Circulating miR-30e-3p induces disruption of neurite development in SH-SY5Y cells by targeting ABI1, a novel biomarker for schizophrenia.

Schizophrenia (SCZ) represents a set of enduring mental illnesses whose underlying etiology remains elusive, posing a significant challenge to public health. Previous studies have shown that the neurodevelopmental process involving small molecules such as miRNA and mRNA is one of the etiological hypotheses of SCZ. We identified and verified that miR-30e-3p and ABI1 can be used as biomarkers in peripheral blood transcriptome sequencing data of patients with SCZ, and confirmed the regulatory relationship between them. To further explore their involvement, we employed retinoic acid (RA)-treated SH-SY5Y differentiated cells as a model system. Our findings indicate that in RA-induced SH-SY5Y cells, ABI1 expression is up-regulated, while miR-30e-3p expression is down-regulated. Functionally, both miR-30e-3p down-regulation and ABI1 up-regulation promote apoptosis and inhibit the proliferation of SH-SY5Y cells. Subsequently, the immunofluorescence assay detected the expression location and abundance of the neuron-specific protein ß-tubulinIII. The expression levels of neuronal marker genes MAPT, TUBB3 and SYP were detected by RT-qPCR. We observed that these changes of miR-30e-3p and ABI1 inhibit the neurite growth of SH-SY5Y cells. Rescue experiments further support that ABI1 silencing can correct miR-30e-3p down-regulation-induced SH-SY5Y neurodevelopmental defects. Collectively, our results establish that miR-30e-3p's regulation of neurite development in SH-SY5Y cells is mediated through ABI1, highlighting a potential mechanism in SCZ pathogenesis.

Immunogenicity and safety of a live-attenuated varicella vaccine in a healthy population aged 13 years and older: A randomized, double-blind, controlled study.

OBJECTIVES: Vaccines for prevention against varicella are important for adolescents and adults, who have an increased risk of severe varicella. This study aimed to evaluate the immunogenicity and safety of a two-dose immunization schedule of a live-attenuated varicella vaccine (VarV) manufactured by Sinovac (Dalian) in healthy adolescents and adults. METHODS: A randomized, double-blind, controlled clinical trial was conducted in healthy population aged ≥ 13 years old in China. Participants in block 1 were randomly assigned (1:1) to receive two doses of either the test vaccine or an active control vaccine, administered 4, 6 or 8 weeks apart. Participants in block 2 were randomly assigned (2:1) to receive two doses of test vaccine or placebo, administered 10 weeks apart. The primary immunogenicity endpoint was the seroconversion rates and GMTs of varicella zoster virus (VZV) antibodies measured by fluorescent-antibody-to-membrane-antigen (FAMA) 4 weeks post-immunization. The primary safety endpoint was the incidence of adverse reactions within 4 weeks after each dose. RESULTS: A total of 2398 participants were enrolled. The seroconversion rates of VZV antibodies were 79.55 % in the test group and 76.41 % in the active control group respectively 4 weeks after two doses of pooled schedule, with the difference of 3.14 % (95 %CI: -0.69 %, 6.97 %). The GMTs were 1:162.07 and 1:160.04 respectively, with the ratio of 1.013 (95 %CI: 0.910, 1.127). Both the seroconversion rates and GMTs reached the prespecified non-inferiority criteria. Two-dose schedule with an interval of 10 weeks could also induce high immune responses, with a seroconversion rate of 83.22 % and a GMT of 1:160.38 in the test group. Safety profiles were similar among the test group, active control group and placebo group. CONCLUSION: VarV, manufactured by Sinovac (Dalian), demonstrated higher immune response and better flexibility in the immunization schedule among heathy population aged 13 years and older, without increased safety risk.

Safety analysis of a live attenuated mumps vaccine in healthy adolescents in China: A phase 4, observational, open-label trial.

Mumps is an acute infectious disease, which was well controlled in the past, but recently it has resurged in some areas. This study aimed to evaluate the safety profile of the live attenuated mumps vaccine after large-scale vaccination. We conducted an observational, open-label phase 4 trial in Shaanxi, China from October 2020 to March 2021. Eligible participants were freshmen of junior high school who were not above 14 years old. Adverse events following immunization (AEFI) monitoring was carried out by active and passive surveillance. Safety follow-ups were conducted during the study participation. Overall, 10057 subjects were enrolled in the active surveillance analysis. A total of 214 subjects reported adverse reactions with an incidence of 2.13% (214/10057). Most adverse reactions were grade 1, and the incidence of grade 1 adverse reactions was 1.44% (145/10057); 0.60% for grade 2 (60/10057); and 0.09% for grade 3 (9/10057). The majority of adverse reactions were solicited (1.73%, 174/10057). Injection-site pain was the most frequently reported local adverse reaction (0.71%, 71/10057), followed by redness (0.29%, 29/10057). The most common systemic adverse reactions were nausea (0.19%, 19/10057) and fever (0.16%, 16/10057). For passive AEFI surveillance, 57 AEFI cases were reported, with an incidence of 19.28/100000 (57/287608). And most AEFI cases were common adverse reactions (66.67%, 38/57). In total, the live attenuated mumps vaccine evaluated in this trial has a favorable safety profile and can be used for large-scale inoculation.

The causal effect of schizophrenia on fractures and bone mineral density: a comprehensive two-sample Mendelian randomization study of European ancestry.

BACKGROUND: Schizophrenia was clinically documented to co-occur with fractures and aberrant bone mineral density (BMD), but the potential causal relationship remained unclear. This study aimed to test the causal effects between schizophrenia and fractures as well as aberrant BMD by conducting Mendelian randomization (MR) analyses. METHODS: Two-sample MR was utilized, based on instrumental variables from large genome-wide association studies (GWAS) of schizophrenia as exposure, to identify the causal association of schizophrenia with mixed fractures, fractures at different body sites (including skull and facial bones, shoulder and upper arm, wrist and hand, and femur) and BMDs of forearm (FA), femoral neck (FN), lumbar spine (LS) and estimated BMD (eBMD). Multivariable Mendelian randomization (MVMR) analysis was performed to minimize the confounding effect of body mass index (BMI). RESULTS: Result from inverse variance weighting (IVW) method provided evidence schizophrenia increased the risk of fractures of skull and facial bones [odds ratio (OR) = 1.0006, 95% confidence interval (CI): 1.0003 to 1.0010] and femur [OR =1.0007, 95% CI: 1.0003 to 1.0011], whereas, decreased the level of eBMD [ß (95%CI): -0.013 (-0.021, -0.004)]. These causal effects still existed after adjusting for BMI. Sensitivity analyses showed similar results. However, no causal effect of schizophrenia on fracture or BMD in other parts was detected. CONCLUSION: The current finding confirmed that schizophrenia was causally associated with the fractures of skull, face and femur as well as eBMD, which might remind psychiatrists to pay close attention to the fracture risk in schizophrenic patients when formulating their treatment strategies.

Assessment of causal relationships between omega-3 and omega-6 polyunsaturated fatty acids in bipolar disorder: a 2-sample bidirectional mendelian randomization study.

Omega-3 fatty acids may be protective against bipolar disorder (BD), whereas omega-6 fatty acids and an increased omega-6:omega-3 ratio may increase the risk of BD. This causal relationship has not yet been established. We attempted to prove the existence of these causal relationships in this study. Datasets on omega-3, omega-6, and omega-6:omega-3 ratios were obtained from the UK Biobank. The EBI database was used to obtain the BD dataset. SNPs associated with fatty acids were identified as instrumental variables (IVs) that met the criteria of P < 5 × 10-8, LD (R2 > 0.01), and kb < 10 000. The main analytical method in this study was the inverse variance weighted (IVW) method. Furthermore, we employ a variety of methods for sensitivity analysis. According to the IVW analysis, higher omega-3 levels were associated with a lower risk of BD (OR = 0.884, 95%CI: 0.796-0.982, P < 0.05). An increase in the omega-6:omega-3 ratio was associated with an increased risk of BD (OR = 1.172, 95%CI: 1.046-1.314, P < 0.05), but no causal relationship between omega-6 levels and BD risk was unearthed. Our MR findings suggest that the ratio of omega-3, omega-6:omega-3 is associated with the risk of BD. It is important to be concerned about the risk of BD in individuals with low serum omega-3 intake and a high omega-6:omega-3 ratio.

Establishment of a schizophrenia classifier based on peripheral blood signatures and investigation of pathogenic miRNA-mRNA regulation.

To date, the diagnosis of schizophrenia (SCZ) mainly relies on patients' or guardians' self-reports and clinical observation, and the pathogenesis of SCZ remains elusive. In this study, we sought to develop a reliable classifier for diagnosing SCZ patients and provide clues to the etiology and pathogenesis of SCZ. Based on the high throughput sequencing analysis of peripheral blood miRNA expression profile and weighted gene co-expression network analysis (WGCNA) in our previous study, we selected eleven hub miRNAs for validation by qRT-PCR in 51 SCZ patients and 51 controls. miR-939-5p, miR-4732-3p let-7d-3p, and miR-142-3p were confirmed to be significantly up-regulated, and miR-30e-3p and miR-23a-3p were down-regulated in SCZ patients. miR-30e-3p with the most considerable fold change and statistically significance was selected for targeting validation. We first performed bioinformatics prediction followed by qRT-PCR and verified the up-regulation of potential target mRNAs (ABI1, NMT1, HMGB1) expression. Next, we found that the expression level of ABI1 was significantly up-regulated in SH-SY5Y cells transfected with miR-30e-3p mimics. Lastly, we conducted a luciferase assay in 293T cells confirming that miR-30e-3p could directly bind with the 3'untranslated region (3'-UTR) of ABI1, revealing that miR-30e-3p might play a role in the polymerization of neuronal actin and the reconstruction of the cytoskeleton via the downstream regulation of ABI1. In addition, we constructed a classifier by a series of bioinformatics algorithms and evaluated its diagnostic performance. It appears that the classifier consists of miRNAs and mRNAs possess a better discrimination performance than individual miRNA or mRNA in SCZ.

Immunogenicity and safety of a live attenuated varicella vaccine co-administered with inactive hepatitis A vaccine: A phase 4, single-center, randomized, controlled trial.

Co-administration of vaccines can facilitate the introduction of new vaccines in immunization schedules. This study aimed to evaluate the immunogenicity and safety of co-administration with live attenuated varicella vaccine (VarV) and inactivated hepatitis A vaccine (HepA) among children aged 12 ~ 15 months. In this phase 4 clinical trial, 450 children were randomized with a ratio of 1:1 to receive VarV and Hep A simultaneously (Group A) or separately (Group B). The primary endpoints were the seroconversion rate of anti-varicella-zoster virus (VZV) antibodies 42 days after vaccination of VarV and the seroconversion rate of anti-Hepatitis A virus (HAV) antibodies 30 days after two-dose vaccination of HepA. After full immunization, the seroconversion rates of anti-VZV antibodies were 91.79% in Group A and 92.15% in Group B; the geometric mean titers (GMTs) were 11.80 and 12.19, respectively. The seroconversion rates of anti-HAV antibodies were 99.48% in Group A and 100.0% in Group B; the geometric mean concentrations (GMCs) reached 9499.11 and 9528.36 mIU/ml, respectively. The lower limits of the 95% CI for the seroconversion difference of anti-VZV antibodies and anti-HAV antibodies were -5.86% and -2.90%, which greater than the predefined non-inferiority margin (-10%). The incidence rate of adverse reactions in Group A was lower than Group B (9.33% vs 16.22%), and only one serious adverse event was reported in Group B, which was unrelated to the study vaccine. In conclusion, the co-administration of VarV with HepA has non-inferior immunogenicity and safety profiles were quite comparable with the separate administration of both vaccines.Trial registration number: NCT05526820 (ClinicalTrials.gov).

Protective role of antioxidant supplementation for depression and anxiety: A meta-analysis of randomized clinical trials.

BACKGROUND: New research supports an integrated approach to treating depression, and lifestyle modifications should be a regular component of both preventative and treatment programs. Therefore, in order to investigate the relationship between various antioxidant supplements and depressive status, we carried out a meta-analysis of randomized controlled trials (RCT). METHODS: We thoroughly searched PubMed, Medline, Scopus, and Web of Science databases to screen publications focusing on the effects of antioxidant supplements on depression status. The meta-analysis mainly compared depression scores between groups that received antioxidant supplements and controls. We also pooled studies reporting changes in anxiety status as a secondary outcome. RESULTS: 52 studies with 4049 participants were eventually identified. The meta-analysis found that the positive effect of antioxidant supplementation, such as magnesium (SMD = 0.16, p = 0.03), zinc (SMD = 0.59, p = 0.01), selenium (SMD = 0.33, p = 0.009), CoQ10 (SMD = 0.97, p = 0.05), tea and coffee (SMD = 1.15, p = 0.001) and crocin (MD = 6.04, p < 0.00001), on depressive status were all significant. And antioxidant supplementation also showed significant improvement in anxiety (SMD = 0.40, p < 0.00001). Subgroup analysis by scale types and countries were performed, and antioxidant supplementation's positive effects on depressive and anxiety states remained significant. LIMITATIONS: This study did not limit the characteristics of the included population, and the diversity of scales also contributed to the heterogeneity. CONCLUSION: Intake of antioxidant supplements is associated with improved depression and anxiety states, further affirms the therapeutic potential of antioxidant supplements as adjunctive therapy to conventional antidepressants.

Long-term effects of antipsychotics on mortality in patients with schizophrenia: a systematic review and meta-analysis

Objective: To gather current evidence on the impact of antipsychotics on long-term mortality in patients with schizophrenia. Methods: We systematically searched for articles in Embase, PubMed, and PsycINFO reporting the long-term mortality (follow-up > 1 year) of patients with schizophrenia who were using any antipsychotics. We then conducted multiple meta-analyses to determine differences in long-term mortality between different types of antipsychotics. Results: We identified 45 articles that provided unadjusted long-term mortality rates, including 46,171 deaths during 2,394,911 person-years. The pooled mortality rate was 9.9 (95%CI = 7.4-12.7) per 1,000 person-years. The unadjusted crude mortality rate of antipsychotic drug users was lower than that of non-users (risk ratio [RR] = 0.546, 95%CI = 0.480-0.621), first-generation antipsychotics caused higher all-cause mortality than second-generation antipsychotics (RR = 1.485, 95%CI = 1.361-1.620), and polypharmacy had better effects than monotherapy on long-term mortality (RR = 0.796, 95%CI = 0.689-0.921). As for the causes of death, heart disease and cardiovascular disease ranked highest among cause-specific mortality (5.6 per 1,000 person-years). Conclusion: Since antipsychotics had a beneficial effect on long-term mortality in schizophrenia, greater precaution should be taken with patients who do not take them. However, since disease severity, comorbidities, and other confounding factors cannot be fully controlled, further research and verification are needed.

ABCB9 polymorphism rs61955196 is associated with schizophrenia in a Chinese Han population.

BACKGROUND: Schizophrenia (SCZ) is a complex disease which can be affected by both genetic and environmental factors. Prenatal famine exposure may cause changes in DNA methylation levels of genes. Meanwhile, maternal nutrition during pregnancy is a pivotal environmental factor in the development of SCZ. DNA methylation may be an intermediate factor mediating exposure to famine during pregnancy and SCZ, and DNA methylation quantitative trait loci might serve as a promising tool for linking SCZ and prenatal famine. AIM: To analyze the association between prenatal famine exposure and SCZ risk in Northeast Han Chinese through analysis of DNA methylation related loci. METHODS: A total of 954 Han Chinese from Northeast China were recruited, including 443 patients with SCZ and 511 healthy controls. The participants were further divided into famine (born in 1960-1962) and non-famine (born in 1963-1965) groups to investigate the effect of prenatal famine exposure. Four single-nucleotide polymorphisms (SNPs) selected according to the relevant literature were genotyped, namely, rs11917047 in PTPRG, rs2239681 in IGF2, rs3842756 in INSIGF, and rs61955196 in ABCB9. DNA were extracted from peripheral blood samples, and the genotypes of these SNP loci were detected using the improved Multiple Ligase Detection Reaction multiple SNP typing technique. The associations of the DNA methylation related SNPs with SCZ risk and prenatal famine, and their interactions were analyzed using logistic regression analysis and generalized multifactor dimensionality reduction (GMDR) software. RESULTS: Based on the sequencing data, genotype distributions and allele frequencies of the four selected SNPs were determined. All genotype frequencies of the four SNPs in the healthy control group were tested for deviation from Hardy-Weinberg equilibrium (P > 0.05). Logistic regression analysis showed that rs61955196 was significantly associated with SCZ risk in the log-additive model [odds ratio (OR): 1.22; 95% confidence interval (CI): 1.01-1.48; P = 0.040]. We also found that the rs61955196 allele was related with an enhanced risk of SCZ (G>C, OR: 1.22; 95%CI: 1.01-1.47; P = 0.042). However, no associations were observed between rs11917047, rs2239681, or rs3842756 and SCZ risk. Under the optimal genetic model, no significant association of famine with the four SNPs was seen. Though the gene-gene interactions between rs2239681 and rs61955196 were found in GMDR analysis, none of the gene-gene interactions and gene-famine interactions were associated with the risk of SCZ. CONCLUSION: Our study suggested that rs61955196 in ABCB9 is associated with SCZ susceptibility in Northeast Han Chinese, providing insight into genetic effects on SCZ.

2D electrene LaH2monolayer: an ideal ferrovalley direct semiconductor with room-temperature ferromagnetic stability.

In developing nonvolatile valleytronic devices, ferromagnetic (FM) ferrovalley semiconductors are critically needed due to the existence of spontaneous valley polarization. At present, however, the known real materials have various drawbacks towards practical applications, including the in-plane FM ground state, low Curie temperature (TC), small valley polarization, narrow energy window with clean polarized valley, and indirect bandgap. From first-principles calculations, here we predict anideal ferrovalley semiconductor, honeycomb LaH2monolayer (ML), whose intrinsic properties can overcome all these shortcomings. We demonstrate that LaH2ML, having satisfied structural stability, is a FM half-semiconducting electrene (La3+2H-⋅e-) with its magnetic moments localized at the lattice interstitial sites rather than La atoms. At the same time, LaH2ML holds the following desired attributes: a robust out-of-plane FM ground state with a highTC(334 K), a sizable valley polarization (166 meV), a wide energy window (137 meV) harboring clean single-valley carriers, and a direct bandgap. These results identify a much needed ideal ferrovalley semiconductor candidate, holding the promising application potential in valleytronics and spintronics devices.

Identification of potential biomarkers and their correlation with immune infiltration cells in schizophrenia using combinative bioinformatics strategy.

Many studies have identified changes in gene expression in brains of schizophrenia patients and their altered molecular processes, but the findings in different datasets were inconsistent and diverse. Here we performed the most comprehensive analysis of gene expression patterns to explore the underlying mechanisms and the potential biomarkers for early diagnosis in schizophrenia. We focused on 10 gene expression datasets in post-mortem human brain samples of schizophrenia downloaded from gene expression omnibus (GEO) database using the integrated bioinformatics analyses including robust rank aggregation (RRA) algorithm, Weighted gene co-expression network analysis (WGCNA) and CIBERSORT. Machine learning algorithm was used to construct the risk prediction model for early diagnosis of schizophrenia. We identified 15 key genes (SLC1A3, AQP4, GJA1, ALDH1L1, SOX9, SLC4A4, EGR1, NOTCH2, PVALB, ID4, ABCG2, METTL7A, ARC, F3 and EMX2) in schizophrenia by performing multiple bioinformatics analysis algorithms. Moreover, the interesting part of the study is that there is a correlation between the expression of hub genes and the immune infiltrating cells estimated by CIBERSORT. Besides, the risk prediction model was constructed by using both these genes and the immune cells with a high accuracy of 0.83 in the training set, and achieved a high AUC of 0.77 for the test set. Our study identified several potential biomarkers for diagnosis of SCZ based on multiple bioinformatics algorithms, and the constructed risk prediction model using these biomarkers achieved high accuracy. The results provide evidence for an improved understanding of the molecular mechanism of schizophrenia.

Identifying crucial biomarkers in peripheral blood of schizophrenia and screening therapeutic agents by comprehensive bioinformatics analysis.

Schizophrenia (SCZ) is a sophisticated neurodevelopmental disorder, but the mechanisms remain ambiguous. Thus, we analyzed the transcriptomic datasets to investigate the molecular mechanisms of SCZ to pinpoint novel biomarkers and suggest treatment agents. Four peripheral blood datasets were retrieved from the Gene Expression Omnibus (GEO) database, altogether 27 robust Differentially Expressed Genes (DEGs) were ascertained by robust rank aggregation (RRA) methodology. Enrichment analysis, which performed by Enrichr platform, demonstrated that DEGs are predominantly engaged in immune and inflammatory. Protein-protein interaction (PPI) network was constructed by STRING then visualized by Cytoscape. Hub genes identified by cytohubba plug-in were CXCL2, TLR9, SLPI, LY96, G0S2, EGR2, SELENBP1, NDUFA4, GNLY, CCL22. CIBERSORT algorithm was applied to evaluate the situation of immune infiltration, which revealed differences in T-cell CD8, T-cell CD4 memory resting and macrophage M0. The NetworkAnalyst platform was adopted to detect transcription factors (TFs), microRNAs (miRNAs), diseases and chemicals that interact with DEGs, while drugs interacted with DEGs were detected by Enrichr. TFs such as FOXC1, GATA2, NFIC, USF2, E2F1, miRNAs like mir-16-5p, mir-1-3p, mir-124-3p, mir-155-5p, mir-27a-3p are essential in the regulation of DEGs. mir-367-SMAD7-EGR1, mir-367-SMAD7-ARNT, mir-21-SMAD7-EGR1 may be promising biomarkers for SCZ. DEGs were intimately associated with Myocardial Ischemia, Inflammation, Reperfusion Injury. Chemicals such as VPA, cyclosporine, Aflatoxin B1, arsenic trioxide, drugs like diphenylpyraline, trimethoprim, 4-Aminobenzohydrazide, lanatoside C, may have significant implications for treatment of SCZ. These results would shed light on the molecular mechanisms of SCZ and suggest promising diagnostic biomarkers in peripheral blood and therapeutic tactics.

Immunogenicity and Safety of a Booster Dose of Live Attenuated Varicella Vaccine, and Immune Persistence of a Primary Dose for Children Aged 2 to 6 Years.

AIM: To evaluate the immunogenicity and safety of a booster dose of live attenuated varicella vaccine (VarV) manufactured by Sinovac (Dalian) Vaccine Technology Co. Ltd., and the immune persistence of a primary dose in 2- to 6-year-old children. METHODS: A phase IV, open-label study was conducted in China. Children previously vaccinated with a single dose of VarV at 1~3 years old received one dose of homologous VarV in the first year, the second year, or the third year after the primary immunization as booster immunization. Immune persistence was evaluated in an immune persistence analysis set, while immunogenicity was evaluated in a per-protocol analysis set, and safety was evaluated in a safety analysis set. The primary endpoint was the seropositive rate and the seroconversion rate of VarV antibody. The trial was registered at ClinicalTrials.gov (NCT02981836). RESULTS: From July 2018 to August 2020, a total of 849 vaccinated children received the booster vaccination of VarV, one booster dose for each child (301 vaccinated in the first year after primary immunization (Group 1), 276 vaccinated in the second year after primary immunization (Group 2), 272 vaccinated in the third year after primary immunization (Group 3)). The seropositive rates were 99.34%, 97.83%, and 98.16% in Groups 1-3, with GMTs of 1:22.56, 1:18.49, and 1:18.45, respectively. Thirty days after the vaccine booster dose, the seropositive rates of the three groups were all 100% and the seroconversion rates were 52.54%, 67.46%, and 66.67%, with GMTs of 1:68.49, 1:76.32 and 1:78.34, respectively. The seroconversion rates in Groups 2 and 3 were both higher than that in Group 1 (p = 0.0005 and p = 0.0008). The overall incidence of adverse reactions was 7.77%, with 7.64%, 8.33%, and 7.35% in Groups 1, 2, and 3, respectively. The main symptom among adverse reactions was fever, the incidence of which ranged from 5.07% to 6.64% in each group, and no vaccine-related serious adverse events occurred. CONCLUSIONS: VarV had good immune persistence in 1~3 years after primary immunization. A vaccine booster dose for children aged 1~3 years after primary immunization recalled specific immune response to varicella-zoster virus, with no safety concerns increased.

Identification of Peripheral Blood miRNA Biomarkers in First-Episode Drug-Free Schizophrenia Patients Using Bioinformatics Strategy.

Schizophrenia (SCZ) is a polygenic, complex mental disorder of which a diagnosis is often made based on psychiatric history and clinical observation with few available objectives and detectable biomarkers. To identify co-expressed miRNA modules in schizophrenia patients and verify the possibility of using peripheral blood miRNAs as novel biomarkers, high-throughput sequencing was performed on 15 first-episode schizophrenia patients (FES) and 15 healthy controls (CTL). We found 79 differential expressed miRNAs (DEMs) in FES patients and three FES-related co-expression miRNA modules by miRNA-seq data standardized difference analysis and weighted gene co-expression network analysis (WGCNA). Then, 41 hub miRNAs were screened from the intersection of key modules and DEMs, among which miR-9-5p, miR-144-3p, miR-328-3p, and miR-4467 were selected for qRT-PCR verification in a larger sample (FES = 35, CTL = 60). The level of miR-9-5p in FES patients was downregulated, and miR-4467 was upregulated with better diagnostic performance (AUC = 0.719). The target genes of miR-9-5p engage in the biological processes (BP) such as body behaviour, neuronal differentiation regulation, nervous system development, and neurotrophin signaling pathways. Their hub target genes were also located, including NEDD4, EIF4G1, FBXL16, and FBXL3. Summarily, miR-9-5p and miR-4467 hold promise in blood diagnosis for SCZ, and miR-9-5p might affect the onset and development of SCZ through target regulation of neurodevelopment-related mRNAs. Our findings revealed the complex relationship between the miRNA co-expression network and FES, providing more verifiable biomarkers for SCZ early diagnosis and clues for the etiology of schizophrenia.

Pan-cancer analysis on the role of PIK3R1 and PIK3R2 in human tumors.

Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1) is believed to function as a tumor suppressor, while Phosphoinositide-3-Kinase Regulatory Subunit 2 (PIK3R2) as a tumor driver. However, there is no systematic pan-cancer analysis of them. The pan-cancer study comprehensively investigated the gene expression, genetic alteration, DNA methylation, and prognostic significance of PIK3R1 and PIK3R2 in 33 different tumors based on the TIMER, GEPIA, UALCAN, HPA, cBioPortal, and Kaplan-Meier Plotter database. The results indicated that PIK3R1 is lowly expressed in most tumors while PIK3R2 is highly expressed in most tumors, and abnormal gene expression may be related to promoter methylation. Moreover, not only mutations, downregulation of PIK3R1 and upregulation of PIK3R2 were found to be detrimental to the survival of most cancer patients as well. Furthermore, the expression of both PIK3R1 and PIK3R2 was associated with the level of immune infiltration in multiple tumors, such as breast invasive carcinoma. Our study conducted a comparatively comprehensive analysis of the role of PIK3R1 and PIK3R2 in a variety of cancers, contributing to further study of their potential mechanisms in cancer occurrence and progression. Our findings suggested that PIK3R1 and PIK3R2 could serve as prognostic markers for several cancers.

Identification of potential blood biomarkers for early diagnosis of schizophrenia through RNA sequencing analysis.

Schizophrenia (SCZ) is a highly heritable, polygenic complex mental disorder with imprecise diagnostic boundaries. Finding sensitive and specific novel biomarkers to improve the biological homogeneity of SCZ diagnosis is still one of the research hotspots. To identify the blood specific diagnostic biomarkers of SCZ, we performed RNA sequencing (RNA-seq) on 30 peripheral blood samples from 15 first-episode drug-naïve SCZ patients and 15 healthy controls (CTL). By performing multiple bioinformatics analysis algorithms based on RNA-seq data and microarray datasets, including differential expression genes (DEGs) analysis, WGCNA and CIBERSORT, we first identified 6 specific key genes (TOMM7, SNRPG, KRT1, AQP10, TMEM14B and CLEC12A) in SCZ. Moreover, we found that the proportions of lymphocyte, monocyte and neutrophils were significantly distinct in SCZ patients with CTL samples. Therefore, combining various features including age, sex and the novel blood biomarkers, we constructed the risk prediction model with three classifiers (RF: Random Forest; SVM: support vector machine; DT: decision tree) through repeated k-fold cross validation ensuring better generalizability. Finest result of Area under Receiver Operating Characteristic (AUROC) score of 0.91 was achieved by RF classifier and with a comparable good performance of AUROC 0.77 in external validation dataset. A lower AUROC of 0.63 was demonstrated when it was further applied to a Bipolar disorder (BPD) cohort. In conclusion, the study identified three peripheral core immunocytes and six key genes associated with the occurrence of SCZ, and further studies are required to test and validate these novel biomarkers for early diagnosis and treatment of SCZ.

Long-term effects of antipsychotics on mortality in patients with schizophrenia: a systematic review and meta-analysis.

OBJECTIVE: To gather current evidence on the impact of antipsychotics on long-term mortality in patients with schizophrenia. METHODS: We systematically searched for articles in Embase, PubMed, and PsycINFO reporting the long-term mortality (follow-up > 1 year) of patients with schizophrenia who were using any antipsychotics. We then conducted multiple meta-analyses to determine differences in long-term mortality between different types of antipsychotics. RESULTS: We identified 45 articles that provided unadjusted long-term mortality rates, including 46,171 deaths during 2,394,911 person-years. The pooled mortality rate was 9.9 (95%CI = 7.4-12.7) per 1,000 person-years. The unadjusted crude mortality rate of antipsychotic drug users was lower than that of non-users (risk ratio [RR] = 0.546, 95%CI = 0.480-0.621), first-generation antipsychotics caused higher all-cause mortality than second-generation antipsychotics (RR = 1.485, 95%CI = 1.361-1.620), and polypharmacy had better effects than monotherapy on long-term mortality (RR = 0.796, 95%CI = 0.689-0.921). As for the causes of death, heart disease and cardiovascular disease ranked highest among cause-specific mortality (5.6 per 1,000 person-years). CONCLUSION: Since antipsychotics had a beneficial effect on long-term mortality in schizophrenia, greater precaution should be taken with patients who do not take them. However, since disease severity, comorbidities, and other confounding factors cannot be fully controlled, further research and verification are needed.

A Retrospective Study of 268 Patients with SARS-CoV-2 Infection to Evaluate the Association Between Blood Glucose and Severity of COVID-19 Pneumonia and Patient Mortality.

BACKGROUND Diabetes is one of the most commonly reported comorbidities among patients infected with SARS-CoV-2. This retrospective study of patients with SARS-CoV-2 infection was conducted to evaluate the association between blood glucose levels and the severity of COVID-19 pneumonia and patient mortality. MATERIAL AND METHODS A total of 268 patients with confirmed SARS-CoV-2 infection were included in this retrospective study. We obtained demographic characteristics, clinical symptoms, laboratory data, and survival information from patients' electronic medical records. Blood glucose was measured on admission to the hospital. Comorbidities, including hypertension, diabetes, chronic kidney disease, chronic liver disease, chronic obstructive pulmonary disease, and cardiovascular disease, were collected by self-reported medical history. RESULTS Significantly higher risks of severe COVID-19 were found in patients with blood glucose levels ranging from 5.53 to 7.27 mmol/L (odds ratio [OR], 3.98; 95% confidence interval [CI], 1.81-8.75) and in patients with blood glucose ≥7.27 mmol/L (OR, 12.10; 95% CI, 5.53-26.48) than in those with blood glucose <5.53 mmol/L. There was a trend toward better survival in patients with blood glucose <5.53 mmol/L than in patients with blood glucose from 5.53 to 7.27 mmol/L (hazard ratio [HR], 6.34; 95% CI, 1.45-27.71) and ≥7.27 mmol/L (HR, 19.37; 95% CI, 4.68-80.17). Estimated 10-day overall survival rates were 96.8%, 90.6%, and 69.3% in patients with blood glucose <5.53 mmol/L, 5.53 to 7.27 mmol/L, and ³7.27 mmol/L, respectively. CONCLUSIONS Hyperglycemia was association with severity of COVID-19 pneumonia and with increased patient mortality. These findings support the need for blood glucose monitoring and control of hyperglycemia in patients with COVID-19 pneumonia.

Past Shift Work and Incident Coronary Heart Disease in Retired Workers: A Prospective Cohort Study.

Present shift work has been associated with coronary heart disease (CHD) among employed workers, but it remains unclear whether shift work performed in the past is still associated with CHD in retired workers. We recruited 21,802 retired workers in Shiyan, China, in 2008-2010 and 2013 and followed them for CHD events occurring up to December 31, 2018. Retired workers with longer durations of past shift work (rounded to 0.25 years) had higher CHD risks (for those with ≤5.00, 5.25-10.00, 10.50-20.00, and >20.00 years of past shift work, hazard ratios were 1.05 (95% confidence interval (CI): 0.94, 1.16), 1.08 (95% CI: 0.94, 1.25), 1.23 (95% CI: 1.07, 1.42), and 1.28 (95% CI: 1.08, 1.51), respectively). The association was substantially higher among service or sales workers than among manufacturing or manual-labor workers (for every 5-year increase in past shift work, hazard ratio = 1.11 (95% CI: 1.05, 1.16) vs. hazard ratio = 1.02 (95% CI: 0.98, 1.06)). Moreover, the risk was lower among those who were physically active than among their inactive counterparts (P for interaction = 0.019). Longer duration of past shift work was associated with higher risk of incident CHD among these retired workers, especially those from the service or sales sectors. Physical exercise might be beneficial in reducing the excess risk.