tbuckley/cabot-search huggingface dataset:
OP0123 Body mass index and physical activity as risk factors for primary osteoarthritis. a cohort study in 50.034 persons
Authors: GB Flugsrud, B Espehaug, LI Havelin, L Nordsletten, HE Meyer
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> As no cure exists for osteoarthritis other than operation, it is important to identify preventable aetiological factors. <h3>Objectives</h3> To describe the association between middle age body mass index (BMI) and physical activity, and later total hip replacement (THR), in a large cohort. <h3>Methods</h3> The Norwegian Arthroplasty Register records all THRs and hip revisions performed in Norwegian hospitals.<sup>1</sup> In three Norwegian counties the National Health Screening Service (NHSS) three times conducted a cardiovascular screening during the years 1974–88. Persons born 1925–42 were screened repeatedly at median ages 42, 47 and 53 years.<sup>2</sup> For 89% of the participants data on body weight and height were available at the NHSS from a screening for tuberculosis, conducted during the years 1963–75 (median age 34 years).<sup>3</sup> The registers were matched and survival analyses performed using the Cox regression model. An event was recorded when a person had his first THR for primary osteoarthritis. Follow up was 1989–98. We controlled for age at screening, body height, marital status and smoking. <h3>Results</h3> Analysing screening data from the second cardiovascular screening only (attendance 92.8%) we found 672 THRs. A dose-response relationship was found between BMI and the risk for THR. Women in the highest BMI quarter had a relative risk of 3.0 (95% CI 2.2–4.2) compared to women in the lowest quarter. The corresponding figure in men was 2.0 (95% CI 1.5–3.0). Physical activity at work also showed a dose-response relationship. Both women and men in the most active group had a relative risk for THR of 2.1 compared to the least active group. Analyses of BMI data from each of the four screenings indicated that the predictive value of BMI for later THR was strongest at the tuberculosis screening and decreased gradually and considerably at the following screenings. <h3>Conclusion</h3> This study confirmed that high physical activity at work increases the risk for THR-demanding osteoarthritis in men. Contrary to earlier findings, the effect was equally strong among women in our population. We found that even for levels of BMI and physical activity at work that were well within the normal ranges an increment in these risk factors increased the risk for THR-demanding osteoarthritis. Our findings indicate that the peak impact of BMI on the development of hip osteoarthritis may be at, or before, the age of 34 years. <h3>References</h3> Havelin LI, Espehaug B, Vollset SE, Engesæter LB, Langeland N. The Norwegian Arthroplasty Register. A survey of 17,444 total hip replacements. Acta Orthop Scand. 1993;64:245–51 National Health Screening Service, The cardiovascular disease study in Norwegian counties: results from second screening. Oslo: National Health Screening Service, 1988 Waaler HT. Height, weight and mortality. Acta Med Scand Suppl. 1984;679:1–56
Opinion leaders vs audit and feedback to implement practice guidelines. Delivery after previous cesarean section
Authors: J. Lomas
Journal: JAMA (1991)

A randomized controlled trial with 76 physicians in 16 community hospitals evaluated audit and feedback and local opinion leader education as methods of encouraging compliance with a guideline for the management of women with a previous cesarean section. The guideline recommended clinical actions to increase trial of labor and vaginal birth rates. Charts for all 3552 cases in the study groups were audited. After 24 months the trial of labor and vaginal birth rates in the audit and feedback group were no different from those in the control group, but rates were 46% and 85% higher, respectively, among physicians educated by an opinion leader. Duration of hospital stay was lower in the opinion leader education group than in the other two groups. The overall cesarean section rate was reduced only in the opinion leader education group. There were no adverse clinical outcomes attributable to the interventions. The use of opinion leaders improved the quality of care.  ( JAMA . 1991;265:2202-2207)
Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas
Authors: Alexander N. Shoushtari, Walid K. Chatila, Arshi Arora, Francisco Sanchez-Vega, Havish S. Kantheti, Jorge A. Rojas Zamalloa, Penina Krieger, Margaret K. Callahan, Allison Betof Warner, Michael A. Postow, Parisa Momtaz, Suresh Nair, Charlotte E. Ariyan, Christopher A. Barker, Mary Susan Brady, Daniel G. Coit, Neal Rosen, Paul B. Chapman, Klaus J. Busam, David B. Solit, Katherine S. Panageas, Jedd D. Wolchok, Nikolaus Schultz
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown. Experimental Design: Patients with melanoma were prospectively offered tumor sequencing of 341–468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received first-line programmed cell death protein 1 (PD-1) monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables. Results: A total of 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy (N = 181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22, and not reached; P &amp;lt; 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N = 141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and eight (30%) derived clinical benefit lasting ≥6 months. Conclusions: Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. TTF of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor–refractory melanoma.
Utility of Restricted Mean Survival Time for Analyzing Time to Nursing Home Placement Among Patients With Dementia
Authors: Dae Hyun Kim, Xihao Li, Shijia Bian, Lee-Jen Wei, Ryan Sun
Journal: JAMA Network Open (2021)

This cohort study assesses the utility of restricted mean survival time as a method for quantifying time to nursing home placement among patients with dementia.
Comparative landscape of actionable somatic alterations in advanced cholangiocarcinoma from circulating tumor and tissue-based DNA profiling.
Authors: Pashtoon Murtaza Kasi, Alexander D Le, Alex Barrett
Journal: Journal of Clinical Oncology (2021)

342 Background: Cholangiocarcinoma (CCA) is a target-rich disease. Despite this, treatment guidelines lack recommendations for broad molecular profiling in CCA to identify potentially actionable targets. Furthermore, comparative data assessing similarities and differences in actionable ctDNA and tissue based genomic biomarkers remain limited. As such, we sought to broadly characterize the genomic alterations that are linked to targeted therapies that may facilitate a more personalized approach to therapy. Methods: We retrospectively analyzed NGS data obtained from 137 advanced cholangiocarcinoma patients via Tempus xT tissue biopsy assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth) and/or Tempus xF liquid biopsy assay (ctDNA sequencing of 105 genes in peripheral blood samples at 5,000x depth) for germline and/or somatic mutations including single nucleotide variants, specific insertion/deletions, amplifications and gene fusions. Results: 110 patients were tested once and 27 patients had two or more tests available. Of the 174 genomic results, 113 were tissue-based NGS results, and 61 were liquid-based NGS results. The total number of unique alterations was found to be 296. Focusing on aberrations for which there are approved therapies in the same or other tumor types or inclusion in guidelines and/or active clinical trials, we found FGFR2 fusions (6.8%), IDH1/2 (8.4%), BRAF-V600E (2.5%), HER2 (3%), MET (0.7%), BRCA1/2/ATM (2%), PIK3CA (4.7%), and ERRFI1 (0.7%). This comprises ~30% (Table). Of note, within this bucket of actionable findings, if we focus on ctDNA liquid biopsy cohort, the proportion goes up to 33.1% vs. 23.2% for tissue based genomic testing. For example, comparison of liquid to tissue, FGFR2 fusion was noted in 11.3% vs. 3.4%, BRAF-V600E in 3% vs. 1% and HER2 0% vs. 3.8%, respectively. Also, no MSI-High patients but two (1.5%) had KRAS-G12C mutation. Notable differences in the prevalence of actionable somatic mutations in solid vs. liquid results were observed (Table). Conclusions: These data provide an updated benchmark for guiding the development of targeted therapies in molecularly profiled CCA and support the use of both solid and liquid biopsy molecular profiling to guide therapy selection in patients with advanced cholangiocarcinoma. Additionally, liquid biopsy molecular profiling can fill the void where tissue may not be readily available. [Table: see text]
In-Hospital Cardiac Arrest in Patients With Covid-19
Authors: O. J. Mitchell, E. Yuriditsky, O. Doran, N. J. Johnson, S. Neefe, P. Zeniecki, F. M. West, R. Seethala, L. Naar, S. Motov, A. Moskowitz, K. C. Ma, J. Lee, K. Griffin, T. Kingsley, M. Mullen-Fortino, P. J. Donnelly, A. Damani, D. Covin, K. Berg, J. Anderson, M. G. Shashaty, J. M. Horowitz, B. Abella, Covid Ihca Study Grp
Journal: Circulation (2020)
Functional diagnostics using fresh uncultured lung tumor cells to guide personalized treatments
Authors: Sarang S. Talwelkar, Mikko I. Mäyränpää, Lars Søraas, Swapnil Potdar, Jie Bao, Annabrita Hemmes, Nora Linnavirta, Jon Lømo, Jari Räsänen, Aija Knuuttila, Krister Wennerberg, Emmy W. Verschuren
Journal: Cell Reports Medicine (2021)

Functional profiling of a cancer patient's tumor cells holds potential to tailor personalized cancer treatment. Here, we report the utility of fresh uncultured tumor-derived EpCAM+ epithelial cells (FUTCs) for ex vivo drug-response interrogation. Analysis of murine Kras mutant FUTCs demonstrates pharmacological and adaptive signaling profiles comparable to subtype-matched cultured cells. By applying FUTC profiling on non-small-cell lung cancer patient samples, we report robust drug-response data in 19 of 20 cases, with cells exhibiting targeted drug sensitivities corresponding to their oncogenic drivers. In one of these cases, an EGFR mutant lung adenocarcinoma patient refractory to osimertinib, FUTC profiling is used to guide compassionate treatment. FUTC profiling identifies selective sensitivity to disulfiram and the combination of carboplatin plus etoposide, and the patient receives substantial clinical benefit from treatment with these agents. We conclude that FUTC profiling provides a robust, rapid, and actionable assessment of personalized cancer treatment options.
Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload
Authors: Mélanie Lambert, Pedro Mendes-Ferreira, Maria-Rosa Ghigna, Hélène LeRibeuz, Rui Adão, Angèle Boet, Véronique Capuano, Catherine Rucker-Martin, Carmen Brás-Silva, Rozenn Quarck, Valérie Domergue, Jean-Luc Vachiéry, Marc Humbert, Frédéric Perros, David Montani, Fabrice Antigny
Journal: Cardiovascular Research (2021)

Abstract Aims Pulmonary hypertension (PH) is a common complication of left heart disease (LHD, Group 2 PH) leading to right ventricular (RV) failure and death. Several loss-of-function (LOF) mutations in KCNK3 were identified in pulmonary arterial hypertension (PAH, Group 1 PH). Additionally, we found that KCNK3 dysfunction is a hallmark of PAH at pulmonary vascular and RV levels. However, the role of KCNK3 in the pathobiology of PH due to LHD is unknown. Methods and results We evaluated the role of KCNK3 on PH induced by ascending aortic constriction (AAC), in WT and Kcnk3-LOF-mutated rats, by echocardiography, RV catheterization, histology analyses, and molecular biology experiments. We found that Kcnk3-LOF-mutation had no consequence on the development of left ventricular (LV) compensated concentric hypertrophy in AAC, while left atrial emptying fraction was impaired in AAC-Kcnk3-mutated rats. AAC-animals (WT and Kcnk3-mutated rats) developed PH secondary to AAC and Kcnk3-mutated rats developed more severe PH than WT. AAC-Kcnk3-mutated rats developed RV and LV fibrosis in association with an increase of Col1a1 mRNA in right ventricle and left ventricle. AAC-Kcnk3-mutated rats developed severe pulmonary vascular (pulmonary artery as well as pulmonary veins) remodelling with intense peri-vascular and peri-bronchial inflammation, perivascular oedema, alveolar wall thickening, and exaggerated lung vascular cell proliferation compared to AAC-WT-rats. Finally, in lung, right ventricle, left ventricle, and left atrium of AAC-Kcnk3-mutated rats, we found a strong increased expression of Il-6 and periostin expression and a reduction of lung Ctnnd1 mRNA (coding for p120 catenin), contributing to the exaggerated pulmonary and heart remodelling and pulmonary vascular oedema in AAC-Kcnk3-mutated rats. Conclusions Our results indicate that Kcnk3-LOF is a key event in the pathobiology of PH due to AAC, suggesting that Kcnk3 channel dysfunction could play a potential key role in the development of PH due to LHD.
FRI0190 Surgical treatment for gastroesophageal reflux disease in systemic sclerosis
Authors: PD Sampaio-Barros, NA Andreollo, LR Lopes, AG Cunha, AM Samara, NA Brandalise, JF Marques-Neto
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To describe the experience with the surgical treatment for gastroesophageal reflux disease (GRD) in systemic sclerosis (SSc). <h3>Methods</h3> From 202 patients with the diagnosis of SSc attended at the Scleroderma outpatient clinic in the period 1991–2000, ten patients (5%) who presented GRD, with severe chronic esophagitis and stricture, were submitted to surgical treatment. All the patients were female and eight were Caucasian, with seven presenting limited SSc (mean age 53 years and mean disease duration 17 years) and three diffuse SSc (mean age 44 years and mean disease duration 6 years). <h3>Results</h3> The correction of the gastroesophageal reflux was performed through videolaparoscopy in nine patients. Seven patients underwent modified Nissen technique and three patients Lind technique. There was satisfactory clinical response, with significant improvement in the heartburn and dysphagia in all the patients. After a mean followup of 34 months (12–76 months), one patient presented clinical relapse (after 54 months) and another patient needed a surgical ressection of a paraesophageal hernia (Y-Roux). <h3>Conclusion</h3> The surgical treatment of GRD represents an efficient therapeutic option in SSc patients with severe esophagitis and stricture.
Infographic. ACL injury journey: an education aid
Authors: Connor Patrick Gleadhill, Christian J Barton
Journal: British Journal of Sports Medicine (2021)

After an anterior cruciate ligament (ACL) injury, patients report feeling angry, depressed, frustrated and uncertain about their future.1 It is recommended that patients and practitioners engage in shared decision-making to ensure an informed choice about treatment is reached.2 Unfortunately, there are limited resources to help patients navigate treatment decisions and set expectations following an ACL injury. We coproduced an infographic (see figures 1 and 2), with input from patients about content and design, to present the best available evidence in an easy to digest format. This infographic (separated into two parts) is an education aid, designed to be used with a health professional, to reduce uncertainty, enhance communication and assist in shared decision-making. Broadly, it aims to cover:



Patients need a clear appraisal of the evidence, to make an informed decision about whether to have ACL reconstruction (ACLR) or not following ACL injury. …
Abstract 15169: Gender Differences in the Risk Factors Associated With Atherosclerosis Evaluated by Carotid Intima-Media Thickness, Plaque Score and Pulse Wave Velocity
Authors: Satoko Ojima, Takuro Kubozono, Shin Kawasoe, Takeko Kawabata, Masaaki Miyata, Hironori Miyahara, Shigeho Maenohara, Mitsuru Ohishi
Journal: Circulation (2019)

Introduction: Carotid intima-media thickness (IMT), carotid plaque score (PS) and brachial-ankle pulse wave velocity (baPWV) are useful atherosclerotic parameters, and these are evaluating the diff...
Increased insulin sensitivity and diminished pancreatic beta-cell function in DNA repair deficient Ercc1 mice
Authors: Ana P. Huerta Guevara, Sara J. McGowan, Melissa Kazantzis, Tania Rozgaja Stallons, Tokio Sano, Niels L. Mulder, Angelika Jurdzinski, Theo H. van Dijk, Bart J.L. Eggen, Johan W. Jonker, Laura J. Niedernhofer, Janine K. Kruit
Journal: Metabolism (2021)

BackgroundType 2 diabetes (T2DM) is an age-associated disease characterized by hyperglycemia due to insulin resistance and decreased beta-cell function. DNA damage accumulation has been associated with T2DM, but whether DNA damage plays a role in the pathogenesis of the disease is unclear. Here, we used mice deficient for the DNA excision-repair gene Ercc1 to study the impact of persistent endogenous DNA damage accumulation on energy metabolism, glucose homeostasis and beta-cell function.MethodsERCC1-XPF is an endonuclease required for multiple DNA repair pathways and reduced expression of ERCC1-XPF causes accelerated accumulation of unrepaired endogenous DNA damage and accelerated aging in humans and mice. In this study, energy metabolism, glucose metabolism, beta-cell function and insulin sensitivity were studied in Ercc1d/− mice, which model a human progeroid syndrome.ResultsErcc1d/− mice displayed suppression of the somatotropic axis and altered energy metabolism. Insulin sensitivity was increased, whereas, plasma insulin levels were decreased in Ercc1d/− mice. Fasting induced hypoglycemia in Ercc1d/− mice, which was the result of increased glucose disposal. Ercc1d/− mice exhibit a significantly reduced beta-cell area, even compared to control mice of similar weight. Glucose-stimulated insulin secretion in vivo was decreased in Ercc1d/− mice. Islets isolated from Ercc1d/− mice showed increased DNA damage markers, decreased glucose-stimulated insulin secretion and increased susceptibility to apoptosis.ConclusionSpontaneous DNA damage accumulation triggers an adaptive response resulting in improved insulin sensitivity. Loss of DNA repair, however, does negatively impacts beta-cell survival and function in Ercc1d/− mice.
Outcomes of COVID-19 Among Hospitalized Health Care Workers in North America
Authors: Jeong Yun Yang, Michael D. Parkins, Andrew Canakis, Olga C. Aroniadis, Dhiraj Yadav, Rebekah E. Dixon, B. Joseph Elmunzer, Nauzer Forbes
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Although health care workers (HCWs) are at higher risk of acquiring coronavirus disease 2019 (COVID-19), it is unclear whether they are at risk of poorer outcomes. <h3>Objective</h3> To evaluate the association between HCW status and outcomes among patients hospitalized with COVID-19. <h3>Design, Setting, and Participants</h3> This retrospective, observational cohort study included consecutive adult patients hospitalized with a diagnosis of laboratory-confirmed COVID-19 across 36 North American centers from April 15 to June 5, 2020. Data were collected from 1992 patients. Data were analyzed from September 10 to October 1, 2020. <h3>Exposures</h3> Data on patient baseline characteristics, comorbidities, presenting symptoms, treatments, and outcomes were collected, including HCW status. <h3>Main Outcomes and Measures</h3> The primary outcome was a requirement for mechanical ventilation or death. Multivariable logistic regression was performed to yield adjusted odds ratios (AORs) and 95% CIs for the association between HCW status and COVID-19–related outcomes in a 3:1 propensity score–matched cohort, adjusting for residual confounding after matching. <h3>Results</h3> In total, 1790 patients were included, comprising 127 HCWs and 1663 non-HCWs. After 3:1 propensity score matching, 122 HCWs were matched to 366 non-HCWs. Women comprised 71 (58.2%) of matched HCWs and 214 (58.5%) of matched non-HCWs. Matched HCWs had a mean (SD) age of 52 (13) years, whereas matched non-HCWs had a mean (SD) age of 57 (17) years. In the matched cohort, the odds of the primary outcome, mechanical ventilation or death, were not significantly different for HCWs compared with non-HCWs (AOR, 0.60; 95% CI, 0.34-1.04). The HCWs were less likely to require admission to an intensive care unit (AOR, 0.56; 95% CI, 0.34-0.92) and were also less likely to require an admission of 7 days or longer (AOR, 0.53; 95% CI, 0.34-0.83). There were no differences between matched HCWs and non-HCWs in terms of mechanical ventilation (AOR, 0.66; 95% CI, 0.37-1.17), death (AOR, 0.47; 95% CI, 0.18-1.27), or vasopressor requirements (AOR, 0.68; 95% CI, 0.37-1.24). <h3>Conclusions and Relevance</h3> In this propensity score–matched multicenter cohort study, HCW status was not associated with poorer outcomes among hospitalized patients with COVID-19 and, in fact, was associated with a shorter length of hospitalization and decreased likelihood of intensive care unit admission. Further research is needed to elucidate the proportion of HCW infections acquired in the workplace and to assess whether HCW type is associated with outcomes.