bluuebunny/crossref_metadata_2025_split huggingface dataset:
Basic electronic health record (EHR) adoption in **Türkiye is nearly complete but challenges persist
Authors: Köse İlker , Cece Sinem , Yener Songül , Seyhan Senanur , Özge Elmas Beytiye , Rayner John , Birinci Şuayip , Mahir Ülgü Mustafa , Zehir Esra , Gündoğdu Berrin 
Published: September 2023

Abstract
Background
The digitalization studies in public hospitals in Türkiye started with the Health Transformation Program in 2003. As digitalization was accomplished, the policymakers needed to measure hospitals’ electronic health record (EHR) usage and adoptions. The ministry of health has been measuring the dissemination of meaningful usage and adoption of EHR since 2013 using Electronic Medical Record Adoption Model (EMRAM). The first published study about this analysis covered the surveys applied between 2013 and 2017. The results showed that 63.1% of all hospitals in Türkiye had at least basic EHR functions, and 36% had comprehensive EHR functions. Measuring the countrywide EHR adoption level is becoming popular in the world. This study aims to measure adoption levels of EHR in public hospitals in Türkiye, indicate the change to the previous study, and make a benchmark with other countries measuring national EHR adoption levels. The research question of this study is to reveal whether there has been a change in the adoption level of EHR in the three years since 2018 in Türkiye. Also, make a benchmark with other countries such as the US, Japan, and China in country-wide EHR adoption in 2021.

Methods
In 2021, 717 public hospitals actively operating in Türkiye completed the EMRAM survey. The survey results, deals with five topics (General Stage Status, Information Technology Security, Electronic Health Record/Clinical Data Repository, Clinical Documentation, Closed-Loop Management), was reviewed by the authors. Survey data were compared according to hospital type (Specialty Hospitals, General Hospitals, Teaching and Research Hospitals) in terms of general stage status. The data obtained from the survey results were analyzed with QlikView Personal Edition. The availability and prevalence of medical information systems and EHR functions and their use were measured.

Results
We found that 33.7% of public hospitals in Türkiye have only basic EHR functions, and 66.3% have extensive EHR functions, which yields that all hospitals (100%) have at least basic EHR functions. That means remarkable progress from the previous study covering 2013 and 2017. This level also indicates that Türkiye has slightly better adoption from the US (96%) and much better than China (85.3%) and Korea (58.1%).

Conclusions
Although there has been outstanding (50%) progress since 2017 in Turkish public hospitals, it seems there is still a long way to disseminate comprehensive EHR functions, such as closed-loop medication administration, clinical decision support systems, patient engagement, etc. Measuring the stage of EHR adoption at regular intervals and on analytical scales is an effective management tool for policymakers. The bottom-up adoption approach established for adopting and managing EHR functions in the US has also yielded successful results in Türkiye.
TGFβ1-RCN3-TGFBR1 loop facilitates pulmonary fibrosis by orchestrating fibroblast activation
Authors: Wu Mingting , Wang Zhenyan , Shi Xiaoqian , Zan Danni , Chen Hong , Yang Shuqiao , Ding Fangping , Yang Liu , Tan Pingping , Ma Runlin Z. , Wang Jing , Ma Lishuang , Ma Yingmin , Jin Jiawei 
Published: September 2023

Abstract
Background
Idiopathic pulmonary fibrosis (IPF) bears high mortality due to unclear pathogenesis and limited therapeutic options. Therefore, identifying novel regulators is required to develop alternative therapeutic strategies.

Methods
The lung fibroblasts from IPF patients and Reticulocalbin 3 (RCN3) fibroblast-selective knockdown mouse model were used to determine the importance of Rcn3 in IPF; the epigenetic analysis and protein interaction assays, including BioID, were used for mechanistic studies.

Results
Reticulocalbin 3 (RCN3) upregulation is associated with the fibrotic activation of lung fibroblasts from IPF patients and Rcn3 overexpression blunts the antifibrotic effects of pirfenidone and nintedanib. Moreover, repressing Rcn3 expression in mouse fibroblasts ameliorates bleomycin-induced lung fibrosis and pulmonary dysfunction in vivo. Mechanistically, RCN3 promotes fibroblast activation by maintaining persistent activation of TGFβ1 signalling via the TGFβ1-RCN3-TGFBR1 positive feedback loop, in which RCN3 upregulated by TGFβ1 exposure detains EZH2 (an epigenetic methyltransferase) in the cytoplasm through RCN3-EZH2 interaction, leading to the release of the EZH2-H3K27me3 epigenetic repression of TGFBR1 and the persistent expression of TGFBR1.

Conclusions
These findings introduce a novel regulating mechanism of TGFβ1 signalling in fibroblasts and uncover a critical role of the RCN3-mediated loop in lung fibrosis. RCN3 upregulation may cause resistance to IPF treatment and targeting RCN3 could be a novel approach to ameliorate pulmonary fibrosis.

Graphical Abstract
High prevalence of Mucosa-Associated extended-spectrum β-Lactamase-producing Escherichia coli and Klebsiella pneumoniae among Iranain patients with inflammatory bowel disease (IBD)
Authors: Kharaghani Ayda Afshari , Harzandi Naser , Khorsand Babak , Rajabnia Mohsen , Kharaghani Azin Afshari , Houri Hamidreza 
Published: September 2023

Abstract
Background
Several pieces of evidence suggest that certain pathobionts belonging to Enterobacterales are associated with the development and progression of inflammatory bowel diseases (IBD). Extended-spectrum β-lactamases (ESBLs) ESBLs are frequently found in the Enterobacterales members, particularly in Escherichia coli and Klebsiella spp., and might trigger antibiotic-induced perturbations of the intestinal microbiota and led to more severe disease activity in IBD. Therefore, the severity of IBD could be influenced by ESBL-producing Enterobacterales, and hence, this study aimed to investigate the presence of ESBLs and carbapenemases among mucosa-associated E. coli and Klebsiella pneumoniae isolated from colonic biopsies of Iranian patients with IBD.

Methods
In this cross-sectional study, E. coli and K. pneumoniae were isolated from inflamed ileum and/or colon tissue of patients with IBD, including Ulcerative colitis (UC) and Crohn’s disease (CD), during colonoscopy. Demographic data and clinical characteristics were recorded, and UC and CD disease activity and extent were evaluated according to the full Mayo score and Crohn’s disease activity index (CDAI), respectively. Phenotypic and molecular detection of ESBL- and carbapenemase-producing E. coli and Klebsiella pneumoniae were carried out. Disease activity and other clinical and microbial features were compared in patients with and without gut colonization with ESBL producers.

Results
A total of 83 IBD patients, including 67 UC and 16 CD, were enrolled in the initial analysis. Intestinal colonization with ESBL-producing E. coli and/or Klebsiella pneumoniae was found in 37 (55.2%) of UC and 9 (56.2%) of DC patients – mostly harbored E. coli containing the blaCTX−M and blaTEM genes. UC patients with intestinal colonization with ESBL-producers had more severe disease compared with patients without colonization. Moreover, 10.2% of tested E. coli and 34.8% of K. pneumoniea were recognized as potential carbapenemase producers.

Conclusion
Intestinal colonization with ESBL producers could arise disease activity in IBD patients. Further large-scale case-control studies should be performed to investigate the possible confounding factors that could contribute to this outcome.
Function and mechanism of MCM8 in the development and progression of colorectal cancer
Authors: Yu Shaojun , Dai Weixing , Zhao Senlin , Yang Yongzhi , Xu Ye , Wang Jianwei , Deng Qun , He Jinghu , Shi Debing 
Published: September 2023

AbstractColorectal cancer (CRC) has become a global health problem which has almost highest morbidity and mortality in all types of cancers. This study aimed to uncover the biological functions and underlying mechanism of MCM8 in the development and progression of CRC. The expression level of MCM8 was found to be upregulated in CRC tissues and significantly associated with tumor grade and patients’ survival. Knocking down MCM8 expression in CRC cells could restrain cell growth and cell motility while promoting cell apoptosis in vitro, as well as inhibit tumor growth in xenograft mice model. Based on the RNA screening performing on CRC cells with or without MCM8 knockdown and the following IPA analysis, CHSY1 was identified as a potential target of MCM8 in CRC, whose expression was also found to be higher in tumor tissues than in normal tissues. Moreover, it was demonstrated that MCM8 may regulate the expression of CHSY1 through affecting its NEDD4-mediated ubiquitination, both of which synergistically execute tumor promotion effects on CRC. In conclusion, the outcomes of our study showed the first evidence that MCM8 act as a tumor promotor in CRC, and may be a promising therapeutic target of CRC treatment.
Tenofovir diphosphate in dried blood spots and HIV-1 resistance in South Africa
Authors: Singh Y. , Castillo-Mancilla J. , Madimabe R. , Jennings L. , Ferraris C. M. , Robbins R. N. , Anderson P. L. , Remien R. H. , Orrell C. 
Published: September 2023

Abstract
Background
Suboptimal antiretroviral (ART) adherence can lead to virologic failure with consequent HIV-1 resistance. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a powerful biomarker of cumulative adherence, predictive of future viremia. It has been associated with resistance in Persons With HIV (PWH) in South Africa and the US. We explored the relationship of TFV-DP concentrations with antiretroviral drug resistance at the time of treatment failure in SA.

Methods
Adult PWH from health clinics in Cape Town, South Africa on efavirenz-based first-line ART containing tenofovir disoproxil fumarate (TDF) with an undetectable (< 50 copies/mL) HIV-1 viral load (VL) were prospectively enrolled in an observational cohort for 12 months. Monthly study visits included blood collection for HIV-1 VL and DBS for TFV-DP. The first confirmed viral breakthrough (VB) > 400 copies/mL triggered HIV-1 genotyping at the subsequent visit. An electronic adherence (EA) device monitored ART adherence in real-time, estimated as a percent for the 30-days prior to VB. Wilcoxon rank sum test was used to compare median [IQR] TFV-DP by genotype outcome.

Results
Of 250 individuals, (n = 195, 78% women), 21 experienced VB, with a median of 5 [4;7] months on study, and a median EA of 33.3 [13.3;53.3]%. Demographic characteristics between those with and without VB were similar. Median VL at VB was 4.0 [3.2;4.5] log copies/mL. TFV-DP concentrations trended down towards the VB visit. Median TFV-DP concentrations were significantly higher in those HIV-1 genotype did not amplify due to being virally suppressed at the subsequent visit (n = 10; 380 [227–661] fmol/punch, p = 0.035; EA 45 [24.9; 59.2]%); than in those who were successfully genotyped with evidence of drug resistance (n = 5, 241 [150–247] fmol/punch, EA 20 [6.7;36.7]%) and in individuals who did not have resistance (n = 3, 39.9 [16.6; 93.9] fmol/punch; EA 33.3 [16–38]%). Three genotype collections were not done. Only non-nucleoside reverse transcriptase inhibitor-associated mutations were identified on resistance testing. (K103N, E138K, Y118H).

Conclusion
TFV-DP in DBS showed a step-wise inverse relationship with VB and drug resistance, with evidence of low cumulative ART adherence in PWH who developed antiretroviral resistance. Monitoring TFV-DP concentrations could be a valuable tool for predicting future VB and future resistance.
Bioinformatics and machine learning were used to validate glutamine metabolism-related genes and immunotherapy in osteoporosis patients
Authors: Wang Lei , Deng Chaosheng , Wu Zixuan , Zhu Kaidong , Yang Zhenguo 
Published: September 2023

Abstract
Background
Osteoporosis (OP), often referred to as the “silent disease of the twenty-first century,” poses a significant public health concern due to its severity, chronic nature, and progressive course, predominantly affecting postmenopausal women and elderly individuals. The pathogenesis and progression of this disease have been associated with dysregulation in tumor metabolic pathways. Notably, the metabolic utilization of glutamine has emerged as a critical player in cancer biology. While metabolic reprogramming has been extensively studied in various malignancies and linked to clinical outcomes, its comprehensive investigation within the context of OP remains lacking.

Methods
This study aimed to identify and validate potential glutamine metabolism genes (GlnMgs) associated with OP through comprehensive bioinformatics analysis. The identification of GlnMgs was achieved by integrating the weighted gene co-expression network analysis and a set of 28 candidate GlnMgs. Subsequently, the putative biological functions and pathways associated with GlnMgs were elucidated using gene set variation analysis. The LASSO method was employed to identify key hub genes, and the diagnostic efficacy of five selected GlnMgs in OP detection was assessed. Additionally, the relationship between hub GlnMgs and clinical characteristics was investigated. Finally, the expression levels of the five GlnMgs were validated using independent datasets (GSE2208, GSE7158, GSE56815, and GSE35956).

Results
Five GlnMgs, namely IGKC, TMEM187, RPS11, IGLL3P, and GOLGA8N, were identified in this study. To gain insights into their biological functions, particular emphasis was placed on synaptic transmission GABAergic, inward rectifier potassium channel activity, and the cytoplasmic side of the lysosomal membrane. Furthermore, the diagnostic potential of these five GlnMgs in distinguishing individuals with OP yielded promising results, indicating their efficacy as discriminative markers for OP.

Conclusions
This study discovered five GlnMgs that are linked to OP. They shed light on potential new biomarkers for OP and tracking its progression.
Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases
Authors: Kingma Sandra D.K. , Neven Julie , Bael An , Meuwissen Marije E.C. , van den Akker Machiel 
Published: September 2023

AbstractImerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder characterized by vitamin B12 malabsorption. Most patients present with non-specific symptoms attributed to vitamin B12 deficiency, and proteinuria. Patients may if untreated, develop severe neurocognitive manifestations. If recognized and treated with sufficient doses of vitamin B12, patients recover completely. We provide, for the first time, an overview of all previously reported cases of IGS. In addition, we provide a complete review of IGS and describe two new patients.
Incidence and prevalence of neurofibromatosis type 1 and 2: a systematic review and meta-analysis
Authors: Lee Tin-Suet Joan , Chopra Meera , Kim Raymond H , Parkin Patricia C. , Barnett-Tapia Carolina 
Published: September 2023

Abstract
Objective
To obtain updated estimates of the incidence and prevalence of neurofibromatosis type 1 (NF1) and type 2 (NF2).

Study design
We conducted a systematic search of NF1 and NF2 incidence or prevalence studies, in OVID Medline, OVID Embase, Web of Science, and Cinahl. Studies were appraised with the Joanna Briggs Institute Prevalence Critical Appraisal tool. Pooled incidence and prevalence rates were estimated through random-effects meta-analysis.

Results
From 1,939 abstracts, 20 studies were fully appraised and 12 were included in the final review. Pooled NF1 prevalence was 1 in 3,164 (95%CI: 1 in 2,132-1 in 4,712). This was higher in studies that screened for NF1, compared to identification of NF1 through medical records (1 in 2,020 and 1 in 4,329, respectively). NF1 pooled birth incidence was 1 in 2,662 (95%CI: 1 in 1,968-1 in 3,601). There were only 2 studies on NF2 prevalence, so data were not pooled. Pooled NF2 birth incidence was 1.08 per 50,000 births (95%CI: 1 in 32,829-1 in 65,019).

Conclusion
We present updated estimates of the incidence and prevalence of NF1 and NF2, to help plan for healthcare access and allocation. The prevalence of NF1 from screening studies is higher than from medical record studies, suggesting that the disease may be under recognized. More studies are needed regarding the prevalence of NF2.
Changes in oligodendroglial subpopulations in Parkinson’s disease
Authors: Bae Eun-Jin , Pérez-Acuña Dayana , Rhee Ka Hyun , Lee Seung-Jae 
Published: September 2023

AbstractParkinson’s disease (PD) is characterized by a selective loss of dopaminergic neurons. While most research on PD conducted to date has focused on neurons and, to a certain extent, glia, few studies have investigated changes in oligodendroglia. Here, we investigated the heterogeneity of oligodendrocytes from PD patients compared with those of control cases by analyzing single-nuclei transcriptomes. These analyses revealed the presence of distinct oligodendrocyte populations in PD patients indicative of corresponding variations in molecular features, notably including activation of inflammatory responses, response to protein folding stress, and myelination abnormalities. We confirmed myelination abnormalities in an α-synuclein preformed fibril-injection mouse model of PD. These results suggest that oligodendrocytes acquire disease-associated phenotypes in PD and may contribute to the accompanying neurodegeneration.
Effects of low-intensity exercise on spontaneously developed knee osteoarthritis in male senescence-accelerated mouse prone 8
Authors: Norimatsu Kosuke , Nakanishi Kazuki , Ijuin Toshiro , Otsuka Shotaro , Takada Seiya , Tani Akira , Matsuzaki Ryoma , Matsuoka Teruki , Sakakima Harutoshi 
Published: September 2023

Abstract
Background
Osteoarthritis (OA) is a degenerative joint disease associated with aging, which often leads to joint stiffness and disability. Exercise is one of the most important non-pharmacological treatments and is prescribed as an indispensable treatment for OA. However, whether physical exercise is beneficial for preventing the progression of OA symptoms with age is poorly understood. We investigated the effects of exercise on spontaneously developed knee OA using male senescence-accelerated mouse prone 8 (SAMP8).

Methods
To examine age-related changes in the knee joints of SAMP8, knee articular cartilage changes, synovitis, knee joint flexion and extension angles, swelling, walking ability, and quadriceps muscle atrophy were analyzed at 3, 5, 7, and 9 months. SAMP8 were required to run at a speed of 10 m/min for 15 min/day from 7 to 9 months of age. The knee joint pathologies and symptoms of exercising and non-exercising mice were compared by histological, immunohistochemical, and morphometrical analyses.

Results
The mice presented with various histological changes, including cartilage destruction, osteocyte formation, synovitis, declined joint angles, and swelling. Notably, medial and posterior cartilage destruction was more severe than that of the lateral and anterior cartilage. Knee joint angles were significantly correlated with the histological scores (modified Mankin and OARSI, osteophyte formation and synovial lining cell layer). Exercise did not attenuate cartilage degeneration in the medial and posterior tibial plateau, although the articular cartilage of the anterior and lateral tibial plateau and its histological scores was remained and significantly improved, respectively, by exercise. Exercise suppressed the age-related decline of collagen type II-positive areas in the remaining articular cartilage and improved the OA symptoms. Exercise reduced the expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-α positive macrophages in the synovium.

Conclusion
This study revealed that SAMP8 developed spontaneous knee OA with age, which resembled the disease symptoms in humans. Low-intensity exercise temporarily alleviated degeneration of the remaining cartilage, synovitis, and age-related decreases in knee flexion angle, stride length, and muscle atrophy in SAMP8. However, exercise during OA progression with age may cause mechanical stress that could be both beneficial and detrimental to joint health.
Evaluation of commercial kits for isolation and bisulfite conversion of circulating cell-free tumor DNA from blood
Authors: Kresse Stine H. , Brandt-Winge Sara , Pharo Heidi , Flatin Bjørnar T. B. , Jeanmougin Marine , Vedeld Hege Marie , Lind Guro E. 
Published: September 2023

Abstract
Background
DNA methylation biomarkers in circulating cell-free DNA (cfDNA) have great clinical potential for cancer management. Most methods for DNA methylation analysis require bisulfite conversion, causing DNA degradation and loss. This is particularly challenging for cfDNA, which is naturally fragmented and normally present in low amounts. The aim of the present study was to identify an optimal combination of cfDNA isolation and bisulfite conversion kits for downstream analysis of DNA methylation biomarkers in plasma.

Results
Of the five tested bisulfite conversion kits (EpiJET Bisulfite Conversion Kit, EpiTect Plus DNA Bisulfite Kit (EpiTect), EZ DNA Methylation-Direct Kit, Imprint DNA Modification Kit (Imprint) and Premium Bisulfite Kit), the highest and lowest DNA yield and recovery were achieved using the EpiTect kit and the Imprint kit, respectively, with more than double the amount of DNA for the EpiTect kit. Of the three tested cfDNA isolation kits (Maxwell RSC ccfDNA Plasma Kit, QIAamp Circulating Nucleic Acid Kit (CNA) and QIAamp MinElute ccfDNA Mini Kit), the CNA kit yielded around twice as much cfDNA compared to the two others kits, although with more high molecular weight DNA present. When comparing various combinations of cfDNA isolation kits and bisulfite conversion kits, the CNA kit and the EpiTect kit were identified as the best-performing combination, resulting in the highest yield of bisulfite converted cfDNA from normal plasma, as measured by droplet digital PCR (ddPCR). As a proof of principle, this kit combination was used to process plasma samples from 13 colorectal cancer patients for subsequent ddPCR methylation analysis of BCAT1 and IKZF1. Methylation of BCAT1 and/or IKZF1 was identified in 6/10 (60%) stage IV patients and 1/3 (33%) stage III patients.

Conclusions
Based on a thorough evaluation of five bisulfite conversion kits and three cfDNA isolation kits, both individually and in combination, the CNA kit and the EpiTect kit were identified as the best-performing kit combination, with highest DNA yield and recovery across a range of DNA input amounts. The combination was successfully used for detection of clinically relevant DNA methylation biomarkers in plasma from cancer patients.