Causal association between gut microbiomes and different types of aneurysms: a Mendelian randomization study.

Background: Previous studies suggests that gut microbiomes are associated with the formation and progression of aneurysms. However, the causal association between them remains unclear. Methods: A two-sample Mendelian randomization was conducted to investigate whether gut microbiomes have a causal effect on the risk of intracerebral aneurysm (IA), thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA), and aortic aneurysm (AA). Single nucleotide polymorphisms (SNPs) smaller than the locus-wide significance level (1 × 10-5) were selected as instrumental variables. We used inverse-variance weighted (IVW) test as the primary method for the evaluation of causal association. MR-Egger, weighted median, weighted mode, and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods were conducted for sensitive analysis. The p-value was adjusted by the false discovery rate (FDR) which adjust the results of multiple comparisons, a p < 0.05 and q < 0.1 was considered a significant causal association. Additionally, a p < 0.05 and q > 0.1 was considered a suggestive causal effect. Additionally, reverse MR was also performed to exclude the possibility of reverse causality. Results: The phylum Firmicutes (OR = 0.62; 95% CI, 0.48-0.81), class Lentisphaeria (OR = 0.75; 95% CI, 0.62-0.89), and order Victivallales (OR = 0.75; 95% CI, 0.62-0.89) have a causal protective effect on the risk of AAA. Additionally, class Verrucomicrobia, class Deltaproteobacteria, order Verrucomicrobiale, family Verrucomicrobiacea, genus Eubacterium rectale group, genus Akkermansia, and genus Clostridium innocuum group were negatively associated with the risk of different types of aneurysms, whereas class Negativicutes, order Selenomonadales, and genus Roseburia had positive causal association with different types of aneurysms (p < 0.05; q > 0.1). Further sensitivity analysis validated the robustness of our MR results, and no reverse causality was found with these gut microbiomes (p > 0.05). Conclusion: Our MR analysis confirmed the causal association of specific gut microbiomes with AAA, and these microbiomes were considered as protective factors. Our result may provide novel insights and theoretical basis for the prevention of aneurysms through regulation of gut microbiomes.

Adjunctive cariprazine as a novel effective strategy for treating major depressive disorder: A systematic review and meta-analysis.

BACKGROUND: Cariprazine has been approved by the Food and Drug Administration for treating bipolar depression and as an adjunctive treatment for Major Depressive Disorder (MDD). However, it remains unclear about its pharmacological efficacy in treating MDD. Therefore, a meta-analysis was conducted to investigate the adjunctive use of cariprazine in MDD. METHODS: Electronic databases were searched for eligible studies evaluating the efficacy and safety of cariprazine in patients with MDD up to November 15, 2023. The changes in Montgomery-Asberg Depression Rating Scale (MADRS) score and incidence of adverse events (AEs), which represents of efficacy and tolerability, are considered as the main outcomes. RESULTS: A total of 3066 patients with MDD included in all across 5 RCTs. With regard to MADRS score, cariprazine group showed better results than control group (SMD = -0.12, 95% CI -0.19 to -0.04, P = 0.002, 5 RCTs, n = 3066). Cariprazine, meanwhile, improved the MADRS response (RR = 1.19, 95% CI 1.08 to 1.31, P = 0.0004, 5 RCTs, n = 3066). For safety outcomes, statistical difference was observed in AEs (RR = 1.26, 95% CI 1.18 to 1.35, P < 0.00001, 5 RCTs, n = 3077). The suicide ideation and SAEs showed no statistical difference between two groups. CONCLUSION: Cariprazine demonstrated antidepressant effect as an augmentation therapy in treating MDD. Meanwhile, the tolerability of it was acceptable as an adjunctive treatment. However, studies with larger sample sizes are still needed to explore the optimal dosage.

Causal association of leisure sedentary behavior and cervical spondylosis, sciatica, intervertebral disk disorders, and low back pain: a Mendelian randomization study.

Background: Some studies suggest sedentary behavior is a risk factor for musculoskeletal disorders. This study aimed to investigate the potential causal association between leisure sedentary behavior (LSB) (including television (TV) viewing, computer use, and driving) and the incidence of sciatica, intervertebral disk degeneration (IVDD), low back pain (LBP), and cervical spondylosis (CS). Methods: We obtained the data of LSB, CS, IVDD, LBP, sciatica and proposed mediators from the gene-wide association studies (GWAS). The causal effects were examined by Inverse Variance Weighted (IVW) test, MR-Egger, weighted median, weighted mode and simple mode. And sensitivity analysis was performed using MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) and MR-Egger intercept test. Multivariable MR (MVMR) was conducted to investigate the independent factor of other LSB; while two-step MR analysis was used to explore the potential mediators including Body mass index (BMI), smoking initiation, type 2 diabetes mellitus (T2DM), major depressive disorder (MDD), schizophrenia, bipolar disorder between the causal association of LSB and these diseases based on previous studies. Results: Genetically associated TV viewing was positively associated with the risk of CS (OR = 1.61, 95%CI = 1.25 to 2.07, p = 0.002), IVDD (OR = 2.10, 95%CI = 1.77 to 2.48, p = 3.79 × 10-18), LBP (OR = 1.84, 95%CI = 1.53 to 2.21, p = 1.04 × 10-10) and sciatica (OR = 1.82, 95% CI = 1.45 to 2.27, p = 1.42 × 10-7). While computer use was associated with a reduced risk of IVDD (OR = 0.66, 95%CI = 0.55 to 0.79, p = 8.06 × 10-6), LBP (OR = 0.49, 95%CI = 0.40 to 0.59, p = 2.68 × 10-13) and sciatica (OR = 0.58, 95%CI = 0.46 to 0.75, p = 1.98 × 10-5). Sensitivity analysis validated the robustness of MR outcomes. MVMR analysis showed that the causal effect of TV viewing on IVDD (OR = 1.59, 95%CI = 1.13 to 2.25, p = 0.008), LBP (OR = 2.15, 95%CI = 1.50 to 3.08, p = 3.38 × 10-5), and sciatica (OR = 1.61, 95%CI = 1.03 to 2.52, p = 0.037) was independent of other LSB. Furthermore, two-step MR analysis indicated that BMI, smoking initiation, T2DM may mediate the causal effect of TV viewing on these diseases. Conclusion: This study provides empirical evidence supporting a positive causal association between TV viewing and sciatica, IVDD and LBP, which were potentially mediated by BMI, smoking initiation and T2DM.

Efficacy and tolerability of zuranolone in patients with depression: a meta-analysis of randomized controlled trials.

Background: As a novel antidepressant drug, zuranolone has been initially applied in treating depression. This study investigated the efficacy and safety of its administration in patients with depression. Methods: The Embase, PubMed, and Cochrane library databases were searched for available studies up to 1 Nov 2023. The primary outcome was the change on day 15 depression severity scores compared to baseline. Secondary outcomes included remission and response rates on day 15. Safety outcomes included incidence of treatment-emergent adverse events (TEAEs) and individual AEs. Trial sequential analysis (TSA) was used to evaluate the ideal samplesize. Results: Six studies with 1884 patients were included. Zuranolone offered significantly greater changes in day 15 depression severity scores (mean difference = 2.43, 95% confidence interval [CI]: 1.36 to 3.49, p < 0.00001) compared to placebo; this was also observed at other time points. Differences in response (relative risk [RR] = 1.33, 95% CI: 1.15 to 1.54, p < 0.0001) and remission (RR = 1.46, 95% CI: 1.15 to 1.85, p = 0.002) rates were also statistically significant. For safety outcomes, zuranolone group showed more incidence of TEAE than the placebo group (RR: 1.15, 95% CI: 1.06 to 1.25, p = 0.0005, I 2 = 0%). As for individual AEs, significant differences were observed in dizziness (RR = 2.17, 95% CI: 1.22 to 3.86, p = 0.008) and somnolence (RR = 2.43, 95% CI: 1.35 to 4.37, p = 0.003. No significant difference was observed in other AEs. The result of TSA indicated that the cumulative curve crossed the conventional (Z = 1.96) boundary but not reach TSA boundary (RIS = 1910). Conclusion: Our findings suggest that zuranolone has a rapid short-term antidepressant effect during administration. Although more TEAEs were observed in zuranolone, most of them were slight and temporary. However, studies with larger sample sizes and longer follow-up are needed. Systematic Review Registration: https://inplasy.com/inplasy-2023-5-0104/, identifier INPLASY202350104.