METHODS AND FINDINGS: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as 'Good', scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p < 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify.
CONCLUSIONS: Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.
DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: A cross-sectional analysis of adult (≥ 18 years) current smokers and ex-smokers from 14 countries participating in the ITC Project. Data from the most recent survey questionnaire for each country were included, which spanned the period 2013-17. Countries were categorized into four groups based on regulations governing NVP sales and marketing (allowable or not), and level of enforcement (strict or weak where NVPs are not permitted to be sold): (1) most restrictive policies (MRPs), not legal to be sold or marketed with strict enforcement: Australia, Brazil, Uruguay; (2) restrictive policies (RPs), not approved for sale or marketing with weak enforcement: Canada, Malaysia, Mexico, New Zealand; (3) less restrictive policies (LRPs), legal to be sold and marketed with regulations: England, the Netherlands, Republic of Korea, United States; and (4) no regulatory policies (NRPs), Bangladesh, China, Zambia. Countries were also grouped by World Bank Income Classifications. Country-specific weighted logistic regression models estimated adjusted NVP prevalence estimates for: awareness, ever/current use, and frequency of use (daily versus non-daily).
FINDINGS: NVP awareness and use were lowest in NRP countries. Generally, ever- and current use of NVPs were lower in MRP countries (ever-use = 7.1-48.9%; current use = 0.3-3.5%) relative to LRP countries (ever-use = 38.9-66.6%; current use = 5.5-17.2%) and RP countries (ever-use = 10.0-62.4%; current use = 1.4-15.5%). NVP use was highest among high-income countries, followed by upper-middle-income countries, and then by lower-middle-income countries.
CONCLUSIONS: With a few exceptions, awareness and use of nicotine vaping products varied by the strength of national regulations governing nicotine vaping product sales/marketing, and by country income. In countries with no regulatory policies, use rates were very low, suggesting that there was little availability, marketing and/or interest in nicotine vaping products in these countries where smoking populations are predominantly poorer. The higher awareness and use of nicotine vaping products in high income countries with moderately (e.g. Canada, New Zealand) and less (e.g. England, United States) restrictive policies, is likely due to the greater availability and affordability of nicotine vaping products.