bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenetic approach to the treatment of functional disorders of the gastrointestinal tract and their intersection: results of the Russian observation retrospective program COMFORT
Authors: Ivashkin Vladimir T. , Poluektova Elena A. , Glazunov Alexey B. , Putilovskiy Mikhail A. , Epstein Oleg I. 
Published: December 2019

AbstractBackgroundThe aim of this study was to investigate the efficacy and safety of the novel complex drug, consisting of released-active form of antibodies to S-100 protein, tumor necrosis factor-α and histamine, (Kolofort) under outpatient conditions in patients with functional dyspepsia (FD), irritable bowel syndrome (IBS), and FD-IBS overlap.MethodsThe subjects of the observational noninterventional retrospective program were the data of 14,362 outpatient records of patients with diagnosed FD, IBS, and/or overlap, who were observed by gastroenterologists from November 01, 2017, through March 30, 2018, who received the drug Kolofort in monotherapy for 12 weeks, 2 tablets twice a day. To assess the presence and severity of symptoms of functional gastrointestinal disorders (FGID), the “7*7” questionnaire developed by a working group from the Russian Gastroenterological Association was used. The evaluated parameters included the proportion of patients: who had a 50% or more reduction in the total score; who have switched to the less severe category of the condition; who have switched to the “healthy” or “borderline ill” severity categories; and the change in the score in domains 1–7.ResultsThe final efficacy analysis included data from 9254 patients. A decrease in the total score by 50% or more was observed in 80.45% of patients with FD, 79.02% of patients with IBS, and in 83% of patients with both IBS and FD. Switch to a lower severity category of the condition at the end of therapy was noted in 93.35% of patients with FD, in 93.80% of cases in patients with IBS, and in 96.17% of cases in patients with a combination of IBS and FD. A total of 94 adverse events (AEs) were reported in 80 patients (0.65%).ConclusionThe COMFORT program has demonstrated the positive effect of treatment in the majority of patients with IBS and FD and their combination in real clinical practice.
An update on hepatitis C virus genotype distribution in Jordan: a 12-year retrospective study from a tertiary care teaching hospital in Amman
Authors: Sallam Malik , Batarseh Rawan , Natsheh Anas , Abbadi Jumana , Al-Fraihat Esraa , Yaseen Alaa’ , Kaddomi Doaa , Khamees Nadia , Mahafzah Azmi , Şahin Gülşen Özkaya 
Published: December 2019

Abstract
Background
Nucleic acid hybridization (NAH) of hepatitis C virus (HCV) is a practical and reliable tool for virus genotyping. Genotype assignment is an important factor in the prediction of treatment success in chronic hepatitis C patients. The aim of this study was to determine the genotype distribution among HCV clinical isolates in Jordan between 2007 and 2018.

Methods
Electronic and paper-based clinical data registry records from 2007 to 2018 at the Jordan University Hospital (JUH) were retrospectively examined for individuals with HCV genotype, HCV viral load, and alanine aminotransferase (ALT) testing results. Genotype determination was based on NAH technique using the HCV 5′ untranslated region (5′ UTR) with 386 requests available from 342 unique individuals.

Results
A total of 263 out of 342 unique individuals (76.9%) had genotyping results available for final analysis with 259 individuals each having a single genotyping result. The most common HCV genotypes in the study were: genotype 4 (n = 142, 54.0%), genotype 1 (n = 87, 33.1%), genotype 3 (n = 16, 6.1%), genotype 2 (n = 9, 3.4%), other undetermined genotypes (n = 5, 1.9%) and mixed infections (n = 4, 1.5%). Sub-genotyping results were available for 46 individuals as follows: sub-genotype 4c/d (n = 13, 28.3%), sub-genotype 1a (n = 11, 23.9%), sub-genotype 1b (n = 10, 21.7%), sub-genotype 4a (n = 8, 17.4%), sub-genotype 3a (n = 2, 4.3%), sub-genotypes 2a/c and 4 h (n = 1, 2.2% for both). Individuals infected with genotype 1 showed higher viral load when compared to those infected with genotype 4 (p = 0.048, t-test). Younger HCV-infected individuals (< 52 years) had higher ALT levels compared to older individuals (p = 0.036, t-test). Self-reported risk factors for HCV acquisition included: history of previous surgery, invasive dental procedures, and blood transfusion, delivery at home, circumcision at home and wet cupping therapy (hijama).

Conclusions
High genetic diversity of HCV was found in Jordan, with genotypes 4 and 1 as the most prevalent genotypes co-circulating in the country. Potential impact of virus genotype on disease markers (viral load, ALT) was detected and needs further assessment. The study can be helpful to plan for future prevention and management of HCV infection in Jordan.
Effect of pregnancy induced hypertension on adverse perinatal outcomes in Tigray regional state, Ethiopia: a prospective cohort study
Authors: Berhe Abadi Kidanemariam , Ilesanmi Abiodun O. , Aimakhu Christopher O. , Mulugeta Afework 
Published: December 2019

AbstractBackgroundThe prevalence of pregnancy-induced hypertension in Ethiopia ranges from 2.2 to 18.3%. However, so far little is known about the adverse perinatal outcomes of pregnancy-induced hypertension in Tigray regional state, Ethiopia. Therefore, the objective of this study was to assess the effect of pregnancy-induced hypertension on adverse perinatal outcomes in Tigray Regional State, Ethiopia.Methodsa prospective cohort study was conducted on a total sample of 782 pregnant women attending antenatal care in hospitals of Tigray regional state, Ethiopia. Pregnant mothers diagnosed with PIH during the data collection period in the selected hospitals were included as exposed group and normotensive women were also enrolled as a control group. This study addresses women diagnosed with preeclampsia, eclampsia and gestational hypertension between 28 and 35 weeks of gestation. Data were collected using an interviewer-administered questionnaire and review of their medical records from February 2018, to February 2019. The adverse perinatal outcome event includes low birth weight, birth asphyxia, small for gestational age, preterm delivery, admission to neonatal intensive care unit and perinatal death. A modified Poisson regression model with robust standard errors was used to analyze relative risk.ResultsIn this study, the overall incidence of adverse perinatal outcome was higher among women with pregnancy-induced hypertension than normotensive women (66.4% vs 22.2%). After adjusted for confounders women with pregnancy-induced hypertension were born babies with a higher risk of low birth weight (adjusted RR (95%CI) = 5.1(3.4,7.8)), birth asphyxia (aRR = 2.6(1.9,3.8)), small for gestational age (aRR = 3.3(2.3,4.6)), preterm delivery (aRR = 5.2(3.4,7.9)), stillbirth (aRR = 3.46(1.40,8.54)), admission to neonatal intensive care unit (aRR = 5.1(3.1,8.4)) and perinatal death (aRR = 3.6(1.8,7.4)) compared to normotensive pregnant women.ConclusionsHigher incidences of adverse perinatal outcomes occurred among women pregnancy-induced hypertension in Tigray regional state, Ethiopia. Hence, health care providers should strengthen prevention, early diagnosis and prompt management of pregnancy-induced hypertension to reduce adverse perinatal outcomes of pregnancy-induced hypertension.
Significant influencing factors and practical solutions in improvement of clinical nursing services: a Delphi study
Authors: Poortaghi Sarieh , Ebadi Abbas , Salsali Mahvash , Raiesifar Afsaneh , Davoudi Nayyereh , Pourgholamamiji Nima 
Published: December 2019

Abstract
Background
Clinical services evaluation with specific indicators are very helpful to identify improvable points. This study was conducted to analyze the factors affecting the quality of clinical nursing services and offer practical solutions for accreditation of clinical nursing services.

Methods
The present study was conducted using Delphi method with two rounds. At the beginning of the study a questionnaire was prepared using results of another project (clinical nursing services audit). This questionnaire was sent to 47 nursing and accreditation professionals. After the first round, causes and solutions were categorized. Then participants were asked to comment on the significance of each strategy on the prepared questionnaire.

Results
In the first round of Delphi in response to the question about the main causes and solutions of low quality of nursing clinical services, 394 causes and 212 solutions were mentioned by the participants. In the second round, considering moralists and specialization in the selection of nursing managers, staffing according to workload and attendance in comprehensive exam after graduation and before entering clinical fields attained the most importance.

Conclusion
Mismatch of human resources with workload and lack of clarity with regard to duties have maximum correlation with poor quality of care. Organizational structure and communication program categories gained the highest and lowest importance respectively. This information could be used by nursing managers and policy makers to plan programs in order to improve the quality of clinical nursing services.
scRNA-seq assessment of the human lung, spleen, and esophagus tissue stability after cold preservation
Authors: Madissoon E. , Wilbrey-Clark A. , Miragaia R. J. , Saeb-Parsy K. , Mahbubani K. T. , Georgakopoulos N. , Harding P. , Polanski K. , Huang N. , Nowicki-Osuch K. , Fitzgerald R. C. , Loudon K. W. , Ferdinand J. R. , Clatworthy M. R. , Tsingene A. , van Dongen S. , Dabrowska M. , Patel M. , Stubbington M. J. T. , Teichmann S. A. , Stegle O. , Meyer K. B. 
Published: December 2019

Abstract
Background
The Human Cell Atlas is a large international collaborative effort to map all cell types of the human body. Single-cell RNA sequencing can generate high-quality data for the delivery of such an atlas. However, delays between fresh sample collection and processing may lead to poor data and difficulties in experimental design.

Results
This study assesses the effect of cold storage on fresh healthy spleen, esophagus, and lung from ≥ 5 donors over 72 h. We collect 240,000 high-quality single-cell transcriptomes with detailed cell type annotations and whole genome sequences of donors, enabling future eQTL studies. Our data provide a valuable resource for the study of these 3 organs and will allow cross-organ comparison of cell types.
We see little effect of cold ischemic time on cell yield, total number of reads per cell, and other quality control metrics in any of the tissues within the first 24 h. However, we observe a decrease in the proportions of lung T cells at 72 h, higher percentage of mitochondrial reads, and increased contamination by background ambient RNA reads in the 72-h samples in the spleen, which is cell type specific.

Conclusions
In conclusion, we present robust protocols for tissue preservation for up to 24 h prior to scRNA-seq analysis. This greatly facilitates the logistics of sample collection for Human Cell Atlas or clinical studies since it increases the time frames for sample processing.
Distinct epigenetic features of tumor-reactive CD8+ T cells in colorectal cancer patients revealed by genome-wide DNA methylation analysis
Authors: Yang Rui , Cheng Sijin , Luo Nan , Gao Ranran , Yu Kezhuo , Kang Boxi , Wang Li , Zhang Qiming , Fang Qiao , Zhang Lei , Li Chen , He Aibin , Hu Xueda , Peng Jirun , Ren Xianwen , Zhang Zemin 
Published: December 2019

Abstract
Background
Tumor-reactive CD8+ tumor-infiltrating lymphocytes (TILs) represent a subtype of T cells that can recognize and destroy tumor specifically. Understanding the regulatory mechanism of tumor-reactive CD8+ T cells has important therapeutic implications. Yet the DNA methylation status of this T cell subtype has not been elucidated.

Results
In this study, we segregate tumor-reactive and bystander CD8+ TILs, as well as naïve and effector memory CD8+ T cell subtypes as controls from colorectal cancer patients, to compare their transcriptome and methylome characteristics. Transcriptome profiling confirms previous conclusions that tumor-reactive TILs have an exhausted tissue-resident memory signature. Whole-genome methylation profiling identifies a distinct methylome pattern of tumor-reactive CD8+ T cells, with tumor-reactive markers CD39 and CD103 being specifically demethylated. In addition, dynamic changes are observed during the transition of naïve T cells into tumor-reactive CD8+ T cells. Transcription factor binding motif enrichment analysis identifies several immune-related transcription factors, including three exhaustion-related genes (NR4A1, BATF, and EGR2) and VDR, which potentially play an important regulatory role in tumor-reactive CD8+ T cells.

Conclusion
Our study supports the involvement of DNA methylation in shaping tumor-reactive and bystander CD8+ TILs, and provides a valuable resource for the development of novel DNA methylation markers and future therapeutics.
Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework
Authors:   On behalf of the Clinical Genome Resource Sequence Variant Interpretation Working Group, Brnich Sarah E. , Abou Tayoun Ahmad N. , Couch Fergus J. , Cutting Garry R. , Greenblatt Marc S. , Heinen Christopher D. , Kanavy Dona M. , Luo Xi , McNulty Shannon M. , Starita Lea M. , Tavtigian Sean V. , Wright Matt W. , Harrison Steven M. , Biesecker Leslie G. , Berg Jonathan S. 
Published: December 2019

Abstract
Background
The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria for different types of evidence. This includes the strong evidence codes PS3 and BS3 for “well-established” functional assays demonstrating a variant has abnormal or normal gene/protein function, respectively. However, they did not provide detailed guidance on how functional evidence should be evaluated, and differences in the application of the PS3/BS3 codes are a contributor to variant interpretation discordance between laboratories. This recommendation seeks to provide a more structured approach to the assessment of functional assays for variant interpretation and guidance on the use of various levels of strength based on assay validation.

Methods
The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation (SVI) Working Group used curated functional evidence from ClinGen Variant Curation Expert Panel-developed rule specifications and expert opinions to refine the PS3/BS3 criteria over multiple in-person and virtual meetings. We estimated the odds of pathogenicity for assays using various numbers of variant controls to determine the minimum controls required to reach moderate level evidence. Feedback from the ClinGen Steering Committee and outside experts were incorporated into the recommendations at multiple stages of development.

Results
The SVI Working Group developed recommendations for evaluators regarding the assessment of the clinical validity of functional data and a four-step provisional framework to determine the appropriate strength of evidence that can be applied in clinical variant interpretation. These steps are as follows: (1) define the disease mechanism, (2) evaluate the applicability of general classes of assays used in the field, (3) evaluate the validity of specific instances of assays, and (4) apply evidence to individual variant interpretation. We found that a minimum of 11 total pathogenic and benign variant controls are required to reach moderate-level evidence in the absence of rigorous statistical analysis.

Conclusions
The recommendations and approach to functional evidence evaluation described here should help clarify the clinical variant interpretation process for functional assays. Further, we hope that these recommendations will help develop productive partnerships with basic scientists who have developed functional assays that are useful for interrogating the function of a variety of genes.
Exome sequencing reveals a high prevalence of BRCA1 and BRCA2 founder variants in a diverse population-based biobank
Authors:   CBIPM Genomics Team, Abul-Husn Noura S. ,   Regeneron Genetics Center, Soper Emily R. , Odgis Jacqueline A. , Cullina Sinead , Bobo Dean , Moscati Arden , Rodriguez Jessica E. , Loos Ruth J. F. , Cho Judy H. , Belbin Gillian M. , Suckiel Sabrina A. , Kenny Eimear E. 
Published: December 2019

Abstract
Background
Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little is known about prevalence in non-European populations. We investigated BRCA1/2 prevalence and impact in the electronic health record (EHR)-linked BioMe Biobank in New York City.

Methods
Exome sequence data from 30,223 adult BioMe participants were evaluated for pathogenic variants in BRCA1/2. Prevalence estimates were made in population groups defined by genetic ancestry and self-report. EHR data were used to evaluate clinical characteristics of variant-positive individuals.

Results
There were 218 (0.7%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. The highest prevalence was in individuals with Ashkenazi Jewish (AJ; 1 in 49), Filipino and other Southeast Asian (1 in 81), and non-AJ European (1 in 103) ancestry. Among 218 variant-positive individuals, 112 (51.4%) harbored known founder variants: 80 had AJ founder variants (BRCA1 c.5266dupC and c.68_69delAG, and BRCA2 c.5946delT), 8 had a Puerto Rican founder variant (BRCA2 c.3922G>T), and 24 had one of 19 other founder variants. Non-European populations were more likely to harbor BRCA1/2 variants that were not classified in ClinVar or that had uncertain or conflicting evidence for pathogenicity (uncertain/conflicting). Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion of African genetic ancestry and the likelihood of harboring an uncertain/conflicting variant. Approximately 28% of variant-positive individuals had a personal history, and 45% had a personal or family history of BRCA1/2-associated cancers. Approximately 27% of variant-positive individuals had prior clinical genetic testing for BRCA1/2. However, individuals with AJ founder variants were twice as likely to have had a clinical test (39%) than those with other pathogenic variants (20%).

Conclusions
These findings deepen our knowledge about BRCA1/2 variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.
An epigenome-wide association study of sex-specific chronological ageing
Authors: McCartney Daniel L. , Zhang Futao , Hillary Robert F. , Zhang Qian , Stevenson Anna J. , Walker Rosie M. , Bermingham Mairead L. , Boutin Thibaud , Morris Stewart W. , Campbell Archie , Murray Alison D. , Whalley Heather C. , Porteous David J. , Hayward Caroline , Evans Kathryn L. , Chandra Tamir , Deary Ian J. , McIntosh Andrew M. , Yang Jian , Visscher Peter M. , McRae Allan F. , Marioni Riccardo E. 
Published: December 2019

Abstract
Background
Advanced age is associated with cognitive and physical decline and is a major risk factor for a multitude of disorders. There is also a gap in life expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. Here, we investigate age-by-sex differences in blood-based DNA methylation in an unrelated cohort of 2586 individuals between the ages of 18 and 87 years, with replication in a further 4450 individuals between the ages of 18 and 93 years.

Methods
Linear regression models were applied, with stringent genome-wide significance thresholds (p < 3.6 × 10−8) used in both the discovery and replication data. A second, highly conservative mixed linear model method that better controls the false-positive rate was also applied, using the same genome-wide significance thresholds.

Results
Using the linear regression method, 52 autosomal and 597 X-linked CpG sites, mapping to 251 unique genes, replicated with concordant effect size directions in the age-by-sex interaction analysis. The site with the greatest difference mapped to GAGE10, an X-linked gene. Here, DNA methylation levels remained stable across the male adult age range (DNA methylation by age r = 0.02) but decreased across female adult age range (DNA methylation by age r = − 0.61). One site (cg23722529) with a significant age-by-sex interaction also had a quantitative trait locus (rs17321482) that is a genome-wide significant variant for prostate cancer. The mixed linear model method identified 11 CpG sites associated with the age-by-sex interaction.

Conclusion
The majority of differences in age-associated DNA methylation trajectories between sexes are present on the X chromosome. Several of these differences occur within genes that have been implicated in sexually dimorphic traits.
Digital twins to personalize medicine
Authors:   on behalf of the Swedish Digital Twin Consortium, Björnsson Bergthor , Borrebaeck Carl , Elander Nils , Gasslander Thomas , Gawel Danuta R. , Gustafsson Mika , Jörnsten Rebecka , Lee Eun Jung , Li Xinxiu , Lilja Sandra , Martínez-Enguita David , Matussek Andreas , Sandström Per , Schäfer Samuel , Stenmarker Margaretha , Sun X. F. , Sysoev Oleg , Zhang Huan , Benson Mikael 
Published: December 2019

AbstractPersonalized medicine requires the integration and processing of vast amounts of data. Here, we propose a solution to this challenge that is based on constructing Digital Twins. These are high-resolution models of individual patients that are computationally treated with thousands of drugs to find the drug that is optimal for the patient.