tbuckley/cabot-search huggingface dataset:
Challenge Trump on women’s health during UK visit, doctors urge May
Authors: Abi Rimmer
Journal: BMJ (2018)

Doctors have urged the prime minister to discuss access to sexual and reproductive healthcare with the US president during his visit to the UK.

Donald Trump arrived in the UK on 12 July ahead of talks with Theresa May. On his first evening in the country he attended a UK state dinner at Blenheim Palace in Oxfordshire while protesters, including doctors, gathered outside the building.

Rachel Clarke, a specialty doctor in palliative medicine, attended the protest holding a banner that read, “Keep your tiny, groping, racist hands off our NHS, Mr …
ICAM-1 controls development and function of ILC2
Authors: Ai-Hua Lei, Qiang Xiao, Gao-Yu Liu, Kun Shi, Qiong Yang, Xing Li, Yu-Feng Liu, Hai-Kun Wang, Wei-Ping Cai, Yu-Juan Guan, Dmitry I. Gabrilovich, Jie Zhou
Journal: The Journal of Experimental Medicine (2018)

Group 2 innate lymphoid cells (ILC2s) are emerging as key players in the pathogenesis of allergic airway inflammation. The mechanisms regulating ILC2, however, are not fully understood. Here, we found that ICAM-1 is required for the development and function of ILC2. ICAM-1-deficient (ICAM-1-/- ) mice displayed significantly lower levels of ILC2s in the bone marrow and peripheral tissues than wild-type controls. CLP transfer and in vitro culture assays revealed that the regulation of ILC2 by ICAM-1 is cell intrinsic. Furthermore, ILC2s from ICAM-1-/- mice were functionally impaired, as indicated by the diminished production of type-2 cytokines in response to IL-33 challenge. The reduction in lung ILC2s caused a clear remission of airway inflammation in ICAM-1-/- mice after administration of papain or Alternaria alternata. We further demonstrate that ILC2 defects caused by ICAM-1 deficiency are due to ERK signaling-dependent down-regulation of GATA3 protein. Collectively, these observations identify ICAM-1 as a novel regulator of ILC2.
Abstract 14914: Inactivation of Neddylation Activating Enzyme 1 (NAE1) in Mice and Rats Leads to Cardiac Developmental and Functional Defects
Authors: Jianqiu Zou, Jie Li, Wenxia Ma, Guihua Yue, Aizhen Zhang, Guoqing Hu, Jiliang Zhou, Huabo Su
Journal: Circulation (2016)

Exploring the molecular mechanisms that govern cardiac development is important for understanding congenital heart disease and for developing strategies for cardiac regeneration. Neddylation is a protein posttranslational modification that covalently conjugates a ubiquitin-like protein NEDD8 to target proteins. Neddylation requires NEDD8 specific E1(a heterodimer consisting of NAE1 and UBA3), E2 (UBC12) and E3 ligases, and is purported to control a variety of cellular processes through modulating the function of its targets, yet its biological functions in vertebrates are largely unknown. Here we report the discovery of an indispensable role of neddylation in cardiac growth, chamber maturation, and embryonic and perinatal survival. NAE1 is expressed as early as E12.5 in mouse hearts. Neddylation is activated in fetal and neonatal hearts but downregulated in adult hearts. Germline knockout of NAE1 in mice led to embryonic lethality before E10.5, revealing its critical role in embryonic development. Mice with cardiomyocyte-restricted knockout of NAE1 (αMHC-Cre Tg/+ ::NAE1 flox/flox ) exhibited myocardial hypoplasia, defective ventricular chamber maturation, heart failure, and embryonic and neonatal lethality. Cardiac hypoplasia was caused by drastically reduced cardiomyocyte proliferation, which was attributable to dysregulated expression of multiple cell cycle genes. Furthermore, transient inhibition of NAE1 with a specific inhibitor MLN4924 in neonatal rats caused a decrease in cardiomyocyte proliferation, which eventually led to ventricular chamber dilation and cardiac dysfunction in adulthood. In vitro, both MLN4924 treatment and silencing of UBC12 resulted in proliferation arrest in isolated cardiomyocytes, indicating a cell autonomous role of neddylation in cardiomyocyte proliferation. Mechanistically, MLN4924 or NAE1 deficiency abolished neddylation of cullin proteins, a major component of cullin-RING ubiquitin ligases (CRLs), and accumulated a panel of negative cell cycle regulators presumably as a consequence of loss of CRLs activities. Taken together, these data identify a heretofore undescribed function of neddylation that regulates cardiomyocyte proliferation in the embryonic and neonatal heart.
Tracking aid for global health goals: a systematic comparison of four approaches applied to reproductive, maternal, newborn, and child health
Authors: Catherine Pitt, Christopher Grollman, Melisa Martinez-Alvarez, Leonardo Arregoces, Josephine Borghi
Journal: The Lancet Global Health (2018)

BackgroundFour initiatives have estimated the value of aid for reproductive, maternal, newborn, and child health (RMNCH): Countdown to 2015, the Institute for Health Metrics and Evaluation (IHME), the Muskoka Initiative, and the Organisation for Economic Co-operation and Development (OECD) policy marker. We aimed to compare the estimates, trends, and methodologies of these initiatives and make recommendations for future aid tracking.MethodsWe compared estimates of aid for RMNCH from the four initiatives for all years available at the time of our analysis (1990–2016). We used publicly available datasets for IHME and Countdown. We produced estimates for Muskoka and the OECD policy marker using data in the OECD Creditor Reporting System. We sought to explain differences in estimates by critically comparing the methods used by each approach to identify and analyse aid, and quantifying the effects of these choices on estimates.FindingsAll four approaches indicated substantial increases over time in global aid for RMNCH, but estimates of aid amounts and year-on-year trends differed substantially, especially for individual donors and recipient countries. Muskoka (US$ 13·0 billion in 2013, constant 2015 US$) and Countdown's RMNCH estimates ($13·1 billion in 2013) tended to be the highest and most similar, although they often indicated different year-on-year trends. IHME produced lower estimates ($10·8 billion in 2013), which often indicated different trends from the other approaches. The OECD policy marker produced by far the lowest estimates ($2·0 billion in 2013) because half of bilateral donors did not report on it consistently and those who did tended to apply it narrowly. Estimates differed across approaches primarily because of differences in methods for distinguishing aid for RMNCH from aid for other purposes; adjustments for inflation, exchange rates, and under-reporting; whether donors were credited for their support to multilateral institutions; and the handling of aid to unspecified recipients.InterpretationThe four approaches are likely to lead to different conclusions about whether individual donors and recipient countries have fulfilled their obligations and commitments and whether aid was sufficient, targeted to countries with greater need, or effective. We recommend that efforts to track aid for the Sustainable Development Goals reflect their multisectoral and interconnected nature and make analytical choices that are appropriate to their objectives, recognising the trade-offs between simplicity, timeliness, precision, accuracy, efficiency, flexibility, replicability, and the incentives that different metrics create for donors.FundingSubgrant OPP1058954 from the US Fund for UNICEF under their Countdown to 2015 for Maternal, Newborn and Child Survival Grant from the Bill & Melinda Gates Foundation.
Effect of providing near glasses on productivity among rural Indian tea workers with presbyopia (PROSPER): a randomised trial
Authors: Priya Adhisesha Reddy, Nathan Congdon, Graeme MacKenzie, Parikshit Gogate, Qing Wen, Catherine Jan, Mike Clarke, Jordan Kassalow, Ella Gudwin, Ciaran O'Neill, Ling Jin, Jianjun Tang, Ken Bassett, David H Cherwek, Rahul Ali
Journal: The Lancet Global Health (2018)

Presbyopia, age-related decline in near vision, is the most common cause of vision impairment globally, but no trials have assessed its workplace effects. We aimed to study the effect of near glasses on the productivity of tea workers with presbyopia.This randomised trial was done in tea pickers aged 40 years or older in Assam, India, with unaided near visual acuity (NVA) lower than 6/12 in both eyes, correctable to 6/7·5 with near glasses; unaided distance vision 6/7·5 or greater; and no eye disease. Participants were randomly assigned (1:1) to receive free glasses optimising NVA at working distance (cost including delivery US$10·20 per person), either immediately (intervention group) or at closeout (control group). Participants were stratified by age, sex, and productivity. The primary outcome (investigator-masked) was the difference between groups in the change in mean daily weight of tea picked (productivity), between the 4-week baseline period (June, 2017) and the 11-week evaluation period (July 24, 2017, to Oct 7, 2017). Workers' income was tied to their productivity. Compliance with study glasses was assessed at seven unannounced visits. Results were analysed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT03228199.Between July 3, 2017, and July 15, 2017, 1297 (48·1%) of 2699 permanent workers met the age criteria and consented for eye examinations. 751 (57·9%) fulfilled vision criteria and were randomly assigned to the intervention (n=376) or control (n=375) groups. Groups did not differ substantially in baseline characteristics. No participants owned glasses at baseline, 707 (94·1%) received the allocated intervention, and all were followed up and analysed. Between the baseline and evaluation periods, mean productivity in the intervention group increased from 25·0 kg per day to 34·8 kg per day (an increase of 9·84 kg per day), a significantly higher increase than in the control group (from 26·0 kg per day to 30·6 kg per day; an increase of 4·59 kg per day), corresponding to a between-group difference of 5·25 kg per day (95% CI 4·50-5·99; 21·7% relative productivity increase; effect size 1·01 [95% CI 0·86-1·16]; p<0·0001). Intervention-group compliance with study glasses reached 84·5% by closeout. Regression model predictors of greater productivity increase included intervention group membership (5·25 kg per day [95% CI 4·60-5·91], p<0·0001) and, among intervention participants, older age (p=0·039) and better compliance with the intervention (p<0·0001).A substantial productivity increase was achieved in this rural cohort by providing glasses to correct presbyopia, with little cost and high intervention uptake.Clearly.
Association Between Offering Limited Left Ventricular Ejection Fraction Echocardiograms and Overall Use of Echocardiography
Authors: Alexander T. Sandhu, Justin Parizo, Narges Moradi-Ragheb, Paul A. Heidenreich
Journal: JAMA Internal Medicine (2018)

desire antibiotics, and clinicians may worry that patients will not return to urgent care in the future if their expectations are not met.Innovations that may help reduce unnecessary prescription of antibiotics may conflict with the business model of urgent care and retail clinics.For example, telephonebased triage lines can provide patients advice and reassurance without them leaving their homes, while identifying those whose symptoms or comorbidities warrant in-person evaluation.These interventions have reduced outpatient visits for upper respiratory tract infection symptoms by up to 50% in some cases, resulting in fewer prescribed antibiotics and lower health care costs without compromising clinical outcomes. 8,9 However, such programs would not align with the business model that supports the creation of urgent and retail care clinics.Unfortunately, we all pay-in increased insurance premiums and increased antibiotic resistance-from the overprescribing of antibiotics for upper respiratory tract infections.
Ischemic Stroke and the Gene for Angiotensin-Converting Enzyme in Japanese Hypertensives
Authors: KazuomiKario, NobuyukiKanai, KenSaito, NaokiNago, TakefumiMatsuo, KazuyukiShimada
Journal: Circulation (1996)

Background The ACE insertion/deletion (I/D) polymorphism is reported to be associated with myocardial infarction in both whites and Japanese. However, there have been no reports on the association of this polymorphism with stroke in each race. Furthermore, there are some racial differences in the demographics of cardiovascular diseases. In Japanese, stroke (especially that which occurs in preexisting hypertension) is more common and coronary artery disease much less common than in whites. We propose that the ACE I/D polymorphism might be associated with hypertensive cerebrovascular disease in Japanese. Methods and Results To study the association between the ACE I/D polymorphism and hypertensive cerebrovascular disease, we identified the ACE I/D genotype in 228 hypertensive and 104 normotensive Japanese subjects. Compared with its frequency (0.31) in the 90 hypertensives without lacunae detected by magnetic resonance imaging, the ACE*D allele frequency was significantly higher (0.47; P<.001) in the 138 hy...
Integrative omics analyses broaden treatment targets in human cancer
Authors: Sohini Sengupta, Sam Q. Sun, Kuan-lin Huang, Clara Oh, Matthew H. Bailey, Rajees Varghese, Matthew A. Wyczalkowski, Jie Ning, Piyush Tripathi, Joshua F. McMichael, Kimberly J. Johnson, Cyriac Kandoth, John Welch, Cynthia Ma, Michael C. Wendl, Samuel H. Payne, David Fenyö, Reid R. Townsend, John F. Dipersio, Feng Chen, Li Ding
Journal: Genome Medicine (2018)

Although large-scale, next-generation sequencing (NGS) studies of cancers hold promise for enabling precision oncology, challenges remain in integrating NGS with clinically validated biomarkers. To overcome such challenges, we utilized the Database of Evidence for Precision Oncology (DEPO) to link druggability to genomic, transcriptomic, and proteomic biomarkers. Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO. Within the pan-cancer cohort of 6570 tumors, we found that 3% are druggable based on FDA-approved drug-mutation interactions in specific cancer types. However, mRNA/phosphoprotein/protein expression outliers and drug repurposing across cancer types suggest potential druggability in up to 16% of tumors. The percentage of potential drug-associated tumors can increase to 48% if we consider preclinical evidence. Further, our analyses showed co-occurring potentially druggable multi-omics alterations in 32% of tumors, indicating a role for individualized combinational therapy, with evidence supporting mTOR/PI3K/ESR1 co-inhibition and BRAF/AKT co-inhibition in 1.6 and 0.8% of tumors, respectively. We experimentally validated a subset of putative druggable mutations in BRAF identified by a protein structure-based computational tool. Finally, analysis of a large-scale drug screening dataset lent further evidence supporting repurposing of drugs across cancer types and the use of expression outliers for inferring druggability. Our results suggest that an integrated analysis platform can nominate multi-omics alterations as biomarkers of druggability and aid ongoing efforts to bring precision oncology to patients.
LDL Cholesterol Rises With BMI Only in Lean Individuals: Cross-sectional U.S. and Spanish Representative Data
Authors: Martin Laclaustra, Esther Lopez-Garcia, Fernando Civeira, Esther Garcia-Esquinas, Auxiliadora Graciani, Pilar Guallar-Castillon, Jose R. Banegas, Fernando Rodriguez-Artalejo
Journal: Diabetes Care (2018)

OBJECTIVE Elevated LDL cholesterol (LDLc) is not strongly associated with obesity or metabolic syndrome (MS), but this relationship repeatedly has been examined assuming a linear association. This study aimed to assess the dose-response relationship between body mass index (BMI) or waist circumference (WC) and LDLc and to evaluate its link to metabolic impairment. RESEARCH DESIGN AND METHODS Participants in the continuous National Health and Nutrition Examination Survey (NHANES, 1999–2010) (n = 12,383) and the Study on Nutrition and Cardiovascular Risk (ENRICA, 2008–2010) (n = 11,765), representative samples of U.S. and Spanish noninstitutionalized populations, were cross-sectionally investigated. LDLc was modeled with age- and sex-adjusted regressions, with BMI and/or WC as explanatory variables included in models as two-segment linear and natural cubic splines. RESULTS In NHANES and ENRICA, slopes of the BMI-LDLc association changed (P &amp;lt; 0.001) at BMI 27.1 and 26.5 kg/m2, respectively, forming an inverted U shape. Below these BMI inflection points, LDLc rose 2.30 and 2.41 mg/dL per kg/m2 (both P &amp;lt; 0.001). However, above said points, LDLc declined −0.37 and −0.38 mg/dL per kg/m2 (both P &amp;lt; 0.001). The WC-LDLc relationship was similar to the BMI-LDLc relationship. Accumulation of MS traits was associated with a weakening of the positive BMI-LDLc association among lean participants (below the BMI inflection point). Aging shifted the inflection point of the BMI-LDLc relationship to lower BMI values. CONCLUSIONS The BMI- and WC-LDLc relationships have inverted U shapes. Diminishing associations between BMI and LDLc might indicate metabolic impairment as a result of aging or other metabolic diseases. In lean individuals, small weight losses might help to lower LDLc for cardiovascular prevention.
<i>IFNL4</i>-ΔG Allele Is Associated with an Interferon Signature in Tumors and Survival of African-American Men with Prostate Cancer
Authors: Wei Tang, Tiffany A. Wallace, Ming Yi, Cristina Magi-Galluzzi, Tiffany H. Dorsey, Olusegun O. Onabajo, Adeola Obajemu, Symone V. Jordan, Christopher A. Loffredo, Robert M. Stephens, Robert H. Silverman, George R. Stark, Eric A. Klein, Ludmila Prokunina-Olsson, Stefan Ambs
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Men of African ancestry experience an excessive prostate cancer mortality that could be related to an aggressive tumor biology. We previously described an immune-inflammation signature in prostate tumors of African-American (AA) patients. Here, we further deconstructed this signature and investigated its relationships with tumor biology, survival, and a common germline variant in the IFNλ4 (IFNL4) gene. Experimental Design: We analyzed gene expression in prostate tissue datasets and performed genotype and survival analyses. We also overexpressed IFNL4 in human prostate cancer cells. Results: We found that a distinct interferon (IFN) signature that is analogous to the previously described “IFN-related DNA damage resistance signature” (IRDS) occurs in prostate tumors. Evaluation of two independent patient cohorts revealed that IRDS is detected about twice as often in prostate tumors of AA than European-American men. Furthermore, analysis in TCGA showed an association of increased IRDS in prostate tumors with decreased disease-free survival. To explain these observations, we assessed whether IRDS is associated with an IFNL4 germline variant (rs368234815-ΔG) that controls production of IFNλ4, a type III IFN, and is most common in individuals of African ancestry. We show that the IFNL4 rs368234815-ΔG allele was significantly associated with IRDS in prostate tumors and overall survival of AA patients. Moreover, IFNL4 overexpression induced IRDS in three human prostate cancer cell lines. Conclusions: Our study links a germline variant that controls production of IFNλ4 to the occurrence of a clinically relevant IFN signature in prostate tumors that may predominantly affect men of African ancestry. Clin Cancer Res; 24(21); 5471–81. ©2018 AACR.
Trends in Use of Transcatheter Aortic Valve Replacement by Age
Authors: Art Sedrakyan, Sanket S. Dhruva, Tianyi Sun, Jialin Mao, Mario F. L. Gaudino, Rita F. Redberg
Journal: JAMA (2018)

TAVR procedures was unchanged.Data are lacking on the durability of the bioprosthetic valves implanted using TAVR, raising concern about use of TAVR and bioprosthetic valves in younger patients. 5,6 Data from the NIS are only available through 2015 and current use of TAVR in 2018 has likely increased further.Younger patients may undergo TAVR due to higher risks for SAVR related to prior cardiac surgery; however, NIS does not have data on previous AVR or coronary artery bypass grafting.Patients 65 years and younger should be informed of the limited evidence for long-term outcomes with TAVR compared with SAVR in this age group.Registries and future trials should collect longer-term follow-up data for these patients.
CALGB 50604: risk-adapted treatment of nonbulky early-stage Hodgkin lymphoma based on interim PET
Authors: David J. Straus, Sin-Ho Jung, Brandelyn Pitcher, Lale Kostakoglu, John C. Grecula, Eric D. Hsi, Heiko Schöder, Leslie L. Popplewell, Julie E. Chang, Craig H. Moskowitz, Nina Wagner-Johnston, John P. Leonard, Jonathan W. Friedberg, Brad S. Kahl, Bruce D. Cheson, Nancy L. Bartlett
Journal: Blood (2018)
PedsQL 3.2 Diabetes Module for Children, Adolescents, and Young Adults: Reliability and Validity in Type 1 Diabetes
Authors: James W. Varni, Alan M. Delamater, Korey K. Hood, Jennifer K. Raymond, Nancy T. Chang, Kimberly A. Driscoll, Jenise C. Wong, Joyce P. Yi-Frazier, Ellen K. Grishman, Melissa A. Faith, Sarah D. Corathers, Jessica C. Kichler, Jennifer L. Miller, Elena M. Doskey, Robert W. Heffer, Don P. Wilson
Journal: Diabetes Care (2018)

OBJECTIVE The objective of the study was to report on the measurement properties of the revised and updated Pediatric Quality of Life Inventory (PedsQL) 3.2 Diabetes Module for children, adolescents, and young adults with type 1 diabetes. RESEARCH DESIGN AND METHODS The 33-item PedsQL 3.2 Diabetes Module and PedsQL Generic Core Scales were completed in a 10-site national field test study by 656 families of patients ages 2–25 years with type 1 diabetes. RESULTS The 15-item Diabetes Symptoms Summary Score and 18-item Diabetes Management Summary Score were derived from the factor analysis of the items. The Diabetes Symptoms and Diabetes Management Summary Scores evidenced excellent reliability (patient self-report α = 0.88–0.90; parent proxy report α = 0.89–0.90). The Diabetes Symptoms and Diabetes Management Summary Scores demonstrated construct validity through medium to large effect size correlations with the Generic Core Scales Total Scale Score (r = 0.43–0.67, P &amp;lt; 0.001). HbA1c was significantly correlated with the Diabetes Symptoms and Diabetes Management Summary Scores (r = −0.21 to −0.29, P &amp;lt; 0.001). Minimal clinically important difference scores ranged from 5.05 to 5.55. CONCLUSIONS The PedsQL 3.2 Diabetes Module Diabetes Symptoms and Diabetes Management Summary Scores demonstrated excellent measurement properties and may be useful as standardized patient-reported outcomes of diabetes symptoms and diabetes management in clinical research, clinical trials, and practice in children, adolescents, and young adults with type 1 diabetes.
Abstract 18820: Persistent Lower Extremity Ulcers: Not Just Skin Deep
Authors: Aaron W Aday, Marie D Gerhard-Herman, Piotr Sobieszczyk, Marc P Bonaca
Journal: Circulation (2016)

A healthy 66-year-old woman presented for evaluation of non-healing lower extremity ulcers. Several years prior, she developed a small ulcer above her left lateral malleolus. Biopsy showed only chr...