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 RESULTS: The phylum 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

Mechanical thrombectomy with intra-arterial alteplase provided better functional outcomes for AIS-LVO: a meta-analysis

BackgroundSeveral clinical trials have shown that intra-arterial thrombolysis using alteplase during mechanical thrombectomy (MT) has a better outcome than MT alone in ischemic stroke management. We performed the current meta-analysis to estimate the efficacy and safety of MT with intra-arterial alteplase therapy.MethodsThe MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched up to Mar. 2022 to identify the clinical trials that compared MT alone versus MT with intra-arterial alteplase therapy. STATA 16.0 was used for statistical analysis. The odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated with a random effect model.ResultsSeven studies involving 1,083 participants were included. The primary outcomes were better functional outcomes, defined as a modified Rankin Scale (mRS) score between 0 and 2 at 90  days, and successful recanalization, defined as a modified thrombolysis in cerebral infarction (mTICI) score  ≥  2b. Compared to MT alone, MT with intra-arterial alteplase did not lead to higher mTICI scores (OR 1.58, 95%CI 0.94 to 2.67, p = 0.085, I2 = 16.8%) but did lead to better mRS (OR 1.37, 95%CI 1.01 to 1.86, p = 0.044). There was no increase in mortality or bleeding events in the overall or subgroup analyses.ConclusionMT with intra-arterial alteplase did not improve the recanalization rate but provided better functional outcomes. The intervention did not increase adverse effects in any subgroup at the same time.Clinical trial registrationhttp://inplasy.com, identifier INPLASY202240027

Analysis on the Effectiveness and Mechanisms of Public Policies to Promote Innovation of High-Tech Startups in Makerspaces

In the context of digital transformation and the rapid development of artificial intelligence, corporate innovation has become increasingly important in leading industrial development and improving national competitiveness. In 2015, China launched a “mass entrepreneurship and innovation program”; in response to the policy, many makerspaces have been established, resulting in clusters of high-tech startups. High-tech startups are the pioneers in innovation development. However, there is still a lack of empirical evidence for whether these firms’ innovative activities, capabilities, and performance can be effectively stimulated by public policy. Drawing from the institutional theory and resource-based view, this paper develops a model of policy perception on innovation response. Using a sample of 500 startups located in the three representative makerspaces in China, this work verifies the effectiveness of innovation and entrepreneurship incentives on startups’ innovative activities, capabilities, and performance, and successfully identifies the mediating role of policy adaptation in the policy perception-innovative responses’ link and the moderating role of makerspace support

Efficacy and tolerability of minocycline in depressive patients with or without treatment-resistant: a meta-analysis of randomized controlled trials

BackgroundMinocycline, an antibiotic with anti-inflammatory, antioxidant, and neuroprotective properties, has been used for treating psychiatric disorders in research. This systematic review aimed to evaluate the efficacy and tolerability of minocycline in patients having depression with or without treatment-resistance.MethodsElectronic databases including Embase, PubMed, and the Cochrane library were searched for relevant studies published up to October 17, 2022. The primary efficacy outcome was the change in depression severity scores and the secondary efficacy outcomes included the changes in Clinical Global Impression (CGI) and Beck Depression Inventory (BDI) scores and the incidence of response and partial response. Safety outcomes were evaluated based on the incidence of classified adverse events and all-cause discontinuation.ResultsFive studies with 374 patients were selected for analysis. The minocycline group demonstrated a significant reduction in depression severity scale (standardized mean difference [SMD]: −0.59, 95% confidence interval [CI]: −0.98 to −0.20, P = 0.003) and CGI (SMD: −0.28, 95% CI: −0.56 to −0.01, P = 0.042) scores; however, no statistical difference was found in terms of the BDI score, response, and partial response. No significant differences were found between the groups in terms of adverse events (other than dizziness) and discontinuation rates. Subgroup analysis showed that minocycline was also effective in reducing depression severity scores in treatment-resistant depression (SMD: −0.36, 95% CI: −0.64 to −0.09, P = 0.010). Subgroup analysis of Hamilton Depression Rating Scale (17-item) scores showed a statistical difference in response in patients with depression (relative risk: 2.51, 95% CI: 1.13 to 5.57, P = 0.024).ConclusionsMinocycline may improve depressive symptoms and augment response to treatment in patients with depression irrespective of treatment-resistance. However, clinical trials with large sample sizes are warranted for evaluating long-term outcomes with minocycline.Systematic review registrationhttps://inplasy.com/inplasy-2022-12-0051/

Metabolome-Wide Mendelian Randomization Assessing the Causal Role of Serum and Cerebrospinal Metabolites in Traumatic Brain Injury

Previous studies have identified metabolites as biomarkers or potential therapeutic targets for traumatic brain injury (TBI). However, the causal association between them remains unknown. Therefore, we investigated the causal effect of serum metabolites and cerebrospinal fluid (CSF) metabolites on TBI susceptibility through Mendelian randomization (MR). Genetic variants related to metabolites and TBI were extracted from a corresponding genome-wide association study (GWAS). Causal effects were estimated through the inverse variance weighted approach, supplemented by a weighted median, weight mode, and the MR–Egger test. In addition, sensitivity analyses were further performed to evaluate the stability of the MR results, including the MR–Egger intercept, leave-one-out analysis, Cochrane’s Q-test, and the MR-PRESSO global test. Metabolic pathway analysis was applied to uncover the underlying pathways of the significant metabolites in TBI. In blood metabolites, substances such as 4-acetaminophen sulfate and kynurenine showed positive links, whereas beta-hydroxyisovalerate and creatinine exhibited negative correlations. CSF metabolites such as N-formylanthranilic acid were positively related, while kynurenate showed negative associations. The metabolic pathway analysis highlighted the potential biological pathways involved in TBI. Of these 16 serum metabolites, 11 CSF metabolites and metabolic pathways may serve as useful circulating biomarkers in clinical screening and prevention, and may be candidate molecules for the exploration of mechanisms and drug targets

Data_Sheet_1_Causal association of leisure sedentary behavior and cervical spondylosis, sciatica, intervertebral disk disorders, and low back pain: a Mendelian randomization study.docx

BackgroundSome 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).MethodsWe 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.ResultsGenetically 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.ConclusionThis 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.</p

Table_2_Causal association between gut microbiomes and different types of aneurysms: a Mendelian randomization study.xlsx

BackgroundPrevious studies suggests that gut microbiomes are associated with the formation and progression of aneurysms. However, the causal association between them remains unclear.MethodsA 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  0.1 was considered a suggestive causal effect. Additionally, reverse MR was also performed to exclude the possibility of reverse causality.ResultsThe 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  0.1). Further sensitivity analysis validated the robustness of our MR results, and no reverse causality was found with these gut microbiomes (p > 0.05).ConclusionOur 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.</p

Table_1_Causal association between gut microbiomes and different types of aneurysms: a Mendelian randomization study.docx

BackgroundPrevious studies suggests that gut microbiomes are associated with the formation and progression of aneurysms. However, the causal association between them remains unclear.MethodsA 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  0.1 was considered a suggestive causal effect. Additionally, reverse MR was also performed to exclude the possibility of reverse causality.ResultsThe 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  0.1). Further sensitivity analysis validated the robustness of our MR results, and no reverse causality was found with these gut microbiomes (p > 0.05).ConclusionOur 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.</p

Data_Sheet_2_Causal association of leisure sedentary behavior and cervical spondylosis, sciatica, intervertebral disk disorders, and low back pain: a Mendelian randomization study.xlsx

BackgroundSome 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).MethodsWe 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.ResultsGenetically 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.ConclusionThis 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.</p

Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages

Pulmonary hypertension (PH) is a devastating disease characterized by irreversible pulmonary vascular remodeling (PVR) that causes right ventricular failure and death. The early alternative activation of macrophages is a critical event in the development of PVR and PH, but the underlying mechanisms remain elusive. Previously we have shown that N6-methyladenosine (m6A) modifications of RNA contribute to phenotypic switching of pulmonary artery smooth muscle cells and PH. In the current study, we identify Ythdf2, an m6A reader, as an important regulator of pulmonary inflammation and redox regulation in PH. In a mouse model of PH, the protein expression of Ythdf2 was increased in alveolar macrophages (AMs) during the early stages of hypoxia. Mice with a myeloid specific knockout of Ythdf2 (Ythdf2Lyz2 Cre) were protected from PH with attenuated right ventricular hypertrophy and PVR compared to control mice and this was accompanied by decreased macrophage polarization and oxidative stress. In the absence of Ythdf2, heme oxygenase 1 (Hmox1) mRNA and protein expression were significantly elevated in hypoxic AMs. Mechanistically, Ythdf2 promoted the degradation of Hmox1 mRNA in a m6A dependent manner. Furthermore, an inhibitor of Hmox1 promoted macrophage alternative activation, and reversed the protection from PH seen in Ythdf2Lyz2 Cre mice under hypoxic exposure. Together, our data reveal a novel mechanism linking m6A RNA modification with changes in macrophage phenotype, inflammation and oxidative stress in PH, and identify Hmox1 as a downstream target of Ythdf2, suggesting that Ythdf2 may be a therapeutic target in PH