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.

Background: Patients with diabetes mellitus (DM) have been found to be at an increased risk of suffering a stroke. However, research on the impact of DM on stroke outcomes is limited. Objectives: We aimed to examine the influence of DM on outcomes in ischaemic (IS) and haemorrhagic stroke (HS) patients. Methods: We included 608,890 consecutive stroke patients from the Thailand national insurance registry. In-hospital mortality, sepsis, pneumonia, acute kidney injury (AKI), urinary tract infection (UTI) and cardiovascular events were evaluated using logistic regressions. Long-term analysis was performed on first-stroke patients with a determined pathology (n = 398,663) using Royston-Parmar models. Median follow-ups were 4.21 and 4.78 years for IS and HS, respectively. All analyses were stratified by stroke sub-type. Results: Mean age (SD) was 64.3 (13.7) years, 44.9% were female with 61% IS, 28% HS and 11% undetermined strokes. DM was associated with in-hospital death, pneumonia, sepsis, AKI and cardiovascular events (odds ratios ranging from 1.13-1.78, p < 0.01) in both stroke types. In IS, DM was associated with long-term mortality and recurrence throughout the follow-up: HR max (99% CI) at t = 4108 days: 1.54 (1.27, 1.86) and HR (99% CI) = 1.27(1.23,1.32), respectively. In HS, HR max (t = 4108 days) for long-term mortality was 2.10 (1.87, 2.37), significant after day 14 post-discharge. HR max (t = 455) for long-term recurrence of HS was 1.29 (1.09, 1.53), significant after day 116 post-discharge. Conclusions: Regardless of stroke type, DM was associated with in-hospital death and complications, long-term mortality and stroke recurrence.

Whilst cancer is a risk factor for acute ischaemic stroke (AIS), its impact on AIS prognosis between metastatic and non-metastatic (MC and NMC) disease is poorly understood. Furthermore, the receipt of intravenous thrombolysis (IVT) and endovascular thrombectomy (ET) and their outcomes is poorly researched. AIS admissions from the National Inpatient Sample (NIS) were included (October 2015–December 2017). Multivariable logistic regressions adjusting for a wide range of confounders analysed the relationship between NMC and MC and AIS in-hospital outcomes (mortality, prolonged hospitalisation >4 days and routine home discharge). Interaction terms with IVT and ET were also computed to explore their impact amongst cancer patients. A total of 221,249 records representative of 1,106,045 admissions were included. There were 38,855 (3.51%) AIS admissions with co-morbid cancer: NMC = 53.78% and MC = 46.22%. NMC was associated with 23% increased odds of in-hospital mortality (odds ratio (95% confidence interval) = 1.23 (1.07–1.42)), which was mainly driven by pancreatic and respiratory cancers. This association was entirely offset by both IVT and ET. MC was associated with two-fold increased odds of in-hospital mortality (2.16 (1.90–2.45)), which was mainly driven by respiratory, pancreatic and colorectal cancers. This association was only offset by ET. Both NMC and MC were significantly associated with prolonged hospitalisation and decreased odds of routine discharge. Cancer patients are at higher odds of acute adverse outcomes after AIS and warrant robust primary prevention. IVT and ET improve these outcomes and should thus be offered routinely unless otherwise contraindicated in this group of stroke patients.

Background and Purpose— We aimed to determine individual and combined effects of atrial fibrillation (AF) and heart failure (HF) on acute ischemic stroke outcomes: in-hospital mortality, length-of-stay, and poststroke disability; long-term mortality and stroke recurrence. Methods— Prospective cohort study of patients with acute ischemic stroke admitted to a UK center with a catchment population of ≈900 000 between 2004 and 2016. Exposure groups were patients with neither AF nor HF (reference group), those with AF but without HF, those with HF but without AF, and those with AF+HF. Logistic and Cox regressions were used to model in-hospital and long-term outcomes, respectively. Results— A total of 10 816 patients with a mean age±SD =77.9±12.1 years, 48% male were included. Only 30 (4.9%) of the patients with HF but not AF were anticoagulated at discharge. Both AF (odds ratio, 1.24 [95% CI, 1.07–1.43]), HF (odds ratio, 1.40 [1.10–1.79]), and their combination (odds ratio, 2.23 [1.83–2.72]) were associated with increased odds of in-hospital mortality. All 3 exposure groups were associated with increased length-of-stay, while only AF predicted increased disability (1.36 [1.12–1.64]). Patients were followed for a median of 5.5 and 3.7 years for mortality and recurrence, respectively. Long-term mortality was associated with AF (hazard ratio, 1.45 [95% CI, 1.33–1.59]), HF (2.07 [1.83–2.36]), and their combination (2.20 [1.96–2.46]). Recurrent stroke was associated with AF 1.50 (1.26–1.78), HF (1.33 [1.01–1.75]), and AF with HF (1.62 [1.28–2.07]). Conclusions— The AF-associated excess risk of stroke recurrence was independent of comorbid HF. HF without AF was also associated with a significant risk of recurrence. Anticoagulation for secondary stroke prevention in patients with HF without AF may require further evaluation in a clinical trial setting.