bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enrichment of damaging missense variants in genes related with axonal guidance signalling in sporadic Meniere’s disease
Authors: Gallego-Martinez Alvaro , Requena Teresa , Roman-Naranjo Pablo , May Patrick , Lopez-Escamez Jose A 
Published: September 2019

IntroductionMeniere’s disease (MD) is a rare inner ear disorder with a significant genetic contribution defined by a core phenotype: episodic vertigo, sensorineural hearing loss and tinnitus. It has been mostly described in sporadic cases, familial cases being around 10% of the observed individuals. It is associated with an accumulation of endolymph in the inner ear, but the molecular underpinnings remain largely unknown. The main molecular pathways showing higher differentially expressed genes in the supporting cells of the inner ear are related to cochlea-vestibular innervation, cell adhesion and leucocyte extravasation. In this study, our objective is to find a burden of rare variants in genes that interact with the main signalling pathways in supporting cells of the inner ear in patients with sporadic MD.MethodsWe designed a targeted-sequencing panel including genes related with the main molecular pathways in supporting cells and sequenced 860 Spanish patients with sporadic MD. Variants with minor allele frequencies <0.1 in the gene panel were compared with three independent reference datasets. Variants were classified as loss of function, missense and synonymous. Missense variants with a combined annotation-dependent depletion score of >20 were classified as damaging missense variants.ResultsWe have observed a significant burden of damaging missense variants in few key genes, including the NTN4 gene, associated with axon guidance signalling pathways in patients with sporadic MD. We have also identified active subnetworks having an enrichment of rare variants in sporadic MD.ConclusionThe burden of missense variants in the NTN4 gene suggests that axonal guidance signalling could be a novel pathway involved in sporadic MD.
High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers
Authors: González-Acosta Maribel , Marín Fátima , Puliafito Benjamin , Bonifaci Nuria , Fernández Anna , Navarro Matilde , Salvador Hector , Balaguer Francesc , Iglesias Silvia , Velasco Angela , Grau Garces Elia , Moreno Victor , Gonzalez-Granado Luis Ignacio , Guerra-García Pilar , Ayala Rosa , Florkin Benoît , Kratz Christian , Ripperger Tim , Rosenbaum Thorsten , Januszkiewicz-Lewandowska Danuta , Azizi Amedeo A , Ragab Iman , Nathrath Michaela , Pander Hans-Jürgen , Lobitz Stephan , Suerink Manon , Dahan Karin , Imschweiler Thomas , Demirsoy Ugur , Brunet Joan , Lázaro Conxi , Rueda Daniel , Wimmer Katharina , Capellá Gabriel , Pineda Marta 
Published: September 2019

IntroductionLynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues.Materials and methodsBlood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers.ResultsThe hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564).ConclusionsThe hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.
Homozygous damaging SOD2 variant causes lethal neonatal dilated cardiomyopathy
Authors: Almomani Rowida , Herkert Johanna C , Posafalvi Anna , Post Jan G , Boven Ludolf G , van der Zwaag Paul A , Willems Peter H G M , van Veen-Hof Ingrid H , Verhagen Judith M A , Wessels Marja W , Nikkels Peter G J , Wintjes Liesbeth T , van den Berg Maarten P , Sinke Richard J , Rodenburg Richard J , Niezen-Koning Klary E , van Tintelen J Peter , Jongbloed Jan D H 
Published: September 2019

BackgroundIdiopathic dilated cardiomyopathy (DCM) is recognised to be a heritable disorder, yet clinical genetic testing does not produce a diagnosis in >50% of paediatric patients. Identifying a genetic cause is crucial because this knowledge can affect management options, cardiac surveillance in relatives and reproductive decision-making. In this study, we sought to identify the underlying genetic defect in a patient born to consanguineous parents with rapidly progressive DCM that led to death in early infancy.Methods and resultsExome sequencing revealed a potentially pathogenic, homozygous missense variant, c.542G>T, p.(Gly181Val), inSOD2. This gene encodes superoxide dismutase 2 (SOD2) or manganese-superoxide dismutase, a mitochondrial matrix protein that scavenges oxygen radicals produced by oxidation-reduction and electron transport reactions occurring in mitochondria via conversion of superoxide anion (O2–·) into H2O2. Measurement of hydroethidine oxidation showed a significant increase in O2−·levels in the patient’s skin fibroblasts, as compared with controls, and this was paralleled by reduced catalytic activity of SOD2 in patient fibroblasts and muscle. Lentiviral complementation experiments demonstrated that mitochondrial SOD2 activity could be completely restored on transduction with wild type SOD2.ConclusionOur results provide evidence that defective SOD2 may lead to toxic increases in the levels of damaging oxygen radicals in the neonatal heart, which can result in rapidly developing heart failure and death. We propose SOD2 as a novel nuclear-encoded mitochondrial protein involved in severe human neonatal cardiomyopathy, thus expanding the wide range of genetic factors involved in paediatric cardiomyopathies.
Association between outdoor PM2.5 and prevalence of COPD: a systematic review and meta-analysis
Authors: Han Feng , Yang Xiaoyan , Xu Donggang , Wang Qin , Xu Dongqun 
Published: September 2019

AbstractThere were conflictions and differences among the results of cross-sectional studies association between PM2.5 and COPD prevalence. We aimed to explore the real association between outdoor PM2.5 and COPD prevalence, analyze the possible cause to the differences and conflictions in previous cross-sectional studies. Cross-sectional literatures about the association between outdoor PM2.5 and COPD prevalence were selected up to 12 September 2018. Subgroup analysis was performed to explore the source of the heterogeneity. Publication bias was tested via funnel plot. Leave-one-out method was used to conduct influential analysis. Variance analysis was used to analyze the influence of concentration, literature quality and age (over 60 or not) on the ln (aOR) values. The initial search revealed 230 studies, of which 8 were selected. The heterogeneity in this study was significant (I2=62, P&lt;0.01), and random effects model was used. The pooled OR for the association between PM2.5 and COPD prevalence is 2.32(95%CI, 1.91-2.82). There was no evidence of publication bias. Subgroup analysis showed the subgroup of age seemed to be the source of heterogeneity (P=0.0143, residual I2=0%). Variance analysis showed that the differences of ln (aOR) among each concentration group(p=0.0075) were statistically significant, the same as age groups(P=0.0234). This meta-analysis study demonstrated a conclusive association between PM2.5 and prevalence of COPD (OR: 2.32, 95%CI 1.91–2.82). The significant heterogeneity among selected studies was mainly caused by age (over 60 or not). High PM2.5 concentration should be needed in further research of the relationship between PM2.5 and chronic diseases.
Decreased expression of long non-coding LOC285194 predicts tumour progression and poor prognosis of hepatocellular carcinoma after curative hepatectomy
Authors: Qiu Jianguo , Pan Gang , Li Ming 
Published: September 2019

AbstractBackgroundLong non-coding RNAs (LncRNAs) have been recently implicated as having oncogenic and tumour suppressor roles. LncRNA LOC285194 (LOC285194) expression was significantly reduced in a variety of tumour tissues and cell lines, which promotes cell proliferation and migration. The aim of the present study is to examine the expression pattern of LOC285194 and its clinical significance in hepatocellular carcinoma (HCC) patients after curative liver resection.Materials and methodsWe examined the expression of LOC285194 in 120 HCC samples and controls from adjacent non-tumour tissues using real-time quantitative reverse transcription-PCR and analysed its correlation with clinical parameters and prognosis in these patients who have undergone curative hepatic resection with a median follow-up of 3.5 years.ResultsThe expression level of LOC285194 was significantly lower in tumour tissues and four liver cancer cell lines compared with adjacent normal tissues and normal liver cell line. Furthermore, a low expression of LOC285194 was significantly correlated with advanced tumour stage, microvascular invasion, tumour number and differentiation. Additionally, survival analysis showed that patients with low LOC285194 expression had a significantly worse overall and disease-free survival. Moreover, univariate and multivariate analyses showed that decreased expression of LOC285194 was an independent predictor of long-term survival.ConclusionsThe low expression level of LOC285194 might be a novel candidate biomarker for predicting tumour progression and poor prognosis in HCC patients who have undergone hepatectomy and might be a potential target for gene therapy.
Settled science or unwarranted variation in local anesthetic dosing? An analysis from an International Registry of Regional Anesthesiology
Authors: Taenzer Andreas H , Sites Brian D , Kluger Roman , Barrington Michael 
Published: September 2019

BackgroundVariation in clinical practice is often considered unwarranted when it does not reflect patient preference or evidence-based medicine. Complications from regional anesthesia such as nerve injury and systemic toxicity are dose dependent. It is currently unclear if there is significant variation with the dosing of local anesthetics (LA) in the context of the modern practice of peripheral regional anesthesia.MethodsWe analyzed data from the International Registry of Regional Anesthesia that include prospective data on peripheral regional anesthesia procedures from 21 centers located around the world. Using data from years 2011 to 2017, our primary aim was to characterize the degree of variation in dosing of LA for the top 10 most commonly performed single injection peripheral nerve blocks. Our secondary aim was to identify potential drivers of this variation.ResultsAmong the 26 457 peripheral blocks performed, mean (±SD) LA dose per block in ropivacaine equivalents was 125.1±51.2 mg and 1.6±0.7 for mg/kg. There was large variation across all block types, with the highest variation (measured by interdecile range) in axillary blocks (143.8 mg) and lowest in interscalene blocks (83.3 mg). In a regression analysis, dose was primarily associated with the hospital (Cohen’s f=0.37) where the block was administered and block type (f=0.38), less so with age (f=0.02), weight (f=0.12), gender (f=0.05) or LA (f=0.17) used. Hospital site had strong impact on variation in LA dose (f=0.88). Variation was not significantly associated with number of blocks performed by hospital site.ConclusionsLarge variation in dosing for regional blocks exists within and among hospitals, which is unlikely to be warranted. For many blocks, the variation of dosing is larger than the mean dose. Hospital site had strong impact on variation in LA dose and moderate impact on mean LA dose.
Measurement properties of the minimal disease activity criteria for psoriatic arthritis
Authors: Coates Laura C , Strand Vibeke , Wilson Hilary , Revicki Dennis , Stolshek Brad , Samad Ahmed , Chung James B , Gladman Dafna , Mease Philip J 
Published: September 2019

ObjectiveTo comprehensively assess evidence on the measurement properties of the minimal disease activity (MDA) criteria, a composite measure of the state of disease activity in psoriatic arthritis (PsA).MethodsA targeted literature review was conducted to identify studies that informed the validity and/or ability of the MDA to detect change among patients known to have experienced a change in clinical status. The search was conducted using MEDLINE and Embase databases (published as of October 2017). Pertinent articles provided by investigators and identified from select conference proceedings were also evaluated.ResultsA total of 20 publications met the inclusion criteria. The MDA criteria were consistently associated with other indicators of disease activity/severity. The ability of the MDA criteria to detect change was supported in randomised controlled trials (n=10), with a greater percentage of patients randomised to active treatments achieving MDA relative to patients in comparator arms. Long-term observational studies (n=2) provided additional support for the ability of the MDA to detect within-subject change in the real-world settings.ConclusionEvidence supports the MDA as a valid measure of disease activity in PsA that can detect between-group and within-subject change. The MDA is a comprehensive measure and clinically meaningful endpoint to assess the impact of interventions on PsA disease activity.
Automated Driving System Collisions: Early Lessons
Authors: Biever Wayne , Angell Linda , Seaman Sean 
Published: September 2019

Objective This research evaluated Automated Driving Systems (ADSs) involved collisions to identify factors relevant to future ADS research and development. Background Rapidly developing ADSs promise improved safety, among other benefits. Properly applied collision research can inform ADS development, to minimize future collisions. Errors and failures that result in collisions come from sources including the system, ADS operators, and external factors including other drivers. Partially automated systems incorporate new equipment and procedures creating new sources of human error. Fully autonomous systems represent a new class of drivers that interact in unique ways. Method ADS collision reports from the California Department of Motor Vehicles and the National Transportation Safety Board were collected. An expert in human factors and collision investigation analyzed and categorized the crashes while extracting common factors. Results ADS vehicles were never at fault but were often affected from the rear during braking, turning, and gap acceptance maneuvers. Side impacts to ADS vehicles were related to passing vehicles and lane keeping behaviors. Unique incidents also provided additional insights. ADS collision rates cannot yet be determined with confidence. Conclusion Conflicts that lead to collision-involvement with ADSs may be caused by differences between ADS and human driving behavior. Conservative ADS behavior may violate the expectations of other nearby human road users. Application The findings from this work help inform the future development of ADS, as well as potentially the testing of ADS and the formation of policy to guide their future deployment.
Mannose-binding lectin has a direct deleterious effect on ischemic brain microvascular endothelial cells
Authors: Neglia Laura , Fumagalli Stefano , Orsini Franca , Zanetti Adriana , Perego Carlo , De Simoni Maria-Grazia 
Published: September 2019

Mannose-binding lectin (MBL), an initiator of the lectin pathway, is detrimental in ischemic stroke. MBL deposition on the ischemic endothelium indicates the beginning of its actions, but downstream mechanisms are not clear yet. We investigated MBL interactions with the ischemic endothelium by exposing human brain microvascular endothelial cells (hBMECs) to protocols of ischemia. Cells were exposed to hypoxia or oxygen–glucose deprivation (OGD), and re-oxygenated with human serum (HS) or recombinant MBL (rhMBL). Hypoxic hBMECs re-oxygenated with HS showed increased complement system activation (C3c deposition, +59%) and MBL deposition (+93%) than normoxic cells. Super-resolution microscopy showed MBL internalization in hypoxic cells and altered cytoskeletal organization, indicating a potential MBL action on the endothelial structure. To isolate MBL effect, hBMECs were re-oxygenated with rhMBL after hypoxia/OGD. In both conditions, MBL reduced viability (hypoxia: −25%, OGD: −34%) compared to conditions without MBL, showing a direct toxic effect. Ischemic cells also showed greater MBL deposition (hypoxia: +143%, OGD: +126%) than normoxic cells. These results were confirmed with primary hBMECs exposed to OGD (increased MBL-induced cell death: +226%, and MBL deposition: +104%). The present findings demonstrate that MBL can exert a direct deleterious effect on ischemic brain endothelial cells in vitro, independently from complement activation.
Comparing amide proton transfer imaging with dynamic susceptibility contrast-enhanced perfusion in predicting histological grades of gliomas: a meta-analysis
Authors: Song Qingxu , Zhang Chencheng , Chen Xin , Cheng Yufeng 
Published: September 2019

Background As a subtype of chemical exchange saturation transfer imaging without contrast agent administration, amide proton transfer (APT) imaging has demonstrated the potential for differentiating the histologic grades of gliomas. Dynamic susceptibility contrast-enhanced perfusion, a perfusion-weighted imaging technique, is a well-established technique in grading gliomas. Purpose To compare the ability of amide proton transfer and dynamic susceptibility contrast-enhanced imaging for predicting the grades of gliomas. Material and Methods A comprehensive literature search was performed independently by two observers to identify articles about the diagnostic performance of amide proton transfer and dynamic susceptibility contrast-enhanced perfusion in predicting the grade of gliomas. Summary estimates of diagnostic accuracy were obtained by using a random-effects model. Results Of 179 studies identified, 23 studies were included the analysis. Eight studies evaluated amide proton transfer and 16 studies evaluated dynamic susceptibility contrast-enhanced perfusion with the parameter rCBV. The pooled sensitivities and specificities of each study’s best performing parameter were 88% (95% confidence interval [CI] 74–95) and 89% (95% CI 78–95) for amide proton transfer, and 95% (95% CI 87–98), 88% (95% CI 81–93) for perfusion-weighted imaging–dynamic susceptibility contrast-enhanced perfusion, respectively. The pooled sensitivities and specificities for grading gliomas using the two most commonly evaluated parameters, were 92% (95% CI 80–97) and 90% (95% CI 75–96) for APTmax, and 97% (95% CI 91–99) and 87% (95% CI 80–92) for rCBVmax, respectively. Conclusion Considering the similar performance of APT and dynamic susceptibility contrast-enhanced (DSC) in predicting glioma grade, the former method appears preferable since it needs no contrast agent.
Developmental coordination disorder in UK children aged 6–18 years: Estimating the cost
Authors: Cleaton Mary Ann Megan , Lorgelly Paula Kate , Kirby Amanda 
Published: September 2019

Introduction Developmental coordination disorder is a neurodevelopmental disorder affecting motor ability, with an estimated prevalence of between 2% and 6% in school-aged children. It is associated with considerable psychosocial impact. However, the financial cost this poses to families and society has never been assessed. We aimed to estimate the direct, indirect and out-of-pocket costs associated with developmental coordination disorder in United Kingdom school-aged children in the 6 months prior to our survey. Method Parents/guardians answered an online questionnaire adapted from the Client Service Receipt Inventory. Results Mean direct healthcare costs were approximately £700 in the 6 months prior to the survey. Almost all children were in mainstream education, but many received additional support. Among children who received therapy, the average indirect cost was £574 in the 6 months prior to the survey. However, this did not include changes to employment made to accommodate caring for the child. Notably, respondents commented that they frequently struggled to access services for their children. Thus, these figures may be a marked underestimation of true need. Conclusion This study represents the first cost-of-illness study for developmental coordination disorder. It demonstrates that developmental coordination disorder incurs a significant cost to society but particularly to families. Improvements to diagnostic pathways and post-diagnosis service provision are much needed.
Umbilical arterial Doppler ultrasonography predicts late pregnancy outcomes in patients with lupus nephritis: a multicenter study from southern China
Authors: Chen D , Yuan S , Lao M , Zhan Y , Xu H , Liang L , Cai X , Wang X , Zhan Z 
Published: September 2019

Objectives To investigate the fetal adverse pregnancy outcomes (APOs) and the predictive value of umbilical arterial Doppler ultrasonography in the third trimester in pregnant women with lupus nephritis (LN). Methods A retrospective cohort study enrolling 203 LN patients from 2007 to 2017 was performed. Ultrasonic parameters were recorded. Results Fetal APOs occurred in 103 patients (103/203, 50.7%). Sixty-six pregnancies (66/203, 32.5%) ended with preterm births. The incidence rate of intrauterine growth restriction (IUGR) was 18.2% (37/203). Fetal distress was noted in 23 pregnancies (23/203, 11.3%). All the Doppler parameters elevated in patients with IUGR, fetal distress, and composite conditions. Resistance index (RI) indicated the highest risk of IUGR and composite APOs. The cutoff values were 0.66 and 0.67, respectively. Sensitivities were 51.4% and 33.7%, and specificities were 87.4% and 92.1%. Peak velocity of the umbilical arteries at end-systole (Vmax, abbreviated as S) to that at end-diastole (Vmin, abbreviated as D) (S/D) ratio was also a best predictor for IUGR, with the optimal cutoff value of 2.88. Sensitivity and specificity were comparable with RI. Pulsatility index (PI) over 0.84 was an ideal indicator for fetal distress with an optimal combination of sensitivity (89.5%) and specificity (51.6%). Conclusions Fetal complications were frequent in patients with LN. Umbilical arterial Doppler ultrasonography was a useful measure to predict late IUGR, fetal distress, and the composite APOs.