bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification and categorisation of relevant outcomes for symptomatic uncomplicated gallstone disease: in-depth analysis to inform the development of a core outcome set
Authors: Cruickshank Moira , Newlands Rumana , Blazeby Jane , Ahmed Irfan , Bekheit Mohamed , Brazzelli Miriam , Croal Bernard , Innes Karen , Ramsay Craig , Gillies Katie 
Published: June 2021

BackgroundMany completed trials of interventions for uncomplicated gallstone disease are not as helpful as they could be due to lack of standardisation across studies, outcome definition, collection and reporting. This heterogeneity of outcomes across studies hampers useful synthesis of primary studies and ultimately negatively impacts on decision making by all stakeholders. Core outcome sets offer a potential solution to this problem of heterogeneity and concerns over whether the ‘right’ outcomes are being measured. One of the first steps in core outcome set generation is to identify the range of outcomes reported (in the literature or by patients directly) that are considered important.ObjectivesTo develop a systematic map that examines the variation in outcome reporting of interventions for uncomplicated symptomatic gallstone disease, and to identify other outcomes of importance to patients with gallstones not previously measured or reported in interventional studies.ResultsThe literature search identified 794 potentially relevant titles and abstracts of which 137 were deemed eligible for inclusion. A total of 129 randomised controlled trials, 4 gallstone disease specific patient-reported outcome measures (PROMs) and 8 qualitative studies were included. This was supplemented with data from 6 individual interviews, 1 focus group (n=5 participants) and analysis of 20 consultations. A total of 386 individual recorded outcomes were identified across the combined evidence: 330 outcomes (which were reported 1147 times) from trials evaluating interventions, 22 outcomes from PROMs, 17 outcomes from existing qualitative studies and 17 outcomes from primary qualitative research. Areas of overlap between the evidence sources existed but also the primary research contributed new, unreported in this context, outcomes.ConclusionsThis study took a rigorous approach to catalogue and map the outcomes of importance in gallstone disease to enhance the development of the COS ‘long’ list. A COS for uncomplicated gallstone disease that considers the views of all relevant stakeholders is needed.
Rehabilitation of the frail older adults in primary healthcare in rural areas: a scoping review protocol
Authors: Hov Jorunn , Alteren Johanne , Kvigne Kari 
Published: June 2021

IntroductionFrail older adults are particularly vulnerable to functional decline and adverse outcomes because they lack the necessary resistance and ability to cope. Rehabilitation services for the frail older adults are thus vital and require clarification. The aim of this review is to identify and map the scope and breadth of literature regarding rehabilitation of the frail older adults to develop a holistic rehabilitation service in primary healthcare in rural areas. The concept of rehabilitation, how rehabilitation services are organised, how patients and next of kin are involved in planning and evaluating services during rehabilitation, as well as reported results will be identified and mapped.Methods and analysisThis scoping review will be conducted based on the methodology developed by Arksey and O’Malley. The search strategy will aim to locate both published and unpublished studies in relevant databases. Key information sources include CINAHL, MEDLINE, Embase, ProQuest and Google Scholar. Data will be extracted from papers that all three reviewers have chosen to include in the review. All three reviewers will participate in screening, assessment and selection of studies against the inclusion criteria for the review and work in teams of two. The full text of selected citations will be assessed in detail against the inclusion criteria by the same teams. Data will be extracted from papers included in the scoping review by two of the reviewers. Modifications will be detailed in the full review report. Any disagreements that arise between two reviewers will be resolved through discussion or with the third reviewer’s mediation. A narrative summary of the findings will be presented accompanied by tables that reflect the objective of the review.Ethics and disseminationData will be obtained only from already publicly available materials. Special ethical approval is, therefore, not required.
Cohort profile: the MUNICH Preterm and Term Clinical study (MUNICH-PreTCl), a neonatal birth cohort with focus on prenatal and postnatal determinants of infant and childhood morbidity
Authors: Pangratz-Fuehrer Susanne , Genzel-Boroviczény Orsolya , Bodensohn Wolfgang , Eisenburger Robin , Scharpenack Janne , Geyer Philipp E , Müller-Reif Johannes B , van Hagen Nadja , Müller Alina M , Jensen Majken Karoline , Klein Christoph , Mann Matthias , Nussbaum Claudia 
Published: June 2021

PurposeThe MUNICH Preterm and Term Clinical (MUNICH-PreTCl) birth cohort was established to uncover pathological processes contributing to infant/childhood morbidity and mortality. We collected comprehensive medical information of healthy and sick newborns and their families, together with infant blood samples for proteomic analysis. MUNICH-PreTCl aims to identify mechanism-based biomarkers in infant health and disease to deliver more precise diagnostic and predictive information for disease prevention. We particularly focused on risk factors for pregnancy complications, family history of genetically influenced health conditions such as diabetes and paediatric long-term health—all to be further monitored and correlated with proteomics data in the future.ParticipantsNewborns and their parents were recruited from the Perinatal Center at the LMU University Hospital, Munich, between February 2017 and June 2019. Infants without congenital anomalies, delivered at 23–41 weeks of gestation, were eligible.FindingsFindings to date concern the clinical data and extensive personal patient information. A total of 662 infants were recruited, 44% were female (36% in preterm, 46% in term). 90% of approached families agreed to participate. Neonates were grouped according to gestational age: extremely preterm (<28 weeks, N=28), very preterm (28 to <32 weeks, N=36), late preterm (32 to <37 weeks, N=97) and term infants (>37+0 weeks, N=501). We collected over 450 data points per child–parent set, (family history, demographics, pregnancy, birth and daily follow-ups throughout hospitalisation) and 841 blood samples longitudinally. The completion rates for medical examinations and blood samples were 100% and 95% for the questionnaire.Future plansThe correlation of large clinical datasets with proteomic phenotypes, together with the use of medical registries, will enable future investigations aiming to decipher mechanisms of disorders in a systems biology perspective.Trial registration numberDRKS (00024189); Pre-results.
Blood RNA sequencing shows overlapping gene expression across COPD phenotype domains
Authors: Ghosh Auyon J , Saferali Aabida , Lee Sool , Chase Robert , Moll Matthew , Morrow Jarrett , Yun Jeong , Castaldi Peter J , Hersh Craig P 
Published: June 2021

RationaleCOPD can be assessed using multidimensional grading systems with components from three domains: pulmonary function tests, symptoms and systemic features. Clinically, measures may be used interchangeably, though it is not known if they share similar pathobiology.ObjectiveTo use RNA sequencing (RNA-seq) to determine if there is an overlap in the underlying biological mechanisms and consequences driving different components of the multidimensional grading systems.MethodsWhole blood was collected for RNA-seq from current and former smokers in the Genetic Epidemiology of COPD study. We tested the overlap in gene expression and biological pathways associated with case–control status and quantitative COPD phenotypes within and between the three domains.ResultsIn 2647 subjects, there were 3030 genes differentially expressed in any of the three domains or case–control status. There were five genes that overlapped between the three domains and case–control status, including G protein-coupled receptor 15(GPR15), sestrin 1 (SESN1) and interferon-induced guanylate-binding protein 1 (GBP1), which were associated with longitudinal decline in FEV1. The overlap between the three domains was enriched for pathways related to cellular components.ConclusionsWe identified gene sets and pathways that overlap between 12 COPD-related phenotypes and case–control status. There were no pathways represented in the overlap between the three domains and case–control status, but we identified multiple genes that demonstrated a consistent pattern of expression across several of the phenotypes. Patterns of gene expression correlation were generally similar to the correlation of clinical phenotypes in the PFT and symptom domains but not the systemic features.
Muon identification in a compact single-layered water Cherenkov detector and gamma/hadron discrimination using machine learning techniques
Authors: Conceição R. , González B. S. , Guillén A. , Pimenta M. , Tomé B. 
Published: June 2021

AbstractThe muon tagging is an essential tool to distinguish between gamma and hadron-induced showers in wide field-of-view gamma-ray observatories. In this work, it is shown that an efficient muon tagging (and counting) can be achieved using a water Cherenkov detector with a reduced water volume and 4 PMTs, provided that the PMT signal spatial and time patterns are interpreted by an analysis based on machine learning (ML). The developed analysis has been tested for different shower and array configurations. The output of the ML analysis, the probability of having a muon in the WCD station, has been used to notably discriminate between gamma and hadron induced showers with$$S/ \sqrt{B} \sim 4$$S/B∼4for shower with energies$$E_0 \sim 1\,$$E0∼1TeV. Finally, for proton-induced showers, an estimator of the number of muons was built by means of the sum of the probabilities of having a muon in the stations. Resolutions about$$20\%$$20%and a negligible bias are obtained for vertical showers with$$N_{\mu } > 10$$Nμ>10.
Variability of SST and ILD in the Arabian Sea and Sea of Oman in Association with the Monsoon Cycle
Authors: Khan Sartaj , Piao Shengchun , Khan Imran U. , Xu Bingchen , Khan Shazia , Ismail Muhammad Asim , Song Yang 
Published: June 2021

Sea surface temperature (SST) and isothermal layer depth (ILD) are important oceanic parameters and could play a significant role in understanding the upper thermal structure as well as improve the predictive capability of monsoons in the tropical oceans. In a disparate departure from the past research, the present study investigates the seasonal variability of SST and ILD in association with the monsoon cycle in the Arabian Sea and Sea of Oman regions by examination of Argo datasets for 2016-17. In this study, the ILD climatology is determined from temperature profiles provided by the Argo floats based on a threshold technique

T

z

≥
SST
−

1

°

C

to investigate the region of stronger and weaker monsoon wind forcing. For SST, values of temperature are used nearest to the sea surface (depth

z

≤

5 m). The region is split into four distinct zones for an accurate description of the monsoon cycle: the south Arabian Sea, the central Arabian Sea, the north Arabian Sea, and the Sea of Oman. It is observed that summer monsoon is more pronounced in the south-central basin of the Arabian Sea, where ILD is deepening (>100 m in September 2016) mainly due to stronger wind forcing in this region. On the contrary, the Sea of Oman region is displayed with smaller ILD amplitude (<10 m in June 2016) with larger SST, meaning that this region is weakly influenced by the summer monsoon. The seasonal relationship established between ILD variability and monsoon cycle for 2016-17 shows that ILD could be a useful indicator for predicting summer monsoon in the Arabian Sea regions. Our analysis results indicate that the dynamics for SST variability are different in these regions and are influenced either by large-scale atmospheric forcing, such as the El Niño-Southern Oscillation (ENSO) and the Indian Ocean Dipole (IOD), or by the effects of mesoscale variations occurring along the Oman-Arabian coast.
The Proteomic Landscape of Growth Factor Signaling Networks Associated withFAT1Mutations in Head and Neck Cancers
Authors: Chen Zhengjia , Zhang Chao , Chen Jianhong , Wang Dongsheng , Tu Jieqi , Van Waes Carter , Saba Nabil F. , Chen Zhuo G. , Chen Zhong 
Published: June 2021

AbstractFAT1 is frequently mutated in head and neck squamous cell carcinoma (HNSCC), but the biological and clinical effects of FAT1 mutations in HNSCC remain to be fully elucidated. We investigated the landscape of altered protein and gene expression associated with FAT1 mutations and clinical outcomes of patients with HNSCC. FAT1 mutation was stratified with clinical information from The Cancer Genome Atlas HNSCC databases with more than 200 proteins or phosphorylated sites. FAT1 mutation was significantly more prevalent among HPV(−), female, and older patients and was enriched in oral, larynx, and hypopharynx primary tumors. FAT1 mutation was also significantly associated with lower FAT1 gene expression and increased protein expression of HER3_pY1289, IRS1, and CAVEOLIN1. From an independent International Cancer Genome Consortium dataset, FAT1 mutation in oral cancer co-occurred with top mutated genes TP53 and CASP8. Poorer overall survival or progression-free survival was observed in patients with FAT1 mutation or altered HER3_pY1289, IRS1, or CAVEOLIN1. Pathway analysis revealed dominant ERBB/neuregulin pathways linked to FAT1 mutations in HNSCC, and protein signature panels uncovered the heterogeneity of patient subgroups. Decreased pEGFR, pHER2, and pERK and upregulated pHER3 and HER3 proteins were observed in two FAT1 knockout HNSCC cell lines, supporting that FAT1 alterations lead to altered EGFR/ERBB signaling. In squamous cancers of the lung and cervix, a strong association of FAT1 and EGFR gene expressions was identified. Collectively, these results suggest that alteration of FAT1 appears to involve mostly HPV(−) HNSCC and may contribute to resistance to EGFR-targeted therapy.Significance:Integrative bioinformatics and statistical analyses reveal a panel of genes and proteins associated with FAT1 mutation in HNSCC, providing important insights into prospective clinical investigations with targeted therapies.
Association between Airport-Related Ultrafine Particles and Risk of Malignant Brain Cancer: A Multiethnic Cohort Study
Authors: Wu Anna H. , Fruin Scott , Larson Timothy V. , Tseng Chiu-Chen , Wu Jun , Yang Juan , Jain Jennifer , Shariff-Marco Salma , Inamdar Pushkar P. , Setiawan Veronica W. , Porcel Jacqueline , Stram Daniel O. , Le Marchand Loic , Ritz Beate , Cheng Iona 
Published: June 2021

Abstract

Ultrafine particles (UFP; diameter less than or equal to 100 nm) may reach the brain via systemic circulation or the olfactory tract and have been implicated in the risk of brain tumors. The effects of airport-related UFP on the risk of brain tumors are not known. Here we determined the association between airport-related UFP and risk of incident malignant brain cancer (n = 155) and meningioma (n = 420) diagnosed during 16.4 years of follow-up among 75,936 men and women residing in Los Angeles County from the Multiethnic Cohort study. UFP exposure from aircrafts was estimated for participants who lived within a 53 km × 43 km grid area around the Los Angeles International Airport (LAX) from date of cohort entry (1993–1996) through December 31, 2013. Cox proportional hazards models were used to estimate the effects of time-varying, airport-related UFP exposure on risk of malignant brain cancer and meningioma, adjusting for sex, race/ethnicity, education, and neighborhood socioeconomic status. Malignant brain cancer risk in all subjects combined increased 12% [95% confidence interval (CI), 0.98–1.27] per interquartile range (IQR) of airport-related UFP exposure (∼6,700 particles/cm3) for subjects with any address in the grid area surrounding the LAX airport. In race/ethnicity-stratified analyses, African Americans, the subgroup who had the highest exposure, showed a HR of 1.32 (95% CI, 1.07–1.64) for malignant brain cancer per IQR in UFP exposure. UFP exposure was not related to risk of meningioma overall or by race/ethnicity. These results support the hypothesis that airport-related UFP exposure may be a risk factor for malignant brain cancers.

Significance:
Malignant brain cancer risk increases with airport-related UFP exposure, particularly among African Americans, suggesting UFP exposure may be a modifiable risk factor for malignant brain cancer.
The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI): A Three-Factor Comorbidity Model
Authors: Gordon Max J. , Kaempf Andy , Sitlinger Andrea , Shouse Geoffrey , Mei Matthew , Brander Danielle M. , Salous Tareq , Hill Brian T. , Alqahtani Hamood , Choi Michael , Churnetski Michael C. , Cohen Jonathon B. , Stephens Deborah M. , Siddiqi Tanya , Rivera Xavier , Persky Daniel , Wisniewski Paul , Patel Krish , Shadman Mazyar , Park Byung , Danilov Alexey V. 
Published: June 2021

Abstract

Purpose:
Comorbid medical conditions define a subset of patients with chronic lymphocytic leukemia (CLL) with poor outcomes. However, which comorbidities are most predictive remains understudied.

Experimental Design:
We conducted a retrospective analysis from 10 academic centers to ascertain the relative importance of comorbidities assessed by the cumulative illness rating scale (CIRS). The influence of specific comorbidities on event-free survival (EFS) was assessed in this derivation dataset using random survival forests to construct a CLL-specific comorbidity index (CLL-CI). Cox models were then fit to this dataset and to a single-center, independent validation dataset.

Results:
The derivation and validation sets comprised 570 patients (59% receiving Bruton tyrosine kinase inhibitor, BTKi) and 167 patients (50% receiving BTKi), respectively. Of the 14 CIRS organ systems, three had a strong and stable influence on EFS: any vascular, moderate/severe endocrine, moderate/severe upper gastrointestinal comorbidity. These were combined to create the CLL-CI score, which was categorized into 3 risk groups. In the derivation dataset, the median EFS values were 58, 33, and 20 months in the low, intermediate, and high-risk groups, correspondingly. Two-year overall survival (OS) rates were 96%, 91%, and 82%. In the validation dataset, median EFS values were 81, 40, and 23 months (two-year OS rates 97%/92%/88%), correspondingly. Adjusting for prognostic factors, CLL-CI was significantly associated with EFS in patients treated with either chemo-immunotherapy or with BTKi in each of our 2 datasets.

Conclusions:
The CLL-CI is a simplified, CLL-specific comorbidity index that can be easily applied in clinical practice and correlates with survival in CLL.
Combined EZH2 Inhibition and IKAROS Degradation Leads to Enhanced Antitumor Activity in Diffuse Large B-cell Lymphoma
Authors: Tong Kit I. , Yoon Sharon , Isaev Keren , Bakhtiari Mehran , Lackraj Tracy , He Michael Y. , Joynt Jesse , Silva Anjali , Xu Maria C. , Privé Gilbert G. , He Housheng Hansen , Tiedemann Rodger E. , Chavez Elizabeth A. , Chong Lauren C. , Boyle Merrill , Scott David W. , Steidl Christian , Kridel Robert 
Published: June 2021

AbstractPurpose:The efficacy of EZH2 inhibition has been modest in the initial clinical exploration of diffuse large B-cell lymphoma (DLBCL), yet EZH2 inhibitors are well tolerated. Herein, we aimed to uncover genetic and pharmacologic opportunities to enhance the clinical efficacy of EZH2 inhibitors in DLBCL.Experimental Design:We conducted a genome-wide sensitizing CRISPR/Cas9 screen with tazemetostat, a catalytic inhibitor of EZH2. The sensitizing effect of IKZF1 loss of function was then validated and leveraged for combination treatment with lenalidomide. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing analyses were performed to elucidate transcriptomic and epigenetic changes underlying synergy.Results:We identified IKZF1 knockout as the top candidate for sensitizing DLBCL cells to tazemetostat. Treating cells with tazemetostat and lenalidomide, an immunomodulatory drug that selectively degrades IKAROS and AIOLOS, phenocopied the effects of the CRISPR/Cas9 screen. The combined drug treatment triggered either cell-cycle arrest or apoptosis in a broad range of DLBCL cell lines, regardless of EZH2 mutational status. Cell-line–based xenografts also showed slower tumor growth and prolonged survival in the combination treatment group. RNA-seq analysis revealed strong upregulation of interferon signaling and antiviral immune response signatures. Gene expression of key immune response factors such as IRF7 and DDX58 were induced in cells treated with lenalidomide and tazemetostat, with a concomitant increase of H3K27 acetylation at their promoters. Furthermore, transcriptome analysis demonstrated derepression of endogenous retroviruses after combination treatment.Conclusions:Our data underscore the synergistic interplay between IKAROS degradation and EZH2 inhibition on modulating epigenetic changes and ultimately enhancing antitumor effects in DLBCL.
Network Meta-Analysis of Ticagrelor for Stroke Prevention in Patients at High Risk for Cardiovascular or Cerebrovascular Events
Authors: Bálint Alexandra , Tornyos Dániel , El Alaoui El Abdallaoui Oumaima , Kupó Péter , Komócsi András 
Published: June 2021

Background and Purpose:
Preventive antiplatelet therapy is recommended for patients with cardiac or cerebrovascular atherosclerosis. Ticagrelor has an improved safety and efficacy profile in patients with acute coronary syndrome; however, data regarding stroke prevention remain controversial. We conducted a network meta-analysis to compare ticagrelor with other receptor antagonists (P2Y12) inhibitors and aspirin in monotherapy or combination in the treatment of patients with high risk for cardiovascular or cerebrovascular disease, defined as coronary artery disease, acute coronary syndrome, stroke or transient ischemic attack, or peripheral artery disease.

Methods:
Systematic searches of MEDLINE, EMBASE, and the Cochrane Library were conducted until August 1, 2020. Search terms included ticagrelor, AZD 6140, and stroke. The risk of bias was assessed using the Cochrane Collaboration assessment tool. Random-effects model was used to combine risk estimates across trials and risk ratio with 95% CIs served as summary statistics. The influence of individual components was evaluated in an additive network meta-analysis model. The primary efficacy end point was the occurrence of stroke. The safety end points included bleeding and all-cause mortality.

Results:

Twenty-six randomized clinical trials comprising 124 495 patients were analyzed. When compared with controls, ticagrelor plus aspirin significantly reduced the risk of ischemic stroke by 20% (risk ratio, 0.80 [95% CI, 0.71–0.89]). Treatment with ticagrelor monotherapy did not significantly affect ischemic stroke (risk ratio, 0.88 [95% CI, 0.77–1.00];
P
=0.05). Compared with aspirin alone, major bleeding was in similar ranges with antiplatelet monotherapies while the relative risk was twice higher with combined antiplatelet therapies. There was no considerable difference in the risk of mortality with ticagrelor plus aspirin (risk ratio, 0.99 [95% CI, 0.91–1.07]).

Conclusions:
Ticagrelor on top of aspirin may provide more favorable outcomes on secondary stroke prevention in patients with vascular risk factors; however, this benefit may come with the price of increased bleeding risk including intracranial bleeding.