Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism. Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E^−/− (Apoe ^−/−) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe ^−/− mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [−15.9 mg/dL (−8.1%) vs. −1.6 mg/dL (−0.5%), P = 0.016], total [−19.6 mg/dL (−7.3%) vs. −5.3 mg/dL (−1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: −18.9 mg/dL (−9.1%) vs. −0.6 mg/dL (−0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels. Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs. The figure illustrates the proposed model of the cholesterol-lowering and atheroprotective properties of propionate. A high-fat high-cholesterol diet causes a disbalance of immune cells in the small intestinal microenvironment, with reduced regulatory T cell frequencies and interleukin-10 concentrations. Altered regulatory T cell levels are rescued upon exogenous propionate supplementation, with increased local levels. This in turn modulates NPC1L1 expression and membrane density, with a subsequent reduction in cholesterol absorption, ultimately leading to reduced atherogenesis. The illustration was adopted from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License. HFD, high-fat diet; IL-10, interleukin-10; NPC1L1, Niemann-Pick C1-like 1; PA, propionic acid; Treg, regulatory T cell.

Background and Purpose—: As stroke in young adults is assumed to have different etiologies and risk factors than in older populations, the aim of this study was to examine the contribution of established potentially modifiable cardiovascular risk factors to the burden of stroke in young adults. Methods—: A German nationwide case–control study based on patients enrolled in the SIFAP1 study (Stroke In Young Fabry Patients) 2007 to 2010 and controls from the population-based GEDA study (German Health Update) 2009 to 2010 was performed. Cases were 2125 consecutive patients aged 18 to 55 years with acute first-ever stroke from 26 clinical stroke centers; controls (age- and sex-matched, n=8500, without previous stroke) were from a nationwide community sample. Adjusted population-attributable risks of 8 risk factors (hypertension, hyperlipidemia, diabetes mellitus, coronary heart disease, smoking, heavy episodic alcohol consumption, low physical activity, and obesity) and their combinations for all stroke, ischemic stroke, and primary intracerebral hemorrhage were calculated. Results—: Low physical activity and hypertension were the most important risk factors, accounting for 59.7% (95% confidence interval, 56.3–63.2) and 27.1% (95% confidence interval, 23.6–30.6) of all strokes, respectively. All 8 risk factors combined explained 78.9% (95% confidence interval, 76.3–81.4) of all strokes. Population-attributable risks of all risk factors were similar for all ischemic stroke subtypes. Population-attributable risks of most risk factors were higher in older age groups and in men. Conclusions—: Modifiable risk factors previously established in older populations also account for a large part of stroke in younger adults, with 4 risk factors explaining almost 80% of stroke risk. Clinical Trial Registration—: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00414583.

BACKGROUND AND PURPOSE: Mechanical thrombectomy for acute ischemic stroke is performed with the patient under local anesthesia, conscious sedation, or general anesthesia. According to recent trials, up to 16% of patients require emergency conversion to general anesthesia during mechanical thrombectomy. This study investigated the procedural and clinical outcomes after emergency conversion in comparison with local anesthesia, conscious sedation, and general anesthesia. MATERIALS AND METHODS: This retrospective study included 254 patients undergoing mechanical thrombectomy for acute large-vessel occlusion. The procedure was started with the patient either under local anesthesia, conscious sedation, or general anesthesia. Emergency conversion was defined as induction of general anesthesia during mechanical thrombectomy. The primary outcomes were successful reperfusion (TICI 2b/3) and functional independence (mRS at 90 days, ≤2). RESULTS: Twenty-five patients (9.8%) required emergency conversion to general anesthesia. The time from admission to flow restoration was increased under general anesthesia (median, 137 minutes) and emergency conversion (median, 138 minutes) compared with local anesthesia (median 110 minutes). After adjustment for confounders, emergency conversion to general anesthesia and primary general anesthesia had comparable chances of successful reperfusion (OR = 1.28; 95% CI, 0.31–5.25). Patients with emergency conversion had a tendency toward higher chances of functional independence (OR = 4.48; 95% CI, 0.49–40.86) compared with primary general anesthesia, but not compared with local anesthesia (OR = 0.86; 95% CI, 0.14–5.11) and conscious sedation (OR = 1.07; 95% CI, 0.17–6.53). CONCLUSIONS: Patients with emergency conversion did not have lower chances of successful reperfusion or functional independence compared those with primary general anesthesia, and time to flow restoration was also similar. We found no evidence supporting the primary induction of general anesthesia in patients at risk for emergency conversion.

Low response rates in epidemiologic research potentially lead to the recruitment of a non-representative sample of controls in case-control studies. Problems in the unbiased estimation of odds ratios arise when characteristics causing the probability of participation are associated with exposure and outcome. This is a specific setting of selection bias and a realistic hazard in many case-control studies. This paper formally describes the problem and shows its potential extent, reviews existing approaches for bias adjustment applicable under certain conditions, compares and applies them. We focus on two scenarios: a characteristic C causing differential participation of controls is linked to the outcome through its association with risk factor E (scenario I), and C is additionally a genuine risk factor itself (scenario II). We further assume external data sources are available which provide an unbiased estimate of C in the underlying population. Given these scenarios, we (i) review available approaches and their performance in the setting of bias due to differential participation; (ii) describe two existing approaches to correct for the bias in both scenarios in more detail; (iii) present the magnitude of the resulting bias by simulation if the selection of a non-representative sample is ignored; and (iv) demonstrate the approaches’ application via data from a case-control study on stroke. The bias of the effect measure for variable E in scenario I and C in scenario II can be large and should therefore be adjusted for in any analysis. It is positively associated with the difference in response rates between groups of the characteristic causing differential participation, and inversely associated with the total response rate in the controls. Adjustment in a standard logistic regression framework is possible in both scenarios if the population distribution of the characteristic causing differential participation is known or can be approximated well.

In industrialized nations, human lead exposure has decreased significantly in recent decades. Nevertheless, due to its toxic effects, this heavy metal remains a public health concern with children and adolescents being particularly at risk. In Europe nowadays, oral intake via food and drinking water is the predominant exposure pathway for lead. The objective of the present study was to investigate the association between dietary factors and blood lead (PbB) level of 3- to 17-year-old children and adolescents living in Germany, using data from the fifth German Environmental Health Survey (GerES V) and the Child and Adolescent Health Survey (KiGGS Wave 2). GerES V and KiGGS Wave 2 are two national population-representative studies conducted between 2014 and 2017, including measurement of lead concentrations in blood from 720 children and adolescents aged 3-17 years (mean age = 10.21, SD age = 4.36). Using multiple linear regression, sociodemographic and environmental characteristics as well as dietary factors could be identified as significant exposure determinants of PbB concentrations. Lead intake via domestic tap water was the strongest predictor of elevated PbB levels with 27.6% (p-value< .001) higher concentrations of highest compared to none lead intake via tap water. Other foods which were found to be relevant to PbB levels were meat, fruit, and fruit juice. While meat or fruit consumption were each associated with about 13% (p-value < .05) lower PbB levels, fruit juice drinking was associated with up to 12.2% (p-value = .04) higher PbB levels. In conclusion, results indicate the importance of dietary habits for lead exposure in children and adolescents. To protect vulnerable groups, it is recommended that future research and lead-reducing measures pay more attention to dietary links.