tbuckley/cabot-search huggingface dataset:
Sliding down the risk factor rankings: reasons for and consequences of the dramatic downgrading of physical activity in the Global Burden of Disease 2019
Authors: Emmanuel Stamatakis, Ding Ding, Ulf Ekelund, Adrian E Bauman
Journal: British Journal of Sports Medicine (2021)

Published in the Lancet in 2020, the Global Burden of Disease (GBD) 2019 provided updated disease burden rankings for 87 risk factors including behavioural and metabolic risks. GBD 2019 ranked low physical activity 19th out of 20 risk factors in terms of disability-adjusted life years, down from 10th in the equivalent 2010 GBD publication.1 The number of attributable deaths has decreased from 3.2 million in 20101 to approximately 1.2 million in 20192; both estimates are substantially lower than the Lancet 2012 physical activity series estimates (5 million deaths/year).3 GBD authors2 do not comment on this remarkable demotion of physical activity’s ranking in 2019, despite the fact that it contradicts the significant progress in the field of physical activity over the last decade.4 Here, we explore this seemingly counterintuitive downgrade to alert policy makers, health professionals and researchers about the caveats of interpreting GBD data. We also offer suggestions on how to improve future physical activity GBD estimates.

Physical activity is a complex multidimensional behaviour whose health effects are determined by its intensity, duration, type (eg, aerobic vs strength training) and domain.4 GBD considered a single physical activity indicator that captures only total volume. This provides a stark contrast with how GBD treated other behaviours such as diet, which was addressed by 15 different risk factor indicators, including a diet low in seafood omega-3 fatty acids intake and low milk …
CLINICAL CHARACTERISTICS AND OUTCOMES AMONG PATIENTS UNDERGOING HIGH-RISK PERCUTANEOUS CORONARY INTERVENTIONS WITH ONE OR TWO OPERATORS: INSIGHTS FROM THE VA CART PROGRAM
Authors: Christopher P. Kovach, Annika Hebbe, Anna Baron, Aaron Strobel, Mary Plomondon, Javier Valle, Stephen Waldo
Journal: Journal of the American College of Cardiology (2021)
Genome-wide association study identifies <i>RNF123</i> locus as associated with chronic widespread musculoskeletal pain
Authors: Md Shafiqur Rahman, Bendik S Winsvold, Sergio O Chavez Chavez, Sigrid Børte, Yakov A Tsepilov, Sodbo Zh Sharapov, Yurii S Aulchenko, Knut Hagen, Egil A Fors, Kristian Hveem, John Anker Zwart, Joyce B van Meurs, Maxim B Freidin, Frances MK Williams
Journal: Annals of the Rheumatic Diseases (2021)

Background and objectives Chronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48%–54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP. Methods Northern Europeans from UK Biobank comprising 6914 cases reporting pain all over the body lasting &gt;3 months and 242 929 controls were studied. Replication of three independent genome-wide significant single nucleotide polymorphisms was attempted in six independent European cohorts (n=43 080; cases=14 177). Genetic correlations with risk factors, tissue specificity and colocalisation were examined. Results Three genome-wide significant loci were identified ( rs1491985, rs10490825, rs165599 ) residing within the genes Ring Finger Protein 123 ( RNF123 ), ATPase secretory pathway Ca 2+ transporting 1 ( ATP2C1 ) and catechol-O-methyltransferase ( COMT ). The RNF123 locus was replicated (meta-analysis p=0.0002), the ATP2C1 locus showed suggestive association (p=0.0227) and the COMT locus was not replicated. Partial genetic correlation between CWP and depressive symptoms, body mass index, age of first birth and years of schooling were identified. Tissue specificity and colocalisation analysis highlight the relevance of skeletal muscle in CWP. Conclusions We report a novel association of RNF123 locus and a suggestive association of ATP2C1 locus with CWP. Both loci are consistent with a role of calcium regulation in CWP. The association with COMT , one of the most studied genes in chronic pain field, was not confirmed in the replication analysis.
EVALUATION OF TRANSTHYRETIN TETRAMER STABILIZATION AND TTR PLASMA CONCENTRATIONS IN THE TAFAMIDIS IN TRANSTHYRETIN CARDIOMYOPATHY CLINICAL TRIAL (ATTR-ACT)
Authors: Jennifer Schumacher, Balarama Gundapaneni, Steve Riley, Denis Keohane, Sandi See Tai, Marla Sultan
Journal: Journal of the American College of Cardiology (2021)
Composite CD79A/CD40 co-stimulatory endodomain enhances CD19CAR-T cell proliferation and survival
Authors: Jakrawadee Julamanee, Seitaro Terakura, Koji Umemura, Yoshitaka Adachi, Kotaro Miyao, Shingo Okuno, Erina Takagi, Toshiyasu Sakai, Daisuke Koyama, Tatsunori Goto, Ryo Hanajiri, Michael Hudecek, Peter Steinberger, Judith Leitner, Tetsuya Nishida, Makoto Murata, Hitoshi Kiyoi
Journal: Molecular Therapy (2021)

Adoptively transferred CD19 chimeric antigen receptor (CAR) T cells have led to impressive clinical outcomes in B cell malignancies. Beyond induction of remission, the persistence of CAR-T cells is required to prevent relapse and provide long-term disease control. To improve CAR-T cell function and persistence, we developed a composite co-stimulatory domain of a B cell signaling moiety, CD79A/CD40, to induce a nuclear translocating signal, NF-κB, to synergize with other T cell signals and improve CAR-T cell function. CD79A/CD40 incorporating CD19CAR-T cells (CD19.79a.40z) exhibited higher NF-κB and p38 activity upon CD19 antigen exposure compared with the CD28 or 4-1BB incorporating CD19CAR-T cells (CD19.28z and CD19.BBz). Notably, we found that CD19.79a.40z CAR-T cells continued to suppress CD19+ target cells throughout the co-culture assay, whereas a tendency for tumor growth was observed with CD19.28z CAR-T cells. Moreover, CD19.79a.40z CAR-T cells exhibited robust T cell proliferation after culturing with CD19+ target cells, regardless of exogenous interleukin-2. In terms of in vivo efficiency, CD19.79a.40z demonstrated superior anti-tumor activity and in vivo CAR-T cell proliferation compared with CD19.28z and CD19.BBz CD19CAR-T cells in Raji-inoculated mice. Our data demonstrate that the CD79A/CD40 co-stimulatory domain endows CAR-T cells with enhanced proliferative capacity and improved anti-tumor efficacy in a murine model.
Monitoring of diverse enteric pathogens across environmental and host reservoirs with TaqMan array cards and standard qPCR: a methodological comparison study
Authors: Rachael Lappan, Rebekah Henry, Steven L Chown, Stephen P Luby, Ellen E Higginson, Lamiya Bata, Thanavit Jirapanjawat, Christelle Schang, John J Openshaw, Joanne O'Toole, Audrie Lin, Autiko Tela, Amelia Turagabeci, Tony H F Wong, Matthew A French, Rebekah R Brown, Karin Leder, Chris Greening, David McCarthy
Journal: The Lancet Planetary Health (2021)
Immunogenicity of the <scp>BNT162b2 mRNA</scp> vaccine in heart transplant <scp>recipients – a</scp> prospective cohort study
Authors: Osnat Itzhaki Ben Zadok, Aviv A. Shaul, Binyamin Ben‐Avraham, Vicky Yaari, Haim Ben Zvi, Yael Shostak, Barak Pertzov, Noa Eliakim‐Raz, Galia Abed, Miriam Abuhazira, Yaron D. Barac, Israel Mats, Mordechai R. Kramer, Dan Aravot, Ran Kornowski, Tuvia Ben‐Gal
Journal: European Journal of Heart Failure (2021)
THE EFFECTS OF SLEEP APNEA ON MARKERS OF CARDIAC MYOCYTE INJURY IN HYPERTROPHIC CARDIOMYOPATHY
Authors: Sai Swetha Alladi, Shahid Karim, Shreyas Venkataraman, Naima Covassin, Jan Bukartyk, Anwar Chahal, Jeffrey Geske, Virend Somers
Journal: Journal of the American College of Cardiology (2021)
MEDIATION ANALYSIS FOR DAPAGLIFLOZIN AND THE REDUCTION IN HOSPITALIZATION FOR HEART FAILURE IN DECLARE-TIMI 58
Authors: David Berg, Stephen Wiviott, Erica Goodrich, Sabina Murphy, Ofri Mosenzon, Deepak Bhatt, Avivit Cahn, Lawrence Leiter, Darren McGuire, John Wilding, Ingrid Gause-Nilsson, Ann Hammarstedt, Cecilia Karlsson, Peter Johansson, Anna-Maria Langkilde, Itamar Raz, Marc Sabatine
Journal: Journal of the American College of Cardiology (2021)
Abstract 16439: Is Pulmonary Venous Flow Pulsatility a Critical Determinant of Left Atrial Appendage Blood Stasis Risk?
Authors: Soroosh Sanatkhani, Sotirios Nedios, Sandeep K Jain, Samir Saba, Prahlad G Menon, Sanjeev G Shroff
Journal: Circulation (2020)

Introduction: Atrial fibrillation (AF) is the most common arrhythmia that leads to thrombus formation, most commonly in the left atrial appendage (LAA), and a resultant five-fold increase in the risk of ischemic stroke. The current standard of stratifying stroke risk, based on the CHA 2 DS 2 -VASc score, does not consider subject-specific LAA hemodynamics and blood stasis risk. We have developed a methodology for computing mean residence time of blood-borne particles in the LAA ( t m ), an index of LAA blood stasis, using 3D left atrial (LA) and LAA geometries and pulmonary venous (PV) inlet blood flow data. While subject-specific 3D geometry can be obtained readily, it is not easy to measure all LA inlet blood flow waveforms in vivo . Therefore, a sensitivity study of LAA t m to the inlet blood flow waveform characteristics (shape and magnitude) is needed. Hypothesis: PV flow pulsatility does not affect LAA t m . Methods: Cardiac computed tomography images of 10 AF subjects were obtained and LA and LAA geometries were reconstructed in 3D and subsequently meshed for computational fluid dynamics (CFD) analysis. We employed CFD analysis, modeling blood cells as neutrally buoyant tracers transported in the blood and used a systems-based approach, to quantify LAA t m . Each subject was simulated using four PV blood flow characteristics: (1) Normal-S , steady PV flow with cardiac output (CO) of 5.5 L/min; (2) AF-S , steady PV flow with reduced CO of 4.4 L/min; (3) Normal-P , normal pulsatile PV flow with normal CO = 5.5 L/min; and (4) AF-P , a typical AF pulsatile waveform where systolic phase and the reversal phase are diminished with reduced CO of 4.4 L/min. Results: Comparing the two steady flow groups, LAA t m significantly increased as CO was decreased ( Normal-S: 2.6±0.3 s, AF-S: 3.1±0.3 s, P =0.02). However, the presence of pulsatility did not affect LAA t m at both levels of CO: Normal-P: 2.4±0.2 s; Normal-S: 2.6±0.3 s, P =0.2 and AF-P: 2.9±0.3 s; AF-S: 3.1±0.3 s, P =0.3. Conclusions: LAA blood stasis risk, as quantified by LAA t m , is significantly affected by the steady PV flow magnitude (i.e., cardiac output) and not by PV flow pulsatility. Therefore, the subject-specific LAA blood stasis risk can be reliably estimated using subject-specific LA and LAA 3D geometries and subject-specific CO.
Evaluation of Drug Trials in High-, Middle-, and Low-Income Countries and Local Commercial Availability of Newly Approved Drugs
Authors: Jennifer E. Miller, Michelle M. Mello, Joshua D. Wallach, Emily M. Gudbranson, Blake Bohlig, Joseph S. Ross, Cary P. Gross, Peter B. Bach
Journal: JAMA Network Open (2021)

Clinical research supporting US Food and Drug Administration (FDA) drug approvals is largely conducted outside the US.To characterize where drugs were tested for FDA approval and to determine how commonly and quickly these drugs received marketing approval in the countries where they were tested, both overall and by country income level and geographical region.This cross-sectional analysis of trials supporting FDA approval of novel drugs in 2012 and 2014, sponsored by large drug companies, did not involve human participants. The settings were the countries hosting trials supporting US drug approval. Data sources included Drugs@FDA, ClinicalTrials.gov, PubMed, Google Scholar, EMBASE, and drug regulatory agency websites. Data analysis was completed March through September 2020.The primary outcomes were the proportion of drugs approved for marketing in the countries where they were tested for FDA approval within 1, 2, 3, 4, and 5 years of FDA approval and the proportion of countries contributing participants to trials supporting FDA approvals receiving market access to the drugs they helped test within 1, 2, 3, 4, and 5 years of FDA approval.In 2012 and 2014, the FDA approved 34 novel drugs sponsored by large companies, on the basis of a total of 898 trials, 563 of which had location information available. Each drug was tested in a median (interquartile range [IQR]) of 25 (18-37) unique countries, including a median (IQR) of 20 (13-25) high-income countries, 6 (4-11) upper-middle-income countries, and 1 (0-2) low-middle-income country. One drug was approved for marketing in all testing countries within 1 year of FDA approval and 15% (5 of 34 drugs) were approved in all testing countries within 5 years of FDA approval. Of the 70 countries contributing research participants for FDA drug approvals, 7% (5 countries) received market access to drugs they helped test within 1 year of FDA approval and 31% (22 countries) did so within 5 years. Access within 1 year occurred in 13% (5 of 39) of high-income countries, 0 of 22 upper-middle-income countries (0%), and 0 of 9 lower-middle-income countries (0%), whereas at 5 years access rates were 46% (18 of 39 countries), 9% (2 of 22 countries), and 22% (2 of 9 countries), respectively. Approvals were faster in high-income countries (median [IQR], 8 [0-11] months) than in upper-middle-income countries (median [IQR], 11 [5-29] months) or lower-middle-income countries (median [IQR], 17 [11-27] months) after FDA approval. Access was lowest in African countries.These findings suggest that substantial gaps exist between where FDA-approved drugs are tested and where they ultimately become available to patients, raising concerns about the equitable distribution of research benefits at the population level.
Risk Factors With Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy
Authors: Fujun Liu, Xin Tang, Liangxue Zhou
Journal: JAMA Neurology (2021)

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DILEMMA OF MANAGEMENT OF CONCOMITANT GIANT PULMONARY ARTERY ANEURYSM WITH THORACIC AORTIC ANEURYSM
Authors: Bilal Saqi, Nikhil Mehta, Rahul Gupta, Mario Caruso, Sagar Vadhar, Nainesh Patel, Yasotha Rajeswaran
Journal: Journal of the American College of Cardiology (2021)
Trends in US Internal Medicine Residency and Fellowship Applications During the COVID-19 Pandemic vs Previous Years
Authors: Laura A. Huppert, Lekshmi Santhosh, Jennifer M. Babik
Journal: JAMA Network Open (2021)

This cross-sectional study evaluates the number of applicants and number of applications submitted per applicant to internal medicine residency and subspecialty fellowships for 2021 compared with 5 prior application cycles.
The progression and regression of metabolic dysfunction-associated fatty liver disease are associated with the development of subclinical atherosclerosis: A prospective analysis
Authors: Shanshan Liu, Jialu Wang, Shujing Wu, Jingya Niu, Ruizhi Zheng, Lizhan Bie, Zhuojun Xin, Shuangyuan Wang, Hong Lin, Zhiyun Zhao, Tiange Wang, Min Xu, Jieli Lu, Yuhong Chen, Yiping Xu, Weiqing Wang, Guang Ning, Yufang Bi, Mian Li, Yu Xu
Journal: Metabolism (2021)
PRIMARY PERCUTANEOUS CORONARY INTERVENTION VIA DISTAL RADIAL ARTERY APPROACH IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION
Authors: Akihiko Takahashi, Takeshi Yamada, Yuki Matsubara, Soichiro Washimi, Sho Hashimoto, Tetsuya Hata, Norimasa Taniguchi, Shunsuke Nakajima
Journal: Journal of the American College of Cardiology (2021)
ATRIOESOPHAGEAL FISTULA AND INJURY USING DIFFERENT ENERGY SOURCES DURING ATRIAL FIBRILLATION ABLATION: A REPORT FROM THE MANUFACTURER AND USER FACILITY DEVICE EXPERIENCE DATABASE
Authors: John Nicholas Catanzaro, Joshua Levine, Shreya Ghetiya, Allen Brown, Claude Elayi, Fabrizio Asis, Harikrishna Tandri, Kun Xiang
Journal: Journal of the American College of Cardiology (2021)
Evaluation of <i>BRCA1</i> and <i>BRCA2</i> as Indicators of Response to Immune Checkpoint Inhibitors
Authors: Zhijun Zhou, Min Li
Journal: JAMA Network Open (2021)

Immune checkpoint inhibitors (ICIs) have achieved impressive success in a subset of malignant tumors. Tumor mutation burden (TMB), programmed cell death ligand 1 expression, and deficient DNA mismatch repair are the few biomarkers known to be associated with response to ICIs. Breast cancer type 1 or 2 susceptibility gene (BRCA1 [OMIM 113705] and BRCA2 [OMIM 600185]) play critical roles in DNA repair. However, the roles of BRCA1/2 alteration in tumor immunotherapy remains uncharacterized, to our knowledge. Several early phase clinical trials are examining the combination of ICIs and poly(ADP-ribose) polymerase inhibitor in BRCA1/2 altered tumors. The role of BRCA1/2 alteration in immunotherapy remains controversial across different tumor types. We hypothesized that BRCA1/2 alteration is associated with TMB and may serve as a novel indicator associated with better treatment outcomes of ICIs.
Abstract 17027: Generalizability of the US FDA Label for Dapagliflozin to Patients With Heart Failure With Reduced Ejection Fraction in the GWTG-HF Registry
Authors: Muthiah Vaduganathan, Stephen Greene, Shuaiqi Zhang, maria v grau-sepulveda, Adam D Devore, Javed Butler, Paul A Heidenreich, Joanna C Huang, Michelle M Kittleson, Karen E Joynt Maddox, Jim McDermott, Anjali T Owens, Pamela Peterson, Scott D Solomon, Orly Vardeny, Clyde W Yancy, Gregg C Fonarow
Journal: Circulation (2020)

Background: In May 2020, dapagliflozin was approved by the US FDA as the first SGLT-2 inhibitor for HF with reduced ejection fraction (HFrEF) based on the pivotal DAPA-HF trial. Limited data are available characterizing its generalizability to US clinical practice. Methods: We studied patients with HFrEF (≤40%) hospitalized at 406 sites in the Get With The Guidelines (GWTG)-HF registry admitted between Jan 2014 - Sept 2019. We excluded patients who left against medical advice, transferred to an acute care facility or to hospice, or had missing critical data. We applied the FDA label (excluding eGFR&lt;30 mL/min/1.73 m 2 , dialysis, or type 1 DM) and eligibility criteria of DAPA-HF to the GWTG-HF registry sample. Results: Among 154,714 patients hospitalized with HFrEF, 125,497 (81.1%) would be candidates for dapagliflozin under the FDA label. Across 355 sites with ≥10 hospitalizations, median proportion of FDA label candidates was 81.1% (77.8%-84.6%). This proportion was similar across all study years (80.4-81.7%) and higher among those without type 2 DM than with type 2 DM (85.5% vs. 75.6%). Among GWTG-HF participants, the most frequent reason for not meeting the FDA label was eGFR&lt;30 mL/min/1.73 m 2 (n=28,605). Among patients with available paired admission and discharge data, 14.2% had eGFR&lt;30 mL/min/1.73 m 2 at both time points, while 3.8% developed eGFR&lt;30 mL/min/1.73 m 2 by discharge. While there were more women, more Black patients, and less Asian patients in GWTG-HF, clinical characteristics were qualitatively similar between DAPA-HF trial and GWTG-HF registry participants. Compared with the DAPA-HF trial cohort, there was lower use of evidence-based HF therapies among GWTG-HF patients ( Table ). Conclusions: These data from a large, contemporary US hospitalized HF registry suggest that 4 out of 5 patients with HFrEF (with or without type 2 DM) would be candidates for initiation of dapagliflozin, and support its broad generalizability to US clinical practice.
Patient-Reported Outcomes in Pediatric Cancer Registration Trials: A US Food and Drug Administration Perspective
Authors: Meena N Murugappan, Bellinda L King-Kallimanis, Gregory H Reaman, Vishal Bhatnagar, Erica G Horodniceanu, Najat Bouchkouj, Paul G Kluetz
Journal: JNCI Journal of the National Cancer Institute (2021)

Pediatric patient-reported outcome (PRO) data can help inform the US Food and Drug Administration's (FDA's) benefit-risk assessment of cancer therapeutics by quantifying symptom and functional outcomes from the patient's perspective.This study assessed use of PROs in commercial pediatric oncology trials submitted to the FDA for regulatory review. FDA databases were searched to identify pediatric oncology product applications approved between 1997 and 2020. Sponsor-submitted documents were reviewed to determine whether PRO data were collected, which instruments were used, and the quality of collected data (ie, sample size, completion rates, and use of fit-for-purpose instruments). The role of PROs in each trial (endpoint hierarchy) was also recorded in addition to whether any PRO endpoints were included in product labeling.We reviewed 17 pediatric oncology applications, 4 of which included PRO data: denosumab, tisagenlecleucel, larotrectinib, and selumetinib. In these 4 instances, PROs served as exploratory endpoints and were not incorporated in product labeling. Trials that collected PRO data were phase II or phase I/II single-arm studies with sample sizes of 28 to 88 patients. Symptomatic adverse events (AEs) were characterized using clinician-reported Common Terminology Criteria for Adverse Events (CTCAE) without additional patient self-report.PROs were infrequently used in pediatric cancer registration trials. When PROs were used, PRO data were limited by lack of a clear research objective and corresponding prospective statistical analysis plan. Contemporary PRO symptom libraries, such as the National Cancer Institute's Pediatric PRO-CTCAE, may provide an opportunity to better evaluate the occurrence and impact of symptomatic AEs, from the patient's perspective, in pediatric oncology trials.
Endosonography-guided gallbladder drainage in a patient with intestinal malrotation
Authors: Takeshi Okamoto, Kenji Nakamura
Journal: Endoscopy (2021)

Endosonography-guided gallbladder drainage (EUS-GBD) is increasingly performed in cholecystitis patients who are not candidates for surgery, with similar success rates and fewer adverse events compared to percutaneous drainage, and with good long-term outcomes [1] [2] [3]. EUS-GBD is also preferred over endoscopic transpapillary naso-gallbladder drainage (ET-GBD) as it is associated with higher success rates and lower rates of recurrent cholecystitis [4].
Immune Checkpoint Inhibitors in EGFR-Mutated NSCLC: Dusk or Dawn?
Authors: Meng Qiao, Tao Jiang, Xinyu Liu, Shiqi Mao, Fei Zhou, Xuefei Li, Chao Zhao, Xiaoxia Chen, Chunxia Su, Shengxiang Ren, Caicun Zhou
Journal: Journal of Thoracic Oncology (2021)