bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting neurological outcome after out-of-hospital cardiac arrest with cumulative information; development and internal validation of an artificial neural network algorithm
Authors: Andersson Peder , Johnsson Jesper , Björnsson Ola , Cronberg Tobias , Hassager Christian , Zetterberg Henrik , Stammet Pascal , Undén Johan , Kjaergaard Jesper , Friberg Hans , Blennow Kaj , Lilja Gisela , Wise Matt P. , Dankiewicz Josef , Nielsen Niklas , Frigyesi Attila 
Published: February 2021

Abstract
Background
Prognostication of neurological outcome in patients who remain comatose after cardiac arrest resuscitation is complex. Clinical variables, as well as biomarkers of brain injury, cardiac injury, and systemic inflammation, all yield some prognostic value. We hypothesised that cumulative information obtained during the first three days of intensive care could produce a reliable model for predicting neurological outcome following out-of-hospital cardiac arrest (OHCA) using artificial neural network (ANN) with and without biomarkers.

Methods
We performed a post hoc analysis of 932 patients from the Target Temperature Management trial. We focused on comatose patients at 24, 48, and 72 h post-cardiac arrest and excluded patients who were awake or deceased at these time points. 80% of the patients were allocated for model development (training set) and 20% for internal validation (test set). To investigate the prognostic potential of different levels of biomarkers (clinically available and research-grade), patients’ background information, and intensive care observation and treatment, we created three models for each time point: (1) clinical variables, (2) adding clinically accessible biomarkers, e.g., neuron-specific enolase (NSE) and (3) adding research-grade biomarkers, e.g., neurofilament light (NFL). Patient outcome was the dichotomised Cerebral Performance Category (CPC) at six months; a good outcome was defined as CPC 1–2 whilst a poor outcome was defined as CPC 3–5. The area under the receiver operating characteristic curve (AUROC) was calculated for all test sets.

Results
AUROC remained below 90% when using only clinical variables throughout the first three days in the ICU. Adding clinically accessible biomarkers such as NSE, AUROC increased from 82 to 94% (p < 0.01). The prognostic accuracy remained excellent from day 1 to day 3 with an AUROC at approximately 95% when adding research-grade biomarkers. The models which included NSE after 72 h and NFL on any of the three days had a low risk of false-positive predictions while retaining a low number of false-negative predictions.

Conclusions
In this exploratory study, ANNs provided good to excellent prognostic accuracy in predicting neurological outcome in comatose patients post OHCA. The models which included NSE after 72 h and NFL on all days showed promising prognostic performance.
Long-term outcome after intensive care for COVID-19: differences between men and women—a nationwide cohort study
Authors: Zettersten Erik , Engerström Lars , Bell Max , Jäderling Gabriella , Mårtensson Johan , Block Linda , Larsson Emma 
Published: February 2021

Abstract
Background
Questions remain about long-term outcome for COVID-19 patients in general, and differences between men and women in particular given the fact that men seem to suffer a more dramatic course of the disease. We therefore analysed outcome beyond 90 days in ICU patients with COVID-19, with special focus on differences between men and women.

Methods
We identified all patient ≥ 18 years with COVID-19 admitted between March 6 and June 30, 2020, in the Swedish Intensive Care Registry. Patients were followed until death or study end-point October 22, 2020. Association with patient sex and mortality, in addition to clinical variables, was estimated using Cox regression. We also performed a logistic regression model estimating factors associated with 90-day mortality.

Results
In total, 2354 patients with COVID-19 were included. Four patients were still in the ICU at study end-point. Median follow-up time was 183 days. Mortality at 90-days was 26.9%, 23.4% in women and 28.2% in men. After 90 days until end of follow-up, only 11 deaths occurred. On multivariable Cox regression analysis, male sex (HR 1.28, 95% CI 1.06–1.54) remained significantly associated with mortality even after adjustments. Additionally, age, COPD/asthma, immune deficiency, malignancy, SAPS3 and admission month were associated with mortality. The logistic regression model of 90-day mortality showed almost identical results.

Conclusions
In this nationwide study of ICU patients with COVID-19, men were at higher risk of poor long-term outcome compared to their female counterparts. The underlying mechanisms for these differences are not fully understood and warrant further studies.
Retrospective evaluation of vector-borne pathogens in cats living in Germany (2012–2020)
Authors: Schäfer Ingo , Kohn Barbara , Volkmann Maria , Müller Elisabeth 
Published: February 2021

Abstract
Background
Blood-feeding arthropods can transmit parasitic, bacterial, or viral pathogens to domestic animals and wildlife. Vector-borne infections are gaining significance because of increasing travel and import of pets from abroad as well as the changing climate in Europe. The main objective of this study was to assess the percentage of cats with positive test results for selected vector-borne pathogens in Germany and explore any possible association of such results with time spent abroad.

Methods
This retrospective study included test results from cats included in the “Feline Travel Profile” established by the LABOKLIN laboratory at the request of veterinarians in Germany between April 2012 and March 2020. This diagnostic panel includes the direct detection of Hepatozoon spp. and Dirofilaria spp. via PCR as well as indirect detection assays (IFAT) for Ehrlichia spp. and Leishmania spp. The panel was expanded to include an IFAT for Rickettsia spp. from July 2015 onwards.

Results
A total of 624 cats were tested using the “Feline Travel Profile.” Serum for indirect detection assays was available for all 624 cats; EDTA samples for direct detection methods were available from 618 cats. Positive test results were as follows: Ehrlichia spp. IFAT 73 out of 624 (12%), Leishmania spp. IFAT 22 out of 624 (4%), Hepatozoon spp. PCR 53 out of 618 (9%), Dirofilaria spp. PCR 1 out of 618 cats (0.2%), and Rickettsia spp. IFAT 52 out of 467 cats (11%) tested from July 2015 onwards. Three cats had positive test results for more than one pathogen before 2015. After testing for Rickettsia spp. was included in 2015, 19 cats had positive test results for more than one pathogen (Rickettsia spp. were involved in 14 out of these 19 cats).

Conclusions
At least one pathogen could be detected in 175 out of 624 cats (28%) via indirect and/or direct detection methods. Four percent had positive test results for more than one pathogen. These data emphasize the importance of considering the above-mentioned vector-borne infections as potential differential diagnoses in clinically symptomatic cats.

Graphical Abstract
Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly
Authors: Macken William L. , Godwin Annie , Wheway Gabrielle , Stals Karen , Nazlamova Liliya , Ellard Sian , Alfares Ahmed , Aloraini Taghrid , AlSubaie Lamia , Alfadhel Majid , Alajaji Sulaiman , Wai Htoo A. , Self Jay , Douglas Andrew G. L. , Kao Alexander P. , Guille Matthew , Baralle Diana 
Published: February 2021

Abstract
Background
Coat protein complex 1 (COPI) is integral in the sorting and retrograde trafficking of proteins and lipids from the Golgi apparatus to the endoplasmic reticulum (ER). In recent years, coat proteins have been implicated in human diseases known collectively as “coatopathies”.

Methods
Whole exome or genome sequencing of two families with a neuro-developmental syndrome, variable microcephaly and cataracts revealed biallelic variants in COPB1, which encodes the beta-subunit of COPI (β-COP). To investigate Family 1’s splice donor site variant, we undertook patient blood RNA studies and CRISPR/Cas9 modelling of this variant in a homologous region of the Xenopus tropicalis genome. To investigate Family 2’s missense variant, we studied cellular phenotypes of human retinal epithelium and embryonic kidney cell lines transfected with a COPB1 expression vector into which we had introduced Family 2’s mutation.

Results
We present a new recessive coatopathy typified by severe developmental delay and cataracts and variable microcephaly. A homozygous splice donor site variant in Family 1 results in two aberrant transcripts, one of which causes skipping of exon 8 in COPB1 pre-mRNA, and a 36 amino acid in-frame deletion, resulting in the loss of a motif at a small interaction interface between β-COP and β’-COP. Xenopus tropicalis animals with a homologous mutation, introduced by CRISPR/Cas9 genome editing, recapitulate features of the human syndrome including microcephaly and cataracts. In vitro modelling of the COPB1 c.1651T>G p.Phe551Val variant in Family 2 identifies defective Golgi to ER recycling of this mutant β-COP, with the mutant protein being retarded in the Golgi.

Conclusions
This adds to the growing body of evidence that COPI subunits are essential in brain development and human health and underlines the utility of exome and genome sequencing coupled with Xenopus tropicalis CRISPR/Cas modelling for the identification and characterisation of novel rare disease genes.
Clinical-grade whole-genome sequencing and 3′ transcriptome analysis of colorectal cancer patients
Authors: Stodolna Agata , He Miao , Vasipalli Mahesh , Kingsbury Zoya , Becq Jennifer , Stockton Joanne D. , Dilworth Mark P. , James Jonathan , Sillo Toju , Blakeway Daniel , Ward Stephen T. , Ismail Tariq , Ross Mark T. , Beggs Andrew D. 
Published: February 2021

Abstract
Background
Clinical-grade whole-genome sequencing (cWGS) has the potential to become the standard of care within the clinic because of its breadth of coverage and lack of bias towards certain regions of the genome. Colorectal cancer presents a difficult treatment paradigm, with over 40% of patients presenting at diagnosis with metastatic disease. We hypothesised that cWGS coupled with 3′ transcriptome analysis would give new insights into colorectal cancer.

Methods
Patients underwent PCR-free whole-genome sequencing and alignment and variant calling using a standardised pipeline to output SNVs, indels, SVs and CNAs. Additional insights into the mutational signatures and tumour biology were gained by the use of 3′ RNA-seq.

Results
Fifty-four patients were studied in total. Driver analysis identified the Wnt pathway gene APC as the only consistently mutated driver in colorectal cancer. Alterations in the PI3K/mTOR pathways were seen as previously observed in CRC. Multiple private CNAs, SVs and gene fusions were unique to individual tumours. Approximately 30% of patients had a tumour mutational burden of > 10 mutations/Mb of DNA, suggesting suitability for immunotherapy.

Conclusions
Clinical whole-genome sequencing offers a potential avenue for the identification of private genomic variation that may confer sensitivity to targeted agents and offer patients new options for targeted therapies.
DNA methylation and cancer incidence: lymphatic–hematopoietic versus solid cancers in the Strong Heart Study
Authors: Domingo-Relloso Arce , Huan Tianxiao , Haack Karin , Riffo-Campos Angela L. , Levy Daniel , Fallin M. Daniele , Terry Mary Beth , Zhang Ying , Rhoades Dorothy A. , Herreros-Martinez Miguel , Garcia-Esquinas Esther , Cole Shelley A. , Tellez-Plaza Maria , Navas-Acien Ana 
Published: February 2021

AbstractBackgroundEpigenetic alterations may contribute to early detection of cancer. We evaluated the association of blood DNA methylation with lymphatic–hematopoietic cancers and, for comparison, with solid cancers. We also evaluated the predictive ability of DNA methylation for lymphatic–hematopoietic cancers.MethodsBlood DNA methylation was measured using the Illumina Infinium methylationEPIC array in 2324 Strong Heart Study participants (41.4% men, mean age 56 years). 788,368 CpG sites were available for differential DNA methylation analysis for lymphatic–hematopoietic, solid and overall cancers using elastic-net and Cox regression models. We conducted replication in an independent population: the Framingham Heart Study. We also analyzed differential variability and conducted bioinformatic analyses to assess for potential biological mechanisms.ResultsOver a follow-up of up to 28 years (mean 15), we identified 41 lymphatic–hematopoietic and 394 solid cancer cases. A total of 126 CpGs for lymphatic–hematopoietic cancers, 396 for solid cancers, and 414 for overall cancers were selected as predictors by the elastic-net model. For lymphatic–hematopoietic cancers, the predictive ability (C index) increased from 0.58 to 0.87 when adding these 126 CpGs to the risk factor model in the discovery set. The association was replicated with hazard ratios in the same direction in 28 CpGs in the Framingham Heart Study. When considering the association of variability, rather than mean differences, we found 432 differentially variable regions for lymphatic–hematopoietic cancers.ConclusionsThis study suggests that differential methylation and differential variability in blood DNA methylation are associated with lymphatic–hematopoietic cancer risk. DNA methylation data may contribute to early detection of lymphatic–hematopoietic cancers.
Osteoclastic effects of mBMMSCs under compressive pressure during orthodontic tooth movement
Authors: Wang Jing , Jiao Delong , Huang Xiaofeng , Bai Yuxing 
Published: February 2021

Abstract
Background
During orthodontic tooth movement (OTM), alveolar bone remodelling is closely related to mechanical force. It is unclear whether stem cells can affect osteoclastogenesis to promote OTM. This study aimed to investigate the role of mouse bone marrow mesenchymal stem cells (mBMMSCs) under compression load in OTM.

Methods
A mouse OTM model was established, and GFP-labelled mBMMSCs and normal saline were injected into different groups of mice by tail vein injection. OTM distance was measured using tissue specimens and micro-computed tomography (micro-CT). The locations of mBMMSCs were traced using GFP immunohistochemistry. Haematoxylin-eosin staining, tartrate-resistant acid phosphate (TRAP) staining and immunohistochemistry of Runx2 and lipoprotein lipase were used to assess changes in the periodontal ligament during OTM. mBMMSCs under compression were co-cultured with mouse bone marrow-derived macrophages (mBMMs), and the gene expression levels of Rankl, Mmp-9, TRAP, Ctsk, Alp, Runx2, Ocn and Osterix were determined by RT-PCR.

Results
Ten days after mBMMSCs were injected into the tail vein of mice, the OTM distance increased from 176 (normal saline) to 298.4 μm, as determined by tissue specimen observation, and 174.2 to 302.6 μm, as determined by micro-CT metrological analysis. GFP-labelled mBMMSCs were mostly located on the compressed side of the periodontal ligament. Compared to the saline group, the number of osteoclasts in the alveolar bone increased significantly (P < 0.01) on the compressed side in the mBMMSC group. Three days after mBMMSC injection, the number of Runx2-GFP double-positive cells on the tension side was significantly higher than that on the compression side. After applying compressive force on the mBMMSCs in vitro for 2 days, RANKL expression was significantly higher than in the non-compression cells, but expression of Alp, Runx2, Ocn and Osterix was significantly decreased (P < 0.05). The numbers of osteoclasts differentiated in response to mBMMs co-cultured with mBMMSCs under pressure load and expression of osteoclast differentiation marker genes (Mmp-9, TRAP and Ctsk) were significantly higher than those in mBMMs stimulated by M-CSF alone (P < 0.05).

Conclusions
mBMMSCs are not only recruited to the compressed side of the periodontal ligament but can also promote osteoclastogenesis by expressing Rankl, improving the efficiency of OTM.
Melatonin promotes bone marrow mesenchymal stem cell osteogenic differentiation and prevents osteoporosis development through modulating circ_0003865 that sponges miR-3653-3p
Authors: Wang Xudong , Chen Taiqiu , Deng Zhihuai , Gao Wenjie , Liang Tongzhou , Qiu Xianjian , Gao Bo , Wu Zizhao , Qiu Jincheng , Zhu Yuanxin , Chen Yanbo , Liang Zhancheng , Zhou Hang , Xu Caixia , Liang Anjing , Su Peiqiang , Peng Yan , Huang Dongsheng 
Published: February 2021

AbstractBackgroundLittle is known about the implications of circRNAs in the effects of melatonin (MEL) on bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation and osteoporosis (OP) progression. The aim of our study was to investigate circRNAs in MEL-regulated BMSC differentiation and OP progression.MethodsBMSC osteogenic differentiation was measured by qRT-PCR, western blot (WB), Alizarin Red, and alkaline phosphatase (ALP) staining. Differential circRNA and mRNA profiles of BMSCs treated by MEL were characterized by deep sequencing, followed by validation using RT-PCR, Sanger sequencing, and qRT-PCR. Silencing and overexpression of circ_0003865 were conducted for functional investigations. The sponged microRNAs and targeted mRNAs were predicted by bioinformatics and validated by qRT-PCR, RNA pull-down, and dual-luciferase reporter assay. The function of miR-3653-3p and circ_0003865/miR-3653-3p/growth arrest-specific gene 1 (GAS1) cascade was validated for the osteogenic differentiation of BMSCs by CCK-8, qRT-PCR, WB, Alizarin Red, and ALP staining. The effects of circ_0003865 on OP development were tested in murine OP model.ResultsMEL promoted osteogenic differentiation of BMSCs. RNA sequencing revealed significant alterations in circRNA and mRNA profiles associated with multiple biological processes and signaling pathways. Circ_0003865 expression in BMSCs was significantly decreased by MEL treatment. Silencing of circ_0003865 had no effect on proliferation while promoted osteogenic differentiation of BMSCs. Overexpression of circ_0003865 abrogated the promotion of BMSC osteogenic differentiation induced by MEL, but proliferation of BMSCs induced by MEL had no change whether circ_0003865 was overexpression or not. Furthermore, circ_0003865 sponged miR-3653-3p to promote GAS1 expression in BMSCs. BMSC osteogenic differentiation was enhanced by miR-3653-3p overexpression while BMSC proliferation was not affected. By contrast, miR-3653-3p silencing mitigated the promoted BMSC osteogenic differentiation caused by circ_0003865 silencing, but had no effect on proliferation. Finally, circ_0003865 silencing repressed OP development in mouse model.ConclusionMEL promotes BMSC osteogenic differentiation and inhibits OP pathogenesis by suppressing the expression of circ_0003865, which regulates GAS1 gene expression via sponging miR-3653-3p.
Robust expansion and functional maturation of human hepatoblasts by chemical strategy
Authors: Pan Tingcai , Tao Jiawang , Chen Yan , Zhang Jiaye , Getachew Anteneh , Zhuang Yuanqi , Wang Ning , Xu Yingying , Tan Shenglin , Fang Ji , Yang Fan , Lin Xianhua , You Kai , Gao Yi , Li Yin-xiong 
Published: February 2021

Abstract
Background
Chemically strategies to generate hepatic cells from human pluripotent stem cells (hPSCs) for the potential clinical application have been improved. However, producing high quality and large quantities of hepatic cells remain challenging, especially in terms of step-wise efficacy and cost-effective production requires more improvements.

Methods
Here, we systematically evaluated chemical compounds for hepatoblast (HB) expansion and maturation to establish a robust, cost-effective, and reproducible methodology for self-renewal HBs and functional hepatocyte-like cell (HLC) production.

Results
The established chemical cocktail could enable HBs to proliferate nearly 3000 folds within 3 weeks with preserved bipotency. Moreover, those expanded HBs could be further efficiently differentiated into homogenous HLCs which displayed typical morphologic features and functionality as mature hepatocytes including hepatocyte identity marker expression and key functional activities such as cytochrome P450 metabolism activities and urea secretion. Importantly, the transplanted HBs in the injured liver of immune-defect mice differentiated as hepatocytes, engraft, and repopulate in the injured loci of the recipient liver.

Conclusion
Together, this chemical compound-based HLC generation method presents an efficient and cost-effective platform for the large-scale production of functional human hepatic cells for cell-based therapy and drug discovery application.
A population-based study of health-promoting behaviors and their predictors in Iranian males, 2019
Authors: Sanaati Fovziye , Geranmayeh Mehrnaz , Behboodi Moghadam Zahra , Zareiyan Armin , Samadaee Gelehkolaee Keshvar , Mirghafourvand Mojgan 
Published: February 2021

Abstract
Background
Health-promoting lifestyle (HPL) is any measure taken to maintain a person’s health. The most important and influential factor in maintaining and enhancing health are health-promoting behaviors (HPB). This study aimed to determine HPB and their predictors among Iranian men.

Methods
In this cross-sectional study, 783 Iranian men, living in Tehran, were selected, using multistage cluster sampling. The employed questionnaires, namely the sociodemographic questionnaire, Health-Promoting Lifestyle Profile II (HPLP-II), and the second part of the Personal Resource Questionnaire (PRQ 85-Part 2), were completed through interviews. The relationship between the dependent variables (HPLP-II and its subdomains) and independent variables (sociodemographic characteristics and social support) was investigated using the adjusted General Linear Model (GLM).

Results
The mean ± standard deviation of the total HPLP-II score was 2.72 ± 0.44 in the range of 1–4. Among the six dimensions of the HPB, the participants achieved the highest score (3.00 ± 0.52) and lowest score (1.96 ± 0.56) in spiritual growth and physical activity, respectively. The Pearson test showed that the perceived social support was significantly correlated with HPLP-II (r = 0.23; p < 0.001) and all of its subdomains (r = 0.09–0.24; p < 0.001). Based on the adjusted general linear model, social support, age, job, and income adequacy were the predictors of HPL in men and could explain 30.9% of the variance of the HPL score.

Conclusions
The research findings confirmed the importance of social support and modifying variables (social and personal) in the incidence of HPB in men.