tbuckley/cabot-search huggingface dataset:
Abstract 15402: A Multi-ethnic Genome Wide Association Study of Aortic Stenosis in the Million Veteran Program Identifies Several Novel Loci
Authors: Aeron M Small, Gina Peloso, Jayashri Aragam, JASON LINEFSKY, Ashley Galloway, Kelly Cho, PETER WILSON, George Thanassoulis, Christopher J O'Donnell
Journal: Circulation (2020)

Introduction: Valvular aortic stenosis (AS) is common with high morbidity and mortality in the absence of surgical intervention, but no current medical therapies are known to prevent or slow disease progression. Previous genetic studies have identified several genetic loci associated with prevalent AS, including LPA and PALMD , although most evidence is limited to populations of European ancestry. Methods: We performed a trans-ethnic genome-wide association study (GWAS) of prevalent AS in the Veterans Administration Million Veteran Program (MVP). Cases were identified by a combination of diagnostic billing and surgical codes and validated by association to the known LPA variant (rs10455872). GWAS was run separately for White, Black, and Hispanic individuals, controlling for age, sex, and six principal components, and combined using fixed effects meta-analysis. Results were limited to variants with a minor allele frequency greater than 1% in the trans-ancestry analysis. Lead independent genome wide significant loci were annotated by nearest gene. Results: 300,182 White, 80,744 Black, and 32,069 Hispanic participants were available for analysis. Of these, there were 12,385 (4.1%) White, 1,444 (1.8%) Black, and 611 (1.9%) Hispanic AS cases. Trans-ethnic analyses identified 10 independent genome wide significant (GWS, p≤5x10 -8 ) loci, replicating 6 known AS genetic loci ( ALPL, PALMD, TEX41, LPA, IL6, FADS1 ), and identifying 4 novel genetic loci ( CEP85L, CELSR2, NCK1, SLMAP ), of which 2 were present at nominal significance in Hispanic ( CELS2R ) or Black ( SLMAP ) individuals. Ethnicity-specific analyses additionally identified 9 novel GWS loci in White individuals, and 3 novel GWS loci in Hispanic individuals. Newly identified loci supported known biological pathways in AS including lipid/metabolic, inflammatory, and calcification, but also implicated new pathways such as those pertaining to QT interval ( SLC35F1 ) and the Brugada Syndrome ( SLMAP ). Conclusions: In this large trans-ethnic GWAS for AS we replicate previously identified genetic loci for AS, and identified several novel loci both in trans-ethnic and in ethnic-specific analyses. These loci implicate known and novel biological mechanisms for future prevention and treatment of AS.
Estimates of the global burden of cervical cancer associated with HIV
Authors: Dominik Stelzle, Luana F Tanaka, Kuan Ken Lee, Ahmadaye Ibrahim Khalil, Iacopo Baussano, Anoop S V Shah, David A McAllister, Sami L Gottlieb, Stefanie J Klug, Andrea S Winkler, Freddie Bray, Rachel Baggaley, Gary M Clifford, Nathalie Broutet, Shona Dalal
Journal: The Lancet Global Health (2020)

HIV enhances human papillomavirus (HPV)-induced carcinogenesis. However, the contribution of HIV to cervical cancer burden at a population level has not been quantified. We aimed to investigate cervical cancer risk among women living with HIV and to estimate the global cervical cancer burden associated with HIV.We did a systematic literature search and meta-analysis of five databases (PubMed, Embase, Global Health [CABI.org], Web of Science, and Global Index Medicus) to identify studies analysing the association between HIV infection and cervical cancer. We estimated the pooled risk of cervical cancer among women living with HIV across four continents (Africa, Asia, Europe, and North America). The risk ratio (RR) was combined with country-specific UNAIDS estimates of HIV prevalence and GLOBOCAN 2018 estimates of cervical cancer to calculate the proportion of women living with HIV among women with cervical cancer and population attributable fractions and age-standardised incidence rates (ASIRs) of HIV-attributable cervical cancer.24 studies met our inclusion criteria, which included 236 127 women living with HIV. The pooled risk of cervical cancer was increased in women living with HIV (RR 6·07, 95% CI 4·40-8·37). Globally, 5·8% (95% CI 4·6-7·3) of new cervical cancer cases in 2018 (33 000 new cases, 95% CI 26 000-42 000) were diagnosed in women living with HIV and 4·9% (95% CI 3·6-6·4) were attributable to HIV infection (28 000 new cases, 20 000-36 000). The most affected regions were southern Africa and eastern Africa. In southern Africa, 63·8% (95% CI 58·9-68·1) of women with cervical cancer (9200 new cases, 95% CI 8500-9800) were living with HIV, as were 27·4% (23·7-31·7) of women in eastern Africa (14 000 new cases, 12 000-17 000). ASIRs of HIV-attributable cervical cancer were more than 20 per 100 000 in six countries, all in southern Africa and eastern Africa.Women living with HIV have a significantly increased risk of cervical cancer. HPV vaccination and cervical cancer screening for women living with HIV are especially important for countries in southern Africa and eastern Africa, where a substantial HIV-attributable cervical cancer burden has added to the existing cervical cancer burden.WHO, US Agency for International Development, and US President's Emergency Plan for AIDS Relief.
Covid-19 vaccines: Should we allow human challenge studies to infect healthy volunteers with SARS-CoV-2?
Authors: Seán O’Neill McPartlin, Josh Morrison, Abie Rohrig, Charles Weijer
Journal: BMJ (2020)

The urgent need for covid-19 vaccines has prompted thousands of otherwise healthy people to volunteer to be infected with the virus to test candidate vaccines. <b>Seán O'Neill McPartlin</b>, <b>Abie Rohrig</b>, and <b>Josh Morrison</b> urge us to embrace the altruism of volunteers, but <b>Charles Weijer</b> argues that it would be dangerous and unjustified
Mechanical ventilation in patients with acute brain injury: recommendations of the European Society of Intensive Care Medicine consensus
Authors: Chiara Robba, Daniele Poole, Molly McNett, Karim Asehnoune, Julian Bösel, Nicolas Bruder, Arturo Chieregato, Raphael Cinotti, Jacques Duranteau, Sharon Einav, Ari Ercole, Niall Ferguson, Claude Guerin, Ilias I. Siempos, Pedro Kurtz, Nicole P. Juffermans, Jordi Mancebo, Luciana Mascia, Victoria McCredie, Nicolas Nin, Mauro Oddo, Paolo Pelosi, Alejandro A. Rabinstein, Ary Serpa Neto, David B. Seder, Markus B. Skrifvars, Jose I. Suarez, Fabio Silvio Taccone, Mathieu van der Jagt, Giuseppe Citerio, Robert D. Stevens
Journal: Intensive Care Medicine (2020)
A sulfur dioxide polymer prodrug showing combined effect with doxorubicin in combating subcutaneous and metastatic melanoma
Authors: Lin An, Peng Zhang, Wei Shen, Xuan Yi, Weitian Yin, Rihua Jiang, Chunsheng Xiao
Journal: Bioactive Materials (2020)

Melanoma, as the most aggressive and treatment-resistant skin malignancy, is responsible for about 80% of all skin cancer mortalities. Prone to invade into the dermis and form distant metastases significantly reduce the patient survival rate. Therefore, early treatment of the melanoma in situ or timely blocking the deterioration of metastases is critical. In this study, a sulfur dioxide (SO
Abstract 15887: Clonal Hematopoiesis Links Premature Menopause to Cardiovascular Disease
Authors: Michael C Honigberg, Seyedeh Zekavat, Abhishek Niroula, Gabirel K Griffin, Alexander G Bick, James Pirruccello, Charles Kooperberg, Joann E Manson, Stacey Gabriel, Peter Libby, Alex Reiner, Benjamin Ebert, Pradeep Natarajan
Journal: Circulation (2020)

Introduction: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown. Methods: We included postmenopausal women from the UK Biobank (N=11,509) aged 40-70 years with whole exome sequences and from the Women’s Health Initiative (WHI, N=8,111) aged 50-79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of (1) any CHIP and (2) CHIP with variant allele fraction (VAF) &gt;0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components, smoking, diabetes mellitus, and hormone therapy use. Results: Across cohorts, prevalence of CHIP in women with vs. without a history of premature menopause was 8.8% vs. 5.5% (P&lt;0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP, driven by associations with natural premature menopause (OR for all CHIP: 1.73, 95% CI 1.23-2.44; OR for CHIP with VAF &gt;0.1: 1.91, 95% CI 1.30-2.80; Figure ). In gene-specific analyses, DNMT3A CHIP had a strong association with natural premature menopause but no association with surgical premature menopause. Among postmenopausal middle-aged women in the UK Biobank and WHI, CHIP was independently associated with incident coronary artery disease (meta-analyzed HR 1.52, 95% CI 1.17-1.99). Conclusions: Premature menopause, especially natural premature menopause, is independently associated with CHIP. CHIP may contribute to the excess cardiovascular risk associated with premature menopause.
THU0120 Polymorphonuclear neutrophil nadph oxidase priming and activation in rheumatoid joints: correlation with disease activity and synovial concentrations of tnf, il-8 and gm-csf
Authors: G Hayem, J El Benna, M Fay, S Chollet-Martin, O Meyer, MA Gougerot-Pocidalo
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Superoxide production by polymorphonuclear neutrophil (PMN) participates in the rheumatoid joint lesions and mainly depends on NADPH oxidase activation. Tumour necrosis factor (TNF), interleukin-8 (IL-8) and granulocyte/macrophage colony stimulating factor (GM-CSF) have a priming effect on NADPH oxidase, depending on the phosphorylation of p47phox, a major cytosolic component of NADPH oxidase. <h3>Objectives</h3> We sought to determine if the status (primed/activated) of NADPH oxidase of articular PMN was correlated with rheumatic disease activity and TNF, IL-8 and GM-CSF synovial concentrations. <h3>Methods</h3> Knee joint fluid aspiration was performed in 17 patients, 11 with RA and 6 with spondyloarthropathy (SpA). Usual clinical and biological data were recorded for each patient, allowing a DAS28 scoring. NADPH oxidase activity was analysed with cytochrome c reduction technique. Phosphorylation of p47phox was evaluated with isoelectrofocusing and immunoblotting using a specific antibody. Cytokines concentrations were measured with ELISA kits. <h3>Results</h3> NADPH oxidase activity was increased in the majority of RA knee joints, and to a lesser extent in the SpA group. In the RA group, the NADPH oxidase activity was correlated positively with DAS28, with the PMN count in the synovial fluid, with the degree of p47phox phosphorylation, and with the synovial concentrations of TNF and IL-8. Concentrations of GM-CSF remained very low or undetectable in all patients. In the RA group only, the DAS28, the PMN count and the phosphorylation of p47phox were correlated with synovial concentrations of TNF and IL-8. <h3>Conclusion</h3> NADPH oxidase activation, through an increased phosphorylation of p47phox, seems to be implicated in joint inflammation during RA. This phenomenon could be related to high level of TNF and IL-8.
Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabetes
Authors: Teresa Quattrin, Michael J. Haller, Andrea K. Steck, Eric I. Felner, Yinglei Li, Yichuan Xia, Jocelyn H. Leu, Ramineh Zoka, Joseph A. Hedrick, Mark R. Rigby, Frank Vercruysse
Journal: New England Journal of Medicine (2020)

Type 1 diabetes is an autoimmune disease characterized by progressive loss of pancreatic beta cells. Golimumab is a human monoclonal antibody specific for tumor necrosis factor α that has already been approved for the treatment of several autoimmune conditions in adults and children. Whether golimumab could preserve beta-cell function in youth with newly diagnosed overt (stage 3) type 1 diabetes is unknown.In this phase 2, multicenter, placebo-controlled, double-blind, parallel-group trial, we randomly assigned, in a 2:1 ratio, children and young adults (age range, 6 to 21 years) with newly diagnosed overt type 1 diabetes to receive subcutaneous golimumab or placebo for 52 weeks. The primary end point was endogenous insulin production, as assessed according to the area under the concentration-time curve for C-peptide level in response to a 4-hour mixed-meal tolerance test (4-hour C-peptide AUC) at week 52. Secondary and additional end points included insulin use, the glycated hemoglobin level, the number of hypoglycemic events, the ratio of fasting proinsulin to C-peptide over time, and response profile.A total of 84 participants underwent randomization - 56 were assigned to the golimumab group and 28 to the placebo group. The mean (±SD) 4-hour C-peptide AUC at week 52 differed significantly between the golimumab group and the placebo group (0.64±0.42 pmol per milliliter vs. 0.43±0.39 pmol per milliliter, P<0.001). A treat-to-target approach led to good glycemic control in both groups, and there was no significant difference between the groups in glycated hemoglobin level. Insulin use was lower with golimumab than with placebo. A partial-remission response (defined as an insulin dose-adjusted glycated hemoglobin level score [calculated as the glycated hemoglobin level plus 4 times the insulin dose] of ≤9) was observed in 43% of participants in the golimumab group and in 7% of those in the placebo group (difference, 36 percentage points; 95% CI, 22 to 55). The mean number of hypoglycemic events did not differ between the trial groups. Hypoglycemic events that were recorded as adverse events at the discretion of investigators were reported in 13 participants (23%) in the golimumab group and in 2 (7%) of those in the placebo group. Antibodies to golimumab were detected in 30 participants who received the drug; 29 had antibody titers lower than 1:1000, of whom 12 had positive results for neutralizing antibodies.Among children and young adults with newly diagnosed overt type 1 diabetes, golimumab resulted in better endogenous insulin production and less exogenous insulin use than placebo. (Funded by Janssen Research and Development; T1GER ClinicalTrials.gov number, NCT02846545.).
Abstract 16662: Central Lymphatic Dysfunction is a Contributing Cause of Tissue Congestion in Heart Failure
Authors: Menekhem M Zviman, Christopher L Smith, Jacquelyn Teson, Edo Birati, Yoav Dori
Journal: Circulation (2020)

Introduction: Symptomatic Heart failure (HF) is a leading cause of morbidity and mortality in the world. HF with right sided symptoms may result in fluid overload including edema and ascites. The pathophysiology of fluid overload is poorly understood with no clear association between symptoms and hemodynamic parameters. Hypothesis: In animals with RHF and elevated CVP, the presence of ascites correlates with changes in lymphatic function and is independent of myocardial function and hemodynamic parameters. Methods: RHF was induced in fifteen swine animals by creating severe tricuspid regurgitation. Hemodynamics and anatomic changes were characterized using fluoroscopy, echocardiogram, and MRI. Measurements of the thoracic duct (TD) were made in the abdomen and thorax and the cross-sectional area was calculated. TD regurgitant flow was identified with ethiodized oil injection into the TD and was noted to be present or absent. Data is reported as median (IQR). Results: All 15 animals developed RHF with a dilated right atrium (RA) and right ventricle (RV). Nine animals developed ascites. Comparing animals with and without ascites, there were no differences in IVC pressure(mmHg) 11.5 (7.7-13.4) vs. 11.9 (10.2-17.4) (p= 0.364), SVC pressure 12.8 (11.3-16.8) vs. 12 (8.3-14.9) (p=0.343). Other hemodynamics parameters including pulmonary artery (PA), RV, and RA pressure were also not significantly different. In addition, left ventricular (LV) ejection fraction was normal in both groups (68.7% (57.9-74.8) vs. 55% (53.1-69.4) (p=0.135)). However, animals in the ascites group had larger relative liver volume (mL/Kg) 59.1 (65.1-51.9) vs. 34.85 (42.3-24.1) (p = 0.003), larger dimension of the minimal TD size (mm) 3.2 (5.8-2.7) vs. 2.2 (2.6-2.0) (p=0.04), and more animals had TD regurgitant flow 89% vs. 16% (p=0.01). Conclusion: In animal model with RV failure, there is no association between hemodynamic parameters and occurrence of ascites, consistent with observations in humans. In contrast, parameters of lymphatic congestion differ significantly between the two groups supporting the notion that lymphatic dysfunction is a contributing cause of tissue congestion in patients with HF and elevated CVP.
Abstract 16726: Impact of Angiotensin Converting Enzyme Inhibitors/angiotensin Receptor Blockers on Mortality and Severity of Covid-19 Pneumonia
Authors: Ankita Aggarwal, Anubhav Jain, Mishita Goel, Jurgena Tusha, Verisha Khanam, Sourabh Bidhan, Ameer Khan, Monica Dhawan, vesna tegeltija, sarwan kumar
Journal: Circulation (2020)

Introduction: Coronaviruses are a large family of viruses that have been around for many years and may cause illness in humans or animals. In early December 2019, the first pneumonia cases related to the coranoavirus were found which has since led a pandemic. Coronaviruses bind to their target cells through angiotensin-converting enzyme 2 (ACE2), which is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels. Hypothesis: Hypothetically, the increased expression of ACE2 would facilitate infection with COVID-19 and treatment with ACE2-stimulating drugs may worsen the infection with COVID-19. The goal of this study was to analyze the severity of COVID-19 in patients who are on ACEi and ARB therapy. Methods: All adult patients admitted with the confirmed diagnosis of COVID 19 pneumonia between March to April 2020 in our community hospital were included in the study. Patients were then be divided into two groups, one group who received ACEi or ARBs and a second group who did not. The baseline characteristics of two groups were compared. Primary outcome was the in-hospital mortality between two groups. Secondary outcomes were severity of pneumonia including rate of intubation, requirement for ICU admission and total length of hospital stay. Results: A total of 200 patients were admitted with the time frame studied. After removing for missing data 194 patients were included in the study of which 64 patients received either ACEi or ARB during the hospital stay. There was no difference in the rate of inpatient mortality in patients who received or did not received the drug (32.3% vs 23.5% p- value 0.19). Similarly, there was no difference in the other outcomes including rate of intubation(22.6% vs 24.4% p- value 0.79), requirement for ICU admission(21% vs 33.3% p-value 0.07) and mean total length of hospital stay between the two groups (9.5 days vs 8.4 days p-value 0.34). Conclusion: There was no difference in the outcomes. Patients who received ACEi or ARBs did not have worse outcomes. Thus, if indicated for other reasons, these drugs can safely be continued in patients with COVID 19 pneumonia. Further large center studies are however, required to confirm our findings.
Abstract 13724: Myocardial Tissue Sensitization With Heat-activated Liposomal Doxorubicin Will Result in Enhanced Lesion Progression After Radiofrequency Ablation
Authors: Duy T Nguyen, Lijun Zheng, Joseph Schuller, William Sauer
Journal: Circulation (2020)

Introduction: Chronic durable lesions after radiofrequency ablation (RFA) of myocardial tissue remain difficult to achieve. Tissue exposed to RFA will often recover electrical activity despite initial dormancy. Heat sensitive liposomes (HSL) carrying doxorubicin has been shown to enhance RF destruction of tumors. Hypothesis: We sought to evaluate whether HSL doxorubicin will improve myocardial RFA lesion durability. Methods: Using an in vivo porcine model, 3 linear RF ablations per animal were performed by blinded operators in the right atrium after systemic HSL doxorubicin infusion or saline control: posterior (20W), septal (30W), and lateral (40W). Each line was created under standardized 3D mapping settings with inter-lesion distances of 4-6 mm to intentionally simulate linear RF gaps. Voltage mapping was performed immediately after ablation (Day 0) and after 2 weeks of survival. Comparisons were made in linear low voltage areas (LVA) from Day 0 to 2 weeks. Pathological staining of porcine RA ablation was also performed to assess for histological linear gaps. Results: There was no immediate difference in Day 0 LVA &lt; 0.5 mV after ablation for HSL and controls. However, a significant increase in LVA &lt; 0.5 mV was observed at 2 weeks in HSL animals (figure) with lesion progression in 3/5, compared to 0/4 controls, p&lt; 0.05. There were fewer gaps identified with voltage remapping and on histology for HSL subjects compared to controls. Conclusions: RFA with concurrent HSL doxorubicin will be more durable and result in lesion progression with fewer linear gaps over time. Further confirmatory studies are needed.