bluuebunny/crossref_metadata_2025_split huggingface dataset:
Respiratory Muscle Function Tests and Diaphragm Ultrasound Predict Nocturnal Hypoventilation in Slowly Progressive Myopathies
Authors: Spiesshoefer Jens , Lutter Riccarda , Kabitz Hans-Joachim , Henke Carolin , Herkenrath Simon , Randerath Winfried , Young Peter , Dreher Michael , Görlich Dennis , Boentert Matthias 
Published: October 2021

Introduction: In slowly progressive myopathies, diaphragm weakness early manifests through sleep-related hypoventilation as reflected by nocturnal hypercapnia. This study investigated whether daytime tests of respiratory muscle function and diaphragm ultrasound predict hypercapnia during sleep.Methods: Twenty-seven patients with genetic myopathies (myotonic dystrophy type 1 and 2, late-onset Pompe disease, facioscapulohumeral dystrophy; 48 ± 11 years) underwent overnight transcutaneous capnometry, spirometry, measurement of mouth occlusion pressures, and diaphragm ultrasound.Results: Sixteen out of 27 patients showed nocturnal hypercapnia (peak ptcCO2 ≥ 50 mmHg for ≥ 30 min or increase in ptcCO2 by 10 mmHg or more from the baseline value). In these patients, forced vital capacity (FVC; % predicted) and maximum inspiratory pressure (MIP; % of lower limit or normal or LLN) were significantly reduced compared to normocapnic individuals. Nocturnal hypercapnia was predicted by reduction in FVC of &lt;60% [sensitivity, 1.0; area under the curve (AUC), 0.82] and MIP (%LLN) &lt;120% (sensitivity, 0.83; AUC, 0.84), the latter reflecting that in patients with neuromuscular disease, pretest likelihood of abnormality is per se higher than in healthy subjects. Diaphragm excursion velocity during a sniff maneuver excluded nocturnal hypercapnia with high sensitivity (0.90) using a cutoff of 8.0 cm/s.Conclusion: In slowly progressive myopathies, nocturnal hypercapnia is predicted by FVC &lt;60% or MIP &lt;120% (LLN). As a novelty, nocturnal hypercapnia can be excluded with acceptable sensitivity by diaphragm excursion velocity &gt;8.0 cm/s on diaphragm ultrasound.
GRIN2A Variants Associated With Idiopathic Generalized Epilepsies
Authors: Liu Xiao-Rong , Xu Xing-Xing , Lin Si-Mei , Fan Cui-Ying , Ye Ting-Ting , Tang Bin , Shi Yi-Wu , Su Tao , Li Bing-Mei , Yi Yong-Hong , Luo Jian-Hong , Liao Wei-Ping 
Published: October 2021

Objective: The objective of this study is to explore the role of GRIN2A gene in idiopathic generalized epilepsies and the potential underlying mechanism for phenotypic variation.Methods: Whole-exome sequencing was performed in a cohort of 88 patients with idiopathic generalized epilepsies. Electro-physiological alterations of the recombinant N-methyl-D-aspartate receptors (NMDARs) containing GluN2A mutants were examined using two-electrode voltage-clamp recordings. The alterations of protein expression were detected by immunofluorescence staining and biotinylation. Previous studies reported that epilepsy related GRIN2A missense mutations were reviewed. The correlation among phenotypes, functional alterations, and molecular locations was analyzed.Results: Three novel heterozygous missense GRIN2A mutations (c.1770A &gt; C/p.K590N, c.2636A &gt; G/p.K879R, and c.3199C &gt; T/p.R1067W) were identified in three unrelated cases. Electrophysiological analysis demonstrated R1067W significantly increased the current density of GluN1/GluN2A NMDARs. Immunofluorescence staining indicated GluN2A mutants had abundant distribution in the membrane and cytoplasm. Western blotting showed the ratios of surface and total expression of the three GluN2A-mutants were significantly increased comparing to the wild type. Further analysis on the reported missense mutations demonstrated that mutations with severe gain-of-function were associated with epileptic encephalopathy, while mutations with mild gain of function were associated with mild phenotypes, suggesting a quantitative correlation between gain-of-function and phenotypic severity. The mutations located around transmembrane domains were more frequently associated with severe phenotypes and absence seizure-related mutations were mostly located in carboxyl-terminal domain, suggesting molecular sub-regional effects.Significance: This study revealed GRIN2A gene was potentially a candidate pathogenic gene of idiopathic generalized epilepsies. The functional quantitative correlation and the molecular sub-regional implication of mutations helped in explaining the relatively mild clinical phenotypes and incomplete penetrance associated with GRIN2A variants.
CircFAM114A2 Promotes Cisplatin Sensitivity via miR-222-3p/P27 and miR-146a-5p/P21 Cascades in Urothelial Carcinoma
Authors: Lv Jiancheng , Zhou Zijian , Wang Jingzi , Yang Xiao , Yu Hao , Han Jie , Feng Dexiang , Yuan Baorui , Wu Qikai , Li Pengchao , Lu Qiang , Yang Haiwei 
Published: October 2021

IntroductionCircular RNAs (circRNAs) are non-coding RNAs that have the structure of a covalently closed loop. Increasing data have proven that circRNAs can influence the progression and chemotherapy sensitivity of tumors. Therefore, the underlying function and mechanisms of more circRNAs in progression and chemotherapy resistance are important.MethodsWe conducted RNA sequencing on five pairs of urothelial carcinoma samples and screened for circRNAs. CircFAM114A2 was found to be low expressed in urothelial carcinoma. The functions of circFAM114A2 in urothelial carcinoma were explored by cell cycle assay, IC50 determination assay, cell proliferation assay, apoptosis assay, and tumorigenesis assay.ResultsWe discovered that the levels of circFAM114A2 were decreased in urothelial carcinoma cell lines and tissues. According to follow-up data, urothelial carcinoma patients with higher circFAM114A2 expression had better survival. Importantly, the levels of circFAM114A2 were associated with the histological grade of urothelial carcinoma. CircFAM114A2 could inhibit cell proliferation and block more urothelial carcinoma cells in the G1 phase and then increase the sensitivity of urothelial carcinoma to cisplatin chemotherapy. Mechanistically, circFAM114A2 directly sponged miR-222-3p/miR-146a-5p and subsequently influenced the expressions of the downstream target genes P27/P21, which, in turn, inhibited the progression of urothelial carcinoma and increased the sensitivity of cancer cells to cisplatin chemotherapy.ConclusionCircFAM114A2 could inhibit progression and promote cisplatin sensitivity in urothelial carcinoma through novel circFAM114A2/miR-222-3p/P27 and circFAM114A2/miR-146a-5p/P21 pathways. CircFAM1142 has therefore great potential as a prognostic biomarker and therapeutic target for urothelial carcinoma.
Redefining Hepatocellular Carcinoma Staging Systems Based on the Bile Duct Invasion Status: A Multicenter Study
Authors: Huang Qizhen , Chen Yufeng , Lin Kongying , Sun Chuandong , Zheng Shuguo , Chen Jinhong , Wang Yifan , Zhou Yanming , Zhou Weiping , Liu Jingfeng , Zeng Yongyi 
Published: October 2021

Background and AimsThe prognostic value of bile duct invasion (BDI) remains controversial. We aimed to investigate the prognostic value of BDI and the stage of BDI in different staging systems.MethodsPatients with hepatocellular carcinoma (HCC) from nine hepatobiliary medical centers who underwent R0 resection were included. Overall survival (OS) was assessed using the Kaplan–Meier method and tested using the log-rank test. The prognostic effect of BDI was analyzed using univariate and multivariate Cox proportional hazard regression analyses. The predictive performance of these models was evaluated using the concordance index and time-dependent receiver operating characteristic curve (tdAUC).ResultsOf 1021 patients with HCC, 177 had BDI. OS was worse in the HCC with BDI group than in the HCC without BDI group (p&lt;0.001); multivariate analysis identified BDI as an independent risk factor for OS. After adjustment for interference of confounding factors using the Cox proportional hazard regression model, HCC with BDI and without macrovascular invasion was classified as Barcelona Clinic Liver Cancer (BCLC) B, eighth edition American Joint Committee on Cancer (AJCC) IIIA, and China Liver Cancer (CNLC) IIb, respectively, whereas HCC with BDI and macrovascular was classified as BCLC C, AJCC IIIB, and CNLC IIIA, respectively. C-indexes and tdAUCs of the adjusted staging systems were superior to those of the corresponding current staging systems.ConclusionWe constructed adjusted staging systems with the BDI status, improved their predictive performance and facilitate clinical use.
Balancing the Risk-Benefit Ratio of Immune Checkpoint Inhibitor and Anti-VEGF Combination Therapy in Renal Cell Carcinoma: A Systematic Review and Meta-Analysis
Authors: Tao Li , Zhang Huiyun , An Guangyu , Lan Haoning , Xu Yaoqi , Ge Yang , Yao Jiannan 
Published: October 2021

BackgroundAlthough immune checkpoint inhibitors (ICIs) combined with vascular endothelial growth factor receptor (VEGFR)-targeted therapy and sunitinib monotherapy have been widely applied to metastatic renal cell carcinoma (mRCC), effectiveness and safety data are still lacking. To optimize clinical decision-making, we conducted a systematic review and meta-analysis of published randomized clinical trials to characterize the efficacy and the risk of adverse events (AEs) in patients treated with ICIs plus anti-VEGF therapy.Materials and MethodsWe used PubMed, EMBASE, and the Cochrane Library to retrieve randomized controlled trials (RCTs) published before March 27, 2021. The efficacy outcomes were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The pooled risk ratio (RR) and 95% confidence intervals (CI) of AEs were calculated in the safety analysis.ResultsSix RCTs involving 4,227 patients were identified after a systematic search. For OS, ICI and anti-VEGF combination therapy decreased mortality approximately 30% in the intention-to-treat population (ITT) (hazard ratio (HR) = 0.70, 95% CI: 0.57–0.87), but there was no statistical difference in patients evaluated as “favorable” by the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) criteria compared with monotherapy (HR = 0.90, 95% CI: 0.55–1.46, p = 0.66). In terms of PFS, the progression risk for all participants declined 35% (HR = 0.65, 95% CI: 0.50–0.83) and patients evaluated as “poor” by IMDC benefited further (HR = 0.46, 95% CI: 0.36–0.58). No evident divergence was found in age and sex subgroups. The RRs of all-grade hypertension, arthralgia, rash, proteinuria, high-grade (grades 3–5) arthralgia, and proteinuria developed after combination therapy were increased compared with sunitinib. The risk of high-grade hypertension and rash showed no statistical difference. However, the risk of hand-foot skin reaction (HFSR), stomatitis, and dysgeusia decreased in combination therapy groups.ConclusionsCompared with sunitinib, OS, PFS, and ORR were significantly improved in patients receiving ICI and anti-VEGF combination therapy at the expense of increased specific AEs. More attention should be paid to individualized application of these combination therapies to achieve the best benefit-risk ratio in the clinic.Systematic Review Registration[https://inplasy.com/] INPLASY: 202130104.
Multiparametric Prostate MRI in Biopsy-Naïve Men: A Prospective Evaluation of Performance and Biopsy Strategies
Authors: Krüger-Stokke Brage , Bertilsson Helena , Langørgen Sverre , Sjøbakk Torill Anita Eidhammer , Bathen Tone Frost , Selnæs Kirsten Margrete 
Published: October 2021

ObjectivesThis study aims to prospectively estimate the diagnostic performance of multiparametric prostate MRI (mpMRI) and compare the detection rates of prostate cancer using cognitive targeted transrectal ultrasound (TRUS) guided biopsies, targeted MR-guided in-bore biopsies (MRGB), or both methods combined in biopsy-naïve men.MethodsThe biopsy-naïve men referred for mpMRI (including T2-weighted, diffusion-weighted and dynamic contrast enhanced MRI) due to prostate cancer suspicion (elevated prostate-specific antigen or abnormal digital rectal examination) were eligible for inclusion. The images were scored according to Prostate Imaging Reporting and Data System (PI-RADS) v2, and men with PI-RADS 1–2 lesions were referred for routine systematic TRUS, while those with PI-RADS 3–5 lesions were randomized to MRGB or cognitive targeted TRUS. Men randomized to MRGB were referred to a secondary TRUS 2 weeks after MRGB. Gleason grade group ≥2 was defined as clinically significant prostate cancer. The performance of mpMRI was estimated using prostate cancer detected by any biopsy method as the reference test.ResultsA total of 210 men were included. There was no suspicion of prostate cancer after mpMRI (PI-RADS 1–2) in 48% of the men. Among these, significant and insignificant prostate cancer was diagnosed in five and 11 men, respectively. Thirty-five men who scored as PI-RADS 1–2 did not undergo biopsy and were therefore excluded from the calculation of diagnostic accuracy. The overall sensitivity, specificity, negative predictive value, and positive predictive value of mpMRI for the detection of significant prostate cancer were 0.94, 0.63, 0.92, and 0.67, respectively. In patients with PI-RADS 3–5 lesions, the detection rates for significant prostate cancer were not significantly different between cognitive targeted TRUS (68.4%), MRGB (57.7%), and the combination of the two biopsy methods (64.4%). The median numbers of biopsy cores taken per patient undergoing systematic TRUS, cognitive targeted TRUS, and MRGB were 14 [8-16], 12 [6-17], and 2 [1-4] respectively.ConclusionsmpMRI, in a cohort of biopsy-naïve men, has high negative predictive value, and our results support that it is safe to avoid biopsy after negative mpMRI. Furthermore, MRGB provides a similar diagnosis to the cognitive targeted TRUS but with fewer biopsies.
Impact of the COVID-19 Lockdown in Malaysia: An Examination of the Psychological Well-Being of Parent-Child Dyads and Child Behavior in Families With Children on the Autism Spectrum
Authors: Fong Hui Xian , Cornish Kim , Kirk Hannah , Ilias Kartini , Shaikh Mohd Farooq , Golden Karen Jennifer 
Published: October 2021

Background: The COVID-19 pandemic lockdowns have adversely impacted children on the autism spectrum and their families, especially in Malaysia where this population is often marginalized. The current quantitative research aimed to investigate the impact of the Malaysian COVID-19 lockdown on the behavior and psychological distress of children formally diagnosed with an autism spectrum condition (ASC) as well as the psychological distress and well-being of their parents, in comparison with a typically developing (TD) control group.Methods: The children's ages ranged between 5 and 17 years. The sample included 72 ASC parent-child dyads and 62 TD parent-child dyads. The primary caregiver completed an online survey including the following: demographic and diagnostic information; ASC symptoms; children's inattention, hyperactivity/impulsivity, perceived stress, depression, and anxiety; parents' perceived stress, depression, anxiety, and well-being based on their experience pre- and mid-lockdown (March 18th to June 9th 2020) in Malaysia.Results: Among the ASC group, no significant pre- and mid-lockdown change was found in ASC symptoms (p &gt; 0.05). There were no significant gender differences (boys/girls) in all the child scales. The 2 [diagnosis (ASC, TD)] × 2 [lockdown (pre-lockdown, mid-lockdown)] mixed-model ANOVAs revealed main effects of lockdown on children's attention, hyperactivity/impulsivity, anxiety, and parents' perceived stress, depression, and psychological well-being (p &lt; 0.005). There was a main effect of diagnosis in all child and parent variables, except parents' perceived stress (p &gt;0.005). However, there was no significant interaction effect between diagnosis and lockdown (p &gt;0.005). All child behavior (inattention and hyperactivity/impulsivity) and child psychological distress (anxiety, depression, and perceived stress) were significantly correlated in both the ASC and TD groups (p &lt; 0.005). On the other hand, only some of the parent variables were significantly correlated with child variables (p &lt; 0.0045) in the ASC group while none of the parent variables were significantly correlated with the child variables (p &gt; 0.005) in the TD group.Conclusion: The results provide preliminary evidence indicating negative effects of the Malaysian lockdown on both children on the autism spectrum and TD children, as well as their parents. These quantitative results will be triangulated with the qualitative interview data to provide a holistic understanding of the impact of the pandemic, informing translational policy and practice recommendations.
Insights Into Adolescents' Substance Use in a Low–Middle-Income Country During the COVID-19 Pandemic
Authors: Sen Lee Thung , Siste Kristiana , Hanafi Enjeline , Murtani Belinda Julivia , Christian Hans , Limawan Albert Prabowo , Adrian  , Siswidiani Levina Putri 
Published: October 2021

Introduction: The COVID-19 pandemic and its lockdown have been a significant life event for many individuals, particularly adolescents. The immense psychological pressure could drive risky behavior, e.g., substance use, while lockdown might lead to decreased use. This study aimed to observe the change in substance use among adolescents in Indonesia and the moderating variables to consumption during the COVID-19 lockdown period.Methods: This study utilized an online survey from April 28, 2020 to June 30, 2020. The hyperlink was disseminated to school administrators and parenting groups through social media and direct messages. A total of 2,932 adolescents (17.4 ± 2.24 and 78.7% females) submitted valid responses. The survey was comprised of a sociodemographic section, substance use details, and psychometric sections, including the Alcohol Use Disorders Identification Test (AUDIT), Cigarette Dependence Scale 12 (CDS-12), Pittsburgh Sleep Quality Index (PSQI), and Strength and Difficulties Questionnaire (SDQ).Results: Overall, adolescent alcohol use during the pandemic was 5.1%, cigarette smoking was 3.1%, and drug consumption was 0.4%. Over half (53.4%) of alcohol drinkers reported increased drinking, and 33.1% had harmful or dependence-like drinking behavior; in contrast, 44.4% of adolescent smokers disclosed reduced cigarette consumption. Around 37.8% of the drug users indicated increased use. During the pandemic, adolescent alcohol use was associated with higher education [adjusted odds ratio (AOR) = 2.67, 95% confidence interval (CI) 1.02–4.86, p = 0.04], higher AUDIT scores (AOR = 1.33, 95% CI 1.25–1.42, p &lt; 0.001), and very low prosocial behavior (AOR = 2.46, 95% CI 1.52–3.88, p &lt; 0.001). Cigarette smoking was correlated with male sex (AOR = 9.56, 95% CI 5.64–16.62, p &lt; 0.001), age (AOR = 1.40, 95% CI 1.14–1.75, p &lt; 0.001), and higher CDS score (AOR = 1.17, 95% CI 1.13–1.20, p &lt; 0.001).Conclusions: Rates of adolescent substance use were significant, with sizeable proportions reporting higher usage. This appeared to occur predominantly in specific demographics and those with a lower protective psychosocial attribute, i.e., prosocial behavior, during the lockdown. These findings should urge the strengthening of adolescent addiction care during and after the pandemic.
All-Cause Mortality Risk Associated With Solid Fuel Use Among Chinese Elderly People: A National Retrospective Longitudinal Study
Authors: Shen Shisi , Luo Min , Meng Xuchen , Deng Ying , Cheng Shuwen 
Published: October 2021

Background: The adverse health effects of air pollutants are widely reported, and the elderly are susceptible to toxic environments. This study aimed to evaluate the association between use of solid fuels for cooking and mortality among the elderly.Methods: A total of 5,732 and 3,869 participants from the Chinese Longitudinal Healthy Longevity Survey were enrolled in two (2014 and 2018) and three surveys (2011, 2014, and 2018) of survey. Cooking fuel was divided into clean and solid fuel. Cox proportional hazards models were used to estimate the mortality hazard ratio (HR). Subgroup analyses were performed to assess the potential interaction effect.Results: Among the participants in the 2011–2018 survey, 53% reported using solid fuel. Such group was associated with a 9% increase in mortality risk relative to clean fuel users (HR = 1.09, 95% CI = 1.01–1.18). Among participants in the 2014–2018 survey, 339 reported a switch from solid to clean fuels and they were not at increased mortality risk relative to the 488 people that reported a stable use of clean fuels (HR = 1.14, 95% CI = 0.99–1.31) although the estimated HR was similar to the one for stable solid fuel users (HR = 1.19, 95%CI = 1.04–1.36 n = 509). Interaction and stratified analyses showed that solid fuel use had an impact on mortality in participants who were non-current smokers, had low dietary diversity scores, and were living in areas with high PM2.5 concentrations (&gt;50 μg/m3) and city population below 8 million (P for interaction &lt; 0.05). The association was robust in the three sensitivity analyses.Conclusion: The finding showed a clear association between solid fuel use and mortality among older Chinese, and an even stronger association between risk of mortality and solid fuel use among individuals exposed to high levels of PM2.5.
Mining Fiskeby III and Mandarin (Ottawa) Expression Profiles to Understand Iron Stress Tolerant Responses in Soybean
Authors: O’Rourke Jamie A. , Morrisey Michael J. , Merry Ryan , Espina Mary Jane , Lorenz Aaron J. , Stupar Robert M. , Graham Michelle A. 
Published: October 2021

The soybean (Glycine max L. merr) genotype Fiskeby III is highly resistant to a multitude of abiotic stresses, including iron deficiency, incurring only mild yield loss during stress conditions. Conversely, Mandarin (Ottawa) is highly susceptible to disease and suffers severe phenotypic damage and yield loss when exposed to abiotic stresses such as iron deficiency, a major challenge to soybean production in the northern Midwestern United States. Using RNA-seq, we characterize the transcriptional response to iron deficiency in both Fiskeby III and Mandarin (Ottawa) to better understand abiotic stress tolerance. Previous work by our group identified a quantitative trait locus (QTL) on chromosome 5 associated with Fiskeby III iron efficiency, indicating Fiskeby III utilizes iron deficiency stress mechanisms not previously characterized in soybean. We targeted 10 of the potential candidate genes in the Williams 82 genome sequence associated with the QTL using virus-induced gene silencing. Coupling virus-induced gene silencing with RNA-seq, we identified a single high priority candidate gene with a significant impact on iron deficiency response pathways. Characterization of the Fiskeby III responses to iron stress and the genes underlying the chromosome 5 QTL provides novel targets for improved abiotic stress tolerance in soybean.