tbuckley/cabot-search huggingface dataset:
Rare <i>BRIP1</i> Missense Alleles Confer Risk for Ovarian and Breast Cancer
Authors: Cassandra L. Moyer, Jennifer Ivanovich, Jessica L. Gillespie, Rachel Doberstein, Marc R. Radke, Marcy E. Richardson, Scott H. Kaufmann, Elizabeth M. Swisher, Paul J. Goodfellow
Journal: Cancer Research (2019)

Abstract Germline loss-of-function mutations in BRCA1 interacting protein C-terminal helicase 1 (BRIP1) are associated with ovarian carcinoma and may also contribute to breast cancer risk, particularly among patients who develop disease at an early age. Normal BRIP1 activity is required for DNA interstrand cross-link (ICL) repair and is thus central to the maintenance of genome stability. Although pathogenic mutations have been identified in BRIP1, genetic testing more often reveals missense variants, for which the impact on molecular function and subsequent roles in cancer risk are uncertain. Next-generation sequencing of germline DNA in 2,160 early-onset breast cancer and 1,199 patients with ovarian cancer revealed nearly 2% of patients carry a very rare missense variant (minor allele frequency &amp;lt; 0.0001) in BRIP1. This is 3-fold higher than the frequency of all rare BRIP1 missense alleles reported in more than 60,000 individuals of the general population (P &amp;lt; 0.0001, χ2 test). Using CRISPR-Cas9 gene editing technology and rescue assays, we functionally characterized 20 of these missense variants, focusing on the altered protein's ability to repair ICL damage. A total of 75% of the characterized variants rendered the protein hypomorph or null. In a clinical cohort of &amp;gt;117,000 patients with breast and ovarian cancer who underwent panel testing, the combined OR associated with BRIP1 hypomorph or null missense carriers compared with the general population was 2.30 (95% confidence interval, 1.60–3.30; P &amp;lt; 0.0001). These findings suggest that novel missense variants within the helicase domain of BRIP1 may confer risk for both breast and ovarian cancer and highlight the importance of functional testing for additional variants. Significance: Functional characterization of rare variants of uncertain significance in BRIP1 revealed that 75% demonstrate loss-of-function activity, suggesting rare missense alleles in BRIP1 confer risk for both breast and ovarian cancer.
Author Correction: c-Kit-positive ILC2s exhibit an ILC3-like signature that may contribute to IL-17-mediated pathologies (Nature Immunology, (2019), 20, 8, (992-1003), 10.1038/s41590-019-0423-0)
Authors: Jochem H. Bernink, Yoichiro Ohne, Marcel B. M. Teunissen, Jingya Wang, Jincheng Wu, Lisette Krabbendam, Christine Guntermann, Richard Volckmann, Jan Koster, Sophie van Tol, Ivan Ramirez, Yashaswi Shrestha, Menno A. de Rie, Hergen Spits, Xavier Romero Ros, Alison A. Humbles
Journal: Nature Immunology (2020)
Dysregulation of amyloid precursor protein impairs adipose tissue mitochondrial function and promotes obesity
Authors: Yu A. An, Clair Crewe, Ingrid Wernstedt Asterholm, Kai Sun, Shiuhwei Chen, Fang Zhang, Mengle Shao, Jan-Bernd Funcke, Zhuzhen Zhang, Leon Straub, Jun Yoshino, Samuel Klein, Christine M. Kusminski, Philipp E. Scherer
Journal: Nature Metabolism (2019)
Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial
Authors: Viola Poeschel, Gerhard Held, Marita Ziepert, Mathias Witzens-Harig, Harald Holte, Lorenz Thurner, Peter Borchmann, Andreas Viardot, Martin Soekler, Ulrich Keller, Christian Schmidt, Lorenz Truemper, Rolf Mahlberg, Reinhard Marks, Heinz-Gert Hoeffkes, Bernd Metzner, Judith Dierlamm, Norbert Frickhofen, Mathias Haenel, Andreas Neubauer, Michael Kneba, Francesco Merli, Alessandra Tucci, Peter de Nully Brown, Massimo Federico, Eva Lengfelder, Alice di Rocco, Ralf Trappe, Andreas Rosenwald, Christian Berdel, Martin Maisenhoelder, Ofer Shpilberg, Josif Amam, Konstantinos Christofyllakis, Frank Hartmann, Niels Murawski, Stephan Stilgenbauer, Maike Nickelsen, Gerald Wulf, Bertram Glass, Norbert Schmitz, Bettina Altmann, Markus Loeffler, Michael Pfreundschuh
Journal: The Lancet (2019)
A multinational assessment of work‐related productivity loss and indirect costs from a survey of patients with psoriasis
Authors: R. Villacorta, A. Teeple, S. Lee, S. Fakharzadeh, J. Lucas, S. McElligott
Journal: British Journal of Dermatology (2019)

Total work productivity loss (WPL) and associated indirect costs contribute to the economic burden of psoriasis.To estimate total WPL and related indirect costs, and identify predictors of WPL associated with psoriasis severity in France, Germany, Spain, the U.K. and Italy (EU5) and the U.S.A.Data from the 2015 Adelphi Real World Psoriasis Disease Specific Programme, analysed for absenteeism, presenteeism and total WPL, were quantified (0-100%) from participants who completed the Work Productivity and Activity Impairment (WPAI) instrument. These measures were converted to indirect costs using the human capital method. Univariate and multivariate statistical analyses controlling for patient demographic and clinical characteristics were conducted.Of the 936 respondents (29·6% U.S.A., 70·4% EU5) who completed the WPAI, 32·6%, 40·7% and 26·6% had mild [body surface area (BSA) 0-2%], moderate (BSA 3-10%) and severe (BSA > 10%) psoriasis, respectively. Average age, Dermatology Life Quality Index (DLQI) score and BSA were, respectively, 42·4 years, 5·1 and 9·6%; and 37·2% of respondents were female. Mean percentages of total WPL for respondents with mild, moderate and severe psoriasis were 10·1%, 18·9% and 29·4%, respectively. Presenteeism contributed considerably more to total WPL than did absenteeism across all countries and disease severity classes. Mean annual indirect costs per patient due to WPL ranged from 3742 U.S. dollars in Spain to 9591 U.S. dollars in the U.S.A. Multivariate regression showed that a one-unit increase in DLQI score increases total WPL by 1·8% (P < 0·001).WPL increased progressively with increasing DLQI scores and BSA, confirming the relationship between psoriasis severity and its economic burden. What's already known about this topic? The economic burden of psoriasis is exceptionally high given the high prevalence and lifelong nature of the condition. Several studies have attempted to assess the overall economic burden of psoriasis but there is a lack of comparative data from different countries, and issues around inconsistent methodologies, including statistical analyses. Total work productivity loss (WPL) and associated indirect costs are believed to contribute to the economic burden of psoriasis. What does this study add? This study measured total WPL and indirect costs via the same method and at the same time point in the U.S.A., France, Germany, Spain, U.K. and Italy. Total WPL increased progressively with psoriasis disease severity. Disease severity and Dermatology Life Quality Index scores significantly correlated with WPL after controlling for patient demographic and clinical characteristics. The U.S.A. had the highest annual mean indirect costs associated with total WPL. Linked Comment: Drabo et al. Br J Dermatol 2020; 183:420-421.
<i>NEJM Catalyst Innovations in Care Delivery</i> — A New Journal Leading the Transformation of Health Care Delivery
Authors: Thomas H. Lee, Namita Seth Mohta, Edward Prewitt, Edward W. Campion, Stephen Morrissey, Jeffrey M. Drazen, Eric J. Rubin
Journal: New England Journal of Medicine (2019)

Four years ago, the NEJM Group launched NEJM Catalyst as a forum for emerging ideas and practical innovations in health care delivery, creating robust dialogue among health care leaders, clinicians, researchers, and other experts.NEJM Catalyst is now entering a new phase with the creation of a peer-reviewed digital journal, NEJM Catalyst Innovations in Care Delivery (https://catalyst .nejm .org/ toc/ catalyst/ current).From the outset, NEJM Catalyst has spread best practices to improve both the effectiveness and the efficiency of patient care as viewed through the lenses of care redesign, patient engagement, organizational leadership, and the new marketplace of health care.Our experience to date demonstrates the broad interest in this discourse; NEJM Catalyst has attracted a wide following, using a mix of online articles, case studies, and interviews; live webcast meetings; and research reports.Just as the New England Journal of Medicine seeks to advance medical science, NEJM Catalyst Innovations in Care Delivery seeks to advance health care delivery.The new journal aims to be a trusted and indispensable source of information on innovations that improve the value of care and ultimately transform care delivery.Beginning with its January-February inaugural issue, NEJM Catalyst Innovations in Care Delivery will appear six times each year, with peerreviewed articles from health care leaders, practitioners, and researchers in several major formats.Among these will be "In Depth" articles that are longer than those in most print journals.
LBA2 First-line durvalumab plus platinum-etoposide in extensive-stage (ES)-SCLC: Safety, pharmacokinetics (PK) and immunogenicity in CASPIAN
Authors: M. Özgüroğlu, J.W. Goldman, N. Reinmuth, Y. Chen, M. Dvorkin, D. Trukhin, G. Statsenko, K. Hotta, J.H. Ji, M.J. Hochmair, O. Voitko, L. Havel, A. Poltoratskiy, G. Losonczy, F. Verderame, M. Thomas, Y. Zheng, A. Lloyd, H. Jiang, L. Paz-Ares
Journal: Annals of Oncology (2019)
Hodgkin lymphoma in a bone marrow aspirate
Authors: Katrina Parsons, Mike Leach, Barbara J. Bain
Journal: American Journal of Hematology (2019)

A previously well 60-year-old man presented with a 6-week history of weight loss, drenching night sweats and fevers. His blood count showed hemoglobin concentration 100 g/L, WBC 15 × 109/L, neutrophils 10 × 109/L, eosinophils 2 × 109/L, lymphocytes 0.6 × 109/L and platelets 550 × 109/L. Computed tomography of neck, thorax, abdomen and pelvis showed splenomegaly without any lymphadenopathy. A bone marrow aspirate was hypercellular with prominent eosinophils, increased myeloid precursors and increased small lymphocytes and plasma cells. In addition, a population of large cells with plentiful agranular cytoplasm (mononuclear Hodgkin cells) and some binucleate cells (Reed-Sternberg cells) were identified (image, May-Grünwald-Giemsa × 50 objective). These appearances are characteristic of classical Hodgkin lymphoma. The diagnosis was confirmed by trephine biopsy with the Hodgkin and Reed-Sternberg cells showing the typical immunophenotype: CD15+, CD30+, CD45− and CD20− . In the era of positron emission tomography staging, bone marrow aspiration and trephine biopsies are now infrequently performed in Hodgkin lymphoma. Even so, it is unusual for Reed-Sternberg and Hodgkin cells to be visualized in an aspirate as the lymphomatous infiltrate generates marrow fibrosis which impairs aspiration. It is important that hematologists retain the ability to recognize the morphology of Hodgkin lymphoma in a bone marrow aspirate on the rare occasions it is encountered. Nothing to report.
Specialty Tough Hydrogels and Their Biomedical Applications
Authors: Stephanie Fuchs, Kaavian Shariati, Minglin Ma
Journal: Advanced Healthcare Materials (2019)

Hydrogels have long been explored as attractive materials for biomedical applications given their outstanding biocompatibility, high water content, and versatile fabrication platforms into materials with different physiochemical properties and geometries. Nonetheless, conventional hydrogels suffer from weak mechanical properties, restricting their use in persistent load-bearing applications often required of materials used in medical settings. Thus, the fabrication of mechanically robust hydrogels that can prolong the lifetime of clinically suitable materials under uncompromising in vivo conditions is of great interest. This review focuses on design considerations and strategies to construct such tough hydrogels. Several promising advances in the proposed use of specialty tough hydrogels for soft actuators, drug delivery vehicles, adhesives, coatings, and in tissue engineering settings are highlighted. While challenges remain before these specialty tough hydrogels will be deemed translationally acceptable for clinical applications, promising preliminary results undoubtedly spur great hope in the potential impact this embryonic research field can have on the biomedical community.
Abstract 15746: Racial/Ethnic Disparities in the Trends of the Prevalence, Awareness, Treatment, and Control of Hypertension Among Young American Adults
Authors: Vibhu Parcha, Nirav Patel, Rajat Kalra, Anirudh Bhargava, Garima Arora, Pankaj Arora
Journal: Circulation (2019)

Introduction: Burden of hypertension among young American Adults is a public health challenge. There is little data about the racial/ethnic disparities in hypertension prevalence, awareness, treatm...
Do polyglycolic acid sheets really prevent bleeding after endoscopic submucosal dissection? An opinion from physiological viewpoints
Authors: Daisuke Murakami, Hideaki Harada, Yuji Amano, Masayuki Yamato
Journal: Endoscopy (2019)

See also:Endoscopic tissue shielding to prevent bleeding after endoscopic submucosal dissection: a prospective multicenter randomized controlled trialEndoscopy 2019; 51(07): 619-627DOI: 10.1055/a-0860-5280See also:Reply to Murakami et al.Endoscopy 2020; 52(01): 77-77DOI: 10.1055/a-1026-6136
Antiretroviral Prescribing Practices Among Pregnant Women Living With HIV in the United States, 2008-2017
Authors: Kathleen M. Powis, Yanling Huo, Paige L. Williams, Deborah Kacanek, Jennifer Jao, Kunjal Patel, George R. Seage, Russell B. Van Dyke, Ellen G. Chadwick
Journal: JAMA Network Open (2019)

Since 1994, the US Department of Health and Human Services has published treatment guidelines for pregnant women living with HIV. Understanding how well prescribing patterns correspond with treatment guidelines could inform health policy and influence future clinical practice.To compare antiretroviral prescribing practices over time among pregnant women living with HIV with Department of Health and Human Services treatment guidelines and identify factors associated with receiving recommended regimens.A prospective cohort study of 1582 pregnant women living with HIV were enrolled in the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART (antiretroviral therapy) Toxicities study between January 1, 2008, and June 30, 2017. The study was conducted at 18 academic research hospitals in the United States.Antiretroviral medications (ARVs) prescribed during pregnancy.Proportion of regimens prescribed to pregnant women living with HIV qualifying as preferred or alternative according to Department of Health and Human Services guidelines, stratified by timing of initiation.Of 1867 pregnancies (among 1582 pregnant women living with HIV with a mean [SD] age of 28.6 [6.1] years at conception), 1264 (67.7%) occurred among women self-identified as black, 480 (25.7%) self-identified as white, and 123 (6.6%) self-identified as other or unreported race/ethnicity. Antiretroviral medications were initiated prior to conception for 790 women (42.3%), resumed during pregnancy for 625 women (33.5%), and initiated during pregnancy for 452 women (24.2%). Only 925 pregnancies (49.5%) were associated with prescribed ARVs designated as preferred or alternative, while 492 (26.4%) involved ARVs with insufficient evidence for use during pregnancy and 136 (7.3%) involved ARVs that were not recommended during pregnancy. A higher proportion of treatment-naive pregnant women initiating ARVs were prescribed preferred or alternative ARVs compared with those resuming ARVs or those treated with ARVs before conception (316 of 452 [69.9%] vs 325 of 625 [52.0%] vs 284 of 790 [35.9%]; P < .001). A total of 91 of 452 women (20.1%) initiating ARVs during pregnancy were prescribed ARVs with insufficient evidence for use during pregnancy or not recommended during pregnancy. Among women resuming ARVs, those with a viral load greater than 1000 copies/mL early in pregnancy had higher odds of being prescribed guideline-recommended ARVs (adjusted odds ratio, 2.03 [95% CI, 1.33-3.10]) compared with those with a viral load of 400 copies/mL or less.This study suggests that US ARV prescribing practices for pregnant women living with HIV do not align well with national guidelines. This finding is particularly concerning when treatment is initiated during pregnancy. Further research is needed to understand disparities between prescribing practices and evidence-based guideline recommendations.
Dose-Response Meta-Analysis of Antipsychotic Drugs for Acute Schizophrenia
Authors: Stefan Leucht, Alessio Crippa, Spyridon Siafis, Maxine X. Patel, Nicola Orsini, John M. Davis
Journal: American Journal of Psychiatry (2019)

Objective: The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses. Methods: A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses. Results: Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice. Conclusions: In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.
Ultraprocessed Food Consumption and Risk of Type 2 Diabetes Among Participants of the NutriNet-Santé Prospective Cohort
Authors: Bernard Srour, Léopold K. Fezeu, Emmanuelle Kesse-Guyot, Benjamin Allès, Charlotte Debras, Nathalie Druesne-Pecollo, Eloi Chazelas, Mélanie Deschasaux, Serge Hercberg, Pilar Galan, Carlos A. Monteiro, Chantal Julia, Mathilde Touvier
Journal: JAMA Internal Medicine (2019)

<h3>Importance</h3> Ultraprocessed foods (UPF) are widespread in Western diets. Their consumption has been associated in recent prospective studies with increased risks of all-cause mortality and chronic diseases such as cancer, cardiovascular diseases, hypertension, and dyslipidemia; however, data regarding diabetes are lacking. <h3>Objective</h3> To assess the associations between consumption of UPF and risk of type 2 diabetes (T2D). <h3>Design, Setting, and Participants</h3> In this population-based prospective cohort study, 104 707 participants aged 18 years or older from the French NutriNet-Santé cohort (2009-2019) were included. Dietary intake data were collected using repeated 24-hour dietary records (5.7 per participant on average), designed to register participants' usual consumption for more than 3500 different food items. These were categorized according to their degree of processing by the NOVA classification system. <h3>Main Outcomes and Measures</h3> Associations between UPF consumption and risk of T2D were assessed using cause-specific multivariable Cox proportional hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors). <h3>Results</h3> A total of 104 707 participants (21 800 [20.8%] men and 82 907 [79.2%] women) were included. Mean (SD) baseline age of participants was 42.7 (14.5) years. Absolute T2D rates in the lowest and highest UPF consumers were 113 and 166 per 100 000 person-years, respectively. Consumption of UPF was associated with a higher risk of T2D (multi-adjusted hazard ratio [HR] for an absolute increment of 10 in the percentage of UPF in the diet, 1.15; 95% CI, 1.06-1.25; median follow-up, 6.0 years; 582 252 person-years; 821 incident cases). These results remained statistically significant after adjustment for several markers of the nutritional quality of the diet, for other metabolic comorbidities (HR, 1.13; 95% CI, 1.03-1.23), and for weight change (HR, 1.13; 95% CI, 1.01-1.27). The absolute amount of UPF consumption (grams per day) was consistently associated with T2D risk, even when adjusting for unprocessed or minimally processed food intake (HR for a 100 g/d increase, 1.05; 95% CI, 1.02-1.08). <h3>Conclusions and Relevance</h3> In this large observational prospective study, a higher proportion of UPF in the diet was associated with a higher risk of T2D. Even though these results need to be confirmed in other populations and settings, they provide evidence to support efforts by public health authorities to recommend limiting UPF consumption. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT03335644