tbuckley/cabot-search huggingface dataset:
Hydroxychloroquine treatment does not reduce COVID-19 mortality; underdosing to the wrong patients? – Authors' reply
Authors: Christopher T Rentsch, Nicholas J DeVito, Brian MacKenna, Caroline E Morton, Krishnan Bhaskaran, Jeremy P Brown, Anna Schultze, William J Hulme, Richard Croker, Alex J Walker, Elizabeth J Williamson, Chris Bates, Seb Bacon, Amir Mehrkar, Helen J Curtis, David Evans, Kevin Wing, Peter Inglesby, Rohini Mathur, Henry Drysdale, Angel Y S Wong, Helen I McDonald, Jonathan Cockburn, Harriet Forbes, John Parry, Frank Hester, Sam Harper, Liam Smeeth, Ian J Douglas, William G Dixon, Stephen J W Evans, Laurie Tomlinson, Ben Goldacre
Journal: The Lancet Rheumatology (2021)
T-Cell Therapy for Lymphoma Using Nonengineered Multiantigen-Targeted T Cells Is Safe and Produces Durable Clinical Effects
Authors: Spyridoula Vasileiou, Premal D. Lulla, Ifigeneia Tzannou, Ayumi Watanabe, Manik Kuvalekar, Wendy L. Callejas, Mrinalini Bilgi, Tao Wang, Mengfen J. Wu, Rammurti Kamble, Carlos A. Ramos, Rayne H. Rouce, Zihua Zeng, Adrian P. Gee, Bambi J. Grilley, Juan F. Vera, Catherine M. Bollard, Malcolm K. Brenner, Helen E. Heslop, Cliona M. Rooney, Ann M. Leen, George Carrum
Journal: Journal of Clinical Oncology (2021)

Patients with relapsed lymphomas often fail salvage therapies including high-dose chemotherapy and mono-antigen-specific T-cell therapies, highlighting the need for nontoxic, novel treatments. To that end, we clinically tested an autologous T-cell product that targets multiple tumor-associated antigens (TAAs) expressed by lymphomas with the intent of treating disease and preventing immune escape.We expanded polyclonal T cells reactive to five TAAs: PRAME, SSX2, MAGEA4, SURVIVIN, and NY-ESO-1. Products were administered to 32 patients with Hodgkin lymphomas (n = 14) or non-Hodgkin lymphomas (n = 18) in a two-part phase I clinical trial, where the objective of the first phase was to establish the safety of targeting all five TAAs (fixed dose, 0.5 × 107 cells/m2) simultaneously and the second stage was to establish the maximum tolerated dose. Patients had received a median of three prior lines of therapy and either were at high risk for relapse (adjuvant arm, n = 17) or had chemorefractory disease (n = 15) at enrollment.Infusions were safe with no dose-limiting toxicities observed in either the antigen- or dose-escalation phases. Although the maximum tolerated dose was not reached, the maximum tested dose at which efficacy was observed (two infusions, 2 × 107 cells/m2) was determined as the recommended phase II dose. Of the patients with chemorefractory lymphomas, two (of seven) with Hodgkin lymphomas and four (of eight) with non-Hodgkin lymphomas achieved durable complete remissions (> 3 years).T cells targeting five TAAs and administered at doses of up to two infusions of 2 × 107 cells/m2 are well-tolerated by patients with lymphoma both as adjuvant and to treat chemorefractory lymphoma. Preliminary indicators of antilymphoma activity were seen in the chemorefractory cohort across both antigen- and dose-escalation phases.
FRI0096 The association between migraine and antiphospholipide antibody in systemic lupus erythematosus
Authors: S Appenzeller, LT Costallat, IB Coimbra, MB Bertolo, A Samara
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Various neurological manifestations have been considered to be important features of Systemic Lupus Erythematosus (SLE) and indicative of Central Nervous System (CNS) involvement. Few studies of SNC include headache and the real prevalence of headache in SLE remain unknown, but some authors consider it one of the most frequent neurological symptoms, especially during acute disease. <h3>Objectives</h3> To determine the point prevalence and the different types of headache in patients with SLE. To investigate associations between headache and clinical and laboratory manifestation of SLE, corticosteroid therapy, disease activity and CNS involvement. <h3>Methods</h3> A cross-sectional study of 40 patients with SLE was compared to 40 patients with rheumatoid arthritis (RA) and 40 controls. To assess the different types of headache an especial questionnaire was elaborated, according with ACR case definition. Systemic disease activity was measured by SLEDAI. Statistics were performed by chi-square test and by Fisher's exact test. <h3>Results</h3> Headache was observed in 62.5% in SLE compared to 47.5% (p = 0.26) in RA and to 35.1% in controls (p = 0.0247). The types of headaches observed in SLE was migraine in 46%, tension headache in 36% and 20% had headaches during their menses. In RA we observed that 15.7% (p = 0.05) had migraine, 21% had tension headache, 37.5% had headache related to visual problems and 26% had headaches during the menses. In the control people group the prevalence of migraine was 23% (p = 0.05), tension headache 38% and headache during the in 38%. There was no significant association between headache and clinical manifestations of SLE, with laboratory abnormalities or the use of corticotherapy. A significant association in SLE was observed between seizures and migraine (p &lt; 0.001) and between headache and disease activity (p &lt; 0.001). When comparing the presence of migraine to clinical and laboratorial results we observe a significant association with Raynauds phenomenon (p &lt; 0.05), LE cels (p &lt; 0.05), antifosfolypid antibodies (p &lt; 0.001). <h3>Conclusion</h3> Migraine was more prevalent in SLE than in the control groups. The positive association between migraine and seizures and a higher score at SLEDAI could be related to a greater CNS involvement in these patients. In our study, migraine was associated to antiphospholipid antibodies. <h3>References</h3> Omdal R, Mellgren SI, Husby G. Clinical neuropsychiatric and neuromuscular manifestations in systemic lupus erythematosus. Scand J Rheumatol. 1988;17:113–17 Adelman DC, Saltiel E, Klinenberg JR. The neuropsychiatric manifestations of systemic lupus erythematosus: an overview. Semin Arthritis Rheum. 1986;15(3):185–99
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity
Authors: Andrew R. Harper, Anuj Goel, Christopher Grace, Kate L. Thomson, Steffen E. Petersen, Xiao Xu, Adam Waring, Elizabeth Ormondroyd, Christopher M. Kramer, Carolyn Y. Ho, Stefan Neubauer, Paul Kolm, Raymond Kwong, Sarahfaye F. Dolman, Patrice Desvigne-Nickens, John P. Dimarco, Nancy Geller, Dong-Yun Kim, Cheng Zhang, William Weintraub, Theodore Abraham, Lisa Anderson, Evan Appelbaum, Camillo Autore, Colin Berry, Elena Biagini, William Bradlow, Chiara Bucciarelli-Ducci, Amedeo Chiribiri, Lubna Choudhury, Andrew Crean, Dana Dawson, Milind Y. Desai, Eleanor Elstein, Andrew Flett, Matthias Friedrich, Stephen Heitner, Adam Helms, Daniel L. Jacoby, Han Kim, Bette Kim, Eric Larose, Masliza Mahmod, Heiko Mahrholdt, Martin Maron, Gerry McCann, Michelle Michels, Saidi Mohiddin, Sherif Nagueh, David Newby, Iacopo Olivotto, Anjali Owens, F. Pierre-Mongeon, Sanjay Prasad, Ornella Rimoldi, Michael Salerno, Jeanette Schulz-Menger, Mark Sherrid, Peter Swoboda, Albert van Rossum, Jonathan Weinsaft, James White, Eric Williamson, Rafik Tadros, James S. Ware, Connie R. Bezzina, Martin Farrall, Hugh Watkins
Journal: Nature Genetics (2021)
Mesenchymal Stem Cell–Secreted Extracellular Vesicles Instruct Stepwise Dedifferentiation of Breast Cancer Cells into Dormancy at the Bone Marrow Perivascular Region
Authors: Oleta A. Sandiford, Robert J. Donnelly, Markos H. El-Far, Lisa M. Burgmeyer, Garima Sinha, Sri Harika Pamarthi, Lauren S. Sherman, Alejandra I. Ferrer, Dariana E. DeVore, Shyam A. Patel, Yahaira Naaldijk, Sara Alonso, Pradeep Barak, Margarette Bryan, Nicholas M. Ponzio, Ramaswamy Narayanan, Jean-Pierre Etchegaray, Rakesh Kumar, Pranela Rameshwar
Journal: Cancer Research (2021)

Abstract In the bone marrow (BM), breast cancer cells (BCC) can survive in dormancy for decades as cancer stem cells (CSC), resurging as tertiary metastasis. The endosteal region where BCCs exist as CSCs poses a challenge to target them, mostly due to the coexistence of endogenous hematopoietic stem cells. This study addresses the early period of dormancy when BCCs enter BM at the perivascular region to begin the transition into CSCs, which we propose as the final step in dormancy. A two-step process comprises the Wnt-β-catenin pathway mediating BCC dedifferentiation into CSCs at the BM perivascular niche. At this site, BCCs responded to two types of mesenchymal stem cell (MSC)–released extracellular vesicles (EV) that may include exosomes. Early released EVs began the transition into cycling quiescence, DNA repair, and reorganization into distinct BCC subsets. After contact with breast cancer, the content of EVs changed (primed) to complete dedifferentiation into a more homogeneous population with CSC properties. BCC progenitors (Oct4alo), which are distant from CSCs in a hierarchical stratification, were sensitive to MSC EVs. Despite CSC function, Oct4alo BCCs expressed multipotent pathways similar to CSCs. Oct4alo BCCs dedifferentiated and colocalized with MSCs (murine and human BM) in vivo. Overall, these findings elucidate a mechanism of early dormancy at the BM perivascular region and provide evidence of epigenome reorganization as a potential new therapy for breast cancer. Significance: These findings describe how the initial process of dormancy and dedifferentiation of breast cancer cells at the bone marrow perivascular niche requires mesenchymal stem cell–derived exosomes, indicating a potential target for therapeutic intervention.
Cardiac troponin and defining myocardial infarction
Authors: Thomas E Kaier, Bashir Alaour, Michael Marber
Journal: Cardiovascular Research (2021)

Abstract The 4th Universal Definition of Myocardial Infarction has stimulated considerable debate since its publication in 2018. The intention was to define the types of myocardial injury through the lens of their underpinning pathophysiology. In this review, we discuss how the 4th Universal Definition of Myocardial Infarction defines infarction and injury and the necessary pragmatic adjustments that appear in clinical guidelines to maximize triage of real-world patients.
Abstract 14614: Comprehensive Cardiac Rehabilitation for Patients With Implantable Cardioverter Defibrillator Seems Cost-saving: Three Year Follow-Up Results From the COPE-ICD Randomized Controlled Trial
Authors: Selina K Berg, Ann-Dorthe Zwisler, Mette B Koch, Jesper H Svendsen, Anne Christensen, Preben U Pedersen, Lau C Thygesen
Journal: Circulation (2013)
Suppression-Replacement <i>KCNQ1</i> Gene Therapy for Type 1 Long QT Syndrome
Authors: Steven M. Dotzler, C.S. John Kim, William A.C. Gendron, Wei Zhou, Dan Ye, J. Martijn Bos, David J. Tester, Michael A. Barry, Michael J. Ackerman
Journal: Circulation (2021)

Background: Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in the KCNQ1 -encoded K v 7.1 potassium channel α-subunit that is essential for cardiac repolarization, providing the slow delayed rectifier current. No current therapies target the molecular cause of LQT1. Methods: A dual-component suppression-and-replacement (SupRep) KCNQ1 gene therapy was created by cloning a KCNQ1 short hairpin RNA and a short hairpin RNA-immune KCNQ1 cDNA modified with synonymous variants in the short hairpin RNA target site, into a single construct. The ability of KCNQ1-SupRep gene therapy to suppress and replace LQT1-causative variants in KCNQ1 was evaluated by means of heterologous expression in TSA201 cells. For a human in vitro cardiac model, induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) were generated from 4 patients with LQT1 (KCNQ1-Y171X, -V254M, -I567S, and -A344A/spl) and an unrelated healthy control. CRISPR-Cas9 corrected isogenic control iPSC-CMs were made for 2 LQT1 lines (correction of KCNQ1-V254M and KCNQ1-A344A/spl). FluoVolt voltage dye was used to measure the cardiac action potential duration (APD) in iPSC-CMs treated with KCNQ1-SupRep. Results: In TSA201 cells, KCNQ1-SupRep achieved mutation-independent suppression of wild-type KCNQ1 and 3 LQT1-causative variants (KCNQ1-Y171X, -V254M, and -I567S) with simultaneous replacement of short hairpin RNA-immune KCNQ1 as measured by allele-specific quantitative reverse transcription polymerase chain reaction and Western blot. Using FluoVolt voltage dye to measure the cardiac APD in the 4 LQT1 patient-derived iPSC-CMs, treatment with KCNQ1-SupRep resulted in shortening of the pathologically prolonged APD at both 90% and 50% repolarization, resulting in APD values similar to those of the 2 isogenic controls. Conclusions: This study provides the first proof-of-principle gene therapy for complete correction of long QT syndrome. As a dual-component gene therapy vector, KCNQ1-SupRep successfully suppressed and replaced KCNQ1 to normal wild-type levels. In TSA201 cells, cotransfection of LQT1-causative variants and KCNQ1-SupRep caused mutation-independent suppression and replacement of KCNQ1 . In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD, thereby eliminating the pathognomonic feature of LQT1.
Increasing the Donor Pool: Organ Transplantation from Donors with HIV to Recipients with HIV
Authors: Puja H. Nambiar, Brianna Doby, Aaron A.R. Tobian, Dorry L. Segev, Christine M. Durand
Journal: Annual Review of Medicine (2021)

Implementation of the HIV Organ Policy Equity (HOPE) Act marks a new era in transplantation, allowing organ transplantation from HIV+ donors to HIV+ recipients (HIV D+/R+ transplantation). In this review, we discuss major milestones in HIV and transplantation which paved the way for this landmark policy change, including excellent outcomes in HIV D–/R+ recipient transplantation and success in the South African experience of HIV D+/R+ deceased donor kidney transplantation. Under the HOPE Act, from March 2016 to December 2018, there were 56 deceased donors, and 102 organs were transplanted (71 kidneys and 31 livers). In 2019, the first HIV D+/R+ living donor kidney transplants occurred. Reaching the full estimated potential of HIV+ donors will require overcoming challenges at the community, organ procurement organization, and transplant center levels. Multiple clinical trials are ongoing, which will provide clinical and scientific data to further extend the frontiers of knowledge in this field.
Risk factors for gastric cancers in the United States: Variation by anatomic site and race/ethnicity.
Authors: Haejin In, Patricia Friedmann, Srawani Sarkar, Bruce Rapkin, Philip E. Castle, Meira Epplein
Journal: Journal of Clinical Oncology (2021)

189 Background: Gastric cancer (GC) is a high mortality cancer in the US. Differences in risk factors by anatomic location and race/ethnicity have been suggested but remain understudied in the US population. Methods: The Multiethnic Cohort (MEC) is a prospective cohort study that collected data on 5 racial/ethnic groups [Whites (W), Blacks (B), Latino (L), Japanese-American (JA), and Hawaiian (HA)] from Hawaii and Los Angeles in 1993-1996. Participants completed a detailed baseline survey and were followed for development of incident cancer. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to identify GC risk factors by anatomic location (cardia, non-cardia) and by race/ethnicity. Results: Data from 192,626 participants was available. The cohort was 25% W, 17% B, 23% L, 28% JA, and 7% HA. During a median follow up of 20.3 years, 1,109 non-cardia and 201 cardia incident GCs were diagnosed. Older age (per year, non-cardia HR 1.08, 95% CI 1.07-1.92; cardia HR 1.06, 95% CI 1.05-1.09), male sex (non-cardia HR 1.6, 95% CI 1.4-1.8; cardia HR 3.0, 95% CI 2.1-4.4), and current (non-cardia HR 1.7, 95% CI 1.5-2.2, cardia HR 3.4, 95% CI 2.2-5.3) or former (non-cardia HR 1.3, 95% CI 1.1-1.5; cardia HR 2.0, 95% CI 1.3-2.9) smoking were associated with both cancer types. Notably, race/ethnicity (ref W: B HR 3.0, 95% CI 2.2-4.0; L HR 2.5, 95% CI 1.8-3.3; JA HR 3.9, 95% CI 3.0-5.1; HA HR 3.9, 95% CI 2.8-5.5), foreign-born (ref: self &amp; parents US born: HR 1.3 95% CI 1.1-1.7), and family history of GC (OR 1.9, 95% CI 1.5-2.3) were associated with non-cardia GC. BMI ≥30 (HR 1.6, 95% CI 1.1-2.3), having ≥1 drink/week (HR 1.6, 95% CI 1.1-2.3), and being JA (ref W: HR 1.9, 95% CI 1.2-2.9) were associated with cardia GC. Risk factors other than age differed by race/ethnicity for non-cardia GC. Male sex was a risk factor for B, L and JA only. Having less than a high school education was a risk factor for B and JA only, smoking a risk factor for L and JA only, and having diabetes a risk factor for B only. Being in the highest sodium intake quartile was a risk factor among W and HA. A family history of GC was a risk factor for W, L, and JA. Having foreign-born parents was a risk factor for W and being foreign-born was a risk factor for JA. Conclusions: GC risk factors differ between subtypes and, for non-cardia, between race/ethnic groups. These differences provide an insight into the etiology of GC and the disproportionate incidence rates in high-risk groups, potentially aiding in the design of targeted intervention strategies.
An Unusual Manifestation of Rapidly Progressing Granulomatosis with Polyangiitis Involving Uterine Adnexa and Lung
Authors: Jae Seok Jeong, Kum Ju Chae, Ki Jae Sung, So Ri Kim, Heung Bum Lee, Yong Chul Lee
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"An Unusual Manifestation of Rapidly Progressing Granulomatosis with Polyangiitis Involving Uterine Adnexa and Lung." American Journal of Respiratory and Critical Care Medicine, 203(11), pp. 1431–1432
ReCab II: A phase II trial of Cabazitaxel +/- Rhenium -188-HEDP in patients with metastatic castration resistant prostate cancer who progressed on or after a docetaxel containing treatment
Authors: E. Bouman-Wammes, J.M. van Dodewaard-De Jong, H. Bloemendal, H.M. Verheul, J.M.H. de Klerk, A.J.M. van den Eertwegh
Journal: Annals of Oncology (2018)
Offline: The case for No-COVID
Authors: Richard Horton
Journal: The Lancet (2021)

As many countries continue to struggle with a third wave of COVID-19—Hong Kong is suffering its fourth wave and is contemplating a fifth and sixth—all governments and public health authorities will need to remain open to new ideas for controlling the pandemic. This past week, Ilona Kickbusch, founding director of the Global Health Centre at the Graduate Institute of International and Development Studies in Geneva, shared a proposal being widely discussed in Germany. The approach devised by a group of clinicians and academics, which in addition to Kickbusch includes Melanie Brinkmann, Michael Hallek, Matthias Schneider, and others, is a "No-COVID strategy".
Return to play with hypertrophic cardiomyopathy: are we moving too fast? A critical review
Authors: Jonathan A Drezner, Aneil Malhotra, Jordan M Prutkin, Michael Papadakis, Kimberly G Harmon, Irfan M Asif, David S Owens, Joseph C Marek, Sanjay Sharma
Journal: British Journal of Sports Medicine (2021)

The diagnosis of a potentially lethal cardiovascular disease in a young athlete presents a complex dilemma regarding athlete safety, patient autonomy, team or institutional risk tolerance and medical decision-making. Consensus cardiology recommendations previously supported the ‘blanket’ disqualification of athletes with hypertrophic cardiomyopathy (HCM) from competitive sport. More recently, epidemiological studies examining the relative contribution of HCM as a cause of sudden cardiac death (SCD) in young athletes and reports from small cohorts of older athletes with HCM that continue to exercise have fueled debate whether it is safe to play with HCM. Shared decision-making is endorsed within the sports cardiology community in which athletes can make an informed decision about treatment options and potentially elect to continue competitive sports participation. This review critically examines the available evidence relevant to sports eligibility decisions in young athletes diagnosed with HCM. Histopathologically, HCM presents an unstable myocardial substrate that is vulnerable to ventricular tachyarrhythmias during exercise. Studies support that young age and intense competitive sports are risk factors for SCD in patients with HCM. We provide an estimate of annual mortality based on our understanding of disease prevalence and the incidence of HCM-related SCD in different athlete populations. Adolescent and young adult male athletes and athletes participating in a higher risk sport such as basketball, soccer and American football exhibit a greater risk. This review explores the potential harms and benefits of sports disqualification in athletes with HCM and details the challenges and limitations of shared decision-making when all parties may not agree.
Microbiome distinctions between the CRC carcinogenic pathways
Authors: Lauren DeDecker, Bretton Coppedge, Julio Avelar-Barragan, William Karnes, Katrine Whiteson
Journal: Gut Microbes (2021)

Colorectal cancer (CRC) is the third most commonly diagnosed cancer, the third leading cause of cancer-related deaths, and has been on the rise among young adults in the United States. Research has established that the colonic microbiome is different in patients with CRC compared to healthy controls, but few studies have investigated if and how the microbiome may relate to CRC progression through the serrated pathway versus the adenoma-carcinoma sequence.Our view is that progress in CRC microbiome research requires consideration of how the microbiome may contribute to CRC carcinogenesis through the distinct pathways that lead to CRC, which could enable the creation of novel and tailored prevention, screening, and therapeutic interventions. We first highlight the limitations in existing CRC microbiome research and offer corresponding solutions for investigating the microbiome's role in the adenoma-carcinoma sequence and serrated pathway. We then summarize the findings in the select human studies that included data points related to the two major carcinogenic pathways. These studies investigate the microbiome in CRC carcinogenesis and 1) utilize mucosal samples and 2) compare polyps or tumors by histopathologic type, molecular/genetic type, or location in the colon.Key findings from these studies include: 1) Fusobacterium is associated with right-sided, more advanced, and serrated lesions; 2) the colons of people with CRC have bacteria typically associated with normal oral flora; and 3) colons from people with CRC have more biofilms, and these biofilms are predominantly located in the proximal colon (single study).