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.

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.

T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), an immune checkpoint, plays a pivotal role in immune suppression. However its role in tumor immunity and correlation with the genetic and epigenetic alterations remains unknown. Here, we comprehensively analyzed the expression patterns of the TIGIT and its value of prognostic prediction among 33 types of cancers based on the data collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression projects (GTEx). Furthermore, the correlations of TIGIT with pathological stages, tumor-infiltrating immune cells (TIICs), signatures of T cells subtypes, immune checkpoint genes, the degree of Estimation of STromal and Immune cells in MAlignant Tumor tissues using the Expression data (ESTIMATE), tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) genes, and DNA methyltransferases (DNMTs) were also explored. Gene functional enrichment was conducted by Gene Set Enrichment Analysis (GSEA). Our results showed that the expression of TIGIT was upregulated in most of the cancer types. Cox regression model showed that high expression of TIGIT in tumor samples correlates with poor prognosis in KIRC, KIRP, LGG, UVM, and with favorable prognosis in BRCA, CECS, HNSC, SKCM. TIGIT expression positively correlated with advanced stages, TIICs, the signatures of effector T cells, exhausted T cells, effector Tregs and the degree of ESTIMATE in KIRC, KIRP and UVM. TIGIT expression also positively correlated with CTLA4, PDCD1 (PD-1), CD274 (PD-L1), ICOS in most of the cancer types. Furthermore, the expression of TIGIT was correlated with TMB, MSI, MMR genes and DNMTs in different types of cancers. GSEA analysis showed that the expression of TIGIT was related to cytokine-cytokine receptor interaction, allograft rejection, oxidative phosphorylation. These findings suggested that TIGIT could serve as a potential biomarker for prognosis and a novel target for immunotherapies in cancers.