bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of a clinical decision support system for rare diseases: a qualitative study
Authors: Schaaf Jannik , Sedlmayr Martin , Sedlmayr Brita , Prokosch Hans-Ulrich , Storf Holger 
Published: February 2021

Abstract
Background
Rare Diseases (RDs) are difficult to diagnose. Clinical Decision Support Systems (CDSS) could support the diagnosis for RDs. The Medical Informatics in Research and Medicine (MIRACUM) consortium developed a CDSS for RDs based on distributed clinical data from eight German university hospitals. To support the diagnosis for difficult patient cases, the CDSS uses data from the different hospitals to perform a patient similarity analysis to obtain an indication of a diagnosis. To optimize our CDSS, we conducted a qualitative study to investigate usability and functionality of our designed CDSS.

Methods
We performed a Thinking Aloud Test (TA-Test) with RDs experts working in Rare Diseases Centers (RDCs) at MIRACUM locations which are specialized in diagnosis and treatment of RDs. An instruction sheet with tasks was prepared that the participants should perform with the CDSS during the study. The TA-Test was recorded on audio and video, whereas the resulting transcripts were analysed with a qualitative content analysis, as a ruled-guided fixed procedure to analyse text-based data. Furthermore, a questionnaire was handed out at the end of the study including the System Usability Scale (SUS).

Results
A total of eight experts from eight MIRACUM locations with an established RDC were included in the study. Results indicate that more detailed information about patients, such as descriptive attributes or findings, can help the system perform better. The system was rated positively in terms of functionality, such as functions that enable the user to obtain an overview of similar patients or medical history of a patient. However, there is a lack of transparency in the results of the CDSS patient similarity analysis. The study participants often stated that the system should present the user with an overview of exact symptoms, diagnosis, and other characteristics that define two patients as similar. In the usability section, the CDSS received a score of 73.21 points, which is ranked as good usability.

Conclusions
This qualitative study investigated the usability and functionality of a CDSS of RDs. Despite positive feedback about functionality of system, the CDSS still requires some revisions and improvement in transparency of the patient similarity analysis.
Extensive antimicrobial resistance and plasmid-carrying resistance genes in mcr-1-positive E. coli sampled in swine, in Guangxi, South China
Authors: Yuan Jingzhi , Wang Xiaoye , Shi Dali , Ge Qiang , Song Xingxing , Hu Wen , Wei Deyuan , Ge Chenling , Li Xun , Hu Chuanhuo 
Published: February 2021

Abstract
Background
The discovery of the superbug mcr-1-positive Escherichia coli (MCRPEC) has drew greet attention. Swine-origin multi-drug resistant MCRPEC has been a potential threat to public health and safety. However, there were few detailed studies have been reported on swine MCRPEC in Guangxi, South China.

Results
In this study, thirty-three MCRPEC strains were detected from 142 E. coli strains from 116 samples in Guangxi in 2018. Which could be classified into eight unique STs and a total of six incompatibility plasmid groups (IncFI, IncHI1, IncY, IncN, IncI1 and IncX1). After that, the susceptibility of MCRPEC isolates to 27 antimicrobial agents belonging to 17 antimicrobial categories was tested. There were nineteen E. coli resistant to 3rd and 4th generation cephalosporins and twelve E. coli resistant to carbapenem resistan. Importantly, the MCRPEC showed high resistance highly resistance for imipenem and meropenem, which were forbidden to use in livestock production. Three MCRPEC strains were further proved to be extensively drug-resistant (XDR), and the other isolates were multi-drug-resistant (MDR). Furthermore, we found that the plasmid-carrying resistance genes coexisted with the mcr-1 gene of the MCRPEC isolates. Which were listed as follows: β-lactamase antimicrobial resistance genes e.g. ESBL genes (blaCTX-M14, blaCTX-M24, blaCTX-M123, blaOXA-1), plasmid-mediated AmpC (pAmpC) gene (blaCMY-2), the carbapenem resistance gene (blaNDM-5), and non-β-lactamase antimicrobial resistance genes (qnrA, qnrB, qnrS, aac (6′)-Ib-cr, tetA, tetB, sul1, sul2, floR, aadA).

Conclusion
Thirty-three mcr-1-positive E. coli isolates in Guangxi displayed a wide profile of antimicrobial resistance. Plasmid-carrying resistance genes might be the main cause of MCRPEC multidrug resistance. This study highlighted the necessity for long-term surveillance of mcr-1-positive E. coli in pigs.
Identification of biomarkers and pathogenesis in severe asthma by coexpression network analysis
Authors: Zhang Zeyi , Wang Jingjing , Chen Ou 
Published: February 2021

Abstract
Background
Severe asthma is a heterogeneous inflammatory disease. The increase in precise immunotherapy for severe asthmatics requires a greater understanding of molecular mechanisms and biomarkers. In this study, we aimed to identify the underlying mechanisms and hub genes that determine asthma severity.

Methods
Differentially expressed genes (DEGs) were identified based on bronchial epithelial brushings from mild and severe asthmatics. Then, weighted gene coexpression network analysis (WGCNA) was used to identify gene networks and the module most significantly associated with asthma severity. Furthermore, hub gene screening and functional enrichment analysis were performed. Replication with another dataset was conducted to validate the hub genes.

Results
DEGs from 14 mild and 11 severe asthmatics were subjected to WGCNA. Six modules associated with asthma severity were identified. Three modules were positively correlated (P < 0.001) with asthma severity and contained genes that were upregulated in severe asthmatics. Functional enrichment analysis showed that genes in the most significant module were mainly enriched in neutrophil activation and degranulation, and cytokine receptor interaction. Hub genes included CXCR1, CXCR2, CCR1, CCR7, TLR2, FPR1, FCGR3B, FCGR2A, ITGAM, and PLEK; CXCR1, CXCR2, and TLR2 were significantly related to asthma severity in the validation dataset. The combination of ten hub genes exhibited a moderate ability to distinguish between severe and mild-moderate asthmatics.

Conclusion
Our results identified biomarkers and characterized potential pathogenesis of severe asthma, providing insight into treatment targets and prognostic markers.
Telomere length dynamics over 10-years and related outcomes in patients with COPD
Authors: Córdoba-Lanús E. , Cazorla-Rivero S. , García-Bello M. A. , Mayato D. , Gonzalvo F. , Ayra-Plasencia J. , Celli B. , Casanova C. 
Published: February 2021

Abstract
Background
Chronic obstructive pulmonary disease (COPD) has been proposed as a disease of accelerated aging. Several cross-sectional studies have related a shorter telomere length (TL), a marker of biological aging, with COPD outcomes. Whether accelerated telomere shortening over time relates to worse outcomes in COPD patients, is not known.

Methods
Relative telomere length (T/S) was determined by qPCR in DNA samples from peripheral blood in 263 patients at baseline and up to 10 years post enrolment. Yearly clinical and lung function data of 134 patients with at least two-time measures of T/S over this time were included in the analysis.

Results
At baseline, T/S inversely correlated with age (r = − 0.236; p < 0.001), but there was no relationship between T/S and clinical and lung function variables (p > 0.05). Over 10 years of observation, there was a median shortening of TL of 183 bp/year for COPD patients. After adjusting for age, gender, active smoking and mean T/S, patients that shortened their telomeres the most over time, had worse gas exchange, more lung hyperinflation and extrapulmonary affection during the follow-up, (PaO2 p < 0.0001; KCO p = 0.042; IC/TLC p < 0.0001; 6MWD p = 0.004 and BODE index p = 0.009). Patients in the lowest tertile of T/S through the follow-up period had an increased risk of death [HR = 5.48, (1.23–24.42) p = 0.026].

Conclusions
This prospective study shows an association between accelerated telomere shortening and progressive worsening of pulmonary gas exchange, lung hyperinflation and extrapulmonary affection in COPD patients. Moreover, persistently shorter telomeres over this observation time increase the risk for all-cause mortality.
Asthma-related inflammation promotes lung metastasis of breast cancer cells through CCL11–CCR3 pathway
Authors: Bekaert S. , Rocks N. , Vanwinge C. , Noel A. , Cataldo D. 
Published: February 2021

Abstract
Background
Mechanisms that preclude lung metastasis are still barely understood. The possible consequences of allergic airways inflammation on cancer dissemination were studied in a mouse model of breast cancer.

Methods
Balb/c mice were immunized and daily exposed to ovalbumin (OVA) from day 21. They were subcutaneously injected with 4T1 mammary tumor cells on day 45 and sacrificed on day 67. Lung metastases were measured by biophotonic imaging (IVIS® 200 Imaging System) and histological measurement of tumor area (Cytomine software). Effects of CCL11 were assessed in vivo by intratracheal instillations of recCCL11 and in vitro using Boyden chambers. CCR3 expression on cell surface was assessed by flow cytometry.

Results
The extent of tumor metastases was significantly higher in lungs of OVA-exposed mice and increased levels of CCL11 expression were measured after OVA exposure. Migration of 4T1 cells and neutrophils was stimulated in vitro and in vivo by recCCL11. 4T1 cells and neutrophils express CCR3 as shown by flow cytometry and a selective CCR3 antagonist (SB-297006) inhibited the induction of 4T1 cells migration and proliferation in response to recCCL11.

Conclusions
Allergic inflammation generated by exposure to allergens triggers the implantation of metastatic cells from primary breast tumor into lung tissues plausibly in a CCL11–CCR3-dependent manner. This indicates that asthma related inflammation in lungs might be a risk factor for lung metastasis in breast cancer patients.
Safety of denervation following targeted lung denervation therapy for COPD: AIRFLOW-1 3-year outcomes
Authors: Pison Christophe , Shah Pallav L. , Slebos Dirk-Jan , Ninane Vincent , Janssens Wim , Perez Thierry , Kessler Romain , Deslee Gaetan , Garner Justin L. , Hartman Jorine E. , Degano Bruno , Mayr Anna , Mayse Martin , Peterson Alexander D. , Valipour Arschang 
Published: February 2021

Abstract
Background
Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung reducing clinical consequences of cholinergic hyperactivity. The AIRFLOW-1 study assessed safety and TLD dose in patients with moderate-to-severe, symptomatic COPD. This analysis evaluated the long-term impact of TLD on COPD exacerbations, pulmonary function, and quality of life over 3 years of follow up.

Methods
TLD was performed in a prospective, energy-level randomized (29 W vs 32 W power), multicenter study (NCT02058459). Additional patients were enrolled in an open label confirmation phase to confirm improved gastrointestinal safety after procedural modifications. Durability of TLD was evaluated at 1, 2, and 3 years post-treatment and assessed through analysis of COPD exacerbations, pulmonary lung function, and quality of life.

Results
Three-year follow-up data were available for 73.9% of patients (n = 34). The annualized rate of moderate to severe COPD exacerbations remained stable over the duration of the study. Lung function (FEV1, FVC, RV, and TLC) and quality of life (SGRQ-C and CAT) remained stable over 3 years of follow-up. No new gastrointestinal adverse events and no unexpected serious adverse events were observed.

Conclusion
TLD in COPD patients demonstrated a positive safety profile out to 3 years, with no late-onset serious adverse events related to denervation therapy. Clinical stability in lung function, quality of life, and exacerbations were observed in TLD treated patients over 3 years of follow up.
The drug war must end: The right to life, liberty and security of the person during the COVID-19 pandemic for people who use drugs
Authors:   VANDU, Maynard Russ ,   WAHRS,   BCAPOM, Jozaghi Ehsan 
Published: February 2021

AbstractSince the start of the opioid epidemic in 2016, the Downtown Eastside community of Vancouver, Canada, has lost many pioneering leaders, activists and visionaries to the war on drugs. The Vancouver Area Network of Drug Users (VANDU), the Western Aboriginal Harm Reduction Society (WAHRS), and the British Columbia Association People on Opiate Maintenance (BCAPOM) are truly concerned about the increasing overdose deaths that have continued since 2016 and have been exacerbated by the novel coronavirus (SARS-COVID-19) despite many unique and timely harm reduction announcements by the British Columbia (B.C.) government. Some of these unique interventions in B.C., although in many cases only mere announcements with limited scope, are based on the philosophy of safe supply to illegal street drugs. Despite all the efforts during the pandemic, overdose deaths have spiked by over 100% compared to the previous year. Therefore, we urge the Canadian federal government, specifically the Honorable Patty Hajdu, the federal Minister of Health, to decriminalize simple possession immediately by granting exemption under the Controlled Drugs and Substances Act. The Canadian federal government has a moral obligation under Sect. 7 of the Canadian Charter of Rights and Freedoms to protect the basic human rights of marginalized Canadians.
Critical roles of sphingosine kinase 1 in the regulation of neuroinflammation and neuronal injury after spinal cord injury
Authors: Wang Chenjian , Xu Tianzhen , Lachance Brittany Bolduc , Zhong Xiqiang , Shen Guangjie , Xu Tao , Tang Chengxuan , Jia Xiaofeng 
Published: February 2021

AbstractBackgroundThe pathological process of traumatic spinal cord injury (SCI) involves excessive activation of microglia leading to the overproduction of proinflammatory cytokines and causing neuronal injury. Sphingosine kinase 1 (Sphk1), a key enzyme responsible for phosphorylating sphingosine into sphingosine-1-phosphate (S1P), plays an important role in mediating inflammation, cell proliferation, survival, and immunity.MethodsWe aim to investigate the mechanism and pathway of the Sphk1-mediated neuroinflammatory response in a rodent model of SCI. Sixty Sprague-Dawley rats were randomly assigned to sham surgery, SCI, or PF543 (a specific Sphk1 inhibitor) groups. Functional outcomes included blinded hindlimb locomotor rating and inclined plane test.ResultsWe discovered that Sphk1 is upregulated in injured spinal cord tissue of rats after SCI and is associated with production of S1P and subsequent NF-κB p65 activation. PF543 attenuated p65 activation, reduced inflammatory response, and relieved neuronal damage, leading to improved functional recovery. Western blot analysis confirmed that expression of S1P receptor 3 (S1PR3) and phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) are activated in microglia of SCI rats and mitigated by PF543. In vitro, we demonstrated that Bay11-7085 suppressed NF-κB p65 and inhibited amplification of the inflammation cascade by S1P, reducing the release of proinflammatory TNF-α. We further confirmed that phosphorylation of p38 MAPK and activation of NF-κB p65 is inhibited by PF543 and CAY10444. p38 MAPK phosphorylation and NF-κB p65 activation were enhanced by exogenous S1P and inhibited by the specific inhibitor SB204580, ultimately indicating that the S1P/S1PR3/p38 MAPK pathway contributes to the NF-κB p65 inflammatory response.ConclusionOur results demonstrate a critical role of Sphk1 in the post-traumatic SCI inflammatory cascade and present the Sphk1/S1P/S1PR3 axis as a potential target for therapeutic intervention to control neuroinflammation, relieve neuronal damage, and improve functional outcomes in SCI.
Accuracy of an MR-only workflow for prostate radiotherapy using semi-automatically burned-in fiducial markers
Authors: Goudschaal Karin , Beeksma F. , Boon M. , Bijveld M. , Visser J. , Hinnen K. , van Kesteren Z. 
Published: February 2021

Abstract
Background
The benefit of MR-only workflow compared to current CT-based workflow for prostate radiotherapy is reduction of systematic errors in the radiotherapy chain by 2–3 mm. Nowadays, MRI is used for target delineation while CT is needed for position verification. In MR-only workflows, MRI based synthetic CT (sCT) replaces CT. Intraprostatic fiducial markers (FMs) are used as a surrogate for the position of the prostate improving targeting. However, FMs are not visible on sCT. Therefore, a semi-automatic method for burning-in FMs on sCT was developed. Accuracy of MR-only workflow using semi-automatically burned-in FMs was assessed and compared to CT/MR workflow.

Methods
Thirty-one prostate cancer patients receiving radiotherapy, underwent an additional MR sequence (mDIXON) to create an sCT for MR-only workflow simulation. Three sources of accuracy in the CT/MR- and MR-only workflow were investigated. To compare image registrations for target delineation, the inter-observer error (IOE) of FM-based CT-to-MR image registrations and soft-tissue-based MR-to-MR image registrations were determined on twenty patients. Secondly, the inter-observer variation of the resulting FM positions was determined on twenty patients. Thirdly, on 26 patients CBCTs were retrospectively registered on sCT with burned-in FMs and compared to CT-CBCT registrations.

Results
Image registration for target delineation shows a three times smaller IOE for MR-only workflow compared to CT/MR workflow. All observers agreed in correctly identifying all FMs for 18 out of 20 patients (90%). The IOE in CC direction of the center of mass (COM) position of the markers was within the CT slice thickness (2.5 mm), the IOE in AP and RL direction were below 1.0 mm and 1.5 mm, respectively. Registrations for IGRT position verification in MR-only workflow compared to CT/MR workflow were equivalent in RL-, CC- and AP-direction, except for a significant difference for random error in rotation.

Conclusions
MR-only workflow using sCT with burned-in FMs is an improvement compared to the current CT/MR workflow, with a three times smaller inter observer error in CT-MR registration and comparable CBCT registration results between CT and sCT reference scans.
Trial registry Medical Research Involving Human Subjects Act (WMO) does apply to this study and was approved by the Medical Ethics review Committee of the Academic Medical Center. Registration number: NL65414.018.18. Date of registration: 21–08-2018.
Correlation between growth differentiation factor 5 (rs143383) gene polymorphism and knee osteoarthritis: an updated systematic review and meta-analysis
Authors: Jia Bin , Jiang Yaping , Xu Yingxing , Wang Yingzhen , Li Tao 
Published: February 2021

AbstractBackgroundA great deal of evidence has supported that growth differentiation factor 5 (GDF5) is associated with the occurrence of knee osteoarthritis (KOA), while their results are not consistent. In the present study, we aimed to explore the association between GDF5 gene polymorphism and KOA for a more credible conclusion.MethodsComprehensive literature searches were carried out in English databases, including PubMed, Embase, Web of Science (WOS), and Cochrane, and Chinese databases, including China National Knowledge Infrastructure (CNKI), WANFANG, and VIP database. After the data were extracted from the required studies, the odds ratios (ORs) and their 95% confidence intervals (CIs) were determined to assess the correlation between GDF5 gene polymorphism and KOA. The publication bias was evaluated by funnel plot.ResultsAccording to the inclusion and exclusion criteria, 15 studies on the correlation between GDF5 gene polymorphism and KOA occurrence were eligible for meta-analysis. Among these articles, four studies showed no apparent correlation, while the other 11 studies indicated an obvious correlation. Meanwhile, we also carried out a subgroup analysis of the population. Due to the inevitable heterogeneity, three genetic models were finally selected for analysis. With the allele model (C versus T: OR = 0.79, 95% CI = 0.73~0.87), recessive model (CC versus CT + TT: OR = 0.76, 95% CI = 0.68~0.86), and homozygous model (CC versus TT: OR = 0.66, 95% CI = 0.58~0.76), GDF5 gene polymorphism decreased the risk of KOA. Besides, a significant association was observed in Caucasians, Asians, and Africans. Meanwhile, the protective effect of genotype C (or CC) in the Asian group was little obvious than that in the Caucasian group and the African group. Although the quality of the included studies was above medium-quality, we obtained results with a low level of evidence.ConclusionsThe results of the meta-analysis showed that the genotype C (or CC) of GDF5 protected against KOA occurrence in Caucasian, Asian, and African populations.
SRPK1/2 and PP1α exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon adenocarcinoma
Authors: Liu Hongda , Gong Zheng , Li Kangshuai , Zhang Qun , Xu Zekuan , Xu Yunfei 
Published: February 2021

Abstract
Background
The Mnk2 kinase, encoded by MKNK2 gene, plays critical roles in MAPK signaling and was involved in oncogenesis. Human MKNK2 pre-mRNA can be alternatively spliced into two splicing isoforms, the MKNK2a and MKNK2b, thus yielding Mnk2a and Mnk2b proteins with different domains. The involvement of Mnk2 alternative splicing in colon cancer has been implicated based on RNA-sequencing data from TCGA database. This study aimed at investigating the upstream modulators and clinical relevance of Mnk2 alternative splicing in colon adenocarcinoma (CAC).

Methods
PCR, western blotting and immunohistochemistry (IHC) were performed to assess the expression of Mnk2 and upstream proteins in CAC. The function of Mnk2 and its regulators were demonstrated in different CAC cell lines as well as in xenograft models. Two independent cohorts of CAC patients were used to reveal the clinical significance of MKNK2 alternative splicing.

Results
Comparing with adjacent nontumorous tissue, CAC specimen showed a decreased MKNK2a level and an increased MKNK2b level, which were correlated with KRAS mutation and tumor size. The SRSF1 (serine/arginine-rich splicing factor 1) was further confirmed to be the major splicing factor targeting MKNK2 in CAC cells. Higher expression of SRPK1/2 or decreased activity of PP1α were responsible for enhancing SRSF1 phosphorylation and nucleus translocation, subsequently resulted in a switch of MKNK2 alternative splicing.

Conclusions
Our data showed that phosphorylation and subcellular localization of SRSF1 were balanced by SRPK1/2 and PP1α in CAC cells. High nucleus SRSF1 promoted MKNK2 splicing into MKNK2b instead of MNK2a, consequently enhanced tumor proliferation.