bluuebunny/crossref_metadata_2025_split huggingface dataset:
Undifferentiated Chordae Tendineae of the Mitral Valve: Large Cohort Study of a Rare Mitral Malformation
Authors: Pang Kunjing , Wang Jingjin , Zhang Tingting , Wu Jinlin , Gao Yiming , Liang Yu , Ma Kai , Mao Fengqun , Pan Xiangbin , Hu Shengshou , Li Shoujun 
Published: July 2021

Aims: This study aimed to investigate the pathology, classification, diagnosis, and surgical prognosis of UCMV.Methods and Results: Consecutive paediatric patients with ≥ moderate-severe mitral regurgitation (MR) and mitral stenosis (MS) were recruited between October 2016 and July 2020. UCMV was diagnosed and classified into three grades according to the involvement of chorda groups and MS presence or absence; other mitral lesions were included as controls. Of 207 eligible patients, 75 with UCMV (10.0 m [interquartile range (IQR): 6.0–21.5]) and 110 with other mitral lesions (16.0 m [IQR: 5.0–43.5]) were diagnosed using echocardiography and surgical exploration. The associated chorda groups of UCMV were confirmed to show high agreement between echocardiography and surgery (kappa = 0.857, p &lt; 0.001). At baseline surgery assessment, the UCMV group exhibited worse New York Heart Association functional class, more severe MR and MS grades, and fewer associated complex anomalies (all, p &lt; 0.05) than the control group. After a mean follow-up of 8.3 (IQR:2.7–14.4) months and adjustment for covariates, the UCMV group required longer cardiopulmonary bypass and aortic clamp times, but there were no differences in the incidence of adverse events (p = 0.584). Class III was associated with higher risk of adverse events than classes I and II (p = 0.002).Conclusions: The UCMV spectrum constitutes a primary pathogenesis of paediatric MV dysfunction, which can be optimally diagnosed using echocardiography. Classification based on mitral anatomy and dysfunction can predict the risk of postoperative adverse events.
Aortic Valve Sclerosis in High-Risk Coronary Artery Disease Patients
Authors: Myasoedova Veronika A. , Genovese Stefano , Cavallotti Laura , Bonomi Alice , Chiesa Mattia , Campodonico Jeness , Rondinelli Maurizio , Cosentino Nicola , Baldassarre Damiano , Veglia Fabrizio , Pepi Mauro , Alamanni Francesco , Colombo Gualtiero I. , Marenzi Giancarlo , Poggio Paolo 
Published: July 2021

Background: Current knowledge regarding the relationship between aortic valve sclerosis (AVSc), cardiovascular risk factors, and mortality in patients with known coronary artery disease (CAD) is still unclear. The present study aimed at investigating the prevalence of AVSc as well as its association with long-term all-cause mortality in high-risk CAD patients that has never been explored in large cohorts thus far.Methods and Results: In this retrospective and observational cohort study we enrolled high-risk CAD patients, hospitalized at Centro Cardiologico Monzino (CCM), Milan, Italy, between January 2006 and December 2016. The morphology and function of the aortic valve were assessed from the recorded echocardiographic images to evaluate the presence of AVSc, defined as a non-uniform thickening of the aortic leaflets with no consequences on hemodynamics. Data on 5-year all-cause mortality was retrieved from a Regional database. Of the 5,489 patients initially screened, 4,938 (mean age 67 ± 11 years, 3,954 [80%] men) were enrolled in the study. In the overall population, AVSc was detected in 2,138 (43%) patients. Multivariable LASSO regression revealed that age, female gender, diabetes mellitus, previous MI, and left ventricular ejection fraction were independently associated with AVSc. All-cause mortality (adjusted hazard ratio: 1.29, 95%CI: 1.05–1.58) was significantly higher in AVSc than in non-AVSc patients.Conclusions: AVSc is frequently detected in high-risk CAD patients and is associated with long-term mortality. Our findings corroborate the hypothesis that AVSc is an underestimated marker of systemic cardiovascular risk. Thus, AVSc detection may be used to improve long-term risk stratification of high-risk CAD patients.
Predictive Biomarkers of Dicycloplatin Resistance or Susceptibility in Prostate Cancer
Authors: Liu Minglu , Zhou Xiaoyu , Liu Jun , Lu Chelong , Zhang Guoqing , Zhang Jing , Jiao Shunchang 
Published: July 2021

BackgroundProstate cancer (PCa) is among the leading causes of cancer mortality. Dicycloplatin is a newer generation platinum-based drug that has less side effects than cisplatin and carboplatin. However, its effects in PCa is mixed due to lack of appropriate stratifying biomarkers. Aiming to search for such biomarkers, here, we analyze a group of PCa patients with different responses to dicycloplatin.MethodsWe carried out whole-exome sequencing on cell-free DNA (cfDNA) and matched leukocyte DNA from 16 PCa patients before treatment with dicycloplatin. We then compared the clinical characteristics, somatic mutations, copy number variants (CNVs), and mutational signatures between the dicycloplatin-sensitive (nine patients) and dicycloplatin-resistant (seven patients) groups and tested the identified mutations, CNV, and their combinations as marker of dicycloplatin response.ResultsThe mutation frequency of seven genes (SP8, HNRNPCL1, FRG1, RBM25, MUC16, ASTE1, and TMBIM4) and CNV rate of four genes (CTAGE4, GAGE2E, GAGE2C, and HORMAD1) were higher in the resistant group than in the sensitive group, while the CNV rate in six genes (CDSN, DPCR1, MUC22, TMSB4Y, VARS, and HISTCH2AC) were lower in the resistant group than in the sensitive group. A combination of simultaneous mutation in two genes (SP8/HNRNPCL1 or SP8/FRG1) and deletion of GAGE2C together were found capable to predict dicycloplatin resistance with 100% sensitivity and 100% specificity.ConclusionWe successfully used cfDNA to monitor mutational profiles of PCa and designed an effective composite marker to select patients for dicycloplatin treatment based on their mutational profile.
mRBioM: An Algorithm for the Identification of Potential mRNA Biomarkers From Complete Transcriptomic Profiles of Gastric Adenocarcinoma
Authors: Dong Changlong , Rao Nini , Du Wenju , Gao Fenglin , Lv Xiaoqin , Wang Guangbin , Zhang Junpeng 
Published: July 2021

PurposeIn this work, an algorithm named mRBioM was developed for the identification of potential mRNA biomarkers (PmBs) from complete transcriptomic RNA profiles of gastric adenocarcinoma (GA).MethodsmRBioM initially extracts differentially expressed (DE) RNAs (mRNAs, miRNAs, and lncRNAs). Next, mRBioM calculates the total information amount of each DE mRNA based on the coexpression network, including three types of RNAs and the protein-protein interaction network encoded by DE mRNAs. Finally, PmBs were identified according to the variation trend of total information amount of all DE mRNAs. Four PmB-based classifiers without learning and with learning were designed to discriminate the sample types to confirm the reliability of PmBs identified by mRBioM. PmB-based survival analysis was performed. Finally, three other cancer datasets were used to confirm the generalization ability of mRBioM.ResultsmRBioM identified 55 PmBs (41 upregulated and 14 downregulated) related to GA. The list included thirteen PmBs that have been verified as biomarkers or potential therapeutic targets of gastric cancer, and some PmBs were newly identified. Most PmBs were primarily enriched in the pathways closely related to the occurrence and development of gastric cancer. Cancer-related factors without learning achieved sensitivity, specificity, and accuracy of 0.90, 1, and 0.90, respectively, in the classification of the GA and control samples. Average accuracy, sensitivity, and specificity of the three classifiers with machine learning ranged within 0.94–0.98, 0.94–0.97, and 0.97–1, respectively. The prognostic risk score model constructed by 4 PmBs was able to correctly and significantly (∗∗∗p &lt; 0.001) classify 269 GA patients into the high-risk (n = 134) and low-risk (n = 135) groups. GA equivalent classification performance was achieved using the complete transcriptomic RNA profiles of colon adenocarcinoma, lung adenocarcinoma, and hepatocellular carcinoma using PmBs identified by mRBioM.ConclusionsGA-related PmBs have high specificity and sensitivity and strong prognostic risk prediction. MRBioM has also good generalization. These PmBs may have good application prospects for early diagnosis of GA and may help to elucidate the mechanism governing the occurrence and development of GA. Additionally, mRBioM is expected to be applied for the identification of other cancer-related biomarkers.
Transcriptome Analysis of CCR9+ T Helper Cells From Primary Sjögren’s Syndrome Patients Identifies CCL5 as a Novel Effector Molecule
Authors: Hinrichs Anneline C. , Blokland Sofie L. M. , Lopes Ana P. , Wichers Catharina G. K. , Kruize Aike A. , Pandit Aridaman , Radstake Timothy R. D. J. , van Roon Joel A. G. 
Published: July 2021

IntroductionCCR9+ Tfh-like pathogenic T helper (Th) cells are elevated in patients with primary Sjögren’s syndrome (pSS) and indicated to play a role in pSS immunopathology. Here we delineate the CCR9+ Th cell-specific transcriptome to study the molecular dysregulation of these cells in pSS patients.MethodsCCR9+, CXCR5+ and CCR9-CXCR5- Th cells from blood of 7 healthy controls (HC) and 7 pSS patients were FACS sorted and RNA sequencing was performed. Computational analysis was used to identify differentially expressed genes (DEGs), coherent gene expression networks and differentially regulated pathways. Target genes were replicated in additional cohorts.Results5131 genes were differentially expressed between CCR9+ and CXCR5+ Th cells; 6493 and 4783 between CCR9+ and CCR9-CXCR5- and between CXCR5+ and CCR9-CXCR5-, respectively. In the CCR9+ Th cell subset 2777 DEGs were identified between HC and pSS patients, 1416 and 1077 in the CXCR5+ and CCR9-CXCR5- subsets, respectively. One gene network was selected based on eigengene expression differences between the Th cell subsets and pathways enriched for genes involved in migration and adhesion, cytokine and chemokine production. Selected DEGs of interest (HOPX, SOX4, ITGAE, ITGA1, NCR3, ABCB1, C3AR1, NT5E, CCR5 and CCL5) from this module were validated and found upregulated in blood CCR9+ Th cells, but were similarly expressed in HC and pSS patients. Increased frequencies of CCR9+ Th cells were shown to express higher levels of CCL5 than CXCR5+ and CCR9-CXCR5- Th cells, with the highest expression confined to effector CCR9+ Th cells. Antigenic triggering and stimulation with IL-7 of the Th cell subsets co-cultured with monocytes strongly induced CCL5 secretion in CCR9+ Th cell cocultures. Additionally, effector CCR9+ Th cells rapidly released CCL5 and secreted the highest CCL5 levels upon stimulation.ConclusionTranscriptomic analysis of circulating CCR9+ Th cells reveals CCR9-specific pathways involved in effector T cell function equally expressed in pSS patients and HC. Given the increased numbers of CCR9+ Th cells in the blood and inflamed glands of pSS patients and presence of inflammatory stimuli to activate these cells this suggests that CCR9-specific functions, such as cell recruitment upon CCL5 secretion, could significantly contribute to immunopathology in pSS.
Non-invasive Diagnostic Tests in Cystic Fibrosis-Related Liver Disease: A Diagnostic Test Accuracy Network Meta-Analysis
Authors: Martonosi Ágnes Rita , Soós Alexandra , Rumbus Zoltán , Hegyi Péter , Izsák Vera , Pázmány Piroska , Imrei Marcell , Váncsa Szilárd , Szakács Zsolt , Párniczky Andrea 
Published: July 2021

Background and Aims: Cystic fibrosis-related liver disease (CFLD) is one of the leading causes of morbidity and mortality in cystic fibrosis (CF). Several non-invasive diagnostic methods have been proposed as screening tools for CFLD. Our aim was to rank all available non-invasive modalities for diagnostic performance.Methods: A systematic search was performed in five medical databases to find studies which reported on any single or composite non-invasive diagnostic test (as an index test) compared to the Debray, the EuroCare or the Colombo criteria (as a reference standard). Ranking was carried out with a Bayesian diagnostic test accuracy network meta-analysis based on superiority indices, calculated for pooled sensitivity (Se) and specificity (Sp) with a 95% confidence interval (CI). The study was registered under CRD42020155846 in PROSPERO.Results: Fifteen studies with 15 index tests and a combination of them were included. The New criteria proposed by Koh et al. – which represent a composite diagnostic definition for CFLD including liver biochemistry, ultrasonography, transient elastography and fibrosis markers—had the best performance for detecting CFLD (Se:94%[CI:58–100], Sp:72%[CI:52–84]); while transient elastography (Se:65%[CI:56–74], Sp:88%[CI:84–91]) and a combination of it with a tissue inhibitor of metalloproteinase-4 measurement (Se:78%[CI:30–100], Sp:64%[CI:18–95%]) proved to be the second and third best options, respectively. In the imaging techniques subgroup, transient elastography (Se:66%[CI:57–72], Sp:88%[CI:85–91%]), acoustic radiation force impulse in the right lobe (Se:54%[CI:33–74], Sp:88%[CI:66–96]) and that in the left lobe (Se:55%[CI:23–81], Sp:82%[CI:50–95]) were ranked the highest. Comparing biochemical markers/fibrosis indices, the measurement of the Forns index (Se:72%[CI:25–99], Sp:63%[CI:16–94]), the aspartate aminotransferase-to-platelet ratio (Se:55%[CI:41–68], Sp:83%[CI:66–89]) and alkaline phosphatase (Se:63%[CI:18–93], Sp:64%[CI:19–95]) were ranked the highest.Conclusion: The New criteria show the best diagnostic performance. In clinical practice, transient elastography seems to be a simple, cheap and non-invasive tool, outperforming imaging, biochemical and fibrosis tests for detecting CFLD. Further studies are needed to validate our findings.
Efficacy and Safety of Remimazolam for Procedural Sedation: A Meta-Analysis of Randomized Controlled Trials With Trial Sequential Analysis
Authors: Jhuang Bo-Jyun , Yeh Bo-Han , Huang Yen-Ta , Lai Pei-Chun 
Published: July 2021

Background: Remimazolam is a new ultrashort-acting benzodiazepine. Remimazolam has been approved for procedural sedation by the US Food and Drug Administration in 2020. However, prior trials and the participants they enrolled were limited.Aim: In this meta-analysis, we investigated the effectiveness and adverse events (AEs) of remimazolam during procedural sedation.Materials and Methods: The study protocol was registered (doi: 10.37766/inplasy2020.8.0043), and six databases were searched. We performed meta-analysis, trial sequential analysis (TSA), and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for judging the certainty of evidence (CoE).Results: A total of five randomized controlled trials with 1,248 participants were included. Compared with the use of midazolam, the utilization of remimazolam resulted in an increase in procedure success rate [odds ratio (OR) = 9.01, 95% confidence interval (CI): 2.35–34.57], a reduction in the application of rescue medication (OR = 13.58, 95% CI: 3.46–53.28), a decrease in time to recovery [minutes, weighted mean difference (WMD) = −5.70, 95% CI: −8.68 to −2.72], and a better cognitive recovery of Hopkins Verbal Learning Test-Revised (WMD = 5.22, 95% CI: 2.88–7.55). No difference was found in completion of procedure (OR = 1.68, 95% CI: 0.72–3.90) with inconclusive in TSA. Despite no difference of total AEs (OR = 0.60, 95% CI: 0.24–1.50), more detailed analysis of AEs remained inconclusive in TSA. The GRADE assessment demonstrated low to very low CoE.Conclusion: Our analysis suggested that remimazolam may be a better choice for procedural sedation than midazolam. Nevertheless, further studies are warranted to conclusively establish its safety.
Presurgical Screening Improves Risk Prediction for Delirium in Elective Surgery of Older Patients: The PAWEL RISK Study
Authors: Eschweiler Gerhard W. , Czornik Manuel , Herrmann Matthias L. , Knauer Yvonne P. , Forkavets Oksana , von Arnim Christine A. F. , Denkinger Michael , Küster Olivia , Conzelmann Lars , Metz Brigitte R. , Maurer Christoph , Kentischer Felix , Deeken Friederike , Sánchez Alba , Wagner Sören , Mennig Eva , Thomas Christine , Rapp Michael A. 
Published: July 2021

Introduction: The number of elective surgeries for patients who are over 70 years of age is continuously growing. At the same time, postoperative delirium (POD) is common in older patients (5–60%) depending on predisposing risk factors, such as multimorbidity, cognitive impairment, neurodegenerative disorders and other dementing disorders, and precipitating factors, such as duration of surgery. Knowledge of individual risk profiles prior to elective surgery may help to identify patients at increased risk for development of POD. In this study, clinical and cognitive risk factors for POD were investigated in patients undergoing various elective cardiac and non-cardiac surgeries.Methods: The PAWEL study is a prospective, interventional trial on delirium prevention. At baseline, 880 inpatients at five surgical centers were recruited for sub-sample PAWEL-R. Multimodal assessments included clinical renal function, medication, American Society of Anesthesiologists (ASA) Physical Status Classification System, geriatric and cognitive assessments, which comprised the Montreal Cognitive Assessment Scale (MoCA), Trail-making Test, and Digit Span backward. Delirium incidence was monitored postoperatively by the Confusion Assessment Method (CAM) and a chart review for up to a week or until discharge. Multivariate regression models and Chi-square Automatic Interaction Detectors (CHAID) analyses were performed using delirium incidence as the primary outcome.Results: Eighteen risk factors were investigated in elective cardiovascular and orthopedic or general surgery. A total of 208 out of 880 patients (24%) developed POD. A global regression model that included all risk variables predicted delirium incidence with high accuracy (AUC = 0.81; 95% CI 0.77, 0.85). A simpler model (clinical and cognitive variables; model CLIN-COG) of 10 factors that only included surgery type, multimorbidity, renal failure, polypharmacy, ASA, cut-to-suture time, and cognition (MoCA, Digit Span backward, and preexisting dementia), however, exhibited similar predictive accuracy (AUC = 0.80; 95% CI 0.76, 0.84).Conclusion: The risk of developing POD can be estimated by preoperative assessments, such as ASA classification, expected cut-to-suture time, and short cognitive screenings. This rather efficient approach predicted POD risk over all types of surgery. Thus, a basic risk assessment including a cognitive screen can help to stratify patients at low, medium, or high POD risk to provide targeted prevention and/or management strategies for patients at risk.
Early Predictors of the Increase in Perihematomal Edema Volume After Intracerebral Hemorrhage: A Retrospective Analysis From the Risa-MIS-ICH Study
Authors: Ye Gengzhao , Huang Shuna , Chen Renlong , Zheng Yan , Huang Wei , Gao Zhuyu , Cai Lueming , Zhao Mingpei , Ma Ke , He Qiu , Lin Fuxin , Lin Yuanxiang , Wang Dengliang , Fang Wenhua , Kang Dezhi , Wu Xiyue 
Published: July 2021

Background and Purpose: Perihematomal edema (PHE) is associated with poor functional outcomes after intracerebral hemorrhage (ICH). Early identification of risk factors associated with PHE growth may allow for targeted therapeutic interventions.Methods: We used data contained in the risk stratification and minimally invasive surgery in acute intracerebral hemorrhage (Risa-MIS-ICH) patients: a prospective multicenter cohort study. Patients' clinical, laboratory, and radiological data within 24 h of admission were obtained from their medical records. The absolute increase in PHE volume from baseline to day 3 was defined as iPHE volume. Poor outcome was defined as modified Rankin Scale (mRS) of 4 to 6 at 90 days. Binary logistic regression was used to assess the relationship between iPHE volume and poor outcome. The receiver operating characteristic curve was used to find the best cutoff. Linear regression was used to identify variables associated with iPHE volume (ClinicalTrials.gov Identifier: NCT03862729).Results: One hundred ninety-seven patients were included in this study. iPHE volume was significantly associated with poor outcome [P = 0.003, odds ratio (OR) 1.049, 95% confidence interval (CI) 1.016–1.082] after adjustment for hematoma volume. The best cutoff point of iPHE volume was 7.98 mL with a specificity of 71.4% and a sensitivity of 47.5%. Diabetes mellitus (P = 0.043, β = 7.66 95% CI 0.26–15.07), black hole sign (P = 0.002, β = 18.93 95% CI 6.84–31.02), and initial ICH volume (P = 0.018, β = 0.20 95% CI 0.03–0.37) were significantly associated with iPHE volume. After adjusting for hematoma expansion, the black hole sign could still independently predict the increase of PHE (P &lt; 0.001, β = 21.62 95% CI 10.10–33.15).Conclusions: An increase of PHE volume &gt;7.98 mL from baseline to day 3 may lead to poor outcome. Patients with diabetes mellitus, black hole sign, and large initial hematoma volume result in more PHE growth, which should garner attention in the treatment.
The C-Terminal Half of SARS-CoV-2 Nucleocapsid Protein, Industrially Produced in Plants, Is Valid as Antigen in COVID-19 Serological Tests
Authors: Williams Laura , Jurado Silvia , Llorente Francisco , Romualdo Alberto , González Sara , Saconne Ana , Bronchalo Isabel , Martínez-Cortes Mercedes , Pérez-Gómez Beatriz , Ponz Fernando , Jiménez-Clavero Miguel Ángel , Lunello Pablo 
Published: July 2021

BackgroundThe fight against the current coronavirus disease 2019 (COVID-19) pandemic has created a huge demand of biotechnological, pharmaceutical, research and sanitary materials at unprecedented scales. One of the most urgent demands affects the diagnostic tests. The growing need for rapid and accurate laboratory diagnostic tests requires the development of biotechnological processes aimed at producing reagents able to cope with this demand in a scalable, cost-effective manner, with rapid turnaround times. This is particularly applicable to the antigens employed in serological tests. Recombinant protein expression using plants as biofactories is particularly suitable for mass production of protein antigens useful in serological diagnosis, with a neat advantage in economic terms.MethodsWe expressed a large portion of the nucleoprotein (N) derived from SARS-CoV-2 in Nicotiana benthamiana plants. After purification, the recombinant N protein obtained was used to develop an indirect enzyme-linked immunosorbent assay (ELISA) for detection of antibodies to SARS-CoV-2 in human sera. To validate the ELISA, a panel of 416 sera from exposed personnel at essential services in Madrid City Council were tested, and the results compared to those obtained by another ELISA, already validated, used as reference. Furthermore, a subset of samples for which RT-PCR results were available were used to confirm sensitivity and specificity of the test.ResultsThe performance of the N protein expressed in plants as antigen in serologic test for SARS-CoV-2 antibody detection was shown to be highly satisfactory, with calculated diagnostic sensitivity of 96.41% (95% CI: 93.05–98.44) and diagnostic specificity of 96.37 (95% CI: 93.05–98.44) as compared to the reference ELISA, with a kappa (K) value of 0.928 (95% CI:0.892–0.964). Furthermore, the ELISA developed with plant-derived N antigen detected SARS-CoV-2 antibodies in 84 out of 93 sera from individuals showing RT-PCR positive results (86/93 for the reference ELISA).ConclusionThis study demonstrates that the N protein part derived from SARS-CoV-2 expressed in plants performs as a perfectly valid antigen for use in COVID-19 diagnosis. Furthermore, our results support the use of this plant platform for expression of recombinant proteins as reagents for COVID-19 diagnosis. This platform stands out as a convenient and advantageous production system, fit-for-purpose to cope with the current demand of this type of biologicals in a cost-effective manner, making diagnostic kits more affordable.