bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicenter randomized trial to assess the efficacy of CONvalescent plasma therapy in patients with Invasive COVID-19 and acute respiratory failure treated with mechanical ventilation: the CONFIDENT trial protocol
Authors: Misset Benoît , Hoste Eric , Donneau Anne-Françoise , Grimaldi David , Meyfroidt Geert , Moutschen Michel , Compernolle Veerle , Gothot André , Desmecht Daniel , Garigliany Mutien , Najdovski Tome , Laterre Pierre-François 
Published: December 2020

Abstract
Background
The COVID-19 pandemic reached Europe in early 2020. Convalescent plasma is used without a consistent evidence of efficacy. Our hypothesis is that passive immunization with plasma collected from patients having contracted COVID-19 and developed specific neutralizing antibodies may alleviate symptoms and reduce mortality in patients treated with mechanical ventilation for severe respiratory failure during the evolution of SARS-CoV-2 pneumonia.

Methods
We plan to include 500 adult patients, hospitalized in 16 Belgian intensive care units between September 2020 and 2022, diagnosed with SARS-CoV-2 pneumonia, under mechanical ventilation for less than 5 days and a clinical frailty scale less than 6. The study treatment will be compared to standard of care and allocated by randomization in a 1 to 1 ratio without blinding. The main endpoint will be mortality at day 28. We will perform an intention to treat analysis. The number of patients to include is based on an expected mortality rate at day 28 of 40 percent and an expected relative reduction with study intervention of 30 percent with α risk of 5 percent and β risk of 20 percent.

Discussion
This study will assess the efficacy of plasma in the population of mechanically ventilated patients. A stratification on the delay from mechanical ventilation and inclusion will allow to approach the optimal time use. Selecting convalescent plasmas with a high titer of neutralizing antibodies against SARS-CoV-2 will allow a homogeneous study treatment. The inclusion in the study is based on the consent of the patient or his/her legal representative, and the approval of the Investigational Review Board of the University hospital of Liège, Belgium. A data safety monitoring board (DSMB) has been implemented. Interim analyses have been planned at 100, 2002, 300 and 400 inclusions in order to decide whether the trail should be discontinued prematurely for ethical issues. We plan to publish our results in a peer-reviewed journal and to present them at national and international conferences.

Funding and registration
The trial is funded by the Belgian Health Care Knowledge Center KCE # COV201004

Trial registration
Clinicaltrials.gov registration number NCT04558476. Registered 14 September 2020—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04558476
Atlantoaxial dislocation with congenital “sandwich fusion” in the craniovertebral junction: a retrospective case series of 70 patients
Authors: Tian Yinglun , Xu Nanfang , Yan Ming , Passias Peter G. , Segreto Frank A. , Wang Shenglin 
Published: December 2020

Abstract
Background
In the setting of congenital C1 occipitalization and C2–3 fusion, significant strain is placed on the atlantoaxial joint. Vertebral fusion both above and below the atlantoaxial joint (i.e., a “sandwich”) creates substantial instability. We retrospectively report on a case series of “sandwich fusion” atlantoaxial dislocation (AAD), describing the associated clinical characteristics and detailing surgical treatment. To the best of our knowledge, the present study is the largest investigation to date of this congenital subgroup of AAD.

Methods
Seventy consecutive patients with sandwich fusion AAD, from one senior surgeon, were retrospectively reviewed. The clinical features and the surgical treatment results were assessed using descriptive statistics. No funding sources or potential conflict of interest-associated biases exist.

Results
The mean patient age was 42.2 years (range: 5–77 years); 36 patients were male, and 34 were female. Fifty-eight patients (82.9%) had myelopathy, with Japanese Orthopaedic Association (JOA) scores ranging 4–16 (mean: 12.9). Cranial neuropathy was involved in 10 cases (14.3%). The most common presentation age group was 31 to 40 years (24 cases, 34.3%). Radiological findings revealed brainstem and/or cervical-medullar compression (58 cases, 82.9%), syringomyelia (16 cases, 22.9%), Chiari malformation (12 cases, 17.1%), cervical spinal stenosis (10 cases, 14.3%), high scapula deformity (1 case, 1.4%), os odontoideum (1 case, 1.4%), and dysplasia of the atlas (1 case, 1.4%). Computed tomography angiography was performed in 27 cases, and vertebral artery (VA) anomalies were identified in 14 cases (51.9%). All 70 patients underwent surgical treatment, without spinal cord or VA injury. Four patients (5.7%) suffered complications, including 1 wound infection, 1 screw loosening, and 2 cases of bulbar paralysis. In the 58 patients with myelopathy, the mean JOA score increased from 12.9 to 14.5. The average follow-up time was 50.5 months (range: 24–120 months). All 70 cases achieved solid atlantoaxial fusion at the final follow-up.

Conclusions
Sandwich fusion AAD, a unique subgroup of AAD, has distinctive clinical features and associated malformations such as cervical-medullar compression, syringomyelia, and VA anomalies. Surgical treatment of AAD was associated with myelopathy improvement and minimal complication occurrence.
Dermatome Mapping Test in the analysis of anatomo-clinical correlations after inguinal hernia repair
Authors: Cirocchi Roberto , Mercurio Isabella , Nazzaro Claudio , De Sol Angelo , Boselli Carlo , Rettagliata George , Vanacore Nicola , Santoro Alberto , Mascagni Domenico , Renzi Claudio , Lancia Massimo , Suadoni Fabio , Zanghì Guido , Palumbo Piergaspare , Bruzzone Paolo , Tellan Guglielmo , Fedeli Piergiorgio , Marsilio Francucci , D’Andrea Vito 
Published: December 2020

AbstractBackgroundNerve identification is recommended in inguinal hernia repair to reduce or avoid postoperative pain. The aim of this prospective observational study was to identify nerve prevalence and find a correlation between neuroanatomy and chronic neuropathic postoperative inguinal pain (CPIP) after 6 months.MaterialA total of 115 patients, who underwent inguinal hernia mesh repair (Lichtenstein tension-free mesh repair) between July 2018 and January 2019, were included in this prospective observational study. The mean age and BMI respectively resulted 64 years and 25.8 with minimal inverse distribution of BMI with respect to age. Most of the hernias were direct (59.1%) and of medium dimension (47.8%). Furthermore, these patients were undergoing Dermatome Mapping Test in preoperatively and postoperatively 6 months evaluation.ResultsIdentification rates of the iliohypogastric (IH), ilioinguinal (II) and genitofemoral (GF) nerves were 72.2%, 82.6% and 48.7% respectively. In the analysis of nerve prevalence according to BMI, the IH was statistically significant higher in patients with BMI < 25 than BMI ≥ 25 P (< 0.05). After inguinal hernia mesh repair, 8 patients (6.9%) had chronic postoperative neuropathic inguinal pain after 6 months. The CPIP prevailed at II/GF dermatome. The relation between the identification/neurectomy of the II nerve and chronic postoperative inguinal pain after 6 months was not significant (P = 0.542).ConclusionThe anatomy of inguinal nerve is very heterogeneous and for this reason an accurate knowledge of these variations is needed during the open mesh repair of inguinal hernias. The new results of our analysis is the statistically significant higher IH nerve prevalence in patients with BMI < 25; probably the identification of inguinal nerve is more complex in obese patients. In the chronic postoperative inguinal pain, the II nerve may have a predominant role in determining postoperative long-term symptoms. Dermatome Mapping Test in an easy and safe method for preoperative and postoperative 6 months evaluation of groin pain. The most important evidence of our analysis is that the prevalence of chronic pain is higher when the nerves were not identified.
MicroRNA-219c-5p regulates bladder fibrosis by targeting FN1
Authors: Liu Bowen , Ding Yafei , Li Peng , Wang Tao , He Siyuan , Jia Zhankui , Yang Jinjian 
Published: December 2020

AbstractBackgroundWe found that the bladders of multiple sclerosis mice were significantly fibrotic. This study aimed to investigate the relationship between fibronectin 1 (FN1) and bladder fibrosis, as well as the microRNAs involved in FN1 regulation.MethodsThe degree of bladder smooth muscle fibrosis was observed by immunohistochemistry. In addition, we used quantitative real-time polymerase chain reaction (RT-qPCR) and Western blotting to determine FN1 expression in bladders with different grades of fibrosis. Bioinformatics analysis revealed that miR-199a-3p, miR-219c-5p and miR-3572-3p could inhibit FN1 synthesis. Therefore, miR-199a-3p, miR-219c-5p and miR-3572-3p were overexpressed or knocked down in bladder smooth muscle cells (BSMCs), and the respective transfection and FN1 knockdown efficiencies were detected by RT-qPCR. Only miR-219c-5p overexpression and knockdown produced the expected results. A dual luciferase reporter assay was used to determine the targeting relationship between miR-219c-5p and FN1. Flow cytometry and Cell Counting Kit 8 (CCK8) experiments confirmed that miR-219c-5p reduced FN1 expression and affected the biological activity of smooth muscle cells. Agomir and anagomir of miR-219c-5p were transfected in vivo to observe the change of bladder fibrosis in mice.ResultsWith increasing bladder fibrosis, FN1 expression increased, while miR-199a-3p, miR-219c-5p, and miR-3572-3p expression levels decreased. The RT-qPCR results after transfection showed that only miR-219c-5p could regulate FN1. Indeed, the dual luciferase reporter assay results indicated that miR-219c-5p targeted FN1 directly. CCK8 and cell cycle assays showed that miR-219c-5p overexpression inhibited BSMC proliferation, while miR-219c-5p knockdown promoted BSMC proliferation. An apoptosis assay showed that miR-219c-5p overexpression promoted apoptosis, while miR-219c-5p knockdown inhibited BSMC apoptosis. The agomir and anagomir transfected with miR-219c-5p in vivo found that the bladder fibrosis of the mice in the agomir group was reduced, and the anagomir group was worse.ConclusionsOur findings indicate that FN1 up-regulation and miR-219c-5p down-regulation play an important role in the development of bladder fibrosis, and miR-219c-5p participates in bladder fibrosis by regulating FN1 expression. Thus, a novel antifibrotic function of miR-219c-5p is proposed, which may represent a potential target for the diagnosis and treatment of bladder fibrosis.
Interplay between traumatic brain injury and intimate partner violence: data driven analysis utilizing electronic health records
Authors: Liu Larry Y. , Bush William S. , Koyutürk Mehmet , Karakurt Günnur 
Published: December 2020

Abstract
Background
It is estimated that a majority of intimate partner violence (IPV) victims suffer from blunt force to the head, neck and the face area. Injuries to head and neck are among the major causes for traumatic brain injury (TBI).

Methods
In this interdisciplinary study, we aimed to characterize the key associations between IPV and TBI by mining de-identified electronic health records data with more than 12 M records between 1999 to 2017 from the IBM Explorys platform. For this purpose, we formulated a data-driven analytical framework to identify significant health correlates among IPV, TBI and six control cohorts. Using this framework, we assessed the co-morbidity, shared prevalence, and synergy between pairs of conditions.

Results
Our findings suggested that health effects attributed to malnutrition, acquired thrombocytopenia, post-traumatic wound infection, local infection of wound, poisoning by cardiovascular drug, alcoholic cirrhosis, alcoholic fatty liver, and drug-induced cirrhosis were highly significant at the joint presence of IPV and TBI.

Conclusion
To develop a better understanding of how IPV is related to negative health effects, it is potentially useful to determine the interactions and relationships between symptom categories. Our results can potentially improve the accuracy and confidence of existing clinical screening techniques on determining IPV-induced TBI diagnoses.
Development of a data-driven COVID-19 prognostication tool to inform triage and step-down care for hospitalised patients in Hong Kong: a population-based cohort study
Authors: Tsui Eva L. H. , Lui Carrie S. M. , Woo Pauline P. S. , Cheung Alan T. L. , Lam Peggo K. W. , Tang Van T. W. , Yiu C. F. , Wan C. H. , Lee Libby H. Y. 
Published: December 2020

Abstract
Background
This is the first study on prognostication in an entire cohort of laboratory-confirmed COVID-19 patients in the city of Hong Kong. Prognostic tool is essential in the contingency response for the next wave of outbreak. This study aims to develop prognostic models to predict COVID-19 patients’ clinical outcome on day 1 and day 5 of hospital admission.

Methods
We did a retrospective analysis of a complete cohort of 1037 COVID-19 laboratory-confirmed patients in Hong Kong as of 30 April 2020, who were admitted to 16 public hospitals with their data sourced from an integrated electronic health records system. It covered demographic information, chronic disease(s) history, presenting symptoms as well as the worst clinical condition status, biomarkers’ readings and Ct value of PCR tests on Day-1 and Day-5 of admission. The study subjects were randomly split into training and testing datasets in a 8:2 ratio. Extreme Gradient Boosting (XGBoost) model was used to classify the training data into three disease severity groups on Day-1 and Day-5.

Results
The 1037 patients had a mean age of 37.8 (SD ± 17.8), 53.8% of them were male. They were grouped under three disease outcome: 4.8% critical/serious, 46.8% stable and 48.4% satisfactory. Under the full models, 30 indicators on Day-1 and Day-5 were used to predict the patients’ disease outcome and achieved an accuracy rate of 92.3% and 99.5%. With a trade-off between practical application and predictive accuracy, the full models were reduced into simpler models with seven common specific predictors, including the worst clinical condition status (4-level), age group, and five biomarkers, namely, CRP, LDH, platelet, neutrophil/lymphocyte ratio and albumin/globulin ratio. Day-1 model’s accuracy rate, macro-/micro-averaged sensitivity and specificity were 91.3%, 84.9%/91.3% and 96.0%/95.7% respectively, as compared to 94.2%, 95.9%/94.2% and 97.8%/97.1% under Day-5 model.

Conclusions
Both Day-1 and Day-5 models can accurately predict the disease severity. Relevant clinical management could be planned according to the predicted patients’ outcome. The model is transformed into a simple online calculator to provide convenient clinical reference tools at the point of care, with an aim to inform clinical decision on triage and step-down care.
Insulin directly stimulates mitochondrial glucose oxidation in the heart
Authors: Karwi Qutuba G. , Wagg Cory S. , Altamimi Tariq R. , Uddin Golam M. , Ho Kim L. , Darwesh Ahmed M. , Seubert John M. , Lopaschuk Gary D. 
Published: December 2020

AbstractBackgroundGlucose oxidation is a major contributor to myocardial energy production and its contribution is orchestrated by insulin. While insulin can increase glucose oxidation indirectly by enhancing glucose uptake and glycolysis, it also directly stimulates mitochondrial glucose oxidation, independent of increasing glucose uptake or glycolysis, through activating mitochondrial pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. However, how insulin directly stimulates PDH is not known. To determine this, we characterized the impacts of modifying mitochondrial insulin signaling kinases, namely protein kinase B (Akt), protein kinase C-delta (PKC-δ) and glycogen synthase kinase-3 beta (GSK-3β), on the direct insulin stimulation of glucose oxidation.MethodsWe employed an isolated working mouse heart model to measure the effect of insulin on cardiac glycolysis, glucose oxidation and fatty acid oxidation and how that could be affected when mitochondrial Akt, PKC-δ or GSK-3β is disturbed using pharmacological modulators. We also used differential centrifugation to isolate mitochondrial and cytosol fraction to examine the activity of Akt, PKC-δ and GSK-3β between these fractions. Data were analyzed using unpaired t-test and two-way ANOVA.ResultsHere we show that insulin-stimulated phosphorylation of mitochondrial Akt is a prerequisite for transducing insulin’s direct stimulation of glucose oxidation. Inhibition of mitochondrial Akt completely abolishes insulin-stimulated glucose oxidation, independent of glucose uptake or glycolysis. We also show a novel role of mitochondrial PKC-δ in modulating mitochondrial glucose oxidation. Inhibition of mitochondrial PKC-δ mimics insulin stimulation of glucose oxidation and mitochondrial Akt. We also demonstrate that inhibition of mitochondrial GSK3β phosphorylation does not influence insulin-stimulated glucose oxidation.ConclusionWe identify, for the first time, insulin-stimulated mitochondrial Akt as a prerequisite transmitter of the insulin signal that directly stimulates cardiac glucose oxidation. These novel findings suggest that targeting mitochondrial Akt is a potential therapeutic approach to enhance cardiac insulin sensitivity in condition such as heart failure, diabetes and obesity.
Enhancement of Monascus yellow pigments production by activating the cAMP signalling pathway in Monascus purpureus HJ11
Authors: Liu Jiawei , Du Yun , Ma Hongmin , Pei Xiaolin , Li Mu 
Published: December 2020

Abstract
Background
Monascus azaphilone pigments (MonAzPs), which were produced by Monascus species, have been used as important food colorant and food supplements for more than one billion people during their daily life. Moreover, MonAzPs recently have received more attention because of their diverse physiological activities. However, the high microbial production of MonAzPs is still not always guaranteed. Herein, the aim of this study was to develop an efficient biotechnological process for MonAzPs production.

Results
In this study, exogenous cyclic adenosine monophosphate (cAMP) treatment not only induced MonAzPs production, but also stimulated the expression of a cAMP phosphodiesterase gene, named as mrPDE, in M. purpureus HJ11. Subsequently, MrPDE was identified as a cAMP phosphodiesterase by in vitro enzymatic reaction with purified enzyme. Further, a gene knockout mutant of mrPDE was constructed to verify the activation of cAMP signalling pathway. Deletion of mrPDE in M. purpureus HJ11 improved cAMP concentration by 378% and enhanced PKA kinase activity 1.5-fold, indicating that activation of cAMP signalling pathway was achieved. The ΔmrPDE strain produced MonAzPs at 8563 U/g, with a 2.3-fold increase compared with the WT strain. Moreover, the NAPDH/NADP+ ratio of the ΔmrPDE strain was obviously higher than that of the wild type strain, which led to a higher proportion of yellow MonAzPs. With fed-batch fermentation of the ΔmrPDE strain, the production and yield of MonAzPs achieved 332.1 U/mL and 8739 U/g.

Conclusions
A engineered M. purpureus strain for high MonAzPs production was successfully developed by activating the cAMP signalling pathway. This study not only describes a novel strategy for development of MonAzPs-producing strain, but also provides a roadmap for engineering efforts towards the production of secondary metabolism in other filamentous fungi.
Development and validation of a VHL-associated immune prognostic signature for clear cell renal cell carcinoma
Authors: Zhang Jin , Yan Aiting , Cao Wei , Shi Honglei , Cao Kai , Liu Xiaowu 
Published: December 2020

Abstract
Background
VHL mutation is the most common mutation in clear cell renal cell carcinoma (ccRCC). Here, we developed and validated an immune-related signature to predict the prognosis of ccRCC with VHL mutations.

Methods
VHL mutation status and RNA expression were analysed in the TCGA datasets and our cohort. LASSO Cox analysis was performed to develop an immune-related signature. Candidate genes for the immune-related signature were differentially expressed between VHLwt and VHLmut ccRCC patients.

Results
VHL mutations resulted in the downregulation of the immune response in ccRCC. To develop an immune-related signature, LASSO Cox analysis was constructed by immune-related genes that were differentially expressed between VHLwt (WHL wild type) and VHLmut (VHL mutation) ccRCC patients. The signature was developed and validated in the TCGA and our own cohort to classify patients into groups based on having a low or high risk of poor survival. Functional enrichment analysis showed that the immune-related pathway represented the major function and pathway. In addition, patients in the high-risk group had a positive correlation with low fractions of CD4 + T cells and dendritic cells and presented a lower expression of CTLA-4 and PD-1 than the low-risk group.

Conclusion
In this study, we proposed a novel immune-related signature, which is a feasible biomarker for predicting the overall survival in VHLmut patients with ccRCC.
CD44, a marker of cancer stem cells, is positively correlated with PD-L1 expression and immune cells infiltration in lung adenocarcinoma
Authors: Zhang Chenyue , Wang Hui , Wang Xia , Zhao Chenglong , Wang Haiyong 
Published: December 2020

AbstractBackgroundPD-L1 inhibitors is widely applied in lung adenocarcinoma patients. Tumor cells with high PD-L1 expression could trigger immune evasion. Cancer stem cells (CSCs) can evade from immunesurveillance due to their immunomodulating effects. However, the correlation between CSC and PD-L1 and some immune-related markers is seldom reported in patients with lung adenocarcinoma. Therefore, we aimed to ascertain their association in lung adenocarcinoma patients.MethodsWe assessed CD44 expression and its association with PD-L1 in lung adenocarcinoma, using Tumor Immune Estimation Resource (TIMER), which was further validated in our patient cohort. The immune cells infiltration was depicted by CIBERSORT using GEO database. The correlation between CD44 and immune cells was also analyzed. We further evaluated the prognostic role of CD44 in patients with lung adenocarcinoma both using Kaplan–Meier plotter and validated in our patient cohort.ResultsPositive association between CD44 and PD-L1 were found in lung adenocarcinoma patients. T cells CD4 memory resting cells and mast cells resting cells varied significantly between patients with CD44 high and those with CD44 low. Furthermore, positive association could be found between CD44 expression and immune cells. Arm-level depletion of CD44 was linked with B cell, CD4+T cell, neutrophil and dendritic cell infiltration. Patients with higher CD44 levels had worsened overall survival (OS).ConclusionsIn summary, these results demonstrate that CD44 was associated with PD-L1 and infiltration of immune cells, and was a negative prognostic factor for predicting worsened OS in lung adenocarcinoma.