tbuckley/cabot-search huggingface dataset:
Sevuparin for the treatment of acute pain crisis in patients with sickle cell disease: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial
Authors: Bart J Biemond, Anil Tombak, Yurdanur Kilinc, Murtadha Al-Khabori, Miguel Abboud, Mohammed Nafea, Adlette Inati, Yasser Wali, Jens Kristensen, Jan Kowalski, Ellen Donnelly, John Ohd, Erfan Nur, Anita W. Rijneveld, Alibülent Antmen, Marvin Reid, Gabriel Ukala, Lisa Kirven-Dawes, Curis Yeates, Hugh Wong, Abdulrahman Al Sultan
Journal: The Lancet Haematology (2021)
The Evolution of Calcification in Reef-Building Corals
Authors: Xin Wang, Didier Zoccola, Yi Jin Liew, Eric Tambutte, Guoxin Cui, Denis Allemand, Sylvie Tambutte, Manuel Aranda
Journal: Molecular Biology and Evolution (2021)

Abstract Corals build the structural foundation of coral reefs, one of the most diverse and productive ecosystems on our planet. Although the process of coral calcification that allows corals to build these immense structures has been extensively investigated, we still know little about the evolutionary processes that allowed the soft-bodied ancestor of corals to become the ecosystem builders they are today. Using a combination of phylogenomics, proteomics, and immunohistochemistry, we show that scleractinian corals likely acquired the ability to calcify sometime between ∼308 and ∼265 Ma through a combination of lineage-specific gene duplications and the co-option of existing genes to the calcification process. Our results suggest that coral calcification did not require extensive evolutionary changes, but rather few coral-specific gene duplications and a series of small, gradual optimizations of ancestral proteins and their co-option to the calcification process.
Cannabis Use, Pulmonary Function, and Lung Cancer Susceptibility: A Mendelian Randomization Study
Authors: Sebastian-Edgar Baumeister, Hansjörg Baurecht, Michael Nolde, Zoheir Alayash, Sven Gläser, Mattias Johansson, Christopher I. Amos, Emma C. Johnson, Rayjean J. Hung
Journal: Journal of Thoracic Oncology (2021)
Long-term mortality risk stratification of liver transplant recipients: real-time application of deep learning algorithms on longitudinal data
Authors: Osvald Nitski, Amirhossein Azhie, Fakhar Ali Qazi-Arisar, Xueqi Wang, Shihao Ma, Leslie Lilly, Kymberly D Watt, Josh Levitsky, Sumeet K Asrani, Douglas S Lee, Barry B Rubin, Mamatha Bhat, Bo Wang
Journal: The Lancet Digital Health (2021)

BackgroundSurvival of liver transplant recipients beyond 1 year since transplantation is compromised by an increased risk of cancer, cardiovascular events, infection, and graft failure. Few clinical tools are available to identify patients at risk of these complications, which would flag them for screening tests and potentially life-saving interventions. In this retrospective analysis, we aimed to assess the ability of deep learning algorithms of longitudinal data from two prospective cohorts to predict complications resulting in death after liver transplantation over multiple timeframes, compared with logistic regression models.MethodsIn this machine learning analysis, model development was done on a set of 42 146 liver transplant recipients (mean age 48·6 years [SD 17·3]; 17 196 [40·8%] women) from the Scientific Registry of Transplant Recipients (SRTR) in the USA. Transferability of the model was further evaluated by fine-tuning on a dataset from the University Health Network (UHN) in Canada (n=3269; mean age 52·5 years [11·1]; 1079 [33·0%] women). The primary outcome was cause of death, as recorded in the databases, due to cardiovascular causes, infection, graft failure, or cancer, within 1 year and 5 years of each follow-up examination after transplantation. We compared the performance of four deep learning models against logistic regression, assessing performance using the area under the receiver operating characteristic curve (AUROC).FindingsIn both datasets, deep learning models outperformed logistic regression, with the Transformer model achieving the highest AUROCs in both datasets (p<0·0001). The AUROC for the Transformer model across all outcomes in the SRTR dataset was 0·804 (99% CI 0·795–0·854) for 1-year predictions and 0·733 (0·729–0·769) for 5-year predictions. In the UHN dataset, the AUROC for the top-performing deep learning model was 0·807 (0·795–0·842) for 1-year predictions and 0·722 (0·705–0·764) for 5-year predictions. AUROCs ranged from 0·695 (0·680–0·713) for prediction of death from infection within 5 years to 0·859 (0·847–0·871) for prediction of death by graft failure within 1 year.InterpretationDeep learning algorithms can incorporate longitudinal information to continuously predict long-term outcomes after liver transplantation, outperforming logistic regression models. Physicians could use these algorithms at routine follow-up visits to identify liver transplant recipients at risk for adverse outcomes and prevent these complications by modifying management based on ranked features.FundingCanadian Donation and Transplant Research Program, CIFAR AI Chairs Program.
Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma
Authors: Maria V. Mateos, Maria Gavriatopoulou, Thierry Facon, Holger W. Auner, Xavier Leleu, Roman Hájek, Meletios A. Dimopoulos, Sosana Delimpasi, Maryana Simonova, Ivan Špička, Ludĕk Pour, Iryna Kriachok, Halyna Pylypenko, Vadim Doronin, Ganna Usenko, Reuben Benjamin, Tuphan K. Dolai, Dinesh K. Sinha, Christopher P. Venner, Mamta Garg, Don A. Stevens, Hang Quach, Sundar Jagannath, Philippe Moreau, Moshe Levy, Ashraf Z. Badros, Larry D. Anderson, Nizar J. Bahlis, Michele Cavo, Yi Chai, Jacqueline Jeha, Melina Arazy, Jatin Shah, Sharon Shacham, Michael G. Kauffman, Paul G. Richardson, Sebastian Grosicki
Journal: Journal of Hematology & Oncology (2021)

Abstract Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m 2 ) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT. Trial registration : ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562 .
mTOR Activation Initiates Renal Cell Carcinoma Development by Coordinating ERK and p38MAPK
Authors: Hongguang Wu, Dan He, Soma Biswas, Md Shafiquzzaman, Xin Zhou, Jean Charron, Yibin Wang, Bijaya K. Nayak, Samy L. Habib, Huijuan Liu, Baojie Li
Journal: Cancer Research (2021)

Abstract Renal cell carcinoma (RCC) mainly originates from renal proximal tubules. Intriguingly, disruption of genes frequently mutated in human RCC samples thus far has only generated RCC originated from other renal tubule parts in mouse models. This hampers our understanding of the pathogenesis of RCC. Here we show that mTOR signaling, often activated in RCC samples, initiates RCC development from renal proximal tubules. Ablation of Tsc1, encoding an mTOR suppressor, in proximal tubule cells led to multiple precancerous renal cysts. mTOR activation increased MEK1 expression and ERK activation, and Mek1 ablation or inhibition diminished cyst formation in Tsc1-deficient mice. mTOR activation also increased MKK6 expression and p38MAPK activation, and ablation of the p38α-encoding gene further enhanced cyst formation and led to RCC with clear cell RCC features. Mechanistically, Tsc1 deletion induced p53 and p16 expression in a p38MAPK-dependent manner, and deleting Tsc1 and Trp53 or Cdkn2a (encoding p16) enhanced renal cell carcinogenesis. Thus, mTOR activation in combination with inactivation of the p38MAPK–p53/p16 pathway drives RCC development from renal proximal tubules. Moreover, this study uncovers previously unidentified mechanisms by which mTOR controls cell proliferation and suggests the MEK–ERK axis to be a potential target for treatment of RCC. Significance: Mouse modeling studies show that mTOR activation in combination with inactivation of the p38MAPK–p53/p16 axis initiates renal cell carcinoma that mimics human disease, identifying potential therapeutic targets for RCC treatment.
Urgently seeking efficiency and sustainability of clinical trials in global health
Authors: Jay J H Park, Rebecca F Grais, Monica Taljaard, Etheldreda Nakimuli-Mpungu, Fyezah Jehan, Jean B Nachega, Nathan Ford, Denis Xavier, Andre P Kengne, Per Ashorn, Maria Eugenia Socias, Zulfiqar A Bhutta, Edward J Mills
Journal: The Lancet Global Health (2021)

This paper shows the scale of global health research and the context in which we frame the subsequent papers in the Series. In this Series paper, we provide a historical perspective on clinical trial research by revisiting the 1948 streptomycin trial for pulmonary tuberculosis, which was the first documented randomised clinical trial in the English language, and we discuss its close connection with global health. We describe the current state of clinical trial research globally by providing an overview of clinical trials that have been registered in the WHO International Clinical Trial Registry since 2010. We discuss challenges with current trial planning and designs that are often used in clinical trial research undertaken in low-income and middle-income countries, as an overview of the global health trials landscape. Finally, we discuss the importance of collaborative work in global health research towards generating sustainable and culturally appropriate research environments.
Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia
Authors: Liza Konnikova, Tanya O. Robinson, Anna H. Owings, James F. Shirley, Elisabeth Davis, Ying Tang, Sarah Wall, Jian Li, Mohammad H. Hasan, Raad Z. Gharaibeh, Lybil B. Mendoza Alvarez, Lisa K. Ryan, Andria Doty, Jack F. Chovanec, Michael P. O’Connell, Dianne E. Grunes, William P. Daley, Emeran Mayer, Lin Chang, Julia Liu, Scott B. Snapper, Joshua D. Milner, Sarah C. Glover, Jonathan J. Lyons
Journal: Journal of Allergy and Clinical Immunology (2021)
Abstract 12881: The Importance of Non-Cardiac Comorbidities in Hospitalized Heart Failure With Preserved Ejection Fraction - A Secondary Analysis of Heart Failure Network Trials
Authors: Yogesh N Reddy, Masaru Obokata, Aaron D Jones, Omar AbouEzzedine, Marat Fudim, Brooke Alhanti, Lynne W Stevenson, Margaret M Redfield, Barry A Borlaug
Journal: Circulation (2019)

Introduction: It is widely appreciated that Heart Failure (HF) with preserved Ejection Fraction (HFpEF) is a heterogeneous syndrome. Some patients develop elevated filling pressures exclusively dur...
Postprandial glycaemic dips predict appetite and energy intake in healthy individuals
Authors: Patrick Wyatt, Sarah E. Berry, Graham Finlayson, Ruairi O’Driscoll, George Hadjigeorgiou, David A. Drew, Haya Al Khatib, Long H. Nguyen, Inbar Linenberg, Andrew T. Chan, Tim D. Spector, Paul W. Franks, Jonathan Wolf, John Blundell, Ana M. Valdes
Journal: Nature Metabolism (2021)
Clinical experience and psychometric properties of the Cardiff Acne Disability Index (CADI)*
Authors: Y.T. Abdelrazik, F.M. Ali, M.S. Salek, A.Y. Finlay
Journal: British Journal of Dermatology (2021)

The Cardiff Acne Disability Index (CADI) is a questionnaire designed to measure the quality of life of teenagers and young adults with acne. It has been used clinically and within therapeutic research globally. This review aims to appraise all published data regarding the clinical and research experience of the CADI, its psychometric properties and validation, from its publication in 1992 until September 2020, in a single reference source. A literature search was conducted using MEDLINE via Ovid, PubMed, EBSCOhost, Web of Science and Scopus. All full articles in the English language were included. A total of 96 clinical studies were identified and analysed. The CADI has been used in 44 different countries, including four multinational studies, and has validated translations in 25 languages. Overall, 29 therapeutic interventions have used the CADI, demonstrating its responsiveness to change. The reliability of the CADI has been assessed in 14 studies through test–retest and internal consistency studies. In total, 57 studies have demonstrated aspects of its validity through correlation to other measures, and five studies have investigated the dimensionality of the CADI. There is evidence of high internal consistency, test–retest reliability, responsiveness to change and significant correlation with other objective measures. The minimal clinically important difference and validated score meaning bands have not yet been reported. This information is needed to improve the interpretability of CADI scores for clinical use and in research. The authors of the CADI have also rephrased Question 2 of the measure to ensure inclusivity.
Radiotherapy to Enhance Chimeric Antigen Receptor T-Cell Therapeutic Efficacy in Solid Tumors
Authors: Franziska Hauth, Alice Y. Ho, Soldano Ferrone, Dan G. Duda
Journal: JAMA Oncology (2021)

<h3>Importance</h3> Immunotherapy has emerged as a new pillar of cancer therapy over the past decade. Adoptive immunotherapy in particular has become a major area of research interest, with advances seen in the development of T-cell engineering. As a result, chimeric antigen receptor (CAR) T-cell therapy has become a new and highly effective treatment option, especially for patients with refractory or resistant blood cell cancers. However, CAR T-cell therapy has shown limited efficacy for the treatment of solid tumors thus far. <h3>Observations</h3> Combinatorial treatment approaches, such as addition of radiotherapy to CAR T cells, may provide a strategy to prevent resistance to CAR T-cell therapy of solid tumors. These approaches need to overcome obstacles that include abnormal vessels and adhesion molecule expression on tumor vasculature, leading to reduced transmigration of effector immune cells, including CAR T cells, and immunosuppressive cues in the tumor microenvironment, including regional hypoxia. <h3>Conclusions and Relevance</h3> This review provides an overview of the current developments in CAR T-cell therapy and highlights the unique opportunities and challenges in combining CAR T-cell therapy with radiotherapy.
Double-wire-guided reopenable-clip closure of a mucosal defect after endoscopic papillectomy
Authors: Tatsuma Nomura, Shinya Sugimoto, Toji Murabayashi, Jun Oyamada, Keiichi Ito, Akira Kamei
Journal: Endoscopy (2021)

Endoscopic papillectomy has been reported as a curative endoscopic treatment for laterally spreading tumors of the duodenal papilla and near the papilla [1] [2]. However, endoscopic papillectomy is associated with postoperative complications such as pancreatitis, cholangiopancreatic stricture, and bleeding. Insertion of a pancreatic ductal stent may prevent these problems and should be performed if possible [3] [4]. In addition, clip closure of mucosal defects may reduce delayed bleeding [5]. However, the presence of pancreatic and bile duct stents may interfere with clip closure and result in incomplete closure of the mucosal defects. We developed a new method, double-wire-guided closure with reopenable clips, which enables closure of mucosal defects before pancreatic and bile duct stents are inserted. With this method, guidewires are inserted into the pancreatic and bile ducts after complete resection of the lesion. The mucosal defect is then securely closed using a reopenable clip (SureClip; Micro-Tech Co., Ltd, Nanjing, China), with two guidewires in place to prevent respiratory movement. The clip can be opened and closed even with the elevator mechanism of conventional duodenoscopes.
Novel Preclinical Patient-Derived Lung Cancer Models Reveal Inhibition of HER3 and MTOR Signaling as Therapeutic Strategies for NRG1 Fusion-Positive Cancers
Authors: Igor Odintsov, Marissa S. Mattar, Allan J.W. Lui, Michael Offin, Christopher Kurzatkowski, Lukas Delasos, Inna Khodos, Marina Asher, Robert M. Daly, Natasha Rekhtman, Elisa de Stanchina, Gopinath Ganji, Marc Ladanyi, Romel Somwar
Journal: Journal of Thoracic Oncology (2021)
Sensitivity of SARS-CoV-2 RNA polymerase chain reaction using a clinical and radiological reference standard
Authors: Alexander J Stockdale, Fred Fyles, Catriona Farrell, Joe Lewis, David Barr, Kathryn Haigh, Michael Abouyannis, Beth Hankinson, Diana Penha, Rashika Fernando, Rebecca Wiles, Sheetal Sharma, Nuria Santamaria, Vijay Chindambaram, Cairine Probert, Muhammad Shamsher Ahmed, James Cruise, Imogen Fordham, Rory Hicks, Alice Maxwell, Nick Moody, Tamsin Paterson, Katharine Stott, Meng-San Wu, Michael Beadsworth, Stacy Todd, Elizabeth Joekes
Journal: Journal of Infection (2021)

ObjectivesDiagnostic tests for SARS-CoV-2 are important for epidemiology, clinical management, and infection control. Limitations of oro-nasopharyngeal real-time PCR sensitivity have been described based on comparisons of single tests with repeated sampling. We assessed SARS-CoV-2 PCR clinical sensitivity using a clinical and radiological reference standard.MethodsBetween March-May 2020, 2060 patients underwent thoracic imaging and SARS-CoV-2 PCR testing. Imaging was independently double- or triple-reported (if discordance) by blinded radiologists according to radiological criteria for COVID-19. We excluded asymptomatic patients and those with alternative diagnoses that could explain imaging findings. Associations with PCR-positivity were assessed with binomial logistic regression.Results901 patients had possible/probable imaging features and clinical symptoms of COVID-19 and 429 patients met the clinical and radiological reference case definition. SARS-CoV-2 PCR sensitivity was 68% (95% confidence interval 64–73), was highest 7-8 days after symptom onset (78% (68–88)) and was lower among current smokers (adjusted odds ratio 0.23 (0.12–0.42) p < 0.001).ConclusionsIn patients with clinical and imaging features of COVID-19, PCR test sensitivity was 68%, and was lower among smokers; a finding that could explain observations of lower disease incidence and that warrants further validation. PCR tests should be interpreted considering imaging, symptom duration and smoking status.
Secondary infection rates and antibiotic prescribing in a COVID-19 hdu population
Authors: S. H. Zhang, G. Bickler, B. Porter, R. Hallifax, N. Rahman, W. Flight
Journal: Gut (2021)

Introduction Secondary infection in COVID-19 has been associated with adverse outcomes and high mortality  The prevalence of secondary infection in COVID-19 and optimal antimicrobial strategies remain unclear  Methods Retrospective case-note review of patients with COVID-19 admitted to our institution's high dependency unit (HDU) from March to June 2020  Patients were PCR-positive for SARS-CoV-2 or had classical CT appearances and a compatible clinical presentation for COVID-19  Microbiological tests, antimicrobial prescriptions and clinical outcomes were recorded  Results 84 patients were identified  Median age was 68 5 years and 29/84 (34 5%) were female  Respiratory support included HFNO (n=39), CPAP (n=56), non-invasive ventilation (n=3) and invasive ventilation (n=14)  Overall mortality was 36/84 (42 9%)  6/84 patients (7 1%) had evidence of secondary infection (>105 CFUs on bronchoalveolar lavage (BAL);positive sputum culture or positive blood culture excluding skin contaminants)  28/84 (33 3%) had a respiratory sample sent: BAL n=10;sputum culture n=2;Legionella antigen n=15;throat swab multiplex PCR n=3;Biofire respiratory viral panel n=7  BAL was positive in 3/10 cases (Enterococcus faecium;Serratia marcescens and Escherichia coli;Pseudomonas aeruginosa)  One sputum culture was positive for M  abscessus  71/84 (84 5%) had blood cultures  8 (11 2%) were positive, of which 6 were considered skin contaminants and not deemed true secondary infection (coagulase negative Staphylococci n=5;Lysinibacillus sp  n=1;Proteus mirabilis n=1;Staphylococcus epidermidis and Serratia marcescens n=1)  All 84 patients received antimicrobials  32 (38 1%) received a macrolide, predominantly azithromycin  Macrolide usage was not associated with mortality or admission length, but was associated with increased intubation rate (28 1% vs 9 6%, p=0 027) Initial antibiotic treatment was monotherapy in 45 (53 6%) cases and dual therapy in 39 (46 4%)  Initial treatment with two antibiotics versus monotherapy was not associated with mortality but was associated with increased intubation rate (25 6% vs 8 9%, p=0 040) and increased mean admission length (16 5 vs 11 6 days, p= 036)  Discussion Robust evidence of secondary infection in patients with COVID-19 was uncommon in our cohort  Increased intubation rates in patients prescribed a macrolide and those initially prescribed dual antibiotic therapy is likely to reflect more severe disease  There is considerable potential for enhanced antimicrobial stewardship in further waves of COVID-19
An Immuno-Cardiac Model for Macrophage-Mediated Inflammation in COVID-19 Hearts
Authors: Liuliu Yang, Yuling Han, Fabrice Jaffré, Benjamin E. Nilsson-Payant, Yaron Bram, Pengfei Wang, Jiajun Zhu, Tuo Zhang, David Redmond, Sean Houghton, Skyler Uhl, Alain Borczuk, Yaoxing Huang, Chanel Richardson, Vasuretha Chandar, Joshua A. Acklin, Jean K. Lim, Zhengming Chen, Jenny Xiang, David D. Ho, Benjamin R. tenOever, Robert E. Schwartz, Todd Evans, Shuibing Chen
Journal: Circulation Research (2021)

[Figure: see text].