Alternation of gene expression in brain-derived exosomes after cerebral ischemic preconditioning in mice.

Aims: Cerebral ischemic preconditioning is a neuroprotective therapy against cerebral ischemia and ischemia-reperfusion injury. This study aims to demonstrate the alternation of gene expression in exosomes from brain tissue of mice after ischemic preconditioning and their potential functions. Methods: Ten mice were divided into the sham and the cerebral ischemic preconditioning groups. Their brain tissues were harvested, from which the exosomes were extracted. The characteristics and protective effects of exosomes were evaluated. Whole transcriptome sequencing was used to demonstrate the gene expression discrepancy between the exosomes from the two groups of mice brains. Volcano graphs and heatmaps were used to picture the difference in expression quantity of mRNA, lncRNA, and circRNA. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to demonstrate the functions of differentially expressed RNAs. Results: Exosomes were successfully extracted, and those from the cerebral ischemic preconditioning group had better protective effects on cells that received oxygen-glucose deprivation and restoration injury. A total of 306 mRNAs and 374 lncRNAs were significantly upregulated, and 320 mRNAs and 405 lncRNAs were significantly downregulated in the preconditioning group. No circRNAs were differentially expressed between the two groups. GO and KEGG pathway analysis indicated that the functions of differentially expressed RNAs were related to both neural protective and injurious effects. Conclusion: The brain-derived exosomes may participate in the neuroprotective effect of cerebral ischemic preconditioning. Thorough research is necessary to investigate exosome functions derived from the ischemic preconditioned brain.

Acute ischemic stroke with or without asymptomatic intracranial hemorrhage after endovascular treatment: a propensity-score matching study.

BACKGROUND: The long-term follow-up of asymptomatic intracranial hemorrhage (aICH) in patients with acute ischemic stroke after endovascular treatment (EVT) remains controversial.ObjectiveTo evaluate the potential effect of aICH in a real-world practice setting using a matched prospective database. METHODS: This observational cohort study enrolled patients between January 2015 and December 2022 in a prospective database. Eligible patients with occlusions in the anterior circulation were given endovascular treatment and achieved successful reperfusion. The primary outcome was functional independence (modified Rankin Scale (mRS) score 0-2). Propensity score (PS)-weighted multivariable logistic regression analyses were adjusted and were repeated in subsequent 1:1 PS-matched cohorts. RESULTS: 732 patients, 516 without any ICH and 216 with aICH, were included. 418 and 348 patients were identified after matching in the aICH substudy and hemorrhagic infarction type aICH substudy, respectively. In the postmatched population, patients with aICH had worse functional outcomes (mRS score 0-2) at 90 days than patients without any ICH (37.8% vs 55.5%: P<0.001). Worse functional outcomes were seen in patients with aICH who were older (OR=5.59 (95% CI 2.91 to 10.74)), had higher baseline National Institutes of Health Stroke Scale score (OR=6.80 (95% CI 3.72 to 12.43)), lower baseline Alberta Stroke Program Early CT Score (OR=2.08 (95% CI 1.23 to 3.51)), and who received general anesthesia (OR=3.37 (95% CI 1.92 to 5.90)). CONCLUSIONS: This matched-control study largely confirmed that asymptomatic ICH after EVT is associated with worse functional outcomes, and the harmful effect is more significant in older patients and those with severe baseline clinical and radiological features.

Heating up the divide: Climate change and the quest for inclusive growth in urban China.

Climate change has profoundly affected human production and development, and also brought new challenges to China's goal of achieving inclusive economic growth. Using the data of 273 cities in China from 2001 to 2019, this research evaluates the impact of climate change on urban inclusive economic growth by constructing a temperature bin variable according to the daily average temperature. It is found that with the temperature bin [18 °C, 21 °C) as the benchmark group, both temperature rise and fall have a negative influence on inclusive economic growth. Notably, the adverse effects of high temperatures (above 27 °C) are statistically and economically significant, exhibiting a trend of increasing magnitude. The mechanism test shows that high temperature affects the inclusive growth level of the urban economy mainly by exacerbating the urban‒rural income gap. The heterogeneity analysis found that cities located in hot regions, southern regions or coastal areas are more sensitive to high temperatures and experience more prominent effects. This research holds significant practical implications for China to achieve a win‒win situation of balanced economic development and climate governance.

Identifying novel risk genes in intracranial aneurysm by integrating human proteomes and genetics.

Genome-wide association studies (GWAS) have become increasingly popular for detecting numerous loci associated with intracranial aneurysm (IA), but how these loci function remains unclear. In this study, we employed an integrative analytical pipeline to efficiently transform genetic associations and identify novel genes for IA. Using multidimensional high-throughput data, we integrated proteome-wide association studies (PWAS), transcriptome-wide association studies (TWAS), Mendelian randomization (MR) and Bayesian co-localization analyses to prioritize genes that can increase IA risk by altering their expression and protein abundances in the brain and blood. Moreover, single-cell RNA sequencing (scRNA-seq) of the circle of Willis was performed to enrich filtered genes in cells, and gene set enrichment analysis (GSEA) was conducted for each gene using bulk RNA-seq data for IA. No significant genes with cis-regulated plasma protein levels were proven to be associated with IA. The protein abundances of five genes in the brain were found to be associated with IA. According to cellular enrichment analysis, these five genes were expressed mainly in the endothelium, fibroblasts and vascular smooth muscle cells. Only three genes, CNNM2, GPRIN3 and UFL1, passed MR and Bayesian co-localization analyses. While UFL1 was not validated in confirmation PWAS as it was not profiled, it was validated in TWAS. GSEA suggested these three genes are associated with the cell cycle. In addition, the protein abundance of CNNM2 was found to be associated with IA rupture (based on PWAS, MR and co-localization analyses). Our findings indicated that CNNM2, GPRIN3 and UFL1 (CNNM2 correlated with IA rupture) are potential IA risk genes that may provide a broad hint for future research on possible mechanisms and therapeutic targets for IA.

Intracranial Aneurysms Managed by Parent Artery Reconstruction Using Tubridge Flow Diverter study: 1-year outcomes.

OBJECTIVE: Previous randomized controlled trials have reported a significantly higher occlusion rate of large and giant aneurysms when utilizing the Tubridge flow diverter (FD). In the present trial, the safety and efficacy of the Tubridge FD in treating unruptured internal carotid artery (ICA) or vertebral artery (VA) aneurysms were assessed in a real-world setting. METHODS: The Intracranial Aneurysms Managed by Parent Artery Reconstruction Using Tubridge Flow Diverter (IMPACT) study is a prospective, multicenter, single-arm clinical trial assessing the efficacy of the Tubridge FD in the management of unruptured aneurysms located in the ICA or VA. The primary endpoint was the complete occlusion (Raymond-Roy class 1) rate at the 1-year follow-up. The secondary endpoints included the technical success rate, the successful occlusion rate of the aneurysm, which is the degree of aneurysm embolization scored as Raymond-Roy class 1 or 2, major (> 50%) in-stent stenosis, and incidence of disabling stroke or neurological death associated with the target aneurysms. RESULTS: This study included 14 interventional neuroradiology centers, with 200 patients and 240 aneurysms. According to angiographic core laboratory assessment, 205 (85.4%) aneurysms were located in the ICA, 34 (14.2%) in the VA, and 1 (0.4%) in the middle cerebral artery. Additionally, 189 (78.8%) aneurysms were small (< 10 mm). At the 12-month follow-up, the total occlusion rate was 79.0% (166/210, 95% CI 72.91%-84.34%). Additionally, the occurrence of disabling stroke or neurological death related to the specified aneurysms was 1% (2/200). CONCLUSIONS: The 1-year results from the IMPACT trial affirm the safety record of use of the Tubridge FD in the treatment of intracranial aneurysms in real-world scenarios. These results reveal low morbidity and mortality rates of 3.5% and 1.5%, respectively. Furthermore, they provide evidence of the effectiveness of the Tubridge FD, as demonstrated by the complete occlusion achieved in 166 of 210 (79%) cases.

Causal relationship between gut microbiota and functional outcomes after ischemic stroke: A comprehensive Mendelian randomization study.

AIMS: To investigate the association of the genetic predisposition of specific gut microbiotas with the clinical outcome of ischemic stroke. METHODS: We leveraged publicly available genome-wide association study (GWAS) data to perform Mendelian randomization (MR) analysis. The gut microbiota-related GWAS data from 18,340 individuals from the international consortium MiBioGen was used. The summary data for functional outcomes after ischemic stroke was obtained from the Genetics of Ischemic Stroke Functional Outcome (GISCOME) network meta-analysis. The primary outcomes were judged by the modified Rankin Scale (mRS). The principal analyses were conducted using the inverse-variance weighted (IVW) MR method. The Cochran's Q test, weighted median, MR-Egger regression, leave-one-SNP-out analysis, MR-Pleiotropy Residual Sum, and Outlier methods were adopted as sensitivity analyses. Furthermore, we performed bi-directional MR analysis and the MR Steiger directionality test to examine the direction of the causal relations. RESULTS: The results demonstrated that the genetic predisposition of genus Lactococcus, genus Ruminococcaceae NK4A214 group, family Peptostreptococcaceae, and genus Odoribacter was positively associated with favorable functional outcome after ischemic stroke. Genus Collinsella, genus Ruminococcaceae UCG005, genus Akkermansia, genus Eubacterium oxidoreducens group, and family Verrucomicrobiaceae were identified to be associated with worse functional outcomes after ischemic stroke. Our results showed no evidence of heterogeneity, directional pleiotropic effects, or collider bias, and the sensitivity of our analysis was acceptable. CONCLUSION: The genetic predisposition of different gut microbiotas was associated with the clinical outcome of ischemic stroke. Microbiota adjustment was a promising method to improve the clinical outcome of ischemic stroke.

PCSK9 expression in fibrous cap possesses a marker for rupture in advanced plaque.

BACKGROUND: To date, PCSK9 inhibitors are well known for eliminating cardiac and cerebral artery ischemia events by lowering the serum lipid level. However, the pathophysiological value of in-plaque PCSK9 expression is still unclear. METHODS: Advanced plaques removed by carotid endarterectomy were sectioned and stained to identify the PCSK9 expression pattern and its co-expression with rupture-relevant markers. To investigate the correlation of PCSK9 expression with regional blood shear flow, hemodynamic characteristics were analyzed using computational fluid dynamics, and representative parameters were compared between PCSK9 positive and negative staining plaques. To explore this phenomenon in vitro, human aortic vascular smooth muscle cells were used to overexpress and knock down PCSK9. The impacts of PCSK9 modulations on mechanical sensor activity were testified by western blot and immunofluorescence. Real-time polymerase chain reaction was used to evaluate the transcription levels of downstream rupture-prone effectors. RESULTS: PCSK9 distribution in plaque preferred cap and shoulder regions, residing predominantly in smooth muscle actin-positive cells. Cap PCSK9 expression correlated with fibrous cap thickness negatively and co-expressed with MMP-9, both pointing to the direction of plaque rupture. A hemodynamic profile indicated a rupture-prone feature of cap PCSK9 expression. In vitro, overexpression and knockdown of PCSK9 in human aortic vascular smooth muscle cells has positive modulation on mechanical sensor Yes-associated protein 1 (YAP) activity and transcription levels of its downstream rupture-prone effectors. Serial section staining verified in situ colocalization among PCSK9, YAP, and downstream effectors. CONCLUSIONS: Cap PCSK9 possesses a biomarker for rupture risk, and its modulation may lead to a novel biomechanical angle for plaque interventions.

Determinants influencing health-promoting behaviors in individuals at high risks of stroke: a cross-sectional study.

Background: Quit smoking, moderate drinking, exercise, and healthy eating habits are all known to decrease the risk of stroke. As a result, understanding the health behaviors of high risk groups for stroke is crucial. Health behavior is influenced by knowledge, social environment, and health beliefs. However, little research has been done on these relationships. For a better grasp of the relationships mentioned above, consider using the COM-B model (capability, opportunity, motivation, and behavior). The purpose of this study was to investigate the variables related to health behavior and to test the mediating effect of health beliefs. Methods: The cross-sectional study was carried out at a physical examination center of a tertiary hospital in Shanghai, China. 986 high-risk populations of stroke have been tested using the Health Behavior Scale (HBS-SP), Stroke Knowledge Questionnaire (SKQ), Health Beliefs Questionnaire (HBS), and Multidimensional Scale of Perceived Social Support (MSPSS). The structural equation modeling was used in this study. Results: The scores for MSPSS, SKQ, HBS, and HBS-SP were 60.64 ± 13.72, 26.60 ± 9.77, 157.71 ± 34.34, and 2.46 ± 0.41, respectively. The revised model fits well (approximate root mean square error = 0.042; comparative fit index = 0.946). The health behavior was obviously and positively correlated to social Support, stroke knowledge, and health beliefs. Moreover, health belief has a mediating effect on the relation of social support, stroke knowledge, and health behavior. Conclusion: Chinese high risk groups for stroke have a mediate level of health behaviors. Factors associated with health behaviors are knowledge of stroke, health beliefs, and social support. The COM-B-based model can be used to explain the health behavior of individuals at risk of stroke and to guide the formulation of effective health management programs.

Impact of premorbid hypertension and renin-angiotensin-aldosterone system inhibitors on the severity of aneurysmal subarachnoid haemorrhage: a multicentre study.

BACKGROUND: Hypertension is widely acknowledged as a significant contributory factor to the heightened risk of intracranial aneurysm rupture. Nevertheless, the impact of hypertension management on the outcomes subsequent to aneurysmal subarachnoid haemorrhage (aSAH), particularly concerning the severity of aSAH, remains an underexplored area. METHODS: We conducted a retrospective analysis using data from a prospectively multicentre cohort of 4545 patients with aSAH in China. Premorbid hypertension status and the utilisation of antihypertensive medications prior to admission were set as key exposure factors. The primary outcomes encompassed unfavourable clinical grading scales observed on admission. Employing multivariable logistic regression, we explored the association between premorbid hypertension status, preadmission use of renin-angiotensin-aldosterone system (RAAS) inhibitors and unfavourable clinical grading scales. RESULTS: In comparison to patients with normal blood pressure, only uncontrolled hypertension demonstrated a significant and independent association with an elevated risk of poor outcomes on the Hunt-Hess scale (OR=1.799, 95% CI 1.413 to 2.291, p<0.001) and the World Federation of Neurological Surgeons (WFNS) scale (OR=1.721, 95% CI 1.425 to 2.079, p<0.001). Furthermore, the antecedent use of RAAS inhibitors before admission was markedly and independently linked to a diminished risk of adverse outcomes on the Hunt-Hess scale (OR=0.653, 95% CI 0.430 to 0.992, p=0.046) and the WFNS scale (OR=0.656, 95% CI 0.469 to 0.918, p=0.014). CONCLUSIONS: Uncontrolled hypertension markedly elevates the risk of adverse clinical outcomes following an aSAH. Conversely, the preadmission utilisation of RAAS inhibitors demonstrates a noteworthy association with a favourable clinical outcome after aSAH.

Evaluation of flow diverters for cerebral aneurysm therapy: recommendations for imaging analyses in clinical studies, endorsed by ESMINT, ESNR, OCIN, SILAN, SNIS, and WFITN.

BACKGROUND: Multiple studies and meta-analyses have described the technical and clinical outcomes in large cohorts of aneurysm patients treated with flow diverters (FDs). Variations in evaluation methodology complicate making comparisons among studies, hinder understanding of the device behavior, and pose an obstacle in the assessment of further advances in FD therapy. METHODS: A multidisciplinary panel of neurointerventionalists, imaging experts, and neuroradiologists convened with the goal of establishing consensus recommendations for the standardization of image analyses in FD studies. RESULTS: A standardized methodology is proposed for evaluating and reporting radiological outcomes of FD treatment of intracranial aneurysms. The recommendations include general imaging considerations for clinical studies and evaluations of longitudinal changes, such as neointimal lining and stenosis. They cover standards for classification of aneurysm location, morphology, measurements, as well as the assessment of aneurysm occlusion, wall apposition, and neck coverage. These reporting standards further define four specific braid deformation patterns: foreshortening, fish-mouthing, braid bump deformation, and braid collapse, collectively termed 'F2B2'. CONCLUSIONS: When widely applied, standardization of methods of measuring and reporting outcomes will help to harmonize the assessment of treatment outcomes in clinical studies, help facilitate communication of results among specialists, and help enable research and development to focus on specific aspects of FD techniques and technology.

Causal effect of blood osteocalcin on the risk of Alzheimer's disease and the mediating role of energy metabolism.

Growing evidence suggests an association between osteocalcin (OCN), a peptide derived from bone and involved in regulating glucose and lipid metabolism, and the risk of Alzheimer's disease (AD). However, the causality of these associations and the underlying mechanisms remain uncertain. We utilized a Mendelian randomization (MR) approach to investigate the causal effects of blood OCN levels on AD and to assess the potential involvement of glucose and lipid metabolism. Independent instrumental variables strongly associated (P < 5E-08) with blood OCN levels were obtained from three independent genome-wide association studies (GWAS) on the human blood proteome (N = 3301 to 35,892). Two distinct summary statistics datasets on AD from the International Genomics of Alzheimer's Project (IGAP, N = 63,926) and a recent study including familial-proxy AD patients (FPAD, N = 472,868) were used. Summary-level data for fasting glucose (FG), 2h-glucose post-challenge, fasting insulin, HbA1c, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol (TC), and triglycerides were incorporated to evaluate the potential role of glucose and lipid metabolism in mediating the impact of OCN on AD risk. Our findings consistently demonstrate a significantly negative correlation between genetically determined blood OCN levels and the risk of AD (IGAP: odds ratio [OR, 95%CI] = 0.83[0.72-0.96], P = 0.013; FPAD: OR = 0.81 [0.70-0.93], P = 0.002). Similar estimates with the same trend direction were obtained using other statistical approaches. Furthermore, employing multivariable MR analysis, we found that the causal relationship between OCN levels and AD was disappeared after adjustment of FG and TC (IGAP: OR = 0.97[0.80-1.17], P = 0.753; FPAD: OR = 0.98 [0.84-1.15], P = 0.831). There were no apparent instances of horizontal pleiotropy, and leave-one-out analysis showed good stability of the estimates. Our study provides evidence supporting a protective effect of blood OCN levels on AD, which is primarily mediated through regulating FG and TC levels. Further studies are warranted to elucidate the underlying physio-pathological mechanisms.

Information infrastructure and corporate green innovation quality incentive.

We use a sample of Chinese firms from 2006 to 2020 to investigate the effect of information infrastructure on the quality of green innovation. Findings show that information infrastructure significantly improves corporate green innovation quality, and information infrastructure improves the pricing efficiency, improves valuation levels, accelerates the flow of innovation resources, and induces the growth effect of corporate innovation resources. Furthermore, we find that executive salary incentives, internal control quality, and market-oriented environmental regulation have adaptive incentives for information infrastructure to improve the quality of green innovation. Our findings provide justification to promote the construction of an information infrastructure and adopt market-oriented environmental regulations to improve corporate green innovation quality.

Advanced gallbladder cancer with high tumor mutation burden: a case report and literature review.

Background: Gallbladder cancer (GBC) is a common malignant tumor of the biliary system. It is characterised by insidious onset, rapid progression and poor prognosis. Symptoms often indicate advanced or late-stage disease, with a 5-year survival rate of only 5-15%. Case Description: We present a case study of a patient with GBC who had a tumor mutation burden (TMB) of 32.5/MB (≥10 muts/MB). The patient received mFOLFIRINOX as first-line chemotherapy, which demonstrated significant efficacy. After stabilizing the disease, a sequential chemotherapy regimen was chosen. This regimen combined the immune checkpoint inhibitor (ICI) toripalimab (JS001), a humanised IgG4 monoclonal antibody targeting programmed cell death protein 1 (PD-1), with S-1 therapy, an oral fluoropyrimidine derivative. However, this treatment did not provide any significant clinical benefit for the patient. Therefore, we hypothesise that combining immunotherapy with chemotherapy may be more effective as a first line treatment for high-TMB advanced GBC. This hypothesis needs to be validated in large-scale clinical studies. Conclusions: In summary, mFOLFIRINOX is a safe and effective first-line chemotherapy regimen for advanced GBC. The timing of combining immunotherapy with chemotherapy requires careful consideration. Further clinical trials involving immunotherapy in advanced GBC are necessary to identify biomarkers that can guide clinical decisions.

Efficacy and safety of tegoprazan in the treatment of gastroesophageal reflux disease: A protocol for meta-analysis and systematic review.

OBJECTIVE: The incidence of gastroesophageal reflux disease (GERD) is increasing year by year, the clinical manifestations are complex and diverse, and the adverse effects of long-term use of proton pump inhibitors and gastrointestinal motility drugs have been of great concern in recent years. The effectiveness of tegoprazan in the treatment of GERD is still controversial. This protocol describes a systematic review and meta-analysis to evaluate the efficacy and safety of tegoprazan in the treatment of gastroesophageal reflux disease. METHODS: PubMed, Embase, Cochrane Library and Web of Science will be searched from the database inception to 1 March 2023. All randomized controlled trials related to tegoprazan for GERD will be included. Extracted data will include publication details, basic information, demographic data, intervention details and patient outcomes. The primary outcome will be complete resolution of major symptoms, complete resolution of heartburn, proportion of heartburn-free days, chronic cough, hoarseness, and adverse events. Risk of bias will be assessed using the Cochrane Collaboration's tool for assessing risk of bias. Article selection, data extraction and risk of bias assessment will be performed in duplicate by two independent reviewers. If the meta-analysis is precluded, we will conduct a descriptive synthesis using a best-evidence synthesis approach. DISCUSSION: The results of this study will provide reliable evidence to evaluate the efficacy and safety of tegoprazan in the treatment of GERD and help patients, physicians and clinical investigators choose the most appropriate treatment.

Modeling an evaluation of the efficacy of the novel neuroanalgesic drug mirogabalin for diabetic peripheral neuropathic pain and postherpetic neuralgia therapy.

Diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN) are challenging and often intractable complex medical conditions, with a substantial impact on the quality of life. Mirogabalin, a novel voltage-gated Ca2+ channel α2δ ligand, was approved for the indication of DPNP and PHN. However, the time course of effects has not yet been clarified.We aimed to establish pharmacodynamic and placebo effect models of mirogabalin and pregabalin in DPNP and PHN, and to quantitatively compare the efficacy characteristics (maximum efficacy, onset time, and other pharmacodynamic parameters) and safety of mirogabalin and pregabalin. Public databases were comprehensively searched for randomized placebo-controlled clinical trials. A model-based meta-analysis (MBMA) was developed to describe the time course of drug efficacy and placebo effects. Adverse events were compared using a fixed-effects meta-analysis. Sixteen studies including 5,147 participants were eligible for this study. The placebo effect was relatively high and gradually increased with time, and it required at least eight weeks to reach a plateau. The pharmacodynamic model revealed that the maximum pure efficacy for mirogabalin and pregabalin was approximately -7.85 % and -8.86 %, respectively; the efficacy of mirogabalin to relieve DPNP and PHN was not superior to that of pregabalin, and both drugs had similar safety. While the rate constant of the onset rate of pregabalin was approximately thrice as high as that of mirogabalin. In addition, the baseline level of pain was an important factor affecting pregabalin efficacy. These findings are helpful in evaluating the clinical extension value of mirogabalin. They suggest that the high placebo effect and the baseline level of pain should be considered when grouping patients in future research and development of voltage-gated Ca2+ channel neuroanalgesic.

Association of cardiovascular disease prevalence with BMD and fracture in men with T2DM.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are predisposed to cardiovascular disease (CVD). Bone mineral density (BMD) is linked to CVD, but most studies focused on women. Our analysis aims to explore the association of BMD and fracture with the prevalence of CVD in men with T2DM. METHODS: In this retrospective cross-sectional study, 856 men with T2DM were enrolled. BMDs at the lumbar spine (L2-4), femoral neck (FN), and total hip (TH) were measured by dual-energy X-ray absorptiometry (DXA). The CVD outcome was determined as the sum of the following conditions: congestive heart failure, coronary heart disease, angina pectoris, myocardial infarction, the requirement for coronary artery revascularization, and stroke. The relationship between BMDs and CVD was investigated by restricted cubic spline curves and logistic regression models. RESULTS: A total of 163 (19.0%) patients developed CVD. The restricted cubic spline curve revealed a linear and negative association between FN-BMD, TH-BMD, and CVD. After full adjustments for confounding covariates, the odds ratios were 1.34 (95% confidence interval [CI] [1.11-1.61], p < .05), 1.3 (95% CI [1.05-1.60], p < .05), and 1.26 (95% CI [1.02-1.55], p < .05) for each 1-SD decrease in BMDs of L2-4, FN and TH, respectively. T-scores of < -1 for BMD of L2-4 and FN were independently associated with CVD (p < .05). Subgroup analyses further supported our findings. CONCLUSIONS: The prevalence of CVD was inversely correlated with BMD levels in men with T2DM, particularly at the FN. We hypothesized that monitoring FN-BMD and early intervention would help reduce CVD risk in men with T2DM, especially those with hypertension.

Outcome and Risk of Poststroke Pneumonia in Patients with Acute Ischemic Stroke After Endovascular Thrombectomy: A Post Hoc Analysis of the DIRECT-MT Trial.

BACKGROUND: In this study, we aimed to investigate the risk factors and impact of poststroke pneumonia (PSP) on mortality and functional outcome in patients with acute ischemic stroke (AIS) after endovascular thrombectomy (EVT). METHODS: This was a post hoc analysis of a prospective randomized trial (Direct intraarterial thrombectomy in order to revascularize AIS patients with large-vessel occlusion efficiently in Chinese tertiary hospitals: a multicenter randomized clinical trial). Patients with AIS who completed EVT were evaluated for the occurrence of PSP during the hospitalization period and their modified Rankin Scale (mRS) scores at 90 days after AIS. Logistic regression analysis was conducted to investigate the independent predictors of PSP. Propensity score matching was conducted for the PSP and non-PSP groups by using the covariates resulting from the logistic regression analysis. The associations between PSP and outcomes were analyzed. The outcomes included 90-day poor functional outcome (mRS scores > 2), 90-day mortality, and early 2-week mortality. RESULTS: A total of 639 patients were enrolled, of whom 29.58% (189) developed PSP. Logistic regression analysis revealed that history of chronic heart failure (unadjusted odds ratio [OR] 2.011, 95% confidence interval [CI] 1.026-3.941; P = 0.042), prethrombectomy reperfusion on initial digital subtraction angiography (OR 0.394, 95% CI 0.161-0.964; P = 0.041), creatinine levels at admission (OR 1.008, 95% CI 1.000-1.016; P = 0.049), and National Institutes of Health Stroke Scale at 24 h (OR 1.023, 95% CI 1.007-1.039; P = 0.004) were independent risk factors for PSP. With propensity scoring matching, poor functional outcome (mRS > 2) was more common in patients with PSP than in patients without PSP (81.03% vs. 71.83%, P = 0.043) at 90 days after EVT. The early 2-week mortality of patients with PSP was lower (5.74% vs. 12.07%, P = 0.038). But there was no statistically significant difference in 90-day mortality between the PSP group and non-PSP group (22.41% vs. 14.94%, P = 0.074). The survivorship curve also shows no statistical significance (P = 0.088) between the two groups. CONCLUSIONS: Nearly one third of patients with AIS and EVT developed PSP. Heart failure, higher creatinine levels, prethrombectomy reperfusion, and National Institutes of Health Stroke Scale at 24 h were associated with PSP in these patients. PSP was associated with poor 90-day functional outcomes in patients with AIS treated with EVT.

Trachelogenin alleviates osteoarthritis by inhibiting osteoclastogenesis and enhancing chondrocyte survival.

BACKGROUND: Osteoarthritis (OA) is a prevalent global health concern associated with the loss of articular cartilage and subchondral bone. The lack of disease-modifying drugs for OA necessitates the exploration of novel therapeutic options. Our previous study has demonstrated that traditional Chinese medical herb Trachelospermum jasminoides (Lindl.) Lem. extract suppressed osteoclastogenesis and identified trachelogenin (TCG) as a representative compound. Here, we delved into TCG's potential to alleviate OA. METHODS: We initially validated the in vivo efficacy of TCG in alleviating OA using a rat OA model. Subsequently, we isolated primary bone marrow-derived macrophages in vitro to investigate TCG's impact on osteoclastogenesis. We further employed a small molecule pull-down assay to verify TCG's binding target within osteoclasts. Finally, we isolated primary mouse chondrocytes in vitro to study TCG's regulatory effects and mechanisms on chondrocyte survival. RESULTS: TCG preserved subchondral bone integrity and protected articular cartilage in a rat OA model. Subsequently, in vitro experiments unveiled TCG's capability to inhibit osteoclastogenesis and function through binding to Ras association proximate 1 (Rap1) and inhibiting its activation. Further study demonstrated that TCG inhibited Rap1/integrin αvß3/c-Src/Pyk2 signaling cascade, and consequently led to failed F-actin ring formation. Besides, TCG promoted the proliferation of mouse primary chondrocytes while suppressing apoptosis in vitro. This is attributed to TCG's ability to upregulate HIF1α, thereby promoting glycolysis. CONCLUSION: TCG exerted inhibitory effects on osteoclastogenesis through binding to Rap1 and inhibiting Rap1 activation, consequently preventing subchondral bone loss. Moreover, TCG enhanced chondrocyte survival by upregulating HIF1α and promoting glycolysis. These dual mechanisms collectively provide a novel approach to prevented against cartilage degradation.