tbuckley/cabot-search huggingface dataset:
Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis
Authors: Jue-Sheng Ong, Jiyuan An, Xikun Han, Matthew H Law, Priyanka Nandakumar, Johannes Schumacher, Ines Gockel, Anne Bohmer, Janusz Jankowski, Claire Palles, Catherine M Olsen, Rachel E Neale, Rebecca Fitzgerald, Aaron P Thrift, Thomas L Vaughan, Matthew F Buas, David A Hinds, Puya Gharahkhani, Bradley J Kendall, Stuart MacGregor
Journal: Gut (2021)

Objective Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. Design We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). Results We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Conclusion Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.
Interim-PET As a Predictive Factor in Patients with Hodgkin's Lymphoma
Authors: Irina Kryachok, Olga Novosad, Ian Pastushenko, Tetiana Skrypets, Tetiana Kadnikova, Iryna Tytorenko, Evgen Kushchevyy, Kateryna Ulianchenko, Kateryna Filonenko, Yana Stepanishyna, Olena Aleksik, Yaroslav Kmetyuk, Olga Karpova, Larisa Mykhalska, Olga Kindrakevych, Halyna Pylypenko, Olena Lukjanec, Viktor Duma, Viktor Kozlov, Liliya Batyuk, Olena Ryzhak, Nataliia Strembitska, Hanna Chikalova, Myroslava Chupryna, Iurii Kozlov, Mykola Novikov, Viktoriia Kosinova, Olena Oliinichenko, Olena Lola, Alina Kholodna, Olga Loza, Nina Kostiukova, Oksana Tkachenko, Oksana Karnabeda, Viktoriya Stratienko, Oleksandr Gorbach, Alexey Danilov
Journal: Blood (2017)
Randomized Trial of Two Induction Therapy Regimens for High-Risk Neuroblastoma: HR-NBL1.5 International Society of Pediatric Oncology European Neuroblastoma Group Study
Authors: Alberto Garaventa, Ulrike Poetschger, Dominique Valteau-Couanet, Roberto Luksch, Victoria Castel, Martin Elliott, Shifra Ash, Godfrey C. F. Chan, Geneviève Laureys, Maja Beck-Popovic, Kim Vettenranta, Walentyna Balwierz, Henrik Schroeder, Cormac Owens, Maja Cesen, Vassilios Papadakis, Toby Trahair, Gudrun Schleiermacher, Peter Ambros, Stefania Sorrentino, Andrew D. J. Pearson, Ruth Lydia Ladenstein
Journal: Journal of Clinical Oncology (2021)

Induction therapy is a critical component of the therapy of high-risk neuroblastoma. We aimed to assess if the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen (MSKCC-N5) would improve metastatic complete response (mCR) rate and 3-year event-free survival (EFS) compared with rapid COJEC (rCOJEC; cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C]).
Clare Gerada: My father and the GMC
Authors: Clare Gerada
Journal: BMJ (2021)

We all have a narrative about why we became doctors. I was influenced by my father, who taught me from a young age to love medicine. His career started as a medical officer of health in Nigeria and ended, 45 years later, working as a volunteer with the blood transfusion service. In the time between he was a GP, with an initial list of 1500 patients in 1964, which expanded to what today would be considered a multipractice, with seven partners and 30 000 patients across three sites.

When he died, I inherited two box files of his papers, which gave details of a complaint he’d received …
Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children and adolescents: a double-blind, randomised, controlled, phase 1/2 clinical trial
Authors: Bihua Han, Yufei Song, Changgui Li, Wanqi Yang, Qingxia Ma, Zhiwei Jiang, Minjie Li, Xiaojuan Lian, Wenbin Jiao, Lei Wang, Qun Shu, Zhiwei Wu, Yuliang Zhao, Qi Li, Qiang Gao
Journal: The Lancet Infectious Diseases (2021)
Genetic Basis and Therapies for Vascular Anomalies
Authors: Angela Queisser, Emmanuel Seront, Laurence M. Boon, Miikka Vikkula
Journal: Circulation Research (2021)

Vascular and lymphatic malformations represent a challenge for clinicians. The identification of inherited and somatic mutations in important signaling pathways, including the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin), RAS (rat sarcoma)/RAF (rapidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinases), HGF (hepatocyte growth factor)/c-Met (hepatocyte growth factor receptor), and VEGF (vascular endothelial growth factor) A/VEGFR (vascular endothelial growth factor receptor) 2 cascades has led to the evaluation of tailored strategies with preexisting cancer drugs that interfere with these signaling pathways. The era of theranostics has started for the treatment of vascular anomalies. Registration: URL: https://www.clinicaltrialsregister.eu ; Unique identifier: 2015-001703-32.
Abstract 319: Structural Reorganization of Cardiac Transcription Factories Mediates Transcriptional Changes in Response to Stress
Authors: Elaheh Karbassi, Manuel Rosa Garrido, Douglas J Chapski, Yong Wu, Emma Monte, Thomas M Vondriska
Journal: Circulation Research (2016)

The heart’s response to stress entails precise gene expression changes to affect the metabolic and structural features of the cardiomyocyte. The changes in gene expression are mediated by structural alterations in the packaging of the genome. However, the manner in which the three-dimensional architecture of the genome is established is unknown. In non-cardiac cells, genes that are actively transcribed are thought to reside in transcriptionally permissive compartments called transcription factories. The structural principles for achieving cardiac-specific transcription are not understood. We sought to understand the functional nature of cardiac transcription factories: whether they are stable structures (to which genes move in and out of) or are transiently formed around genes in response to cardiac stimuli. Using 5-fluorouridine incorporation into nascent RNA, we quantified changes in RNA polymerase II-mediated transcription in cardiomyocytes upon hypertrophic stress. Furthermore, we characterized the spatial distribution of transcription factories, marked by RNA polymerase II, from adult mice subjected to pressure overload. Using super-resolution microscopy, our analyses revealed reorganization of RNA polymerase II, evidenced by a significant increase in the distance between clusters (130nm in sham to 132.5nm in failing hearts, p=0.02) and a 38% increase in cluster intensity in failing hearts. To understand regulation of cardiac gene expression, we used DNA fluorescence in situ hybridization to map the nuclear position of the gene for SERCA2a (atp2a2), which is down regulated in disease. In failing hearts, we measured increased association of atp2a2 with the nuclear envelope (0/159 loci in sham to 11/278 loci in failure) and increased colocalization with heterochromatin (53/160 loci in sham versus 139/290 loci in failure), providing a structural mechanism for the decrease in SERCA2a expression. In contrast, atp2a2 positioning in the liver remained unaffected, with the majority of loci colocalizing with heterochromatin. These findings show that RNA polymerase II is redistributed to affect transcriptional programming and characterize for the first time the structural rearrangements in chromatin that underpin cardiac pathology.
Allogeneic hematopoietic cell transplantation in older myelofibrosis patients: A study of the chronic malignancies working party of <scp>EBMT</scp> and the Spanish Myelofibrosis Registry
Authors: Juan‐Carlos Hernández‐Boluda, Arturo Pereira, Nicolaus Kröger, Jan J. Cornelissen, Jürgen Finke, Dietrich Beelen, Moniek de Witte, Keith Wilson, Uwe Platzbecker, Henrik Sengeloev, Didier Blaise, Hermann Einsele, Katja Sockel, William Krüger, Stig Lenhoff, Adriano Salaroli, Hans Martin, Valentín García‐Gutiérrez, Vicenzo Pavone, Alberto Alvarez‐Larrán, José‐María Raya, Nienke Zinger, Luuk Gras, Patrick Hayden, Tomasz Czerw, Donal P. McLornan, Ibrahim Yakoub‐Agha
Journal: American Journal of Hematology (2021)

Abstract Allogeneic hematopoietic cell transplantation (allo‐HCT) is increasingly used in older myelofibrosis (MF) patients, but its risk/benefit ratio compared to non‐transplant approaches has not been evaluated in this population. We analyzed the outcomes of allo‐HCT in 556 MF patients aged ≥65 years from the EBMT registry, and determined the excess mortality over the matched general population of MF patients ≥65 years managed with allo‐HCT (n = 556) or conventional drug treatment (n = 176). The non‐transplant cohort included patients with intermediate‐2 or high risk DIPSS from the Spanish Myelofibrosis Registry. After a median follow‐up of 3.4 years, the estimated 5‐year survival rate, non‐relapse mortality (NRM), and relapse incidence after transplantation was 40%, 37%, and 25%, respectively. Busulfan‐based conditioning was associated with decreased mortality (HR: 0.7, 95% CI: 0.5–0.9) whereas the recipient CMV+/donor CMV‐ combination (HR: 1.7, 95% CI: 1.2–2.4) and the JAK2 mutated genotype (HR: 1.9, 95% CI: 1.1–3.5) predicted higher mortality. Busulfan‐based conditioning correlated with improved survival due to less NRM, despite its higher relapse rate when compared with melphalan‐based regimens. Excess mortality was higher in transplanted patients than in the non‐HCT cohort in the first year of follow‐up (ratio: 1.93, 95% CI: 1.13–2.80), whereas the opposite occurred between the fourth and eighth follow‐up years (ratio: 0.31, 95% CI: 0.18–0.53). Comparing the excess mortality of the two treatments, male patients seemed to benefit more than females from allo‐HCT, mainly due to their worse prognosis with non‐transplant approaches. These findings could potentially enhance counseling and treatment decision‐making in elderly transplant‐eligible MF patients.
Club, country and clinicians united: ensuring collaborative care in elite sport medical handovers
Authors: Richard Weiler, Richard Collinge, Josh Ewens, Vincent Gouttebarge, Andrew Massey, Pippa Bennett, Kelly Smith, Osman Hassan Ahmed
Journal: British Journal of Sports Medicine (2021)

Medical handovers are fundamental to optimal patient care but can be a source of errors in clinical care with important implications on patient welfare and safety.1–4 Care of international athletes presents unique challenges to open and effective communication between medical teams. Handover of complete medical records should occur with athlete consent between medical teams on the transfer of an athlete between clubs. There are currently no specific guidelines or published recommendations advising sports and exercise medicine clinicians about medical handovers. The aim of this editorial is to provide a checklist of recommendations for the handover of elite athlete care between clubs and national medical and sports science teams, with lessons shared from professional football (soccer).

Accurate clinical records are key to patient safety and protect patients and clinicians in sports medicine and science. In professional football for instance, there are currently 211 men’s5 and 159 women’s6 FIFA registered international football teams. Squads generally consist of 23 players, resulting in up to 8487 players being available for ‘call up’ to international fixtures. Medical and sports science resources vary widely across clubs, sports, sexes, countries, age groups and Para sports, and information available for handover will vary accordingly, creating challenges to meet …
Abstract LB148: Gamma delta T cells engineered with a chimeric PD-1 receptor effectively control PD-L1 positive tumors in vitro and in vivo with minimal toxicities
Authors: Amorette Barber, Xiaohong Wang, Anupama Gopisetty, Leonardo Mirandola, Maurizio Chiriva-Internati
Journal: Cancer Research (2021)

Abstract Introduction. Despite the overwhelming success of anti-CD19 CAR T cell therapies in recent years, it is still impossible to date to replicate comparable results in patients with solid tumors. Such obstacle is due to many factors, but the three most relevant ones are: a) the complex and immune-suppressive tumor microenvironment, b) the lack of optimal tumor targets that are not also expressed on normal cells and c) the use of autologous, patient-derived cells, which are frequently sub-optimal due to chemotherapy. Here we investigated a novel strategy to overcome these three barriers by using unconventional, MHC-independent gamma delta T cells and a chimeric PD-1 protein that was previously validated in murine conventional alpha-beta T cells. We tested the hypothesis that our strategy could specifically target cancer cells without a CAR for a specific tumor-associated antigen by turning PD-1 immune suppression into T-cell activation and using donor-derived, “off-the-shelf” effector cells. Experimental procedures. We built a chimeric PD-1 receptor consisting of the extracellular portion of PD-1 fused to the intracellular domains of DAP10 and CD3z. Gamma delta T cells from healthy donors were expanded ex vivo and stably transduced with a gamma-retrovirus-derived viral vector carrying the chimeric construct. Cells were tested for killing efficiency, cytokines secretion, and memory differentiation in vitro. We then evaluated the in vivo efficacy and tolerability in murine xenografts. Results. chPD1-gdT cells selectively killed PDL-1+ tumor cells, with minimal on-target/off-tumor toxicities and without off-target toxicities. Cells were well tolerated in mice, without damage to normal PD-L1+ cells. Upon contact with PD-L1+ cancers, chPD1-gdT cells, but not untransduced gdT cells, expressed markers of memory phenotype and secreted inflammatory cytokines. In vivo, chPD1-gdT cells, but not untransduced gdT cells, cleared PD-L1+ tumors without significant elevation of CRS-related cytokines nor off-tumor toxicities. Conclusions. chPD1-gdT cells are potent and safe in vitro and in vivo and will be assessed in a Phase I/II clinical trial. Citation Format: Amorette Barber, Xiaohong Wang, Anupama Gopisetty, Leonardo Mirandola, Maurizio Chiriva-Internati. Gamma delta T cells engineered with a chimeric PD-1 receptor effectively control PD-L1 positive tumors in vitro and in vivo with minimal toxicities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB148.
Response to: ‘Correspondence on ‘Five-year treat-to-target outcomes after methotrexate induction therapy with or without other csDMARDs and temporary glucocorticoids for rheumatoid arthritis in the CareRA trial’’ by Jain and Dhir<i>et al</i>
Authors: Veerle Stouten, René Westhovens, Sofia Pazmino, Diederik De Cock, Kristien Van der Elst, Johan Joly, Delphine Bertrand, Patrick Verschueren
Journal: Annals of the Rheumatic Diseases (2021)

We thank Dr Dhir et al for their kind words and would like to address some of the points raised.1

First, in patients without markers of poor prognosis, the COBRA-Slim scheme with methotrexate (MTX) and prednisone bridging led to a more rapid response than initial MTX monotherapy in the first 16 weeks.2 Subsequently, remission rates did not differ until year 5, but patients starting a COBRA-Slim scheme had a lower disease activity and better functionality longitudinally over 5 years.3–5 This long-term effect of prednisone bridging seems counterintuitive to Dr Dhir, given the results of the 'BehandelStrategieen in Reumatoide Arthritis' (BeSt) study and the 'Treatment of Early Aggressive Rheumatoid Arthritis' (TEAR) trial, showing that long-term outcomes were essentially determined by treating-to-target.6 7 Unfortunately, differences in design and follow-up duration hamper direct comparisons of the Care in early Rheumatoid Arthritis (CareRA) study with these trials. The 2-year TEAR trial did not include a glucocorticoid bridging scheme in its MTX step-up arms, but 40% of patients were already on low-dose oral glucocorticoids at baseline, which was prohibited per protocol in the MTX-Tight-Step-Up (TSU) arm of CareRA. Moreover, only about one in …
Abstract 203: A Shh Coreceptor Cdo is Required for Efficient Cardiomyogenesis of Pluripotent Stem Cells
Authors: Myong-Ho Jeong, Young-Eun Leem, Hyun-Ji Kim, Kyungjin Kang, Hana Cho, Jong-Sun Kang
Journal: Circulation Research (2016)

Sonic hedgehog (Shh) signaling plays an important role for early heart development, such as heart looping and cardiomyogenesis of pluripotent stem cells. A multifunctional receptor Cdo functions as a Shh coreceptor together with Boc and Gas1 to activate Shh signaling and these coreceptors seem to play compensatory roles in early heart development. Thus in this study, we examined the role of Cdo in cardiomyogenesis by utilizing an in vitro differentiation of pluripotent stem cells. Here we show that Cdo is required for efficient cardiomyogenesis of pluripotent stem cells by activation of Shh signaling. Cdo is induced concurrently with Shh signaling activation upon induction of cardiomyogenesis of P19 embryonal carcinoma (EC) cells. Cdo -depleted P19 EC and Cdo –/– mouse embryonic stem (ES) cells display decreased expression of key cardiac regulators, including Gata4, Nkx2.5 and Mef2c and this decrease coincides with reduced Shh signaling activities. Furthermore Cdo deficiency causes a stark reduction in formation of mature contractile cardiomyocytes. This defect in cardiomyogenesis is overcome by reactivation of Shh signaling at the early specification stage of cardiomyogenesis. The Shh agonist treatment restores differentiation capacities of Cdo -deficient ES cells into contractile cardiomyocytes by recovering both the expression of early cardiac regulators and structural genes such as cardiac troponin T and Connexin 43. Therefore Cdo is required for efficient cardiomyogenesis of pluripotent stem cells and an excellent target to improve the differentiation potential of stem cells for generation of transplantable cells to treat cardiomyopathies.
Defining comprehensive models of care for NAFLD
Authors: Jeffrey V. Lazarus, Quentin M. Anstee, Hannes Hagström, Kenneth Cusi, Helena Cortez-Pinto, Henry E. Mark, Michael Roden, Emmanuel A. Tsochatzis, Vincent Wai-Sun Wong, Zobair M. Younossi, Shira Zelber-Sagi, Manuel Romero-Gómez, Jörn M. Schattenberg
Journal: Nature Reviews Gastroenterology & Hepatology (2021)
Symptoms of Depression, Anxiety, Post-Traumatic Stress Disorder, and Suicidal Ideation Among State, Tribal, Local, and Territorial Public Health Workers During the COVID-19 Pandemic — United States, March–April 2021
Authors: Jonathan Bryant-Genevier, Carol Y. Rao, Barbara Lopes-Cardozo, Ahoua Kone, Charles Rose, Isabel Thomas, Diana Orquiola, Ruth Lynfield, Dhara Shah, Lori Freeman, Scott Becker, Amber Williams, Deborah W. Gould, Hope Tiesman, Geremy Lloyd, Laura Hill, Ramona Byrkit
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Increases in mental health conditions have been documented among the general population and health care workers since the start of the COVID-19 pandemic (1-3). Public health workers might be at similar risk for negative mental health consequences because of the prolonged demand for responding to the pandemic and for implementing an unprecedented vaccination campaign. The extent of mental health conditions among public health workers during the COVID-19 pandemic, however, is uncertain. A 2014 survey estimated that there were nearly 250,000 state and local public health workers in the United States (4). To evaluate mental health conditions among these workers, a nonprobability-based online survey was conducted during March 29-April 16, 2021, to assess symptoms of depression, anxiety, post-traumatic stress disorder (PTSD), and suicidal ideation among public health workers in state, tribal, local, and territorial public health departments. Among 26,174 respondents, 53.0% reported symptoms of at least one mental health condition in the preceding 2 weeks, including depression (32.0%), anxiety (30.3%), PTSD (36.8%), or suicidal ideation (8.4%). The highest prevalence of symptoms of a mental health condition was among respondents aged ≤29 years (range = 13.6%-47.4%) and transgender or nonbinary persons (i.e., those who identified as neither male nor female) of all ages (range = 30.4%-65.5%). Public health workers who reported being unable to take time off from work were more likely to report adverse mental health symptoms. Severity of symptoms increased with increasing weekly work hours and percentage of work time dedicated to COVID-19 response activities. Implementing prevention and control practices that eliminate, reduce, and manage factors that cause or contribute to public health workers' poor mental health might improve mental health outcomes during emergencies.