bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of cells from both innate and adaptive immunity with lower nerve conduction velocity: the Maastricht Study
Authors: Maalmi Haifa , Wouters Kristiaan , Savelberg Hans H C M , van der Velde Jeroen H P M , Reulen Jos P H , Mess Werner , Schalkwijk Casper G , Stehouwer Coen D A , Roden Michael , Ziegler Dan , Herder Christian , Schaper Nicolaas C 
Published: January 2021

IntroductionDistal sensorimotor polyneuropathy (DSPN) is common in people with diabetes but is also found in pre-diabetes. Peripheral nerve myelin damage, which can be assessed by reduced nerve conduction velocity (NCV), is an essential feature of DSPN. Emerging evidence indicates that the development of DSPN may involve the activation of the immune system. However, available studies have mainly investigated circulating immune mediators, whereas the role of immune cells remains unclear. Therefore, we aimed to test whether leukocyte subsets are associated with NCV.Research design and methodsThis cross-sectional study analyzed data from 850 individuals (of whom 252 and 118 had type 2 diabetes and pre-diabetes, respectively) of the Maastricht Study. NCV was measured in the peroneal and tibial motor nerves and the sural sensory nerve and summed to calculate a standardized NCV sum score. Associations between percentages of leukocyte subsets and NCV sum scores were estimated using linear regression models adjusted for demographic, lifestyle, metabolic and clinical covariates.ResultsAfter adjustment for covariates, higher percentages of basophils and CD4+T cells were associated with lower NCV (p=0.014 and p=0.005, respectively). The percentage of CD8+T cells was positively associated with NCV (p=0.022). These associations were not modified by glucose metabolism status (all pinteraction>0.05). No associations were found for monocytes, eosinophils, neutrophils, lymphocytes, total T cells, Treg cells and B cells.ConclusionsThe associations of basophils, CD4+and CD8+T cells with NCV suggest that cell types from both innate and adaptive immunity may be implicated in the development of DSPN.
Association of the Diabetes Health Plan with emergency room and inpatient hospital utilization: a Natural Experiment for Translation in Diabetes (NEXT-D) Study
Authors: Moin Tannaz , Steers Neil , Ettner Susan L , Duru Kenrik , Turk Norman , Chan Charles , Keckhafer Abigail M , Luchs Robert H , Ho Sam , Mangione Carol M 
Published: January 2021

IntroductionTo examine the association of a novel disease-specific health plan, known as the Diabetes Health Plan (DHP), with emergency room (ER) and hospital utilization among patients with diabetes and pre-diabetes.Research design and methodsQuasi-experimental design, with employer group as the unit of analysis, comparing changes in any ER and inpatient hospital utilization over a 3-year period. Inverse probability weighting was used to control for differences between employers purchasing DHP versus standard plans. Estimated differences in utilization are calculated as average treatment effects on the treated. We used employees and dependents from employer groups contracting with a large, national private insurer between 2009 and 2012. Eligibility and claims data from continuously covered employees and dependents with diabetes and pre-diabetes (n=74 058) were aggregated to the employer level. The analysis included 9 DHP employers (n=7004) and 183 control employers (n=67 054).ResultsDHP purchase was associated with 2.4 and 1.8 percentage points absolute reduction in mean rates of any ER utilization, representing 13% and 10% relative reductions at 1 and 2 years post-DHP (p=0.012 and p=0.046, respectively). There was no significant association between DHP purchase and hospital utilization.ConclusionEmployers purchasing diabetes-specific health benefit designs may experience lower rates of resource-intensive services such as ER utilization.
Coffee consumption and risk of prostate cancer: a systematic review and meta-analysis
Authors: Chen Xiaonan , Zhao Yiqiao , Tao Zijia , Wang Kefeng 
Published: January 2021

ObjectivesTo conduct a systematic review with meta-analysis of cohort studies to evaluate the association of coffee consumption with the risk of prostate cancer.Data sourcesPubMed, Web of Science and Embase were searched for eligible studies up to September 2020.Study selectionCohort studies were included.Data extraction and synthesisTwo researchers independently reviewed the studies and extracted the data. Data synthesis was performed via systematic review and meta-analysis of eligible cohort studies. Meta-analysis was performed with the “metan” and “glst” commands in Stata 14.0.Main outcomes and measuresProstate cancer was the main outcome. It was classified as localised prostate cancer which included localised or non-aggressive cancers; advanced prostate cancer which included advanced or aggressive cancers; or fatal prostate cancer which included fatal/lethal cancers or prostate cancer-specific deaths.ResultsSixteen prospective cohort studies were finally included, with 57 732 cases of prostate cancer and 1 081 586 total cohort members. Higher coffee consumption was significantly associated with a lower risk of prostate cancer. Compared with the lowest category of coffee consumption, the pooled relative risk (RR) was 0.91 (95% CI 0.84 to 0.98), I2= 53.2%) for the highest category of coffee consumption. There was a significant linear trend for the association (p=0.006 for linear trend), with a pooled RR of 0.988 (95% CI 0.981 to 0.995) for each increment of one cup of coffee per day. For localised, advanced and fatal prostate cancer, the pooled RRs were 0.93 (95% CI 0.87 to 0.99), 0.88 (95% CI 0.71 to 1.09) and 0.84 (95% CI 0.66 to 1.08), respectively. No evidence of publication bias was indicated in this meta-analysis.ConclusionsThis study suggests that a higher intake of coffee may be associated with a lower risk of prostate cancer.
Demand for self-managed online telemedicine abortion in eight European countries during the COVID-19 pandemic: a regression discontinuity analysis
Authors: Aiken Abigail R A , Starling Jennifer E , Gomperts Rebecca , Scott James G , Aiken Catherine E 
Published: January 2021

ObjectivesIn most European countries, patients seeking medication abortion during the COVID-19 pandemic are still required to attend healthcare settings in person. We assessed whether demand for self-managed medication abortion provided by online telemedicine increased following the emergence of COVID-19.MethodsWe examined 3915 requests for self-managed abortion to online telemedicine service Women on Web (WoW) between 1 January 2019 and 1 June 2020. We used regression discontinuity to compare request rates in eight European countries before and after they implemented lockdown measures to slow COVID-19 transmission. We examined the prevalence of COVID-19 infection, the degree of government-provided economic support, the severity of lockdown travel restrictions and the medication abortion service provision model in countries with and without significant changes in requests.ResultsFive countries showed significant increases in requests to WoW, ranging from 28% in Northern Ireland (97 requests vs 75.8 expected requests, p=0.001) to 139% in Portugal (34 requests vs 14.2 expected requests, p<0.001). Two countries showed no significant change in requests, and one country, Great Britain, showed an 88% decrease in requests (1 request vs 8.1 expected requests, p<0.001). Among countries with significant increases in requests, abortion services are provided mainly in person in hospitals or abortion is unavailable and international travel was prohibited during lockdown. By contrast, Great Britain implemented a fully remote no-test telemedicine service.ConclusionThese marked changes in requests for self-managed medication abortion during the COVID-19 pandemic demonstrate demand for remote models of care, which could be fulfilled by expanding access to medication abortion by telemedicine.
Sex differences in heart failure hospitalisation risk following acute myocardial infarction
Authors: Yandrapalli Srikanth , Malik Aaqib , Pemmasani Gayatri , Aronow Wilbert , Shah Falak , Lanier Gregg , Cooper Howard , Jain Diwakar , Naidu Srihari , Frishman William , Panza Julio 
Published: January 2021

ObjectiveWe evaluated the sex differences in 6-month heart failure (HF) hospitalisation risk in acute myocardial infarction (AMI) survivors.MethodsFor this retrospective cohort analysis, adult survivors of an AMI between January and June 2014 were identified from the US Nationwide Readmissions Database. The primary outcome was a HF hospitalisation within 6 months. Secondary outcomes were fatal HF hospitalisation and the composite of index in-hospital HF or 6-month HF hospitalisation.ResultsOf 237 549 AMI survivors, females (37.9%) were older (70±14 years vs 65±13 years; p<0.001), had a higher prevalence of cardiac comorbidities and a lower revascularisation rate compared with males. The primary outcome occurred in 12 934 patients (5.4%), at a 49% higher rate in females (6.8% vs 4.6% in males, p<0.001), which was attenuated to a 19% higher risk after multivariable adjustment. Findings were consistent across subgroups of age, AMI type and major risk factors. In the propensity-matched time-to-event analysis, female sex was associated with a 13% higher risk for 6-month HF readmission (6.4% vs 5.8% in males; HR 1.13, 95% CI 1.05 to 1.21, p<0.001), and the increased risk was evident early on after the AMI. Fatal HF rate was similar between groups (4.7% vs 4.6%, p=0.936), but females had a higher rate of the composite HF outcome (36.2% vs 27.5%, p<0.001).ConclusionIn a large all-comers AMI survivors’ cohort, females had a higher HF hospitalisation risk that persisted after adjustment for baseline risk differences. This was consistent across several clinically relevant subgroups and was evident early on after the AMI.
Another gender data gap: female drowning in Aotearoa, New Zealand
Authors: Richardson Karen , Peden Amy E 
Published: January 2021

IntroductionA gender gap is present in drowning research and prevention interventions, resulting in an inequitable focus on males. This study aimed to address the gender data gap, exploring female drowning in Aotearoa, New Zealand.MethodsNational data on female fatal and non-fatal drowning requiring hospitalisation between 2003 and 2019 were sourced from DrownBase, Water Safety New Zealand’s drowning database. Univariate and χ2analyses were conducted for fatal and hospitalisation data. Crude rates were calculated and used to explore temporal trends and RR by age groups and ethnicity for fatal and non-fatal drowning. Ratios for drowning-related hospitalisations and Accident Compensation Corporation (ACC) claims to drowning deaths were also calculated.ResultsFrom 2003 to 2019, a total of 1087 female drowning fatalities and non-fatal (76.0%) drowning incidents requiring hospitalisation occurred. Linear trends indicate hospitalisations increased (y=0.0766x+1.4271; R2=0.4438), while fatal drowning decreased (y=−0.0101x+0.7671; R2=0.1011). The highest fatal (1.60) and non-fatal (8.22) drowning rates were seen among children aged 0–4 years. For every one female drowning fatality, there are 3.46 hospital admissions and 675.55 ACC claims.DiscussionFemale drowning represents a significant burden on the health system and the community in New Zealand. Further investment in interventions targeting females about their own risky behaviours around water (not only children in their care) is suggested, including interventions focused on hazardous conditions and alcohol consumption.ConclusionFor decades, the focus of drowning prevention among adolescents and adults has been on males. However, efforts must be broadened to prevent any further increase in drowning-related incidents among females in Aotearoa, New Zealand.
Behavior of high-performance RC composite corbels with inclined stirrups
Authors: Shakir Qasim M. 
Published: January 2021

In the present work, a new modified arrangement for shear reinforcement in corbels is proposed. Inclined, rather than horizontal, alignment of stirrups was studied. In addition, the performance of composite corbels incorporated with the usual and proposed alignments of the shear reinforcement were investigated. The experimental work consisted of testing 12 specimens. Four corbels are non-composite and eight are composite with two shapes of rolled steel, namely, WF and tapered WT sections. Two values of shear span to depth ratio (av/d) have been considered, which are 0.70 and 1.0, to study both when shear is dominant and when bending moment is dominant. The behavior of the tested specimens was discussed in terms of the history of loading, first cracking load, failure load, ductility, toughness, and history of the first crack development. It was found that the proposed configuration of shear reinforcement improved the ductility and toughness with respect to the conventional arrangement by 16% and 38%, respectively, for av/d value of 0.70, and 55% and 64%, respectively, for an av/d value of 1.0. Furthermore, the results revealed that using the composite corbel with the proposed alignment rather than RC corbel improved the ductility and toughness by 35%–80% and 45%–173%, respectively, for av/d = 0.70. The values for corbels with av/d = 1.0 are 38%–101% and 67%–88%, respectively. Moreover, tests revealed that the composite WF-steel corbel with diagonally aligned stirrups showed relative performance indicators (with respect to the conventional corbel) for av/d = 0.7 of 82%, 98%, 105%, and 273% for the first cracking load, failure load, ductility, and toughness, respectively. The respective values for av/d = 1.0 were 111%, 115%, 138%, and 188%, respectively.
Cell-Intrinsic Tumorigenic Functions of PPARγ in Bladder Urothelial Carcinoma
Authors: Sanchez Danielle J. , Missiaen Rindert , Skuli Nicolas , Steger David J. , Simon M. Celeste 
Published: January 2021

Abstract

The role of PPAR gamma (PPARγ) has been well characterized in the developmental process of adipogenesis, yet its aberrant expression patterns and functions in cancer subtypes are less understood. Although PPARγ has been recently demonstrated to play non–cell-autonomous roles in promoting bladder urothelial carcinoma (UC) progression, underlying mechanisms of the cell-intrinsic oncogenic activity remain unknown. Here, we report robust expression and nuclear accumulation of PPARγ in 47% of samples of patients with UC, exceeding mRNA expression patterns published by The Cancer Genome Atlas. In vitro assays revealed for the first time that treatment of UC cells with PPARγ inverse agonist or PPARG knockout by CRISPR-Cas9 reduces proliferation, migration, and invasion of multiple established UC cell lines, most strongly in those characterized by PPARG genomic amplification or activating mutations of RXRA, the obligate heterodimer of PPARγ. Through genome-wide approaches including chromatin immunoprecipitation sequencing and RNA sequencing, we define a novel set of PPARγ-regulated genes in UC, including Sonic Hedgehog (SHH). Similar to PPARγ, genetic inhibition of SHH reduces proliferation and motility. Finally, we demonstrate the PPARγ dependency of UC tumors in vivo by genetic and pharmacologic PPARγ inhibition in subcutaneous xenografts. Collectively, our data indicate that PPARγ promotes UC progression in a subset of patients, at least in part, through cell-autonomous mechanisms linked to SHH signaling.

Implications:
Genome-wide analysis of DNA-binding sites for oncogenic factor PPARγ revealed SHH as a novel downstream target involved in UC progression, providing important insight into the tumorigenic nature and molecular mechanism of PPARγ signaling in UC.
Serine Biosynthesis Is a Metabolic Vulnerability in FLT3-ITD–Driven Acute Myeloid Leukemia
Authors: Bjelosevic Stefan , Gruber Emily , Newbold Andrea , Shembrey Carolyn , Devlin Jennifer R. , Hogg Simon J. , Kats Lev , Todorovski Izabela , Fan Zheng , Abrehart Thomas C. , Pomilio Giovanna , Wei Andrew , Gregory Gareth P. , Vervoort Stephin J. , Brown Kristin K. , Johnstone Ricky W. 
Published: January 2021

Abstract

Internal tandem duplication of the FMS-like tyrosine kinase 3 gene (FLT3-ITD) occurs in 30% of all acute myeloid leukemias (AML). Limited clinical efficacy of FLT3 inhibitors highlights the need for alternative therapeutic modalities in this subset of disease. Using human and murine models of FLT3-ITD–driven AML, we demonstrate that FLT3-ITD promotes serine synthesis and uptake via ATF4-dependent transcriptional regulation of genes in the de novo serine biosynthesis pathway and neutral amino acid transport. Genetic or pharmacologic inhibition of PHGDH, the rate-limiting enzyme of de novo serine biosynthesis, selectively inhibited proliferation of FLT3-ITD AMLs in vitro and in vivo. Moreover, pharmacologic inhibition of PHGDH sensitized FLT3-ITD AMLs to the standard-of-care chemotherapeutic cytarabine. Collectively, these data reveal novel insights into FLT3-ITD–induced metabolic reprogramming and reveal a targetable vulnerability in FLT3-ITD AML.

Significance:
FLT3-ITD mutations are common in AML and are associated with poor prognosis. We show that FLT3-ITD stimulates serine biosynthesis, thereby rendering FLT3-ITD–driven leukemias dependent upon serine for proliferation and survival. This metabolic dependency can be exploited pharmacologically to sensitize FLT3-ITD–driven AMLs to chemotherapy.
This article is highlighted in the In This Issue feature, p. 1307
Targeting the p300/CBP Axis in Lethal Prostate Cancer
Authors: Welti Jonathan , Sharp Adam , Brooks Nigel , Yuan Wei , McNair Christopher , Chand Saswati N. , Pal Abhijit , Figueiredo Ines , Riisnaes Ruth , Gurel Bora , Rekowski Jan , Bogdan Denisa , West William , Young Barbara , Raja Meera , Prosser Amy , Lane Jordan , Thomson Stuart , Worthington Jenny , Onions Stuart , Shannon Jonathan , Paoletta Silvia , Brown Richard , Smyth Don , Harbottle Gareth W. , Gil Veronica S. , Miranda Susana , Crespo Mateus , Ferreira Ana , Pereira Rita , Tunariu Nina , Carreira Suzanne , Neeb Antje J. , Ning Jian , Swain Amanda , Taddei David ,   SU2C/PCF International Prostate Cancer Dream Team, Schiewer Matthew J. , Knudsen Karen E. , Pegg Neil , de Bono Johann S. 
Published: January 2021

Abstract

Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. We show that CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases AR- and C-MYC–regulated gene expression. In AR-SV–driven models, CCS1477 has antitumor activity, regulating AR and C-MYC signaling. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced prostate cancer.

Significance:
Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR coactivators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, inhibits growth and AR activity in CRPC models, and can affect metastatic CRPC target expression in serial clinical biopsies.
See related commentary by Rasool et al., p. 1011.
This article is highlighted in the In This Issue feature, p. 995
A Machine Learning Approach Yields a Multiparameter Prognostic Marker in Liver Cancer
Authors: Liu Xiaoli , Lu Jilin , Zhang Guanxiong , Han Junyan , Zhou Wei , Chen Huan , Zhang Henghui , Yang Zhiyun 
Published: January 2021

Abstract
A number of staging systems have been developed to predict clinical outcomes in hepatocellular carcinoma (HCC). However, no general consensus has been reached regarding the optimal model. New approaches such as machine learning (ML) strategies are powerful tools for incorporating risk factors from multiple platforms. We retrospectively reviewed the baseline information, including clinicopathologic characteristics, laboratory parameters, and peripheral immune features reflecting T-cell function, from three HCC cohorts. A gradient-boosting survival (GBS) classifier was trained with prognosis-related variables in the training dataset and validated in two independent cohorts. We constructed a 20-feature GBS model classifier incorporating one clinical feature, 14 laboratory parameters, and five T-cell function parameters obtained from peripheral blood mononuclear cells. The GBS model–derived risk scores demonstrated high concordance indexes (C-indexes): 0.844, 0.827, and 0.806 in the training set and validation sets 1 and 2, respectively. The GBS classifier could separate patients into high-, medium- and low-risk subgroups with respect to death in all datasets (P &lt; 0.05 for all comparisons). A higher risk score was positively correlated with a higher clinical stage and the presence of portal vein tumor thrombus (PVTT). Subgroup analyses with respect to Child–Pugh class, Barcelona Clinic Liver Cancer stage, and PVTT status supported the prognostic relevance of the GBS-derived risk algorithm independent of the conventional tumor staging system. In summary, a multiparameter ML algorithm incorporating clinical characteristics, laboratory parameters, and peripheral immune signatures offers a different approach to identify patients with the greatest risk of HCC-related death.
Interactions Between Enhanced Polygenic Risk Scores and Lifestyle for Cardiovascular Disease, Diabetes, and Lipid Levels
Authors: Ye Yixuan , Chen Xi , Han James , Jiang Wei , Natarajan Pradeep , Zhao Hongyu 
Published: January 2021

Background:
Both lifestyle and genetic factors confer risk for cardiovascular diseases, type 2 diabetes, and dyslipidemia. However, the interactions between these 2 groups of risk factors were not comprehensively understood due to previous poor estimation of genetic risk. Here we set out to develop enhanced polygenic risk scores (PRS) and systematically investigate multiplicative and additive interactions between PRS and lifestyle for coronary artery disease, atrial fibrillation, type 2 diabetes, total cholesterol, triglyceride, and LDL-cholesterol.

Methods:
Our study included 276 096 unrelated White British participants from the UK Biobank. We investigated several PRS methods (P+T, LDpred, PRS continuous shrinkage, and AnnoPred) and showed that AnnoPred achieved consistently improved prediction accuracy for all 6 diseases/traits. With enhanced PRS and combined lifestyle status categorized by smoking, body mass index, physical activity, and diet, we investigated both multiplicative and additive interactions between PRS and lifestyle using regression models.

Results:
We observed that healthy lifestyle reduced disease incidence by similar multiplicative magnitude across different PRS groups. The absolute risk reduction from lifestyle adherence was, however, significantly greater in individuals with higher PRS. Specifically, for type 2 diabetes, the absolute risk reduction from lifestyle adherence was 12.4% (95% CI, 10.0%–14.9%) in the top 1% PRS versus 2.8% (95% CI, 2.3%–3.3%) in the bottom PRS decile, leading to a ratio of >4.4. We also observed a significant interaction effect between PRS and lifestyle on triglyceride level.

Conclusions:
By leveraging functional annotations, AnnoPred outperforms state-of-the-art methods on quantifying genetic risk through PRS. Our analyses based on enhanced PRS suggest that individuals with high genetic risk may derive similar relative but greater absolute benefit from lifestyle adherence.