Application of Organoids in Regenerative Medicine.

Regenerative medicine mainly relies on heterologous transplantation, often hindered by sample availability and ethical issues. Furthermore, patients are required to take immunosuppressive medications to prevent adverse side effects. Stem cell-derived 3D-organoid culture has provided new alternatives for transplantation and regenerative medicine. Scholars have combined organoids with tissue engineering technology to improve reproducibility, the accuracy of constitution and throughput, and genetic correction to achieve a more personalized therapy. Here, we review the available applications of organoids in regenerative medicine and the current challenges concerning this field.

Tumor buster - where will the CAR-T cell therapy 'missile' go?

Chimeric antigen receptor (CAR) T cell (CAR-T cell) therapy based on gene editing technology represents a significant breakthrough in personalized immunotherapy for human cancer. This strategy uses genetic modification to enable T cells to target tumor-specific antigens, attack specific cancer cells, and bypass tumor cell apoptosis avoidance mechanisms to some extent. This method has been extensively used to treat hematologic diseases, but the therapeutic effect in solid tumors is not ideal. Tumor antigen escape, treatment-related toxicity, and the immunosuppressive tumor microenvironment (TME) limit their use of it. Target selection is the most critical aspect in determining the prognosis of patients receiving this treatment. This review provides a comprehensive summary of all therapeutic targets used in the clinic or shown promising potential. We summarize CAR-T cell therapies' clinical trials, applications, research frontiers, and limitations in treating different cancers. We also explore coping strategies when encountering sub-optimal tumor-associated antigens (TAA) or TAA loss. Moreover, the importance of CAR-T cell therapy in cancer immunotherapy is emphasized.

Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials.

BACKGROUND: To investigate whether metformin monotherapy or adjunctive therapy improves the prognosis in patients with any type of cancer compared to non-metformin users (age ≥18). METHODS: Databases (Medline, Embase, and the Cochrane Central Register of Controlled Trials) and clinical trial registries ( ClinicalTrials.gov ; the World Health Organization International Clinical Trials Registry Platform) were screened for randomized, controlled trials (RCT) reporting at least progression-free survival (PFS) and/or overall survival (OS). Main outcome measures included hazard ratios (HR), and combined HRs and 95% confidence intervals (CI) were calculated using random-effects models. RESULTS: Of the 8419 records screened, 22 RCTs comprising 5943 participants were included. Pooled HRs were not statistically significant in both PFS (HR 0.97, 95% CI 0.82-1.15, I2 = 50%) and OS (HR 0.98, 95% CI 0.86-1.13, I2 = 33%) for patients with cancer between the metformin and control groups. Subgroup analyses demonstrated that metformin treatment was associated with a marginally significant improvement in PFS in reproductive system cancers (HR 0.86, 95% CI 0.74-1.00) and a significantly worse PFS in digestive system cancers (HR 1.45, 95% CI 1.03-2.04). The PFS or OS was observed consistently across maintenance dose, diabetes exclusion, median follow-up, risk of bias, and combined antitumoral therapies. CONCLUSION: Metformin treatment was not associated with cancer-related mortality in adults compared with placebo or no treatment. However, metformin implied beneficial effects in the PFS of the patients with reproductive system cancers but was related to a worse PFS in digestive system cancers. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42022324672.

Natural killer cell-related gene signature predicts malignancy of glioma and the survival of patients.

BACKGROUND: Natural killer (NK) cells-based therapies are one of the most promising strategies against cancer. The aim of this study is to investigate the natural killer cell related genes and its prognostic value in glioma. METHODS: The Chinese Glioma Genome Atlas (CGGA) was used to develop the natural killer cell-related signature. Risk score was built by multivariate Cox proportional hazards model. A cohort of 326 glioma samples with whole transcriptome expression data from the CGGA database was included for discovery. The Cancer Genome Atlas (TCGA) datasets was used for validation. GO and KEGG were used to reveal the biological process and function associated with the natural killer cell-related signature. We also collected the clinical pathological features of patients with gliomas to analyze the association with tumor malignancy and patients' survival. RESULTS: We screened for NK-related genes to build a prognostic signature, and identified the risk score based on the signature. We found that NK-related risk score was independent of various clinical factors. Nature-killer cell gene expression is correlated with clinicopathological features of gliomas. Innovatively, we demonstrated the tight relation between the risk score and immune checkpoints, and found NK-related risk score combined with PD1/PDL1 patients could predict the patient outcome. CONCLUSION: Natural killer cell-related gene signature can predict malignancy of glioma and the survival of patients, these results might provide new view for the research of glioma malignancy and individual immunotherapy.

Correction to: Clinical characterization, genetic profiling, and immune infiltration of TOX in diffuse gliomas.

An amendment to this paper has been published and can be accessed via the original article.

Clinical characterization, genetic profiling, and immune infiltration of TOX in diffuse gliomas.

BACKGROUND: Immunotherapies targeting glioblastoma (GBM) have led to significant improvements in patient outcomes. TOX is closely associated with the immune environment surrounding tumors, but its role in gliomas is not fully understood. METHODS: Using data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), we analyzed the transcriptomes of 1691 WHO grade I-IV human glioma samples. The R language was used to perform most of the statistical analyses. Somatic mutations and somatic copy number variation (CNV) were analyzed using GISTIC 2.0. RESULTS: TOX was down-regulated in malignant gliomas compared to low grade gliomas, and upregulated in the proneural and IDH mutant subtypes of GBM. TOXlow tumours are associated with the loss of PTEN and amplification of EGFR, while TOXhigh tumours harbor frequent mutations in IDH1 (91%). TOX was highly expressed in leading edge regions of tumours. Gene ontology and pathway analyses demonstrated that TOX was enriched in multiple immune related processes including lymphocyte migration in GBM. Finally, TOX had a negative association with the infiltration of several immune cell types in the tumour microenvironment. CONCLUSION: TOX has the potential to be a new prognostic marker for GBM.

CTLA-4 correlates with immune and clinical characteristics of glioma.

BACKGROUND: CTLA-4 is a well-studied immune checkpoint protein that negatively regulates T cell-mediated immune responses. However, the expression of CTLA-4 in glioma and the effects of CTLA-4 on prognosis in patients with glioma have not yet been examined. METHODS: We investigated the protein level of CTLA-4 in human glioma samples, extracted genetic and clinical data from 1024 glioma patients to characterize CTLA-4 expression and its relationship with immune functions in gliomas. R language was used for statistical analysis. RESULTS: Higher CTLA-4 expression was found in patients with higher grade, isocitrate dehydrogenase (IDH)-wild-type, and mesenchymal-molecular subtype gliomas than in patients with lower grade, IDH-mutant, and other molecular subtype gliomas. Further analysis showed that there was a strong positive correlation between CTLA-4 and the specific marker gene expression of immune cells, including CD8+ T cells, regulatory T cells, and macrophages in both databases, suggesting that higher CTLA-4 expression in the glioma microenvironment induced greater immune cell infiltration compared with that in gliomas with lower CTLA-4 expression. We further explored the associations between CTLA-4 and other immune-related molecules. Pearson correlation analysis showed that CTLA-4 was associated with PD-1, CD40, ICOS, CXCR3, CXCR6, CXCL12 and TIGIT. Patients with glioma with lower CTLA-4 expression exhibited significantly longer overall survival. Thus, these findings suggested that increased CTLA-4 expression conferred a worse outcome in glioma. CONCLUSIONS: In summary, our findings revealed the expression patterns and clinical characteristics of CTLA-4 in glioma and may be helpful for expanding our understanding of antitumor immunotherapy in gliomas.

Sensory stimulation to improve arousal in comatose patients after traumatic brain injury: a systematic review of the literature.

BACKGROUND: No standard rehabilitative treatment for coma arousal after traumatic brain injury (TBI) exists. Based on our clinical experience, we hypothesized that sensory stimulation (SS) is a promising protocol to improve outcomes in these patients. METHODS: We performed a literature review on the progress of sensory stimulation to enhance coma arousal after traumatic brain injury. We searched the databases on Medline, Embase, and Cochrane to gain access to relevant publications using the key words "traumatic brain injury," "disorders of consciousness," "sensory stimulation," and "coma scale." RESULTS: We included all original studies published in English with patients presenting severe disorders of consciousness due to traumatic brain injury who had received SS and whose behavioral/neural responses had been measured. We compared data on ten selected studies and analyzed the SS effects in comatose patient outcomes after TBI. Our review outlines the role of SS in patients with TBI and provides guidance for its implementation in the clinical practice. CONCLUSIONS: The literature suggests the SS program improves coma arousal after TBI. However, high-quality clinical trials are needed to establish standard SS protocols.

Screening for distress in patients with primary brain tumor using distress thermometer: a systematic review and meta-analysis.

BACKGROUND: Patients with primary brain tumors are reported to have an elevated level of distress prevalence, due to the functional sequelae and the unfavorable prognosis, but the estimated prevalence of this disorder varies among studies. The Distress Thermometer (DT) is widely used distress screening tools to identify patients suffering from elevated psychosocial distress. The objective of this meta-analysis is to get a summarized estimate of distress prevalence in adult primary brain tumor patients screened by the DT instrument to identify distress in brain tumor patients. METHOD: We searched studies published in PubMed, PsycINFO, and Cochrane library through August 2017 and checked related reviews and meta-analyses for eligible studies. Studies were eligible if they were published in the peer-reviewed literature and evaluated distress level by Distress Thermometer. The prevalence of distress symptoms in patients with the intracranial tumor was estimated by study-level characteristics using stratified meta-analysis. The prevalence of distress level or symptoms during the follow-up examination at different time points was detected by secondary analysis of the longitudinal studies included. RESULTS: Twelve studies including a total of 2145 brain tumor patients were included in this analysis. Eight used a cross-sectional design and four were longitudinal. The pooled prevalence of distress was 38.2% (95% confidence interval (CI) 28.7%-47.7%) for the overall sample. The pooled prevalence of distress DT ≥4 was 41.1% (642/1686, 95% CI 28.6%-53.5%) and the pooled prevalence of distress by DT ≥6 was 29.7% (137/459, 95% CI 19.5%-39.9%). The distress symptom did not decrease in follow-up studies (Relative Increase Ratio:1.02, 95% CI, (0.78, 1.35)). A huge heterogeneity in different studies was detected, and different screening scales were not compared. CONCLUSION: The high prevalence of distress becomes an enormous challenge for primary brain tumor patients. Routine screening and evaluation of distress in brain tumor patients may assist medical workers to develop proper interventions, which may lead to better quality of life and oncology management.

Preoperative walking exercise to improve prognosis in patients with supratentorial brain tumours after craniotomy: protocol for a randomised controlled trial.

INTRODUCTION: Cardiopulmonary complications and cognitive impairment following craniotomy have a significantly impact on the general health of individuals with brain tumours. Observational research indicates that engaging in walking is linked to better prognosis in patient after surgery. This trial aims to explore whether walking exercise prior to craniotomy in brain tumour patients can reduce the incidence of cardiopulmonary complications and preserve patients' cognitive function. METHODS AND ANALYSIS: In this randomised controlled trial, 160 participants with supratentorial brain tumours aged 18-65 years, with a preoperative waiting time of more than 3-4 weeks and without conditions that would interfere with the trial such as cognitive impairment, will be randomly assigned in a ratio of 1:1 to either receive traditional treatment or additional combined with a period of 3-4 weeks of walking exercise of 10 000-15 000 steps per day. Wearable pedometer devices will be used to record step counts. The researchers will evaluate participants at enrolment, baseline, 14 days preoperatively, 3 days prior to surgery and 1 week after surgery or discharge (select which occurs first). The primary outcomes include the incidence of postoperative cardiopulmonary complications and changes in cognitive function (gauged by the Montreal Cognitive Assessment test). Secondary outcomes include the average length of hospital stay, postoperative pain, participant contentment, healthcare-associated costs and incidence of other postoperative surgery-related complications. We anticipate that short-term preoperative walking exercises will reduce the incidence of surgery-related complications in the short term after craniotomy, protect patients' cognitive function, aid patients' postoperative recovery and reduce the financial cost of treatment. ETHICS AND DISSEMINATION: The study protocol has been approved by Ethics Committee of Xiangya Hospital of Central South University (approval number: 202305117). The findings of the research will be shared via publications that have been reviewed by experts in the field and through presentations at conferences. TRIAL REGISTRATION NUMBER: NCT05930288.

Modifiable lifestyle factors influencing psychiatric disorders mediated by plasma proteins: A systemic Mendelian randomization study.

BACKGROUND: Psychiatric disorders are emerging as a serious public health hazard, influencing an increasing number of individuals worldwide. However, the effect of modifiable lifestyle factors on psychiatric disorders remains unclear. METHODS: Genome-wide association studies (GWAS) summary statistics were obtained mainly from Psychiatric Genomics Consortium and UK Biobank, with sample sizes varying between 10,000 and 1,200,000. The two-sample Mendelian randomization (MR) method was applied to investigate the causal associations between 45 lifestyle factors and 13 psychiatric disorders, and screen potential mediator proteins from 2992 candidate plasma proteins. We implemented a four-step framework with step-by-step screening incorporating two-step, univariable, and multivariable MR. RESULTS: We found causal effects of strenuous sports or other exercise on Tourette's syndrome (OR [95%CI]: 0.0047 [5.24E-04-0.042]); lifelong smoking index on attention-deficit hyperactivity disorder (10.53 [6.96-15.93]), anxiety disorders (3.44 [1.95-6.05]), bipolar disorder (BD) (2.25 [1.64-3.09]), BD II (2.89 [1.81-4.62]), and major depressive disorder (MDD) (2.47 [1.90-3.20]); and educational years on anorexia nervosa (AN) (1.47 [1.22-1.76]), and MDD (0.74 [0.66-0.83]). Five proteins were found to have causal associations with psychiatric disorders, namely ADH1B, GHDC, STOM, CD226, and TP63. STOM, a membrane protein deficient in the erythrocytes of hereditary stomatocytosis patients, may mediate the effect of educational attainment on AN. LIMITATIONS: The mechanisms underlying the effects of lifestyle factors on psychiatric disorders require further investigation. CONCLUSIONS: These findings could help assess the risk of psychiatric disorders based on lifestyle factors and also support lifestyle interventions as a prevention strategy for mental illness.

A comprehensive assessment of the association between common drugs and psychiatric disorders using Mendelian randomization and real-world pharmacovigilance database.

BACKGROUND: Medications prescribed for chronic diseases can lead to short-term neuropsychiatric symptoms, but their long-term effects on brain structures and psychiatric conditions remain unclear. METHODS: We comprehensively analyzed the FDA Adverse Event Reporting System database and conducted drug target Mendelian Randomization (MR) studies on six categories of common drugs, 477 brain imaging-derived phenotypes (IDPs) and eight psychiatric disorders. Genetic instruments were extracted from expression quantitative trait loci (eQTLs) in blood, brain, and other target tissues, protein quantitative trait loci (pQTLs) in blood, and genome-wide association studies (GWAS) of hemoglobin and cholesterol. Summary statistics for brain IDPs, psychiatric disorders, and gut microbiome were obtained from the BIG40, Psychiatric Genomics Consortium, and MiBioGen. A two-step MR and mediation analysis were employed to screen possible mediators of drug-IDP effects from 119 gut microbiota genera and identify their mediation proportions. FINDINGS: Among 19 drug classes, six drugs were found to be associated with higher risks of psychiatric adverse events, while 11 drugs were associated with higher risks of gastrointestinal adverse events in the FAERS analysis. We identified ten drug-psychiatric disorder associations, 202 drug-IDP associations, 16 drug-microbiota associations, and four drug-microbiota-IDP causal links. For example, PPARG activation mediated HbA1c reduction caused a higher risk of bipolar disorder (BD) II. Genetically proxied GLP-1R agonists were significantly associated with an increase in the volume of the CA3-head of the right hippocampus and the area of the left precuneus cortex, both of which have been shown to correlate with cognition in previous studies. INTERPRETATION: Common drugs may affect brain structure and risk of psychiatric disorder. Oral medications in particular may exert some of these effects by influencing gut microbiota. This study calls for greater attention to be paid to the neuropsychiatric adverse effects of drugs and encourages drug repurposing. FUNDING: National Natural Science Foundation of China (grant No. 82330035, 82130043, 82172685, and 82001223), National Natural Science Foundation of Hunan Province (grant No. 2021SK1010), and the Science Foundation for Distinguished Young Scholars of Changsha (grant No. kq2209006).

Clinical sequencing reveals diagnostic, therapeutic, and prognostic biomarkers for adult-type diffuse gliomas.

Diffuse gliomas in adults are highly infiltrative and largely incurable. Whole exome sequencing (WES) has been demonstrated very useful in genetic analysis. Here WES was performed to characterize genomic landscape of adult-type diffuse gliomas to discover the diagnostic, therapeutic and prognostic biomarkers. Somatic and germline variants of 66 patients with adult-type diffuse gliomas were detected by WES based on the next-generation sequencing. TCGA and CGGA datasets were included to analyze the integrated diagnosis and prognosis. Among 66 patients, the diagnosis of 9 cases was changed, in which 8 cases of astrocytoma were corrected into IDH-wildtype glioblastoma (GBM), and 1 oligodendroglioma without 1p/19q co-deletion into astrocytoma. The distribution of mutations including ATRX/TP53 differed in three cohorts. The genetic mutations in GBM mainly concentrated on the cell cycle, PI3K and RTK pathways. The mutational landscape of astrocytoma was more similar to that of GBM, with the highest frequency in germline variants. Patients with IDH-mutant astrocytoma harboring SNVs of PIK3CA and PIK3R1 showed a significantly worse overall survival (OS) than wild-type patients. AEBP1 amplification was associated with shorter OS in GBM. Our study suggests that clinical sequencing can recapitulate previous findings, which may provide a powerful approach to discover diagnostic, therapeutic and prognostic markers for precision medicine in adult-type diffuse gliomas.

PD-L1-related IncRNAs are associated with malignant characteristics and immune microenvironment in glioma.

BACKGROUND: The expression of long non-coding RNA (lncRNA) can function as diagnostic and therapeutic biomarker for tumors. This research explores the role of PD-L1-related lncRNAs in affecting malignant characteristics and the immune microenvironment of glioma. METHODS: Downloading gene expression profiles and clinicopathological information of glioma from TCGA and CGGA databases, 6 PD-L1-related lncRNAs were identified through correlation analysis, Cox and LASSO regression analysis, establishing the risk score model based on them. Bioinformatics analysis and cell experiments in vitro were adopted to verify the effects of LINC01271 on glioma. RESULTS: Risk scores based on 6 PD-L1-related lncRNAs (AL355974.3, LINC01271, AC011899.3, MIR4500HG, LINC02594, AL357055.3) can reflect malignant characteristics and immunotherapy response of glioma. Patients with high LINC01271 expression had a worse prognosis, a higher abundance of M1 subtype macrophages in the immune microenvironment, and a higher degree of tumor malignancy. Experiments in vitro confirmed its positive regulatory effect on the proliferation and migration of glioma cells. CONCLUSIONS: The risk score model based on 6 PD-L1-related lncRNAs can reflect the malignant characteristics and prognosis of glioma. LINC01271 can independently be used as a new target for prognosis evaluation and therapy.

Applications of organoid technology to brain tumors.

Lacking appropriate model impedes basic and preclinical researches of brain tumors. Organoids technology applying on brain tumors enables great recapitulation of the original tumors. Here, we compared brain tumor organoids (BTOs) with common models including cell lines, tumor spheroids, and patient-derived xenografts. Different BTOs can be customized to research objectives and particular brain tumor features. We systematically introduce the establishments and strengths of four different BTOs. BTOs derived from patient somatic cells are suitable for mimicking brain tumors caused by germline mutations and abnormal neurodevelopment, such as the tuberous sclerosis complex. BTOs derived from human pluripotent stem cells with genetic manipulations endow for identifying and understanding the roles of oncogenes and processes of oncogenesis. Brain tumoroids are the most clinically applicable BTOs, which could be generated within clinically relevant timescale and applied for drug screening, immunotherapy testing, biobanking, and investigating brain tumor mechanisms, such as cancer stem cells and therapy resistance. Brain organoids co-cultured with brain tumors (BO-BTs) own the greatest recapitulation of brain tumors. Tumor invasion and interactions between tumor cells and brain components could be greatly explored in this model. BO-BTs also offer a humanized platform for testing the therapeutic efficacy and side effects on neurons in preclinical trials. We also introduce the BTOs establishment fused with other advanced techniques, such as 3D bioprinting. So far, over 11 brain tumor types of BTOs have been established, especially for glioblastoma. We conclude BTOs could be a reliable model to understand brain tumors and develop targeted therapies.

Metformin improves cognitive impairment in patients with schizophrenia: associated with enhanced functional connectivity of dorsolateral prefrontal cortex.

Cognitive impairment is a core feature of schizophrenia, which is aggravated by antipsychotics-induced metabolic disturbance and lacks effective pharmacologic treatments in clinical practice. Our previous study demonstrated the efficiency of metformin in alleviating metabolic disturbance following antipsychotic administration. Here we report that metformin could ameliorate cognitive impairment and improve functional connectivity (FC) in prefrontal regions. This is an open-labeled, evaluator-blinded study. Clinically stable patients with schizophrenia were randomly assigned to receive antipsychotics plus metformin (N = 48) or antipsychotics alone (N = 24) for 24 weeks. The improvement in cognition was assessed by the MATRICS Consensus Cognitive Battery (MCCB). Its association with metabolic measurements, and voxel-wise whole-brain FC with dorsolateral prefrontal cortex (DLPFC) subregions as seeds were evaluated. When compared to the antipsychotics alone group, the addition of metformin resulted in significantly greater improvements in the MCCB composite score, speed of processing, working memory, verbal learning, and visual learning. A significant time × group interaction effect of increased FC between DLPFC and the anterior cingulate cortex (ACC)/middle cingulate cortex (MCC), and between DLPFC subregions were observed after metformin treatment, which was positively correlated with MCCB cognitive performance. Furthermore, the FC between left DLPFC A9/46d to right ACC/MCC significantly mediated metformin-induced speed of processing improvement; the FC between left A46 to right ACC significantly mediated metformin-induced verbal learning improvement. Collectively, these findings demonstrate that metformin can improve cognitive impairments in schizophrenia patients and is partly related to the FC changes in the DLPFC. Trial Registration: The trial was registered with ClinicalTrials.gov (NCT03271866). The full trial protocol is provided in Supplementary Material.

Role of CD68 in tumor immunity and prognosis prediction in pan-cancer.

CD68 plays a critical role in promoting phagocytosis; however, the function of CD68 in tumor immunity and prognosis remains unknown. We analyzed CD68 expression among 33 tumor and normal tissues from The Cancer Genome Atlas and Genotype-Tissue Expression datasets. The relationship between CD68 expression and cancer prognosis, immune infiltration, checkpoint markers, and drug response was explored. Upregulated CD68 levels were observed in various cancer types, which were verified through tumor tissue chips using immunohistochemistry. High levels of CD68 in tumor samples correlated with an adverse prognosis in glioblastoma, kidney renal clear cell carcinoma, lower-grade glioma, liver hepatocellular carcinoma, lung squamous cell carcinoma, thyroid carcinoma, and thymoma and a favorable prognosis in kidney chromophobe. The top three negatively enriched Kyoto Encyclopedia of Genes and Genomes terms in the high CD68 subgroup were chemokine signaling pathway, cytokine-cytokine receptor interaction, and cell adhesion molecule cams. The top negatively enriched HALLMARK terms included complement, allograft rejection, and inflammatory response. A series of targeted drugs and small-molecule drugs with promising therapeutic effects were predicted. The clinical prognosis and immune infiltration of high expression levels of CD68 differ across tumor types. Inhibiting CD68-dependent signaling could be a promising therapeutic strategy for immunotherapy in many tumor types.

Gestational diabetes mellitus and adverse pregnancy outcomes: systematic review and meta-analysis.

OBJECTIVE: To investigate the association between gestational diabetes mellitus and adverse outcomes of pregnancy after adjustment for at least minimal confounding factors. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Web of Science, PubMed, Medline, and Cochrane Database of Systematic Reviews, from 1 January 1990 to 1 November 2021. REVIEW METHODS: Cohort studies and control arms of trials reporting complications of pregnancy in women with gestational diabetes mellitus were eligible for inclusion. Based on the use of insulin, studies were divided into three subgroups: no insulin use (patients never used insulin during the course of the disease), insulin use (different proportions of patients were treated with insulin), and insulin use not reported. Subgroup analyses were performed based on the status of the country (developed or developing), quality of the study, diagnostic criteria, and screening method. Meta-regression models were applied based on the proportion of patients who had received insulin. RESULTS: 156 studies with 7 506 061 pregnancies were included, and 50 (32.1%) showed a low or medium risk of bias. In studies with no insulin use, when adjusted for confounders, women with gestational diabetes mellitus had increased odds of caesarean section (odds ratio 1.16, 95% confidence interval 1.03 to 1.32), preterm delivery (1.51, 1.26 to 1.80), low one minute Apgar score (1.43, 1.01 to 2.03), macrosomia (1.70, 1.23 to 2.36), and infant born large for gestational age (1.57, 1.25 to 1.97). In studies with insulin use, when adjusted for confounders, the odds of having an infant large for gestational age (odds ratio 1.61, 1.09 to 2.37), or with respiratory distress syndrome (1.57, 1.19 to 2.08) or neonatal jaundice (1.28, 1.02 to 1.62), or requiring admission to the neonatal intensive care unit (2.29, 1.59 to 3.31), were higher in women with gestational diabetes mellitus than in those without diabetes. No clear evidence was found for differences in the odds of instrumental delivery, shoulder dystocia, postpartum haemorrhage, stillbirth, neonatal death, low five minute Apgar score, low birth weight, and small for gestational age between women with and without gestational diabetes mellitus after adjusting for confounders. Country status, adjustment for body mass index, and screening methods significantly contributed to heterogeneity between studies for several adverse outcomes of pregnancy. CONCLUSIONS: When adjusted for confounders, gestational diabetes mellitus was significantly associated with pregnancy complications. The findings contribute to a more comprehensive understanding of the adverse outcomes of pregnancy related to gestational diabetes mellitus. Future primary studies should routinely consider adjusting for a more complete set of prognostic factors. REVIEW REGISTRATION: PROSPERO CRD42021265837.

Metagenomics next-generation sequencing for the diagnosis of central nervous system infection: A systematic review and meta-analysis.

Objective: It is widely acknowledged that central nervous system (CNS) infection is a serious infectious disease accompanied by various complications. However, the accuracy of current detection methods is limited, leading to delayed diagnosis and treatment. In recent years, metagenomic next-generation sequencing (mNGS) has been increasingly adopted to improve the diagnostic yield. The present study sought to evaluate the value of mNGS in CNS infection diagnosis. Methods: Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2022 guidelines, we searched relevant articles published in seven databases, including PubMed, Web of Science, and Cochrane Library, published from January 2014 to January 2022. High-quality articles related to mNGS applications in the CNS infection diagnosis were included. The comparison between mNGS and the gold standard of CNS infection, such as culture, PCR or serology, and microscopy, was conducted to obtain true positive (TP), true negative (TN), false positive (FP), and false negative (FN) values, which were extracted for sensitivity and specificity calculation. Results: A total of 272 related studies were retrieved and strictly selected according to the inclusion and exclusion criteria. Finally, 12 studies were included for meta-analysis and the pooled sensitivity was 77% (95% CI: 70-82%, I 2 = 39.69%) and specificity was 96% (95% CI: 93-98%, I 2 = 72.07%). Although no significant heterogeneity in sensitivity was observed, a sub-group analysis was conducted based on the pathogen, region, age, and sample pretreatment method to ascertain potential confounders. The area under the curve (AUC) of the summary receiver operating characteristic curve (SROC) of mNGS for CNS infection was 0.91 (95% CI: 0.88-0.93). Besides, Deek's Funnel Plot Asymmetry Test indicated no publication bias in the included studies (Figure 3, p > 0.05). Conclusion: Overall, mNGS exhibits good sensitivity and specificity for diagnosing CNS infection and diagnostic performance during clinical application by assisting in identifying the pathogen. However, the efficacy remains inconsistent, warranting subsequent studies for further performance improvement during its clinical application. Study registration number: INPLASY202120002.