OBJECTIVE: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.

DATA SOURCES: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.

STUDY SELECTION: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria.

DATA EXTRACTION AND SYNTHESIS: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality.

MAIN OUTCOMES AND MEASURES: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.

RESULTS: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16).

CONCLUSIONS AND RELEVANCE: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

Objective: To identify any associations between depressive symptoms and incident CVD and all-cause mortality in countries at different levels of economic development and in urban and rural areas.

Design, Setting, and Participants: This multicenter, population-based cohort study was conducted between January 2005 and June 2019 (median follow-up, 9.3 years) and included 370 urban and 314 rural communities from 21 economically diverse countries on 5 continents. Eligible participants aged 35 to 70 years were enrolled. Analysis began February 2018 and ended September 2019.

Exposures: Four or more self-reported depressive symptoms from the Short-Form Composite International Diagnostic Interview.

Main Outcomes and Measures: Incident CVD, all-cause mortality, and a combined measure of either incident CVD or all-cause mortality.

METHODS: This is a retrospective study of post mortem cases at Hospital Kuala Lumpur from 2014 to 2016. Deaths from RTC were included while decomposed and homicide cases were excluded. We performed Spearman Correlation statistical test to relate RTC and positive DoA results.

RESULTS: A total of 523 RTC cases were identified in which either blood or urine or both samples were taken for toxicology. 93 cases were positive for both DoA and therapeutic drugs. A total of 37 cases were positive for DoA. Alcohol was present in 5 out of 37 DoA positive cases. Most of the cases seen among 16 to 45 years old (69%) and predominantly in males (93.1%). 29 out of 37 were motorcyclist and the rest were pillion rider and pedestrian. Spearman Correlation statistical test showed a negative relationship between RTC and positive DoA results.

METHODS: The Prospective Urban Rural Epidemiology (PURE) study is a large, epidemiological cohort study of individuals aged 35-70 years (enrolled between Jan 1, 2003, and March 31, 2013) in 18 countries with a median follow-up of 7·4 years (IQR 5·3-9·3). Dietary intake of 135 335 individuals was recorded using validated food frequency questionnaires. The primary outcomes were total mortality and major cardiovascular events (fatal cardiovascular disease, non-fatal myocardial infarction, stroke, and heart failure). Secondary outcomes were all myocardial infarctions, stroke, cardiovascular disease mortality, and non-cardiovascular disease mortality. Participants were categorised into quintiles of nutrient intake (carbohydrate, fats, and protein) based on percentage of energy provided by nutrients. We assessed the associations between consumption of carbohydrate, total fat, and each type of fat with cardiovascular disease and total mortality. We calculated hazard ratios (HRs) using a multivariable Cox frailty model with random intercepts to account for centre clustering.

FINDINGS: During follow-up, we documented 5796 deaths and 4784 major cardiovascular disease events. Higher carbohydrate intake was associated with an increased risk of total mortality (highest [quintile 5] vs lowest quintile [quintile 1] category, HR 1·28 [95% CI 1·12-1·46], ptrend=0·0001) but not with the risk of cardiovascular disease or cardiovascular disease mortality. Intake of total fat and each type of fat was associated with lower risk of total mortality (quintile 5 vs quintile 1, total fat: HR 0·77 [95% CI 0·67-0·87], ptrend<0·0001; saturated fat, HR 0·86 [0·76-0·99], ptrend=0·0088; monounsaturated fat: HR 0·81 [0·71-0·92], ptrend<0·0001; and polyunsaturated fat: HR 0·80 [0·71-0·89], ptrend<0·0001). Higher saturated fat intake was associated with lower risk of stroke (quintile 5 vs quintile 1, HR 0·79 [95% CI 0·64-0·98], ptrend=0·0498). Total fat and saturated and unsaturated fats were not significantly associated with risk of myocardial infarction or cardiovascular disease mortality.

INTERPRETATION: High carbohydrate intake was associated with higher risk of total mortality, whereas total fat and individual types of fat were related to lower total mortality. Total fat and types of fat were not associated with cardiovascular disease, myocardial infarction, or cardiovascular disease mortality, whereas saturated fat had an inverse association with stroke. Global dietary guidelines should be reconsidered in light of these findings.

OBJECTIVES: To compare the efficacy and safety of autologous cells derived from different sources, prepared using different protocols, administered at different doses, and delivered via different routes for the treatment of 'no-option' CLI patients.

SEARCH METHODS: The Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), and trials registries (16 May 2018). Review authors searched PubMed until February 2017.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) involving 'no-option' CLI patients comparing a particular source or regimen of autologous cell-based therapy against another source or regimen of autologous cell-based therapy.

DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the eligibility and methodological quality of the trials. We extracted outcome data from each trial and pooled them for meta-analysis. We calculated effect estimates using a risk ratio (RR) with 95% confidence interval (CI), or a mean difference (MD) with 95% CI.

MAIN RESULTS: We included seven RCTs with a total of 359 participants. These studies compared bone marrow-mononuclear cells (BM-MNCs) versus mobilised peripheral blood stem cells (mPBSCs), BM-MNCs versus bone marrow-mesenchymal stem cells (BM-MSCs), high cell dose versus low cell dose, and intramuscular (IM) versus intra-arterial (IA) routes of cell implantation. We identified no other comparisons in these studies. We considered most studies to be at low risk of bias in random sequence generation, incomplete outcome data, and selective outcome reporting; at high risk of bias in blinding of patients and personnel; and at unclear risk of bias in allocation concealment and blinding of outcome assessors. The quality of evidence was most often low to very low, with risk of bias, imprecision, and indirectness of outcomes the major downgrading factors.Three RCTs (100 participants) reported a total of nine deaths during the study follow-up period. These studies did not report deaths according to treatment group.Results show no clear difference in amputation rates between IM and IA routes (RR 0.80, 95% CI 0.54 to 1.18; three RCTs, 95 participants; low-quality evidence). Single-study data show no clear difference in amputation rates between BM-MNC- and mPBSC-treated groups (RR 1.54, 95% CI 0.45 to 5.24; 150 participants; low-quality evidence) and between high and low cell dose (RR 3.21, 95% CI 0.87 to 11.90; 16 participants; very low-quality evidence). The study comparing BM-MNCs versus BM-MSCs reported no amputations.Single-study data with low-quality evidence show similar numbers of participants with healing ulcers between BM-MNCs and mPBSCs (RR 0.89, 95% CI 0.44 to 1.83; 49 participants) and between IM and IA routes (RR 1.13, 95% CI 0.73 to 1.76; 41 participants). In contrast, more participants appeared to have healing ulcers in the BM-MSC group than in the BM-MNC group (RR 2.00, 95% CI 1.02 to 3.92; one RCT, 22 participants; moderate-quality evidence). Researchers comparing high versus low cell doses did not report ulcer healing.Single-study data show similar numbers of participants with reduction in rest pain between BM-MNCs and mPBSCs (RR 0.99, 95% CI 0.93 to 1.06; 104 participants; moderate-quality evidence) and between IM and IA routes (RR 1.22, 95% CI 0.91 to 1.64; 32 participants; low-quality evidence). One study reported no clear difference in rest pain scores between BM-MNC and BM-MSC (MD 0.00, 95% CI -0.61 to 0.61; 37 participants; moderate-quality evidence). Trials comparing high versus low cell doses did not report rest pain.Single-study data show no clear difference in the number of participants with increased ankle-brachial index (ABI; increase of > 0.1 from pretreatment), between BM-MNCs and mPBSCs (RR 1.00, 95% CI 0.71 to 1.40; 104 participants; moderate-quality evidence), and between IM and IA routes (RR 0.93, 95% CI 0.43 to 2.00; 35 participants; very low-quality evidence). In contrast, ABI scores appeared higher in BM-MSC versus BM-MNC groups (MD 0.05, 95% CI 0.01 to 0.09; one RCT, 37 participants; low-quality evidence). ABI was not reported in the high versus low cell dose comparison.Similar numbers of participants had improved transcutaneous oxygen tension (TcO₂) with IM versus IA routes (RR 1.22, 95% CI 0.86 to 1.72; two RCTs, 62 participants; very low-quality evidence). Single-study data with low-quality evidence show a higher TcO₂ reading in BM-MSC versus BM-MNC groups (MD 8.00, 95% CI 3.46 to 12.54; 37 participants) and in mPBSC- versus BM-MNC-treated groups (MD 1.70, 95% CI 0.41 to 2.99; 150 participants). TcO₂ was not reported in the high versus low cell dose comparison.Study authors reported no significant short-term adverse effects attributed to autologous cell implantation.