Clinical efficacy and adverse events of baricitinib treatment for coronavirus disease-2019 (COVID-19): A systematic review and meta-analysis.

The benefits of baricitinib in coronavirus disease-2019 are inadequately defined. We performed a systematic review and meta-analysis of studies of baricitinib to determine its clinical efficacy and adverse events in patients with COVID-19. Databases were searched from their inception to September 5, 2021. The primary outcome was the coefficient of mortality. We also compared secondary indicators and adverse events between baricitinib treatment and placebo or other treatments. Twelve studies of 3564 patients were included and assessed qualitatively (modified Jadad and Newcastle-Ottawa Scale scores). Baricitinib effectively improved the mortality rate (relative risk of mortality = 0.56; 95% confidence interval: 0.46-0.69; p < 0.001; I2 = 2%), and this result was unchanged by subgroup analysis. Baricitinib improved intensive care unit admission, the requirement for invasive mechanical ventilation, and improved the oxygenation index. Data from these studies also showed that baricitinib slightly reduced the risk of adverse events. Regarding the choice of the drug dosage of baricitinib, the high-dose group appeared to have additional benefits for clinical efficacy. Our study shows that baricitinib may be a promising, safe, and effective anti-severe acute respiratory syndrome-coronavirus-2 drug candidate, with the advantages of low cost, easy production, and convenient storage.

Primary angiitis of the central nervous system mimicking a cerebellar tumor.

Primary angiitis of the central nervous system (PACNS), is a rare and poorly understood disease mainly characterized by multifocal segmental inflammation of the small and medium vessels of the central nervous system. Most PACNS are multiple lesions, occurring in the supratentorial subcortical and deep white matter, and only a few cases present as a tumor-like mass lesion. Herein, we describe an extremely rare case of PACNS occurred in the cerebellum, which mimicked a cerebellar tumor. To the best of our knowledge, this is the first reported case of cerebellar tumor-like PACNS proved by histopathological examination.

Basal Ganglionic Germinoma With Syncytiotrophoblastic Giant Cells Mimicking a Growing Hematoma.

Basal ganglionic germinoma (BGG) with syncytiotrophoblastic giant cells (STGC) is a rare type of ectopic germ cell tumors with mild elevation of human chorionic gonadotropin level. Intratumoral hemorrhage is not uncommon for BGG, but presenting with repeated hemorrhage is very rare. Herein, we described an extremely rare case of BGG with STGC mimicking a growing hematoma. Furthermore, the characteristics, treatment, and prognosis of BGG with STGC were investigated and reviewed.

Ferroptosis was involved in the oleic acid-induced acute lung injury in mice.

The aim of the present study was to investigate the role of ferroptosis in acute lung injury (ALI) mouse model induced by oleic acid (OA). ALI was induced in the mice via the lateral tail vein injection of pure OA. The histopathological score of lung, lung wet-dry weight ratio and the protein content of bronchoalveolar lavage fluid (BALF) were used as the evaluation indexes of ALI. Iron concentration, glutathione (GSH) and malondialdehyde (MDA) contents in the lung tissues were measured using corresponding assay kits. The ultrastructure of pulmonary cells was observed by transmission electron microscope (TEM), and the expression level of prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA was detected by quantitative polymerase chain reaction (q-PCR). Protein expression levels of glutathione peroxidase 4 (GPX4), ferritin and transferrin receptor 1 (TfR1) in lung tissues were determined by Western blot. The results showed that histopathological scores of lung tissues, lung wet-dry weight ratio and protein in BALF in the OA group were higher than those of the control group. In the OA group, the mitochondria of pulmonary cells were shrunken, and the mitochondrial membrane was ruptured. The expression level of PTGS2 mRNA in the OA group was seven folds over that in the control group. Iron overload, GSH depletion and accumulation of MDA were observed in the OA group. Compared with the control group, the protein expression levels of GPX4 and ferritin in lung tissue were down-regulated in the OA group. These results suggest that ferroptosis plays a potential role in the pathogenesis of ALI in our mouse model, which may provide new insights for development of new drugs for ALI.

Prognostic Significance of Zinc Finger E-Box-Binding Homeobox Family in Glioblastoma.

BACKGROUND Epithelial-mesenchymal transition (EMT) is an essential progress for tumor cell invasion to both epithelial and non-epithelial cancers, and zinc finger E-box-binding homeobox 1/2 (ZEB1/2) is a well-known promoter of EMT. In glioma cell lines, both ZEB1 and ZEB2 have been demonstrated to facilitate cancer cell proliferation and invasion with experiments in vitro. However, the clinical significance of ZEB1 and ZEB2 in glioblastoma (GBM) is still controversial. MATERIAL AND METHODS We detected the expression of ZEB1 and ZEB2 in 91 cases of GBM with immunohistochemistry and investigated the correlation between clinicopathological factors and ZEB family expression with Fisher test. By univariate analysis with Kaplan-Meier test, we explored the prognostic significance of ZEB1/2 expression and the clinicopathological factors in GBM. By multivariate analysis with the Cox regression model, we identified the independent prognostic factors in GBM. RESULTS The percentages of ZEB1 high expression and ZEB2 high expression were 31.9% (29/91) and 41.9% (36/91), respectively. High expression of ZEB2 was significantly associated with lower survival rate of GBM patients (P=0.001). ZEB2, lower KPS score (P=0.004), gross total resection (P<0.001) and higher Ki67 percentage (P=0.001) were notably correlated to worse prognosis of GBM. With multivariate analysis, high expression of ZEB2 was demonstrated to be an independent prognostic factor indicating unfavorable prognosis of GBM (P=0.001, HR=3.86, and 95%CI=1.61-9.23). CONCLUSIONS High expression of ZEB2 is an independent prognostic factor predicting unfavorable prognosis of GBM, indicating that ZEB2 or its downstream proteins may be potential drug targets of GBM therapy.

Endoscopic Transsphenoidal Surgery for an Adult Patient With Giant Exophytic Chiasmatic/Hypothalamic Glioma.

Optic pathway hypothalamic gliomas are intrinsic low-grade gliomas involving the optic nerve, chiasm, optic tract, and hypothalamus. The rarity of these tumors and their unpredictable course make assessment and standardization of treatment modalities difficult. Tumor debulking via various transcranial approaches was considered to be effective at controlling tumor growth, but with high rates of severe surgery-related complications. In the present case, endoscopic transsphenoidal surgery was initiated to debulk the exophytic chiasmatic/hypothalamic glioma with good preservation of hypothalamic and endocrine functions. The authors suggest transsphenoidal surgery with tumor debulking could be an effective and safe treatment for patients with chiasmatic/hypothalamic gliomas.

[Analysis of SMPD1 gene mutations in Chinese patients with Parkinson's disease].

OBJECTIVE: To explore the role of sphingomyedlin phosphodiesterase 1 (SMPD1) gene mutations in the pathogenesis of Parkinson's disease (PD). METHODS: For 110 Chinese patients with PD, all exons of the SMPD1 gene were sequenced, and the results were compared with reference sequence from GenBank to identify possible mutations. RESULTS: A novel heterozygous mutation Ex2:c.677C>A/p.P226Q (likely pathogenic) was identified in a patient, which resulted in substitution of Glutamic acid by Proline at position 226. In addition, two known single nucleotide polymorphisms (SNPs) Ex1:c.107T>C/p.V36A (benign) and Ex6:c.1522G>A/p.G508R (benign), and three previously reported SMPD1 mutations Ex2:c.T371T>G/p.L124R (uncertain significance), Ex2:c.636T>C/P.(=)(benign) and Ex6:c.1598C>T/p.P533L (uncertain significance) were identified. The novel p.P226Q mutation and p.P533L mutation were predicted to have a possibly damaging effect on the structure and function of SMPD1 protein, which in turn may lead to PD. CONCLUSION: The mutation rate of the SMPD1 gene was 3.64% among Chinese PD patients. Genetic variants of SMPD1 may increase the risk of PD.

2',3'-Dideoxycytidine Protects Dopaminergic Neurons in a Mouse Model of Parkinson's Disease.

DNA polymerase-ß (DNA pol-ß) plays a crucial role in the pathogenesis of Parkinson's disease (PD). The aim of this study was to investigate the neuroprotective effects of a DNA polymerase-ß inhibitor 2',3'-dideoxycytidine (DDC) in PD models. In the in vitro studies, primary cultured neurons were challenged with 1-methyl-4-phenylpyridinium ion (MPP+). The expression of DNA pol-ß was assessed using western blot. The neuroprotective effect of DNA pol-ß knockdown and DNA pol-ß inhibitor DDC was determined using cell viability assay and caspase-3 activity assay. We found that MPP+ induced neuronal death and the activation of caspase-3 in a dose-dependent manner. The expression of DNA pol-ß increased after the neurons were exposed to MPP+. DNA pol-ß siRNA or DNA pol-ß inhibitor DDC attenuated neuronal death induced by MPP+. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, MPTP treatment triggered behavioral deficits and nigrostriatal lesions. Pretreatment with DDC attenuated MPTP-induced behavioral deficits, dopaminergic neuronal death and striatal dopamine depletion in the MPTP mouse model. These results indicate that DNA pol-ß inhibitors may present a novel promising therapeutic option for the neuroprotective treatment of PD.

Gamma-synuclein binds to AKT and promotes cancer cell survival and proliferation.

Hyperactivation of AKT plays a critical role in the survival and proliferation of cancer cells. However, the molecular mechanisms underlying AKT activation remain elusive. Here, we tested the effect of γ-synuclein, a member of the synuclein family of proteins, on the activation of AKT. We show that the expression level of γ-synuclein is increased in non-small cell lung cancer (NSCLC) tissues. γ-Synuclein binds to the protein kinase domain of AKT and promotes its phosphorylation. Overexpression of γ-synuclein in H157 cells enhances cell proliferation and protects the cells from staurosporine-induced cytotoxicity. Knockdown of γ-synuclein attenuates AKT activation and cell proliferation induced by epidermal growth factor. The effect of γ-synuclein is abolished when AKT is depleted. Thus, γ-synuclein promotes cell survival and proliferation via activating AKT and may play a causal role in the pathogenesis of NSCLC.

The Coexistence of Rathke Cleft Cyst and Pituitary Adenoma.

Both of Pituitary adenoma (PA) and Rathke cleft cyst (RCC) are the most common and benign sellar lesions. Generally, the origin of RCC is considered to be derived from remnants of Rathke punch, while PA is formed by proliferation of the anterior wall of Rathke pouch. Although they have a possibility to share a common embryological origin, the coexistence of PA and RCC is extremely rare. Here, the authors report a 50-year-old male patient who was found to have a large cystic sellar lesion, and surgical resection revealed components of a RCC coexisting with a PA. This collision reminded us of the possibility of RCC coexisting with PA. Furthermore, a clinicopathologic relation of them were reviewed and investigated.

A Primary Cerebellar Glioblastoma Multiforme Mimicking Vestibular Schwannoma.

Cerebellar glioblastoma multiforme (cGBM) is rare in adults, accounting for <1% of all patients with glioblastoma multiforme (GBM). The accurate diagnosis of cGBM is important for establishing a suitable therapeutic schedule. However, the diagnosis of cerebellar GBM is not usually suspected preoperatively because of its rarity. Generally, patients with cGBMs typically presented with symptoms of raised intracranial pressure, and infrequently cerebellar symptoms such as gait ataxia and disequilibrium. Nevertheless, the authors reported a cGMB patient, with his clinical presentations and imaging characteristics mimicking a vestibular schwannoma. To the best of our knowledge, this is the first reported patient with cGBM mimicking a vestibular schwannoma. Furthermore, the diagnosis, treatment, and prognosis for cGBM were broadly investigated.

Primary Spinal Oligoastrocytoma.

Astrocytomas are the most common intramedullary spinal cord tumors in pediatric and adolescent patients and the incidence decreases with age. Spinal oligoastrocytoma, which is a mixed glioma with distinct astrocytic and oligodendroglial components, is an extremely rare pathology of the spinal cord. To authors' best of knowledge, there are only 7 spinal oligoastrocytomas reported in the English literature. Here, the authors report a patient of a pathologically confirmed spinal oligoastrocytoma, who presented with severe left leg pain and numbness. This patient reminds us of the rarity of spinal oligoastrocytoma, and the treatment and prognosis were also investigated and reviewed.

The down-regulation of neuroligin-2 and the correlative clinical significance of serum GABA over-expression in Hirschsprung's disease.

The goal of this study was to investigate the expression level of neuroligin-2 in different colon tissue segments of children with Hirschsprung's disease (HSCR) and the correlative clinical significance of serum Gamma-Aminobutyric Acid (serum GABA) in HSCR. Neuroligin-2 was assessed by Immunohistochemistry staining method on routine paraffin section from different colon tissue segments of HSCR (ganglionic colonic segment, transitional colonic segment and aganglionic colonic segment). Western-blot analysis and real-time fluorescence quantitative PCR(qRT-PCR) were applied to compare and evaluate the expression levels of neuroligin-2 from three segments of HSCR, and we used Enzyme-linked Immunosorbent Assay (ELISA) method to detect and compare the serum GABA between HSCR and non-HSCR. Immunohistochemistry staining demonstrated that intensive neuroligin-2 staining was detected in the ganglion cells in the ganglionic colonic and transitional colonic segments from the HSCR children; however, neuroligin-2 staining was down-regulated significantly in the aganglionic colonic segments. The expression levels of neuroligin-2 mRNA and protein in the aganglionic colonic segment were decreased compared to the ganglionic colonic segment and transitional colonic segment (P < 0.05). And the level of serum GABA was significantly higher in HSCR than that in non-HSCR. The expression of neuroligin-2 varies from different segments of HSCR. The down-regulation of neuroligin-2 in aganglionic colonic segments may be correlated with the excessive intestine contraction and further result in HSCR. The over-expression of serum GABA may be considered as a new diagnostic method of HSCR.

Prognostic analysis of high-flow nasal cannula therapy and non-invasive ventilation in mild to moderate hypoxemia patients and construction of a machine learning model for 48-h intubation prediction-a retrospective analysis of the MIMIC database.

Background: This study aims to investigate the clinical outcome between high-flow nasal cannula (HFNC) and non-invasive ventilation (NIV) therapy in mild to moderate hypoxemic patients on the first ICU day and to develop a predictive model of 48-h intubation. Methods: The study included adult patients from the MIMIC III and IV databases who first initiated HFNC or NIV therapy due to mild to moderate hypoxemia (100 < PaO2/FiO2 ≤ 300). The 48-h and 30-day intubation rates were compared using cross-sectional and survival analysis. Nine machine learning and six ensemble algorithms were deployed to construct the 48-h intubation predictive models, of which the optimal model was determined by its prediction accuracy. The top 10 risk and protective factors were identified using the Shapley interpretation algorithm. Result: A total of 123,042 patients were screened, of which, 673 were from the MIMIC IV database for ventilation therapy comparison (HFNC n = 363, NIV n = 310) and 48-h intubation predictive model construction (training dataset n = 471, internal validation set n = 202) and 408 were from the MIMIC III database for external validation. The NIV group had a lower intubation rate (23.1% vs. 16.1%, p = 0.001), ICU 28-day mortality (18.5% vs. 11.6%, p = 0.014), and in-hospital mortality (19.6% vs. 11.9%, p = 0.007) compared to the HFNC group. Survival analysis showed that the total and 48-h intubation rates were not significantly different. The ensemble AdaBoost decision tree model (internal and external validation set AUROC 0.878, 0.726) had the best predictive accuracy performance. The model Shapley algorithm showed Sequential Organ Failure Assessment (SOFA), acute physiology scores (APSIII), the minimum and maximum lactate value as risk factors for early failure and age, the maximum PaCO2 and PH value, Glasgow Coma Scale (GCS), the minimum PaO2/FiO2 ratio, and PaO2 value as protective factors. Conclusion: NIV was associated with lower intubation rate and ICU 28-day and in-hospital mortality. Further survival analysis reinforced that the effect of NIV on the intubation rate might partly be attributed to the other impact factors. The ensemble AdaBoost decision tree model may assist clinicians in making clinical decisions, and early organ function support to improve patients' SOFA, APSIII, GCS, PaCO2, PaO2, PH, PaO2/FiO2 ratio, and lactate values can reduce the early failure rate and improve patient prognosis.

Prophylactic antibiotics for preventing ventilator-associated pneumonia: a pairwise and Bayesian network meta-analysis.

BACKGROUND: The role of prophylactic antibiotics in preventing ventilator-associated pneumonia (VAP) in patients undergoing invasive mechanical ventilation (IMV) remains unclear. This network meta-analysis compared the efficacy and safety of antibiotic prophylaxis in preventing VAP in an IMV population in intensive-care units (ICUs). METHODS: We searched the PubMed, Web of Science, Embase, and Cochrane Library databases from inception to December 2021, to identify relevant studies assessing the impact of prophylactic antibiotics on the incidence of VAP, the mortality, and the duration of ICU stays and hospitalization to perform a meta-analysis. RESULTS: Thirteen studies (2144 patients) were included, 12 of which were selected for the primary analysis, which revealed that treatment with prophylactic antibiotics resulted in a lower VAP rate compared with control groups [risk ratio (RR) = 0.62]. Bayesian network meta-analysis indicated that aerosolized tobramycin and intravenous ampicillin-sulbactam presented the greatest likelihood being the most efficient regimen for reducing VAP. CONCLUSIONS: Antibiotic prophylaxis may reduce the incidence of VAP, but not the mortality, for adult patients undergoing IMV in ICUs. Tobramycin via nebulization and ampicillin-sulbactam via intravenous administration presented the greatest likelihood of being the most efficient regimen for preventing VAP. However, well-designed randomized studies are warranted before definite recommendations can be made.

Janus kinases inhibitors for coronavirus disease-2019: A pairwise and Bayesian network meta-analysis.

Background: JAK (Janus kinases) inhibitors have been proposed as a promising treatment option for the coronavirus disease-2019 (COVID-19). However, the benefits of JAK inhibitors and the optimum thereof for COVID-19 have not been adequately defined. Methods: Databases were searched from their inception dates to 17 June 2022. Eligible studies included randomized controlled trials and observational studies. Extracted data were analyzed by pairwise and network meta-analysis. The primary outcome was the coefficient of mortality. Results: Twenty-eight studies of 8,206 patients were included and assessed qualitatively (modified Jadad and Newcastle-Ottawa Scale scores). A pairwise meta-analysis revealed that JAK inhibitors effectively reduced the mortality (OR = 0.54; 95% CI: 0.46-0.63; P < 0.00001; I 2 = 32%) without increasing the risk of adverse events (OR = 1.02; 95% CI: 0.88-1.18; P = 0.79; I 2 = 12%). In a network meta-analysis, clinical efficacy benefits were seen among different types of JAK inhibitors (baricitinib, ruxolitinib, and tofacitinib) without the observation of a declined incidence of adverse events. The assessment of rank probabilities indicated that ruxolitinib presented the greatest likelihood of benefits regarding mortality and adverse events. Conclusion: JAK inhibitors appear to be a promising treatment for COVID-19 concerning reducing mortality, and they do not increase the risk of adverse events vs. standard of care. A network meta-analysis suggests that mortality benefits are associated with specific JAK inhibitors, and among these, ruxolitinib presents the greatest likelihood of having benefits for mortality and adverse events. Systematic review registration: [www.crd.york.ac.uk/prospero], identifier [CRD42022343338].

Efficacy of positive airway pressure therapy and high flow nasal cannula oxygen in acute cardiogenic pulmonary oedema: A protocol for systematic review and network meta-analysis.

Introduction: Positive airway pressure (PAP) therapy is currently the first-line respiratory support technique for acute respiratory failure (ARF) due to acute cardiogenic pulmonary edema (ACPE), but the accompanied adverse events and patient's intolerance with treatment in some cases limited its use in clinical practice. Some recent trials indicated that high-flow nasal cannula oxygen (HFNO) is a promising alternative to PAP therapy. In order to choose the optimum treatment for patients with ACPE, this network meta-analysis will firstly compares the efficacy of HFNO, PAP, and conventional oxygen therapy (COT). Methods and analysis: The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 statement and its extension for network meta-analysis will be followed in the conduct of this investigation. We will examine these databases: PubMed, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science. The ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform Search Portal will be used to search ongoing trials. Only randomized controlled trials meeting the eligibility criteria will be included. Through the Cochrane Collaboration's tool, the included studies' risk of bias will be assessed. The pairwise meta-analysis will be performed with RevMan 5.4.1 software. A Bayesian network meta-analysis will use random-effects models to derive odds ratios for the treatment effects of all interventions compared to each other using R software (version 3.6.1), and the rjags and gemtc packages. The Q statistic and I2 index will be used for investigating the heterogeneity, and subgroup analysis or sensitivity analysis will be used to explore the source of heterogeneity. In addition, the Grading of Recommendations Assessment, Development and Evaluation system will be used to inspect the quality of evidence.