The Lancet. Gastroenterology & hepatology (2024)
Reporting of surrogate endpoints in randomised controlled trial reports (CONSORT-Surrogate): extension checklist with explanation and elaboration
Authors: Anthony Muchai Manyara, Philippa Davies, Derek Stewart, Christopher J Weir, Amber E Young, Jane Blazeby, Nancy J Butcher, Sylwia Bujkiewicz, An-Wen Chan, Dalia Dawoud, Martin Offringa, Mario Ouwens, Asbjørn Hróbjartssson, Alain Amstutz, Luca Bertolaccini, Vito Domenico Bruno, Declan Devane, Christina D C M Faria, Peter B Gilbert, Ray Harris, Marissa Lassere, Lucio Marinelli, Sarah Markham, John H Powers, Yousef Rezaei, Laura Richert, Falk Schwendicke, Larisa G Tereshchenko, Achilles Thoma, Alparslan Turan, Andrew Worrall, Robin Christensen, Gary S Collins, Joseph S Ross, Rod S Taylor, Oriana Ciani
Journal: BMJ (2024)
Reply to Kuo-Chin Hung and Chia-Ter Chao’s Letter to the Editor re: Jennifer Kranz, Riccardo Bartoletti, Franck Bruyère, et al. European Association of Urology Guidelines on Urological Infections: Summary of the 2024 Guidelines. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2024.03.035
Authors: Jennifer Kranz, Gernot Bonkat
Journal: European Urology (2024)
Re: Jennifer Kranz, Riccardo Bartoletti, Franck Bruyère, et al. European Association of Urology Guidelines on Urological Infections: Summary of the 2024 Guidelines. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2024.03.035
Authors: Kuo-Chin Hung, Chia-Ter Chao
Journal: European Urology (2024)
Re: Thomas Powles, Begoña Pérez-Valderrama, Shilpa Gupta, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med 2024;390:875–88
Authors: Enrique Grande, Alison Jane Birtle, Ashish M. Kamat
Journal: European Urology (2024)
Neutralizing Antibodies Targeting BK Polyomavirus
Authors: Francois Helle, Aurélien Aubry, Virginie Morel, Véronique Descamps, Baptiste Demey, Etienne Brochot
Journal: Journal of the American Society of Nephrology (2024)

Most of the world's adult population is latently infected by the BK polyomavirus. It causes asymptomatic infection in healthy individuals but emerged as a threat to kidney transplant recipients because of virus-associated nephropathy caused by immunosuppressive therapy. In these conditions, when a functional cellular response is impaired by immunosuppression, neutralizing antibodies may play a major role because they can directly prevent infection of target cells, independently of cell-mediated immunity, by binding to the viral particles. Studying the contribution of anti-BK virus neutralizing antibodies in viral control has long been hampered by the lack of convenient in vitro models, but major progress has been made in the past decade. The four BK virus genotypes have been demonstrated to behave as distinct serotypes. A low recipient neutralizing antibody titer against the donor's serotype before kidney transplant has been significantly associated with BK virus replication after transplant. Different mechanisms exploited by the BK virus to evade neutralizing antibodies have been described. Recent studies also support the potential benefit of administering intravenous Igs or monoclonal neutralizing antibodies as a therapeutic strategy, and more interestingly, this could also be used as preventive or preemptive therapy before advanced kidney damage has occurred. Besides, neutralizing antibodies could be induced by vaccination. In this review, we summarize accumulated knowledge on anti-BK virus neutralizing antibodies as well as their clinical importance and therapeutic potential for kidney transplant recipients.
From mesenchymal stem cells to their extracellular vesicles: Progress and prospects for asthma therapy
Authors: Shihan Chen, Jianqing Gao, Tianyuan Zhang
Journal: Asian Journal of Pharmaceutical Sciences (2024)

Asthma is a widespread public health concern, with an increasing incidence. Despite the implementation of current treatment strategies, asthma control, particularly for severe cases, remains suboptimal. Recent research has revealed the encouraging prospects of extracellular vesicles (EVs) secreted by mesenchymal stem cells (MSCs) as a viable therapeutic option for alleviating asthma symptoms. Therefore, the present review aims to provide an overview of the current progress and the therapeutic mechanisms of using MSC-derived EVs (MSC-EVs) for asthma treatment. Additionally, different administration approaches for EVs and their impacts on biodistribution and the curative outcomes of EVs are summarized. Notably, the potential benefits of nebulized inhalation of MSC-EVs are addressed. Also, the possibilities and challenges of using MSC-EVs for asthma treatment in clinics are highlighted. Overall, this review is intended to give new insight into the utilization of MSC-EVs as a potential biological drug for asthma treatment.
From silos to synergy: integrating academic health informatics with operational IT for healthcare transformation
Authors: Devin M. Mann, Elizabeth R. Stevens, Paul Testa, Nader Mherabi
Journal: npj Digital Medicine (2024)

We have entered a new age of health informatics—applied health informatics—where digital health innovation cannot be pursued without considering operational needs. In this new digital health era, creating an integrated applied health informatics system will be essential for health systems to achieve informatics healthcare goals. Integration of information technology (IT) and health informatics does not naturally occur without a deliberate and intentional shift towards unification. Recognizing this, NYU Langone Health's (NYULH) Medical Center IT (MCIT) has taken proactive measures to vertically integrate academic informatics and operational IT through the establishment of the MCIT Department of Health Informatics (DHI). The creation of the NYULH DHI showcases the drivers, challenges, and ultimate successes of our enterprise effort to align academic health informatics with IT; providing a model for the creation of the applied health informatics programs required for academic health systems to thrive in the increasingly digitized healthcare landscape.
Plasma soluble fms‐like tyrosine kinase‐1, placental growth factor, and vascular endothelial growth factor system gene variants as predictors of survival in heart failure
Authors: Melinda A. Paterson, Anna P. Pilbrow, Chris M. Frampton, Vicky A. Cameron, Richard W. Troughton, Chris J. Pemberton, Mayanna Lund, Gerard P. Devlin, A. Mark Richards, Robert N. Doughty, Barry R. Palmer
Journal: European Journal of Heart Failure (2024)

Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt-1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF.
Safety and efficacy of baricitinib in steroid‐resistant or relapsed immune thrombocytopenia: An open‐label pilot study
Authors: Peng Zhao, Zhuo‐Yu An, Hai‐Xia Fu, Hui‐Xin Liu, Cheng‐Jie Feng, Qiu‐Sha Huang, Jin Wu, Ye‐Jun Wu, Li‐Ping Yang, Qing‐Yuan Qu, Yu‐Xiu Chen, Meng‐Lin Li, Chen‐Cong Wang, Qi Chen, Xiao‐Lu Zhu, Yun He, Yuan‐Yuan Zhang, Qian Jiang, Hao Jiang, Jin Lu, Ying‐Jun Chang, Xiao‐Su Zhao, Xiang‐Yu Zhao, Xiao‐Jun Huang, Xiao‐Hui Zhang
Journal: American Journal of Hematology (2024)

Abstract Patients with steroid‐resistant or relapsed immune thrombocytopenia (ITP) suffer increased bleeding risk and impaired quality of life. Baricitinib, an oral Janus‐associated kinases (JAK) inhibitor, could alleviate both innate and adaptive immune disorders without inducing thrombocytopenia in several autoimmune diseases. Accordingly, an open‐label, single‐arm, phase 2 trial (NCT05446831) was initiated to explore the safety and efficacy of baricitinib in ITP. Eligible patients were adults with primary ITP who were refractory to corticosteroids and at least one subsequent treatment, and had platelet counts below 30 × 10 9 /L at enrolment. Participants received baricitinib 4 mg daily for 6 months. The primary endpoint was durable response at the 6‐month follow‐up. A total of 35 patients were enrolled. Durable response was achieved in 20 patients (57.1%, 95% confidence interval, 39.9 to 74.4), and initial response in 23 (65.7%) patients. For patients responding to baricitinib, the median time to response was 12 (IQR 6–20) days, and the median peak platelet count was 94 (IQR 72–128) × 10 9 /L. Among the 27 patients undergoing extend observation, 12 (44.4%) remained responsive for a median duration of approximately 20 weeks after baricitinib discontinuation. Adverse events were reported in 11 (31.4%) patients, including infections in 6 (17.1%) patients during the treatment period. Treatment discontinuation due to an adverse event was reported in 2 (5.7%) patients. Evidence from this pilot study suggested that baricitinib might be a novel candidate for the armamentarium of ITP‐modifying agents. Future studies are warranted to validate the safety, efficacy, and optimal dosing of baricitinib in patients with ITP.
Asthma Inception: Epidemiologic Risk Factors and Natural History Across the Life-Course
Authors: Erik Melén, Heather J Zar, Valerie Siroux, Dominic Shaw, Sejal Saglani, Gerard H Koppelman, Tina Hartert, James E. Gern, Benjamin Gaston, Andrew Bush, Joe Zein
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Asthma is a descriptive label for an obstructive inflammatory disease in the lower airways manifesting with symptoms including breathlessness, cough, difficulty in breathing, and wheezing. From a clinician's point of view, asthma symptoms can commence at any age, although most patients with asthma-regardless of their age of onset-seem to have had some form of airway problems during childhood. Asthma inception and related pathophysiologic processes are therefore very likely to occur early in life, further evidenced by recent lung physiologic and mechanistic research. Herein, we present state-of-the-art updates on the role of genetics and epigenetics, early viral and bacterial infections, immune response, and pathophysiology, as well as lifestyle and environmental exposures, in asthma across the life course. We conclude that early environmental insults in genetically vulnerable individuals inducing abnormal, pre-asthmatic airway responses are key events in asthma inception, and we highlight disease heterogeneity across ages and the potential shortsightedness of treating all patients with asthma using the same treatments. Although there are no interventions that, at present, can modify long-term outcomes, a precision-medicine approach should be implemented to optimize treatment and tailor follow-up for all patients with asthma.
A kinome drug screen identifies multi-TKI synergies and ERBB2 signaling as a therapeutic vulnerability in MYC/TYR subgroup ATRTs
Authors: Brian Golbourn, Ben Ho, Andrew Bondoc, Amanda Luck, Xiaolian Fan, Elizabeth Richardson, Richard Marcellus, Michael Prakesch, Mathew Halbert, Nishant Agrawal, Christian Smith, Annie Huang, James T Rutka
Journal: Neuro-Oncology (2024)

Abstract Background Atypical teratoid rhabdoid tumor (ATRT) is a rare, devastating, and largely incurable pediatric brain tumor. Although recent studies have uncovered 3 molecular subgroups of ATRTs with distinct disease patterns, and signaling features, the therapeutic profiles of ATRT subgroups remain incompletely elucidated. Methods We examined the effect of 465 kinase inhibitors on a panel of ATRT subgroup-specific cell lines. We then applied multiomics analyses to investigate the underlying molecular mechanism of kinase inhibitor efficacy in ATRT subgroups. Results We observed that ATRT cell lines are broadly sensitive to inhibitors of the PI3K and MAPK signaling pathways, as well as CDKs, AURKA/B kinases, and polo-like kinase 1. We identified 2 classes of multikinase inhibitors predominantly targeting receptor tyrosine kinases including PDGFR and EGFR/ERBB2 in MYC/TYR ATRT cells. The PDGFRB inhibitor, Dasatinib, synergistically affected MYC/TYR ATRT cell growth when combined with broad-acting PI3K and MAPK pathway inhibitors, including Rapamycin and Trametinib. We observed that MYC/TYR ATRT cells were also distinctly sensitive to various inhibitors of ERBB2 signaling. Transcriptional, H3K27Ac ChIPSeq, ATACSeq, and HiChIP analyses of primary MYC/TYR ATRTs revealed ERBB2 expression, which correlated with differential methylation and activation of a distinct enhancer element by DNA looping. Significantly, we show the brain penetrant EGFR/ERBB2 inhibitor, Afatinib, specifically inhibited in vitro and in vivo growth of MYC/TYR ATRT cells. Conclusions Taken together, our studies suggest combined treatments with PDGFR and ERBB2-directed TKIs with inhibitors of the PI3K and MAPK pathways as an important new therapeutic strategy for the MYC/TYR subgroup of ATRTs.
Identification of Parkinson’s disease PACE subtypes and repurposing treatments through integrative analyses of multimodal data
Authors: Chang Su, Yu Hou, Jielin Xu, Zhenxing Xu, Manqi Zhou, Alison Ke, Haoyang Li, Jie Xu, Matthew Brendel, Jacqueline R. M. A. Maasch, Zilong Bai, Haotan Zhang, Yingying Zhu, Molly C. Cincotta, Xinghua Shi, Claire Henchcliffe, James B. Leverenz, Jeffrey Cummings, Michael S. Okun, Jiang Bian, Feixiong Cheng, Fei Wang
Journal: npj Digital Medicine (2024)

Abstract Parkinson’s disease (PD) is a serious neurodegenerative disorder marked by significant clinical and progression heterogeneity. This study aimed at addressing heterogeneity of PD through integrative analysis of various data modalities. We analyzed clinical progression data (≥5 years) of individuals with de novo PD using machine learning and deep learning, to characterize individuals’ phenotypic progression trajectories for PD subtyping. We discovered three pace subtypes of PD exhibiting distinct progression patterns: the Inching Pace subtype (PD-I) with mild baseline severity and mild progression speed; the Moderate Pace subtype (PD-M) with mild baseline severity but advancing at a moderate progression rate; and the Rapid Pace subtype (PD-R) with the most rapid symptom progression rate. We found cerebrospinal fluid P-tau/α-synuclein ratio and atrophy in certain brain regions as potential markers of these subtypes. Analyses of genetic and transcriptomic profiles with network-based approaches identified molecular modules associated with each subtype. For instance, the PD-R-specific module suggested STAT3 , FYN , BECN1 , APOA1 , NEDD4 , and GATA2 as potential driver genes of PD-R. It also suggested neuroinflammation, oxidative stress, metabolism, PI3K/AKT, and angiogenesis pathways as potential drivers for rapid PD progression (i.e., PD-R). Moreover, we identified repurposable drug candidates by targeting these subtype-specific molecular modules using network-based approach and cell line drug-gene signature data. We further estimated their treatment effects using two large-scale real-world patient databases; the real-world evidence we gained highlighted the potential of metformin in ameliorating PD progression. In conclusion, this work helps better understand clinical and pathophysiological complexity of PD progression and accelerate precision medicine.
Hemolytic versus malproductive anemia in large granular lymphocytic leukemia
Authors: Olisaemeka Ogbue, Tariq Kewan, Carlos Bravo-Perez, Serhan Unlu, Naomi Kawashima, Nakisha D. Williams, Arooj Ahmed, Luca Guarnera, Carmelo Gurnari, Valeria Visconte, Jaroslaw P. Maciejewski
Journal: Leukemia (2024)
Exome sequencing in undiagnosed congenital myopathy reveals new genes and refines genes–phenotypes correlations
Authors: Yvan de Feraudy, Marie Vandroux, Norma Beatriz Romero, Raphaël Schneider, Safaa Saker, Anne Boland, Jean-François Deleuze, Valérie Biancalana, Johann Böhm, Jocelyn Laporte
Journal: Genome Medicine (2024)

Abstract Background Congenital myopathies are severe genetic diseases with a strong impact on patient autonomy and often on survival. A large number of patients do not have a genetic diagnosis, precluding genetic counseling and appropriate clinical management. Our objective was to find novel pathogenic variants and genes associated with congenital myopathies and to decrease diagnostic odysseys and dead-end. Methods To identify pathogenic variants and genes implicated in congenital myopathies, we established and conducted the MYOCAPTURE project from 2009 to 2018 to perform exome sequencing in a large cohort of 310 families partially excluded for the main known genes. Results Pathogenic variants were identified in 156 families (50%), among which 123 families (40%) had a conclusive diagnosis. Only 44 (36%) of the resolved cases were linked to a known myopathy gene with the corresponding phenotype, while 55 (44%) were linked to pathogenic variants in a known myopathy gene with atypical signs, highlighting that most genetic diagnosis could not be anticipated based on clinical–histological assessments in this cohort. An important phenotypic and genetic heterogeneity was observed for the different genes and for the different congenital myopathy subtypes, respectively. In addition, we identified 14 new myopathy genes not previously associated with muscle diseases (20% of all diagnosed cases) that we previously reported in the literature, revealing novel pathomechanisms and potential therapeutic targets. Conclusions Overall, this approach illustrates the importance of massive parallel gene sequencing as a comprehensive tool for establishing a molecular diagnosis for families with congenital myopathies. It also emphasizes the contribution of clinical data, histological findings on muscle biopsies, and the availability of DNA samples from additional family members to the diagnostic success rate. This study facilitated and accelerated the genetic diagnosis of congenital myopathies, improved health care for several patients, and opened novel perspectives for either repurposing of existing molecules or the development of novel treatments.
Transcriptional phenocopies of deleterious KEAP1 mutations correlate with survival outcomes in lung cancer treated with immunotherapy
Authors: Stefano Scalera, Biagio Ricciuti, Daniele Marinelli, Marco Mazzotta, Laura Cipriani, Giulia Bon, Giulia Schiavoni, Irene Terrenato, Alessandro Di Federico, Joao V. Alessi, Maurizio Fanciulli, Ludovica Ciuffreda, Francesca De Nicola, Frauke Goeman, Giulio Caravagna, Daniele Santini, Ruggero De Maria, Federico Cappuzzo, Gennaro Ciliberto, Mariam Jamal-Hanjani, Mark M. Awad, Nicholas McGranahan, Marcello Maugeri-Saccà
Journal: Clinical Cancer Research (2024)

Co-occurring mutations in KEAP1 and STK11/KRAS have emerged as determinants of survival outcomes in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy. However, these mutational contexts identify a fraction of nonresponders to immune checkpoint inhibitors. We hypothesized that KEAP1 wild-type tumors recapitulate the transcriptional footprint of KEAP1 mutations and that this KEAPness phenotype can determine immune responsiveness with higher precision compared to mutation-based models. The Cancer Genome Atlas was used to infer the KEAPness phenotype and explore its immunological correlates at the pan-cancer level. The association between KEAPness and survival outcomes was tested in two independent cohorts of patients with advanced NSCLC treated with immunotherapy and profiled by RNA sequencing (SU2C n = 153; OAK/POPLAR n = 439). The NSCLC TRACERx421 multiregion sequencing study (tumor regions, n = 947) was used to investigate evolutionary trajectories. KEAPness-dominant tumors represented 50% of all NSCLCs and were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAPness-free cases in independent cohorts of patients with NSCLC treated with immunotherapy (SU2C PFS P = 0.042, OS P = 0.008; OAK/POPLAR PFS P = 0.0014, OS P < 0.001). Patients with KEAPness tumors had survival outcomes comparable to those with KEAP1-mutant tumors. In the TRACERx421, KEAPness exhibited limited transcriptional intratumoral heterogeneity and immune exclusion, resembling the KEAP1-mutant disease. This phenotypic state occurred across genetically divergent tumors, exhibiting shared and private cancer genes under positive selection when compared to KEAP1-mutant tumors. We identified a KEAPness phenotype across evolutionary divergent tumors. KEAPness outperforms mutation-based classifiers as a biomarker of inferior survival outcomes in patients with NSCLC treated with immunotherapy.