bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study of variants associated with ventricular septal defects (VSDs) highlights the unique genetic structure of the Pakistani population
Authors: Sarwar Sumbal , Shabana  , Tahir Amna , Liaqat Zainab , Naseer Saher , Seme Rani Summeya , Mehmood Sabahat , Shahid Saleem Ullah , Hasnain Shahida 
Published: July 2022

AbstractBackgroundVentricular septal defects (VSDs) are one of the leading causes of death due to cardiac anomalies during the first months of life. The prevalence of VSD in neonates is reported up to 4%. Despite the remarkable progress in medication, treatment and surgical procedure for VSDs, the genetic etiology of VSDs is still in infancy because of the complex genetic and environmental interactions.MethodsThree hundred fifty subjects (200 VSD children and 150 healthy controls) were recruited from different pediatric cardiac units. Pediatric clinical and demographic data were collected. A total of six variants, rs1017 (ISL1), rs7240256 (NFATc1), rs36208048 (VEGF), variant of HEY2, rs11067075 (TBX5) and rs1801133 (MTHFR) genes were genotyped by tetra-ARMS PCR and PCR–RFLP methods.ResultsThe results showed that in cases, the rs1017 (g.16138A > T) variant in the ISL1 gene has an allele frequency of 0.42 and 0.58 respectively for the T and A alleles, and 0.75 and 0.25 respectively in the controls. The frequencies of the AA, TA and TT genotypes were, 52%, 11% and 37% in cases versus 21%, 8% and 71% respectively in the controls. For the NFATc1 variant rs7240256, minor allele frequency (MAF) was 0.43 in cases while 0.23 in controls. For the variant in the VEGF gene, genotype frequencies were 0% (A), 32% (CA) and 68% (CC) in cases and 0.0%, 33% and 67% respectively in controls. The allele frequency of C and A were 0.84 and 0.16 in cases and 0.83 and 0.17 respectively in controls. The TBX5 polymorphism rs11067075 (g.51682G > T) had an allelic frequency of 0.44 and 0.56 respectively for T and G alleles in cases, versus 0.26 and 0.74 in the controls. We did not detect the presence of the HEY2 gene variant (g.126117350A > C) in our pediatric cohort. For the rs1801133 (g.14783C > T) variant in the MTHFR gene, the genotype frequencies were 25% (CC), 62% (CT) and 13% (TT) in cases, versus 88%, 10% and 2% in controls. The ISL1, NFATc1, TBX5 and MTHFR variants were found to be in association with VSD in the Pakistani pediatric cohort whilst the VEGF and HEY2 variants were completely absent in our cohort.ConclusionWe propose that a wider programme of genetic screening of the Pakistani population for genetic markers in heart development genes would be helpful in reducing the risk of VSDs.
Vitiligo International Task force for an Agreed List of core data (VITAL): study protocol of a vitiligo core outcome set (COS) and contextual factors for clinical trials, registries, and clinical practice
Authors: van Geel Nanja , Hamzavi Iltefat H. , Pandya Amit G. , Wolkerstorfer Albert , Seneschal Julien , Garg Amit , Spuls Phyllis , Terwee Caroline B. , Mallett Sue , Speeckaert Reinhart , Meurant Jean Marie , Eleftheriadou Viktoria , Ezzedine Khaled 
Published: July 2022

Abstract
Background
There is a lack of consensus related to the collection of standardized data for individuals with vitiligo enrolled in clinical trials and registries as well as those seen in clinical practice which causes difficulty in accurately interpreting, comparing, and pooling of data.
Several years ago, efforts to initiate work on developing core outcome sets were performed and a consensus was reached in 2015 on the first core domain set for vitiligo clinical trials.

Methods/design
This project aims to further develop a core outcome set for vitiligo clinical trials as well as create internationally agreed-upon core outcome sets for registries and clinical practice. These core outcome sets will include a core domain set and a core measurement instruments set and will be supplemented by contextual factors, including baseline and treatment-related characteristics. In a preparatory exercise, the 2015 core domain set will be re-evaluated and will serve as the basis for the list of outcome domains used to initiate the consensus process. This project will consist of two parts. Part 1 will focus on the selection of a core domain set, or “what to measure” and contextual factors, for each setting based on electronic surveys (e-Delphi technique) and a conclusive consensus meeting by a large group of international stakeholders. Part 2 will include selection of core measurement instruments, or “how to measure,” and measurement details (e.g., scale and timing) for the core domain sets and contextual factors agreed upon in part 1. Part 2 will be based on consensus meetings with stakeholders involved in part 1 and will be guided by C3 (CHORD-COUSIN Collaboration), Harmonising Outcome Measures for Eczema (HOME), COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN), and Outcome Measures in Rheumatology (OMERACT) recommendations including information on measurement properties of available instruments (systematic review and expert/patient opinion). At the end of part 2, all stakeholders involved will be invited to participate in a final meeting in which the ultimate core data sets (core outcome sets and contextual factors) will be presented and the dissemination plan and implementation goals will be defined.

Discussion
This project will harmonize data collection between clinical trials, registries, and clinical practices, facilitating new insights in vitiligo.

Trial registration
This study is registered in the Core Outcome Measures for Effectiveness Trials (COMET) database and on the C3 (CHORD-COUSIN Collaboration) website.
Autoimmune thyroiditis and celiac disease do not worsen endothelial function in subjects with type 1 diabetes: an observational study
Authors: Parise Martina , Cutruzzolà Antonio , Scavelli Faustina Barbara , Carallo Claudio , Gnasso Agostino , Irace Concetta 
Published: July 2022

Abstract
Background
Type 1 diabetes (T1D) is frequently associated with autoimmune thyroiditis (AT) and coeliac disease (CD). Whether the coexistence of multiple autoimmune diseases increases cardiovascular risk is uncertain. We evaluated the effects of AT and CD on arterial wall thickening and endothelial function in patients with T1D.

Methods
This observational study analyzed data from T1D patients regularly followed by the Diabetes Care Centre. Clinical and biochemical characteristics and micro and macrovascular complications were collected from the electronic medical records. All subjects performed Echo-Doppler to evaluate Intima-Media Thickness (IMT) of the common carotid artery (CCA) and endothelial function by the flow-mediated dilation (FMD) technique. The statistical analyses were performed by SPSS for Macintosh. Comparison between means was performed using the t-test for unpaired data and the Mann–Whitney U test. The ANalysis Of VAriance and the Tukey posthoc test were applied to compare patients with and without other autoimmune diseases, and control subjects. The p-value for statistical significance was set at p < 0.05.

Results
A total of 110 patients were enrolled. Among these, 69 had T1D and 41 T1D and AT and or CD, of whom 33 AT, 7 CD, and 1 both AT and CD. The mean age was 35 years, mean HbA1c was 7.6%, and mean diabetes duration 18 years. The IMT of the CCA was not significantly different between T1D patients with and without concomitant autoimmune diseases (with AT and CD: right CCA 603 ± 186 µ, left 635 ± 175 µ; without AT and CD: right CCA 611 ± 176 µ, left CCA 631 ± 200 µ). FMD was also comparable between T1D groups, with AT and CD 7.9 ± 4.2%; without AT and CD 8.8 ± 4.4%.

Conclusion
Patients with T1D and concomitant AT and or CD show no worse morphological or functional vascular damage, evaluated by CCA IMT and brachial artery flow-mediated dilation, than patients with T1D alone.
Rapid screening for antigenic characterization of GII.17 norovirus strains with variations in capsid gene
Authors: Liao Yingyin , Xue Liang , Gao Junshan , Zuo Yueting , Liang Yanhui , Jiang Yueting , Cai Weicheng , Yang Jiale , Zhang Jumei , Ding Yu , Chen Moutong , Wu Aiwu , Kou Xiaoxia , Wu Qingping 
Published: July 2022

AbstractThe emergence of the novel GII.17 Kawasaki 2014 norovirus variant raising the interest of the public, has replaced GII.4 as the predominant cause of noroviruses outbreaks in East Asia during 2014–2015. Antigenic variation of the capsid protein is considered as one of the key mechanisms of norovirus evolution. In this study, we screened a panel of GII.17 mutants. First, we produced norovirus P proteins using cell-free protein synthesis (CFPS) system, comparing the results to pure proteins expressed in a cell-based system. Next, we determined the binding capability of specific monoclonal antibody (mAb) 2D11 using a unique set of wild-type GII.17 strains. Results of the EIA involving a panel of mutant cell-free proteins indicated that Q298 was the key residue within loop 1. These data highlighted the essential residues in the linear antibody binding characteristics of novel GII.17. Furthermore, it supported the CFPS as a promising tool for rapidly screening mutants via the scalable expression of norovirus P proteins.
Orthostatic intolerance as a potential contributor to prolonged fatigue and inconsistent performance in elite swimmers
Authors: Petracek Lindsay S. , Eastin Ella F. , Rowe Ian R. , Rowe Peter C. 
Published: July 2022

Abstract
Background
Athletic underperformance is characterized by fatigue and an inability to sustain a consistent exercise workload. We describe five elite swimmers with prolonged fatigue and athletic underperformance. Based on our work in myalgic encephalomyelitis /chronic fatigue syndrome, we focused on orthostatic intolerance as a possible contributor to symptoms.

Methods
Participants were referred for evaluation of fatigue and underperformance to the Chronic Fatigue Clinic at the Johns Hopkins Children’s Center. All patients were evaluated for overtraining syndrome, as well as for features commonly seen in myalgic encephalomyelitis/chronic fatigue syndrome. The latter included joint hypermobility, orthostatic intolerance, and non-IgE mediated milk protein intolerance. Orthostatic intolerance was tested by performing a ten-minute passive standing test or a head-up tilt table test.

Results
Orthostatic testing provoked fatigue and other symptoms in all five swimmers, two of whom met heart rate criteria for postural tachycardia syndrome. Treatment was individualized, primarily consisting of an increased intake of sodium chloride and fluids to address orthostasis. All patients experienced a relatively prompt improvement in fatigue and other orthostatic symptoms and were able to either return to their expected level of performance or improve their practice consistency.

Conclusions
Orthostatic intolerance was an easily measured and treatable contributor to athletic underperformance in the five elite swimmers we describe. We suggest that passive standing tests or formal tilt table tests be incorporated into the clinical evaluation of athletes with fatigue and underperformance as well as into scientific studies of this topic. Recognition and treatment of orthostatic intolerance provides a new avenue for improving outcomes in underperforming athletes.
Willingness to be the recipient during the dictator game
Authors: Hashimoto Hirofumi , Maeda Kaede , Yamamoto Keisuke , Mifune Nobuhiro 
Published: July 2022

Abstract
Objective
Researchers have investigated human altruism toward strangers for decades, using economic games such as the dictator game (DG) in their experiments. However, factors that cause the allocating behavior exhibited by those participants willing to be recipients in the DG have not been identified and the psychological mechanism of avoiding decision-making in economic games has not been widely addressed in previous studies. This study aimed to replicate previous findings regarding the number of people who are willing to be assigned the role of recipient and their allocation behavior and to explore why they share more than people who are willing to be dictators.

Results
We demonstrate that there are people willing to be assigned the role of the recipient, rather than the role of the dictator during the dictator game. In addition, we find evidence indicating that people who are willing to be recipients behave more altruistically in the dictator game than those who prefer to be dictators. Based on our results, we argue that willingness to be a recipient, in relation to the psychological unwillingness to assume responsibility and reputational concerns, is a strategic consideration.
Persistent blood DNA methylation changes one year after SARS-CoV-2 infection
Authors: Balnis Joseph , Madrid Andy , Hogan Kirk J. , Drake Lisa A. , Adhikari Anish , Vancavage Rachel , Singer Harold A. , Alisch Reid S. , Jaitovich Ariel 
Published: July 2022

AbstractWe recently reported the COVID-19-induced circulating leukocytes DNA methylation profile. Here, we hypothesized that some of these genes would persist differentially methylated after disease resolution. Fifteen participants previously hospitalized for SARS-CoV-2 infection were epityped one year after discharge. Of the 1505 acute illness-induced differentially methylated regions (DMRs) previously identified, we found 71 regions with persisted differentially methylated, with an average of 7 serial CpG positions per DMR. Sixty-four DMRs persisted hypermethylated, and 7 DMR persisted hypomethylated. These data are the first reported evidence that DNA methylation changes in circulating leukocytes endure long after recovery from acute illness.
Identification of clinical implications and potential prognostic models of chromatin regulator mutations in multiple myeloma
Authors: Zhang Lina , Zhang Run , Wang Jing , Chen Ying , Qiao Chun , Shi Qinglin , Jin Yuanyuan , Shen Xuxing , Li Jianyong , Chen Lijuan 
Published: July 2022

Abstract
Background
With the rapid development of next-generation sequencing (NGS) technologies, researchers are making efforts to reveal the genomic landscape of multiple myeloma (MM). However, the clinical significance of many mutations remains poorly defined due to the genetic heterogeneity of MM. To systematically explore the clinical implications of gene mutations and build practical prognostic models, we performed DNA sequencing in newly diagnosed MM patients.

Methods
MM cells were purified from bone marrow aspirates using CD138 microbeads and subjected to sequencing with a 387-gene Panel. Nomogram was developed using Cox’s proportional hazards model, and candidate variables were screened by stepwise regression. Internal validation was carried out by the bootstrap method.

Results
Between July 2016 and December 2020, a total of 147 patients were included in our study. We found patients with a higher mutational load had a significantly shorter progress-free survival (PFS) (19.0 vs. 32.0 months, P = 0.0098) and overall survival (OS) (3-year OS rates were 66.1% and 80.0%, P = 0.0290). Mutations in chromatin regulators (CRs) including KMT2C (14.3%), KMT2D (14.3%), EP300 (11.6%) and ARID gene family (31.3%) were highly frequent in newly diagnosed MM patients. Interestingly, proteins encoded by these genes could form a complex called KMT2C/D COMPASS (KCDCOMs). Patients with mutations of ARID gene family had a significantly shorter PFS (15.5 vs. 34.0 months, P = 0.0003) and OS (3-year OS rates were 64.9% and 81.0%, P = 0.0351) than patients without ARID gene mutations. Incorporating ARID gene mutations into the current staging system could successfully improve their prognostic performance. The PFS and OS nomogram models (including 1q21 copies, ARID gene mutations, extramedullary disease, mutational load and TP53 mutations) showed good predicting performance in both training and validation sets.

Conclusion
Our findings emphasized the importance of CRs mutations in newly diagnosed MM patients and indicated the mutations affecting KCDCOMs might promote the development of MM. High mutational load and harboring mutations in the ARID gene family were novel predictors of adverse prognosis in MM. Prognostic models based on gene mutations were commendably prognostic evaluation methods that could provide a reference for clinical practices.
Decreased visual acuity is related to thinner cortex in cognitively normal adults: cross-sectional, single-center cohort study
Authors: Han Gyule , Kim Ji Sun , Park Yu Hyun , Kang Sung Hoon , Kim Hang-Rai , Hwangbo Song , Chung Tae-Young , Shin Hee Young , Na Duk L. , Seo Sang Won , Lim Dong Hui , Kim Hee Jin 
Published: July 2022

AbstractBackgroundDecreased visual acuity (VA) is reported to be a risk factor for dementia. However, the association between VA and cortical thickness has not been established. We investigated the association between VA and cortical thickness in cognitively normal adults.MethodWe conducted a cross-sectional, single-center cohort study with cognitively normal adults (aged ≥ 45) who received medical screening examinations at the Health Promotion Center at Samsung Medical Center. Subjects were categorized as bad (VA ≤ 20/40), fair (20/40 < VA ≤ 20/25), and good (VA > 20/25) VA group by using corrected VA in the Snellen system. Using 3D volumetric brain MRI, cortical thickness was calculated using the Euclidean distance between the linked vertices of the inner and outer surfaces. We analyzed the association between VA and cortical thickness after controlling for age, sex, hypertension, diabetes, dyslipidemia, intracranial volume, and education level.ResultsA total of 2756 subjects were analyzed in this study. Compared to the good VA group, the bad VA group showed overall thinner cortex (p= 0.015), especially in the parietal (p= 0.018) and occipital (p= 0.011) lobes. Topographical color maps of vertex-wise analysis also showed that the bad VA group showed a thinner cortex in the parieto-temporo-occipital area. These results were more robust in younger adults (aged 45 to 65) as decreased VA was associated with thinner cortex in more widespread regions in the parieto-temporo-occipital area.ConclusionOur results suggest that a thinner cortex in the visual processing area of the brain is related to decreased visual stimuli.
IFN-γ enhances the efficacy of mesenchymal stromal cell-derived exosomes via miR-21 in myocardial infarction rats
Authors: Zhang Jian , Lu Yao , Mao Yangming , Yu Yue , Wu Tianyu , Zhao Wei , Zhu Yeqian , Zhao Pengcheng , Zhang Fengxiang 
Published: July 2022

Abstract
Background
Mesenchymal stromal cells (MSCs) activated with IFN-γ elicit stronger physical effects. Exosomes (Exos) secreted from MSCs show protective effects against myocardial injury. This study aimed to determine whether Exos derived from IFN-γ-treated MSCs exhibit more potent cardioprotective function and the underlying mechanisms.

Methods
H9c2 cells or human umbilical vein endothelial cells (HUVECs) were treated with Exos isolated from MSCs (Ctrl-Exo) or IFN-γ-primed MSCs (IFN-γ-Exo) under oxygen and glucose deprivation (OGD) conditions in vitro and in vivo in an infarcted rat heart. RNA sequencing was used to identify differentially expressed functional transcription factors (TFs). Quantitative reverse transcription-PCR (qPCR) was used to confirm the upregulated TFs and miRNA in IFN-γ-primed MSCs. Dual-luciferase reporter gene assay was used to analyze the transcriptional regulation of miRNAs by STAT1. The target of miR-21-5p (miR-21) was determined by luciferase reporter assays and qPCR. The function of BTG2 was verified in vitro under OGD conditions.

Result
IFN-γ-Exo accelerated migration and tube-like structure formation and prevented OGD-induced apoptosis in H9c2. Similarly, IFN-γ-Exo treatment caused a decrease in fibrosis, reduced cardiomyocyte apoptosis, and improved cardiac function compared to Ctrl-Exo treatment. MiR-21 was significantly upregulated in IFN-γ-primed MSCs and IFN-γ-Exo. STAT1 transcriptionally induced miR-21 expression. Up-regulated miR-21 could inhibit BTG anti-proliferation factor 2 (BTG2) expressions. BTG2 promoted H9c2 cell apoptosis and reversed the protective effects of miR-21 under OGD conditions.

Conclusion
IFN-γ-Exo showed enhanced therapeutic efficacy against acute MI, possibly by promoting angiogenesis and reducing apoptosis by upregulating miR-21, which directly targeted BTG2.
miR-126-3p-loaded small extracellular vesicles secreted by urine-derived stem cells released from a phototriggered imine crosslink hydrogel could enhance vaginal epithelization after vaginoplasty
Authors: Xu Yiyun , Qiu Yu , Lin Qiuning , Huang Chengsheng , Li Jie , Chen Liqi , Xue Zhuowei , Wu Qingkai , Wang Yang 
Published: July 2022

AbstractBackgroundDue to the large area and deep width of the artificial neovagina after vaginoplasty, it takes a considerable amount of time to achieve complete epithelization of the neovagina. Currently, the clinical therapies for vaginal epithelization after vaginoplasty are still dissatisfactory. Recent studies showed that small extracellular vesicles (sEVs) derived from stem cells could accelerate wound epithelization. The sustained release of sEVs from optimized hydrogels may be a promising strategy to accelerate vaginal epithelization after vaginoplasty.MethodsThe efficacy of phototriggered imine crosslink hydrogels (piGEL) containing sEVs derived from human urine-derived stem cells (hUSC-sEVs, piGEL-sEVs) on vaginal mucosa defects in rabbits was assessed by wound closure rates, histological analysis and immunofluorescence staining analysis. Cell counting kit-8, 5-ethynyl-2′-deoxyuridine and scratch wound assays were performed to assess the effects of hUSC-sEVs on the proliferation and migration ability of vaginal epithelial cells (VK2/E6E7). Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to test the expression of epithelial differentiation markers in VK2 cells. Moreover, a microRNA (miRNA) microarray was used to find hUSC-sEVs-specific miRNAs that potentially affected the proliferation, migration and differentiation ability of VK2 cells.ResultsThe in vitro release profile revealed that the piGEL could ensure sustained release of hUSC-sEVs. The in vivo results showed that piGEL-sEVs effectively promoted epithelization and angiogenesis of vaginal mucosa defects in rabbits. According to miRNA microarray and qRT-PCR results, miR-126-3p might be the crucial molecule among the various miRNAs contained in hUSC-sEVs. The data showed that hUSC-sEVs promoted the migration and differentiation of VK2 cells by delivering miR-126-3p to suppress the expression of Spred1 and PIK3R2, thereby activating the ERK1/2 and ATK signaling pathways.ConclusionThe results indicated that piGEL-sEVs could be a novel promising approach for enhancing the epithelization of the neovagina after vaginoplasty and provided useful data for understanding the underlying mechanism of the effect of hUSC-sEVs on epithelization.