Comprehensive clinical and genetic analyses of circulating bile acids and their associations with diabetes and its indices.

Bile acids (BAs) are cholesterol-derived compounds that regulate glucose, lipid, and energy metabolism. Despite their significance in glucose homeostasis, the association between specific BA molecular species and their synthetic pathways with diabetes mellitus (DM) is unclear. Here, we used a recently validated stable-isotope dilution highperformance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method to quantify a panel of BAs in fasting plasma from subjects (n=2,145) and explored structural and genetic determinants of BAs linked to DM, insulin resistance and obesity. Multiple 12α-hydroxylated BAs were associated with DM [adjusted odds ratios (aORs):1.3-1.9 (all P<0.05)] and insulin resistance [aORs:1.3-2.2 (all P<0.05)]. Conversely, multiple 6a-hydroxylated BAs and isolithocholic acid (Iso-LCA) were inversely associated with DM and obesity [aORs:0.3-0.9 (all P<0.05)]. Genome-wide association studies (GWAS) revealed multiple genome-wide significant loci linked with nine of the 14 DM-associated BAs, including a locus for Iso-LCA (rs11866815). Mendelian randomization analyses showed genetically elevated DCA levels were causally associated with higher BMI, and Iso-LCA levels were causally associated with reduced BMI and DM risk. In conclusion, comprehensive large-scale quantitative mass spectrometry and genetics analyses show circulating levels of multiple structurally specific BAs, especially DCA and Iso-LCA, are clinically associated with and genetically linked to obesity and DM.

Exploratory Transcriptomic Profiling Reveals the Role of Gut Microbiota in Vascular Dementia.

Stroke is the second most common cause of cognitive impairment and dementia. Vascular dementia (VaD), a cognitive impairment following a stroke, is common and significantly impacts the quality of life. We recently demonstrated via gut microbe transplant studies that the gut microbe-dependent trimethylamine-N-oxide (TMAO) pathway impacts stroke severity, both infarct size and long-term cognitive outcomes. However, the molecular mechanisms that underly the role of the microbiome in VaD have not been explored in depth. To address this issue, we performed a comprehensive RNA-sequencing analysis to identify differentially expressed (DE) genes in the ischemic cerebral cortex of mouse brains at pre-stroke and post-stroke day 1 and day 3. A total of 4016, 3752 and 7861 DE genes were identified at pre-stroke and post-stroke day 1 and day 3, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated pathways of neurodegeneration in multiple diseases, chemokine signaling, calcium signaling, and IL-17 signaling as the key enriched pathways. Inflammatory response genes interleukin-1 beta (Il-1ß), chemokines (C-X-C motif chemokine ligand 10 (Cxcl10), chemokine ligand 2 (Ccl2)), and immune system genes (S100 calcium binding protein 8 (S100a8), lipocalin-2 (Lcn2)) were among the most significantly upregulated genes. Hypocretin neuropeptide precursor (Hcrt), a neuropeptide, and transcription factors such as neuronal PAS domain protein 4 (Npas4), GATA binding protein 3 (Gata3), and paired box 7 (Pax7) were among the most significantly downregulated genes. In conclusion, our results indicate that higher plasma TMAO levels induce differential mRNA expression profiles in the ischemic brain tissue in our pre-clinical stroke model, and the predicted pathways provide the molecular basis for regulating the TMAO-enhanced neuroinflammatory response in the brain.

Development and validation of a prediction model for outcomes after transaxillary first rib resection for neurogenic thoracic outlet syndrome following strict Society for Vascular Surgery diagnostic criteria.

OBJECTIVE: Neurogenic thoracic outlet syndrome (NTOS) is the most common form of thoracic outlet syndrome. However, NTOS has remained difficult to diagnose and treat successfully. The purpose of the present study was to generate a predictive clinical calculator for postoperative outcomes after first rib resection (FRR) for NTOS. METHODS: We performed a retrospective review of patients who had undergone FRR for NTOS at a single tertiary care institution between 2016 and 2020. A multivariate stepwise logistic regression analysis was performed to assess the association of the percentage of improvement after FRR with the patient baseline characteristics, pertinent clinical characteristics, and diagnostic criteria set by the Society for Vascular Surgery. The primary outcome was subjective patient improvement after FRR. A prediction risk calculator was developed using backward stepwise multivariate logistic regression coefficients. Bootstrapping was used for internal validation. RESULTS: A total of 208 patients (22.2% male; mean age, 35.8 ± 12.8 years; median follow-up, 44.9 months) had undergone 243 FRRs. Of the 208 patients, 94.7% had had symptoms localized to the supraclavicular area, and 97.6% had had symptoms in the hand. All the patients had had positive symptoms reproduced by the elevated arm stress test and upper limb tension test. Another reasonably likely diagnosis was absent for all the patients. Of the 196 patients who had received a lidocaine injection, 180 (93.3%) had experienced improvement of NTOS symptoms. Of the 95 patients who had received a Botox injection, 82 (74.6%) had experienced improvement of NTOS symptoms. Receiver operating characteristic curve analysis was used to assess the model. The area under the curve for the backward stepwise multivariate logistic regression model was 0.8. The multivariate logistic regression analyses revealed that the significant predictors of worsened clinical outcomes included hand weakness (adjusted odds ratio [aOR], 4.28; 95% confidence interval [CI], 1.04-17.74), increasing age (aOR, 0.93; 95% CI, 0.88-0.99), workers' compensation or litigation case (aOR, 0.09; 95% CI, 0.01-0.82), and symptoms in the dominant hand (aOR, 0.20; 95% CI, 0.05-0.88). CONCLUSIONS: Using retrospective data from a single-institution database, we have developed a prediction calculator with moderate to high predictive ability, as demonstrated by an area under the curve of 0.8. The tool (available at: https://jhhntosriskcalculator.shinyapps.io/NTOS_calc/) is an important adjunct to clinical decision-making that can offer patients and providers realistic and personalized expectations of the postoperative outcome after FRR for NTOS. The findings from the present study have reinforced the diagnostic criteria set by the Society for Vascular Surgery. The calculator could aid physicians in surgical planning, referrals, and counseling patients on whether to proceed with surgery.

Data Velocity in HIV-Related Implementation Research: Estimating Time From Funding to Publication.

BACKGROUND: Given available effective biomedical and behavioral prevention and treatment interventions, HIV-related implementation research (IR) is expanding. The rapid generation and dissemination of IR to inform guidelines and practice has the potential to optimize the impact of the Ending the Epidemic Initiative and the HIV pandemic response more broadly. METHODS: We leveraged a prior mapping review of NIH-funded awards in HIV and IR from January 2013 to March 2018 and identified all publications linked to those grants in NIH RePORTER through January 1, 2021 (n = 1509). Deduplication and screening of nonoriginal research reduced the count to 1032 articles, of which 952 were eligible and included in this review. Publication volume and timing were summarized; Kaplan-Meier plots estimated time to publication. RESULTS: Among the 215 NIH-funded IR-related awards, 127 of 215 (59%) published original research directly related to the grant, averaging 2.0 articles (SD: 3.3) per award, largely in the early IR phases. Many articles (521 of 952, 55%) attributed to grants did not report grant-related data. Time from article submission to publication averaged 205 days (SD: 107). The median time-to-first publication from funding start was 4 years. Data dissemination velocity varied by award type, trending toward faster publication in recent years. Delays in data velocity included (1) time from funding to enrollment, (2) enrollment length, and (3) time from data collection completion to publication. CONCLUSION: Research publication was high overall, and time-to-publication is accelerating; however, over 40% of grants have yet to publish findings from grant-related data. Addressing bottlenecks in the production and dissemination of HIV-related IR would reinforce its programmatic and policy relevance in the HIV response.

Association between Race and Perioperative Outcomes after Carotid Endarterectomy for Asymptomatic Carotid Artery Stenosis in NSQIP.

BACKGROUND: Previous studies have documented that Black patients have worse outcomes after lower extremity revascularization procedures compared with White patients. However, the association of race on carotid endarterectomy (CEA) outcomes is not well described. The aim of this study was to compare perioperative outcomes of CEA for Black vs White patients with asymptomatic carotid artery stenosis. STUDY DESIGN: All patients who underwent CEA for asymptomatic carotid stenosis in the ACS-NSQIP targeted vascular database (2011-2019) were included. Perioperative (30-day) outcomes were compared for Black vs White patients using multivariable logistic regression adjusting for age/sex, comorbidities, and disease characteristics. RESULTS: Of 16,764 asymptomatic CEA patients, 95.2% (N = 15,960) were White and 4.8% (N = 804) were Black. Black patients were slightly younger (mean age 71.4 ± 0.1 vs 69.9 ± 0.3 years, P < 0.001) and more frequently had high-grade carotid artery stenosis compared to White patients (79.5% vs 74.0%, p = 0.001). Comorbidities including hypertension, diabetes, kidney disease, congestive heart failure, and coronary artery disease were all more prevalent among Black patients (p ≤ 0.01). Crude perioperative stroke (2.4% vs 1.3%, p = 0.007) and stroke/death (2.6% vs 1.4%, p = 0.003) were higher for Black patients, but myocardial infarction (1.7% vs 1.5%, p = 0.67) and death (0.4% vs 0.2%, p = 0.12) were similar. After adjusting for baseline differences between groups, the risk of perioperative stroke (odds ratio 1.66, 95% CI 1.01 to 2.73) and stroke/death (odds ratio 1.75, 95% CI 1.10 to 2.81) remained significantly higher for Black patients compared with White patients. CONCLUSIONS: Black patients undergoing CEA for asymptomatic carotid artery stenosis had more severe stenosis, more comorbidities, and worse perioperative outcomes compared to White patients. Overall, our data suggest substantial differences in the treatment and outcomes of asymptomatic carotid artery stenosis based on race.

A systematic review of sutureless vascular anastomosis technologies.

Vascular anastomoses typically involve a handsewn technique requiring significant surgical training, expertise, and time. The aim of our systematic review was to identify and describe sutureless vascular anastomosis techniques. We performed a systematic review of all sutureless vascular anastomosis technologies published in MEDLINE, PubMed, Embase, CINAHL, Cochrane, Web of Science, and Scopus Library databases and a patent review using US Patent and Trade Office Application, US Patent and Trademark Office Patent, Google Patents, Lens, Patent Quality Through Artificial Intelligence, SureChEMBL, and E-Space Net. Data from inclusion studies and patents published between January 1, 1980 and July 15, 2021 were abstracted to describe their category, anastomosis type and configuration, study types, and advantages and disadvantages encountered with each technology. Two hundred eleven original studies and 475 patents describing sutureless vascular anastomosis technologies were identified. In the literature, stents/stent-grafts/grafts (n = 61), lasers (n = 53), and couplers (n = 27) were the predominant device categories. In the patent review, adhesive technologies (n = 103), stents/stent-grafts/grafts (n = 68), and mechanical connectors (n = 61) predominated. The majority of studies involved in vivo animal studies (n = 193); 32.2% (n = 68) of investigations involved human trials; and 17.9% (n = 85) of patent technologies were approved by the US Food and Drug Administration. The main advantages described for sutureless anastomosis technologies included faster procedure time and greater patency rates compared with handsewn anastomoses. The main disadvantages included reduced vessel compliance, stenosis, leakage, and device costs. The appeal of sutureless technology is substantiated by numerous animal trials, but their use in humans remains limited. This may be a reflection of strict regulatory criteria and/or vascular complications associated with currently available technologies.