Georgakis et al. Circulating monocyte chemoattractant protein-1 and risk of stroke: a meta-analysis of population-based studies involving 17,180 individuals. Appendix I. Search strategy. Online Table I. Summary of the study design, population characteristics, methods used for quantifying circulating MCP-1 levels, stroke outcome definitions, and assessments in the cohorts included in the meta-analysis. Online Table II. Quality characteristics of the included studies according to the Newcastle-Ottawa Scale. Online Table III. Associations between baseline circulating MCP-1 levels and risk of any stroke. Shown are the results from random-effects meta-analyses across the different models in the pooled sample consisting of six population-based studies. Online Table IV. Associations between baseline circulating MCP-1 levels and risk of ischemic stroke. Shown are the results from random-effects meta-analyses across the different models in the pooled sample consisting of six population-based studies. Online Table V. Associations between baseline circulating MCP-1 levels and risk of hemorrhagic stroke. Shown are the results from random-effects meta-analyses across the different models in the pooled sample consisting of six population-based studies. Online Table VI. Meta-regression analyses for the effect of different study characteristics on the association between ln-transformed MCP-1 circulating levels at baseline (1 SD increment) with any stroke and etiological stroke subtypes (ischemic and hemorrhagic stroke). Online Table VII. Associations between baseline circulating hsCRP, IL-6, and MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke. Shown are the results from random-effects metaanalyses of the pooled sample consisting of four population-based studies, where both hsCRP and IL-6 levels were available. Online Figure I. Flowchart of the study selection for the systematic review. Online Figure II. Study-specific and pooled hazard ratios for incident any stroke per standard deviation increase in ln-transformed circulating MCP-1 levels and across MCP-1 level quartiles. Shown are the results from random-effects meta-analyses. Online Figure III. Study-specific and pooled hazard ratios for incident ischemic stroke per standard deviation increase in ln-transformed circulating MCP-1 levels and across MCP-1 level quartiles. Shown are the results from random-effects meta-analyses (Model 2). Online Figure IV. Study-specific and pooled hazard ratios for incident hemorrhagic stroke per standard deviation increase in ln-transformed circulating MCP-1 levels and across MCP-1 level quartiles. Shown are the results from random-effects meta-analyses (Model 2). Online Figure V. Pooled hazard ratios for incident fatal and non-fatal stroke per circulating MCP-1 levels, as derived from random-effects meta-analyses (Model 2). Online Figure VI. Pooled hazard ratios for incident any stroke per standard deviation increase in lntransformed circulating MCP-1 levels and across MCP-1 level quartiles in sensitivity analyses ...

Human genetics and studies in experimental models support a key role of monocyte-chemoattractant protein-1 (MCP-1) in atherosclerosis. Yet, the associations of circulating MCP-1 levels with risk of coronary heart disease and cardiovascular death in the general population remain largely unexplored. OBJECTIVE To explore whether circulating levels of MCP-1 are associated with risk of incident coronary heart disease, myocardial infarction, and cardiovascular mortality in the general population.DATA SOURCES AND SELECTION Population-based cohort studies, identified through a systematic review, that have examined associations of circulating MCP-1 levels with cardiovascular end points.DATA EXTRACTION AND SYNTHESIS Using a prespecified harmonized analysis plan, study-specific summary data were obtained from Cox regression models after excluding individuals with overt cardiovascular disease at baseline. Derived hazard ratios (HRs) were synthesized using random-effects meta-analyses. MAIN OUTCOMES AND MEASURESIncident coronary heart disease (myocardial infarction, coronary revascularization, and unstable angina), nonfatal myocardial infarction, and cardiovascular death (from cardiac or cerebrovascular causes). RESULTSThe meta-analysis included 7 cohort studies involving 21 401 individuals (mean [SD] age, 53.7 [10.2] years; 10 012 men [46.8%]). Mean (SD) follow-up was 15.3 (4.5) years (326 392 person-years at risk). In models adjusting for age, sex, and race/ethnicity, higher MCP-1 levels at baseline were associated with increased risk of coronary heart disease (HR per 1-SD increment in MCP-1 levels: 1.06 [95% CI, 1.01-1.11]; P = .01), nonfatal myocardial infarction (HR, 1.07 [95% CI, 1.01-1.13]; P = .02), and cardiovascular death (HR, 1.12 [95% CI, 1.05-1.20]; P < .001). In analyses comparing MCP-1 quartiles, these associations followed dose-response patterns. After additionally adjusting for vascular risk factors, the risk estimates were attenuated, but the associations of MCP-1 levels with cardiovascular death remained statistically significant, as did the association of MCP-1 levels in the upper quartile with coronary heart disease. There was no significant heterogeneity; the results did not change in sensitivity analyses excluding events occurring in the first 5 years after MCP-1 measurement, and the risk estimates were stable after additional adjustments for circulating levels of interleukin-6 and high-sensitivity C-reactive protein.CONCLUSIONS AND RELEVANCE Higher circulating MCP-1 levels are associated with higher long-term cardiovascular mortality in community-dwelling individuals free of overt cardiovascular disease. These findings provide further support for a key role of MCP-1-signaling in cardiovascular disease.

ObjectiveWe aimed to identify the country-level determinants of the severity of the first wave of the COVID-19 pandemic.DesignEcological study of publicly available data. Countries reporting >25 COVID-19 related deaths until 8 June 2020 were included. The outcome was log mean mortality rate from COVID-19, an estimate of the country-level daily increase in reported deaths during the ascending phase of the epidemic curve. Potential determinants assessed were most recently published demographic parameters (population and population density, percentage population living in urban areas, population >65 years, average body mass index and smoking prevalence); economic parameters (gross domestic product per capita); environmental parameters (pollution levels and mean temperature (January–May); comorbidities (prevalence of diabetes, hypertension and cancer); health system parameters (WHO Health Index and hospital beds per 10 000 population); international arrivals; the stringency index, as a measure of country-level response to COVID-19; BCG vaccination coverage; UV radiation exposure; and testing capacity. Multivariable linear regression was used to analyse the data.Primary outcomeCountry-level mean mortality rate: the mean slope of the COVID-19 mortality curve during its ascending phase.ParticipantsThirty-seven countries were included: Algeria, Argentina, Austria, Belgium, Brazil, Canada, Chile, Colombia, the Dominican Republic, Ecuador, Egypt, Finland, France, Germany, Hungary, India, Indonesia, Ireland, Italy, Japan, Mexico, the Netherlands, Peru, the Philippines, Poland, Portugal, Romania, the Russian Federation, Saudi Arabia, South Africa, Spain, Sweden, Switzerland, Turkey, Ukraine, the UK and the USA.ResultsOf all country-level determinants included in the multivariable model, total number of international arrivals (beta 0.033 (95% CI 0.012 to 0.054)) and BCG vaccination coverage (−0.018 (95% CI −0.034 to –0.002)), were significantly associated with the natural logarithm of the mean death rate.ConclusionsInternational travel was directly associated with the mortality slope and thus potentially the spread of COVID-19. Very early restrictions on international travel should be considered to control COVID-19 outbreaks and prevent related deaths.

Context and Objective:The impact of existing malnutrition on stroke outcomes is poorly recognised and treated. Evidence was systematically reviewed and quantified by meta-analysis. Methods: MEDLINE, EMBASE and Web of Science were searched from inception to 11 January 2021 and updated in July. Prospective cohort studies, in English, evaluating anthropometric and biomarkers of nutrition on stroke outcomes were included. Risk of bias was assessed using the Scottish Intercollegiate Guidelines Network checklist. Results: Twenty-six studies (n ¼ 156 249) were eligible (follow-up: One month-14 years). Underweight patients had increased risk of long-term mortality (adjusted hazard ratio ¼ 1.65,1.41-1.95), whilst overweight (0.80,0.74-0.86) and obese patients (0.80,0.75-0.85) had decreased risk compared to normal weight. Odds of mortality decreased in those with high serum albumin (odds ratio ¼ 0.29,0.18-0.48) and increased with low serum albumin (odds ratio ¼ 3.46,1.78-6.74) compared to normal serum albumin (30-35 g/ L). Being malnourished compared to well-nourished, as assessed by the Subjective Global Assessment (SGA) or by a combination of anthropometric and biochemical markers increased all-cause mortality (odds ratio ¼ 2.38,1.85-3.06) and poor functional status (adjusted odds ratio ¼ 2.21,1.40-3.49). Conclusion: Nutritional status at the time of stroke predicts adverse stroke outcomes.

The role of dietary calcium in cardiovascular disease prevention is unclear. We aimed to determine the association between calcium intake and incident cardiovascular disease and mortality. Data were extracted from the European Prospective Investigation of Cancer, Norfolk (EPIC-Norfolk). Multivariable Cox regressions analysed associations between calcium intake (dietary and supplemental) and cardiovascular disease (myocardial infarction, stroke, heart failure, aortic stenosis, peripheral vascular disease) and mortality (cardiovascular and all-cause). The results of this study were pooled with those from published prospective cohort studies in a meta-analsyis, stratifying by average calcium intake using a 700 mg/day threshold. A total of 17,968 participants aged 40–79 years were followed up for a median of 20.36 years (20.32–20.38). Compared to the first quintile of calcium intake (< 770 mg/day), intakes between 771 and 926 mg/day (second quintile) and 1074–1254 mg/day (fourth quintile) were associated with reduced all-cause mortality (HR 0.91 (0.83–0.99) and 0.85 (0.77–0.93), respectively) and cardiovascular mortality [HR 0.95 (0.87–1.04) and 0.93 (0.83-1.04)]. Compared to the first quintile of calcium intake, second, third, fourth, but not fifth quintiles were associated with fewer incident strokes: respective HR 0.84 (0.72–0.97), 0.83 (0.71–0.97), 0.78 (0.66–0.92) and 0.95 (0.78–1.15). The meta-analysis results suggest that high levels of calcium intake were associated with decreased all-cause mortality, but not cardiovascular mortality, regardless of average calcium intake. Calcium supplementation was associated with cardiovascular and all-cause mortality amongst women, but not men. Moderate dietary calcium intake may protect against cardiovascular and all-cause mortality and incident stroke. Calcium supplementation may reduce mortality in women.