Causal relationship between inflammatory factors and cerebral small vessel disease: Univariate, multivariate, and summary-data-based mendelian randomization analysis.

OBJECTIVE: To explore the impact of inflammatory factors on the incidence of cerebral small vessel disease (CSVD), we performed a mendelian randomization (MR) study to analyze the causal relationship between multiple inflammatory factors and CSVD imaging markers and utilized summary-data-based mendelian randomization (SMR) analysis to infer whether the impact of instrumental variables (IVs) on disease is mediated by gene expression or DNA methylation. METHODS: Using public databases such as UKB and IEU, and original genome-wide association studies, we obtained IVs related to exposure (inflammatory factors) and outcome (CSVD imaging markers). We performed the inverse variance weighted, weighted median, and MR-Egger methods to assess causal effects between exposure and outcome in univariate MR analysis. To evaluate their heterogeneity, a series of sensitivity analyses were conducted, including the Cochrane Q test, MR-Egger intercept test, MR-Presso, and leave-one-out analysis. We also applied mediation and multivariate MR analysis to explore the interactions between positive exposures on the same outcome. Additionally, we conducted the SMR, which utilizes instruments within or near relevant genes in blood or brain tissues, to elucidate the causal associations with CSVD markers. RESULTS: ABO Univariate MR of multiple cohorts revealed that the risk of small vessel stroke (SVS) increases with elevated levels of TNF-related apoptosis-inducing ligand (TRAIL, OR, 1.23, 95% CI, 1.08-1.39) and interleukin-1 receptor-like 2, (IL-1RL2, OR, 1.29, 95% CI, 1.04-1.61). IL-18 was a potential risk factor for extensive basal ganglia perivascular space burden (BGPVS, OR, 1.02, 95% CI, 1.00-1.05). Moreover, the risk of extensive white matter perivascular space burden (WMPVS) decreased with rising levels of E-selectin (OR, .98, 95% CI, .97-1.00), IL-1RL2 (OR, .97, 95% CI, .95-1.00), IL-3 receptor subunit alpha (IL-3Ra, OR, .98, 95% CI, .97-1.00), and IL-5 receptor subunit alpha (IL-5Ra, OR, .98, 95% CI, .97-1.00). Mediation and multivariate MR analysis indicated that E-selectin and IL-3Ra might interact during the pathogenesis of WMPVS. SMR estimates showed that TRAIL-related IVs rs5030044 and rs2304456 increased the risk of SVS by increasing the expression of gene Kininogen-1 (KNG1) in the cerebral cortex, particularly in the frontal cortex (ßsmr = .10, Psmr = .003, FDR = .04). Instruments (rs507666 and rs2519093) related to E-selectin and IL-3Ra could increase the risk of WMPVS by enhancing DNA methylation of the gene ABO in blood tissue (ßsmr = .01-.02, Psmr = .001, FDR = .01-.03). CONCLUSION: According to MR and SMR analysis, higher levels of TRAIL increased the risk of SVS by upregulating gene expression of KNG1 in brain cortex tissues. In addition, protective effects of E-selectin and IL-3a levels on WMPVS were regulated by increased DNA methylation of gene ABO in blood tissue.

The effects of P2 segment of posterior cerebral artery to thalamus blood supply pattern on gait in cerebral small vessel disease: A 7 T MRI based study.

Gait disturbance is a manifestation of cerebral small vessel disease (CSVD). The posterolateral thalamus (PL), whose blood is mainly supplied by the P2 segment of posterior cerebral artery (P2-PCA), plays pivotal roles in gait regulation. We investigated the influence of the distance between P2-PCA and PL on gait with varying CSVD burden. 71 participants were divided into low and high CSVD burden groups. The distance from P2-PCA to PL was measured using 7 T TOF-MRA and categorized into an immediate or distant PCA-to-thalamus pattern. Functional connectivity (FC) and voxel-based morphometry were assessed to evaluate functional and structural alterations. In the low CSVD burden group, immediate PCA-to-thalamus supply strongly correlates with longer step length and higher wave phase time percent, and exhibited enhanced FCs in left supplementary motor area, right precentral cortex (PreCG.R). While in the high CSVD burden group, no association between PCA-to-thalamus pattern and gait was found, and we observed reduced FC in PreCG.R with immediate PCA-to-thalamus pattern. Higher CSVD burden was associated with decreased gray matter density in bilateral thalamus. However, no significant structural thalamic change was observed between the two types of PCA-to-thalamus patterns in all patients. Our study demonstrated patients with immediate PCA-to-thalamus supply exhibited better gait performance in low CSVD burden populations, which also correlated with enhanced FCs in motor-related cortex, indicating the beneficial effects of the immediate PCA-to-thalamus supply pattern. In the higher burden CSVD populations, the effects of PCA-to-thalamus pattern on gait are void, attributable to the CSVD-related thalamic destruction and impairment of thalamus-related FC.

Unraveling shared risk factors for diabetic foot ulcer: a comprehensive Mendelian randomization analysis.

INTRODUCTION: Diabetic foot ulcer (DFU) stands as a severe diabetic lower extremity complication, characterized by high amputation rates, mortality, and economic burden. We propose using Mendelian randomization studies to explore shared and distinct risk factors for diabetic lower extremity complications. RESEARCH DESIGN AND METHODS: We selected uncorrelated genetic variants associated with 85 phenotypes in five categories at the genome-wide significance level as instrumental variables. Genetic associations with DFU, diabetic polyneuropathy (DPN), and diabetic peripheral artery disease (DPAD) were obtained from the FinnGen and UK Biobank studies. RESULTS: Body mass index (BMI) emerged as the only significant risk factor for DPAD, DPN, and DFU, independent of type 2 diabetes, fasting glucose, fasting insulin, and HbA1c. Educational attainment stood out as the sole significant protective factor against DPAD, DPN, and DFU. Glycemic traits below the type 2 diabetes diagnosis threshold showed associations with DPAD and DPN. While smoking history exhibited suggestive associations with DFU, indicators of poor nutrition, particularly total protein, mean corpuscular hemoglobin, and mean corpuscular volume, may also signal potential DFU occurrence. CONCLUSIONS: Enhanced glycemic control and foot care are essential for the diabetic population with high BMI, limited education, smoking history, and indicators of poor nutrition. By focusing on these specific risk factors, healthcare interventions can be better tailored to prevent and manage DFU effectively.

Factors associated with depression among healthcare workers during the COVID-19 pandemic: a systematic review and meta-analysis.

The COVID-19 pandemic has had a profound impact on the mental health of healthcare workers (HCWs). We aimed to identify the factors associated with depression among HCWs during the pandemic. We conducted literature search using eight electronic databases up to July 27 2022. Observational studies with more than 200 participants investigating correlates of depression in HCWs after COVID-19 outbreak were included. We used fixed- and random-effects models to pool odds ratios (ORs) across studies, and Cochran's chi-squared test and I 2 statistics to assess study heterogeneity. Publication bias was evaluated by funnel plots. Thirty-five studies involving 44,362 HCWs met the inclusion criteria. Female (OR=1.50, 95% CI [1.23,1.84]), single (OR=1.36, 95% CI [1.21,1.54]), nurse (OR=1.69, 95% CI [1.28,2.25]), history of mental diseases (OR=2.53, 95% CI [1.78,3.58]), frontline (OR=1.79, 95% CI [1.38,2.32]), health anxiety due to COVID-19 (OR=1.88, 95% CI [1.29,2.76]), working in isolation wards (OR=1.98, 95% CI [1.38,2.84]), and insufficient personal protective equipment (OR=1.49, 95% CI [1.33,1.67]) were associated with increased risk of depression. Instead, HCWs with a positive professional prospect (OR=0.34, 95% CI [0.24,0.49]) were less likely to be depressed. This meta-analysis provides up-to-date evidence on the factors linked to depression among HCWs during the COVID-19 pandemic. Given the persistent threats posed by COVID-19, early screening is crucial for the intervention and prevention of depression in HCWs.

3D Visualization of Whole Brain Vessels and Quantification of Vascular Pathology in a Chronic Hypoperfusion Model Causing White Matter Damage.

Chronic cerebral hypoperfusion is an important pathological factor in many neurodegenerative diseases, such as cerebral small vessel disease (CSVD). One of the most used animal models for chronic cerebral hypoperfusion is the bilateral common carotid artery stenosis (BCAS) mouse. For the therapy of CSVD and other diseases, it will be beneficial to understand the pathological alterations of the BCAS mouse, particularly vascular pathological changes. A mouse model of BCAS was used, and 8 weeks later, cognitive function of the mice was examined by using novel object recognition test and eight-arm radial maze test. 11.7 T magnetic resonance imaging (MRI) and luxol fast blue staining were used to evaluate the injury of the corpus callosum (CC), anterior commissure (AC), internal capsule (IC), and optic tract (Opt) in the cerebral white matter of mice. Three-dimensional vascular images of the whole brain of mice were acquired using fluorescence micro-optical sectioning tomography (fMOST) with a high resolution of 0.32 × 0.32 × 1.00 µm3. Then, the damaged white matter regions were further extracted to analyze the vessel length density, volume fraction, tortuosity, and the number of vessels of different internal diameters. The mouse cerebral caudal rhinal vein was also extracted and analyzed for its branch number and divergent angle in this study. BCAS modeling for 8 weeks resulted in impaired spatial working memory, reduced brain white matter integrity, and myelin degradation in mice, and CC showed the most severe white matter damage. 3D revascularization of the whole mouse brain showed that the number of large vessels was reduced and the number of small vessels was increased in BCAS mice. Further analysis revealed that the vessel length density and volume fraction in the damaged white matter region of BCAS mice were significantly reduced, and the vascular lesions were most noticeable in the CC. At the same time, the number of small vessels in the above white matter regions was significantly reduced, while the number of microvessels was significantly increased in BCAS mice, and the vascular tortuosity was also significantly increased. In addition, the analysis of caudal rhinal vein extraction revealed that the number of branches and the average divergent angle in BCAS mice were significantly reduced. The BCAS modeling for 8 weeks will lead to vascular lesions in whole brain of mice, and the caudal nasal vein was also damaged, while BCAS mice mainly mitigated the damages by increasing microvessels. What is more, the vascular lesions in white matter of mouse brain can cause white matter damage and spatial working memory deficit. These results provide evidence for the vascular pathological alterations caused by chronic hypoperfusion.

Obesity in children and adolescents and the risk of ovarian cancer: A systematic review and dose‒response meta-analysis.

OBJECTIVE: The relationship between obesity in children and adolescents and the risk of ovarian cancer remains controversial. The aim of this meta-analysis was to explore the exact shape of this relationship. METHODS: We conducted dose‒response meta-analyses of cohort and case‒control studies, including published studies derived from searches in the PubMed, Embase, Web of Science and Cochrane Library databases until October 2022. Pooled effect size estimates are expressed as relative risks (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs) and were evaluated by fixed-effect models. A nonlinear dose‒response meta-analysis was performed by using a restricted cubic spline model. RESULTS: After screening 4215 publications, 10 studies were included in the present meta-analysis. Overall analyses revealed statistically significant associations of obesity in children and adolescents with ovarian cancer (adjusted RR = 1.19, 95% CI: 1.11 to 1.28, P < 0.001). Moreover, the association was consistently significant in most subgroup analyses, for example, using geographic stratification, the results remained stable both in the Americas(RR = 1.11; 95% CI: 1.01 to 1.21; P = 0.022) and Europe (RR = 1.46; 95% CI: 1.21 to 1.77; P<0.001). For the dose‒response analyses, the risk of ovarian cancer increased with the degree of obesity, and the trend increased rapidly when body mass index (BMI) was over 25.95 kg/m2. CONCLUSION: Our findings indicate that obesity in children and adolescents is a risk factor for ovarian cancer, and the risk increases with increasing BMI.

Association of Serum Interleukin-8 and Serum Amyloid A With Anxiety Symptoms in Patients With Cerebral Small Vessel Disease.

Objective: Cerebral small vessel disease (CSVD) is a clinical syndrome caused by pathological changes in small vessels. Anxiety is a common symptom of CSVD. Previous studies have reported the association between inflammatory factors and anxiety in other diseases, but this association in patients with CSVD remains uncovered. Our study aimed to investigate whether serum inflammatory factors correlated with anxiety in patients with CSVD. Methods: A total of 245 CSVD patients confirmed using brain magnetic resonance imaging (MRI) were recruited from December 2019 to December 2021. Hamilton Anxiety Rating Scale (HAMA) was used to assess the anxiety symptoms of CSVD patients. Patients with HAMA scores ≥7 were considered to have anxiety symptoms. The serum levels of interleukin-1ß (IL-1ß), IL-2R, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), serum amyloid A (SAA), C-reactive protein (CRP), high-sensitivity C-reactive protein (hs-CRP) and erythrocyte sedimentation rate (ESR) were detected. We compared levels of inflammatory factors between the anxiety and non-anxiety groups. Logistic regression analyses examined the correlation between inflammatory factors and anxiety symptoms. We further performed a gender subgroup analysis to investigate whether this association differed by gender. Results: In the fully adjusted multivariate logistic regression analysis model, we found that lower levels of IL-8 were linked to a higher risk of anxiety symptoms. Moreover, higher levels of SAA were linked to a lower risk of anxiety symptoms. Our study identified sex-specific effects, and the correlation between IL-8 and anxiety symptoms remained significant among males, while the correlation between SAA and anxiety symptoms remained significant among females. Conclusions: In this study, we found a suggestive association between IL-8, SAA, and anxiety symptoms in CSVD participants. Furthermore, IL-8 and SAA may have a sex-specific relationship with anxiety symptoms.

Abdominal obesity increases the risk of reflux esophagitis: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: The association between abdominal obesity and reflux esophagitis (RE) has been extensively evaluated, but the current findings are mixed and more convincing epidemiological evidence urgently needs to be established. To thoroughly explore this relationship, we summarized the latest studies, performed an updated meta-analysis, and examined the dose-response relationship. METHODS: We performed a systematic search of PubMed, Web of Science, and Embase up to 28 March 2021, using prespecified terms to identify studies investigating the association between abdominal obesity and RE. Odds ratios (ORs) with 95% confidence intervals (CIs), mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs were taken as effect-size estimates. RESULTS: Forty-two observational studies, including 11 cohort studies, were meta-analyzed. Overall, a statistically significant association was observed between abdominal obesity and RE, by both the pooled OR (adjusted OR = 1.51, 95% CI: 1.37-1.66, p < .001) and the pooled SMD (SMD = 0.36, 95% CI: 0.30-0.42, p < .001). Moreover, this significant relationship persisted with subgroup stratification. In subgroup analyses, we found that study design, abdominal obesity measurement, adjustment for covariates and sex were possible sources of between-study heterogeneity. For the dose-response analyses, the risk of RE increased with the degree of abdominal obesity, and the increasing trend accelerated when waist circumference (WC) reached 87.0 cm. CONCLUSION: This meta-analysis indicated a significant association between abdominal obesity and RE, and the risk of RE increased with abdominal obesity especially when the WC was over 87.0 cm.

The Relationship Between Elevated Serum Uric Acid and Risk of Stroke in Adult: An Updated and Dose-Response Meta-Analysis.

Background: Uric acid (UA) is proposed as a potential risk factor for stroke in adult, yet the results from published studies are not generally accordant. Method: We included prospective studies that explored the relationship between serum UA (SUA) and strokes. In this study, strokes include ischemic stroke and hemorrhagic stroke, which consists of intracerebral hemorrhage and subarachnoid hemorrhage. The effect-size estimates were expressed as hazard ratio (HR) and 95% confidence interval (CI). Sensitivity and subgroup analyses were performed to assess the robustness of the pooled estimation and potential sources of heterogeneity between studies. Results: We meta-analyzed 19 prospective cohort articles, which involve 37,386 males and 31,163 females. Overall analyses results showed a significant association between a 1 mg/dl increase in high levels of SUA and the risk of total stroke (HR = 1.13; 95% CI: 1.09-1.18; P < 0.001), ischemic stroke (HR = 1.15; 95% CI: 1.10-1.21; P < 0.001), and hemorrhagic stroke (HR = 1.07; 95% CI: 1.00 to 1.15; P = 0.046). No significant difference was found between ischemic stroke and hemorrhagic stroke. In the subgroup analyses, the association of high SUA levels and the risk of total stroke was statistically significant in females (HR = 1.19; 95% CI: 1.12-1.26; P < 0.001) and males (HR = 1.11; 95% CI: 1.05-1.17; P < 0.001). Coincidentally, the association was also statistically significant for ischemic stroke, both in females (HR = 1.26; 95% CI: 1.17-1.36; P < 0.001) and in males (HR = 1.12; 95% CI: 1.06-1.19; P < 0.001). However, for hemorrhagic stroke, it was only statistically significant in females (HR = 1.19; 95% CI: 1.04-1.35; P = 0.01). Our dose-response research indicated the J-shaped trend between the ascending SUA levels and the higher risk of suffering from a stroke. Conclusions: Our findings indicate that elevated SUA is a significant risk factor for adult stroke, both for ischemic stroke and hemorrhagic stroke, and especially in females.