In a factorial randomized trial conducted in Sri Lanka, de Silva and colleagues evaluate the safety and efficacy of pretreatments intended to reduce the risk of serious reactions to antivenom following snakebite.

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Background -Viscoelastic secretions in cystic fibrosis cause impaired mucus clearance and persistence of bacteria within the lung. The abnormal rheology is partly due to the presence of high molecular weight deoxyribonucleic acid (DNA). Recombinant human DNase I (rhDNase) has been shown to depolymerise DNA and thereby reduce the in vitro viscoelasticity of sputum in patients with cystic fibrosis. A phase II double blind placebo controlled study showed that rhDNase improved pulmonary function in patients with cystic fibrosis. The object of the present study was to evaluate the in vivo effects of rhDNase on sputum rheology and to determine whether these were correlated with changes in pulmonary function. Methods -Patients were randomised to receive either placebo or rhDNase 2-5 mg twice daily for 10 days. Sputum samples were collected in sterile containers during screening and during treatment with the study drug. Pulmonary function and rheological analysis were the primary outcomes evaluated. Other parameters assessed were quantitative sputum bacteriology, sputum DNA concentration, and change in molecular mass of DNA polymers.Results -The viscoelasticity of the sputum in untreated patients with cystic fibrosis was high and treatment with rhDNase reduced all the rheological parameters measured: dynamic storage modulus (a measure of elasticity), dynamic loss modulus (a measure ofviscosity), and log complex modulus (a measure of mucus rigidity). The calculated cough clearance index was also improved following treatment with rhDNase. These rheological parameters showed a correlation with forced expiratory volume in one second (FEV1) which was improved by a mean (SE) of 13'3 (5-6)% on day 10 of treatment with rhDNase compared with a change of 0-2 (3.1)% in the placebo group. There was no change in bacterial colony counts or sputum DNA concentrations following treatment with rhDNase, but a small decrease in high molecular weight DNA was observed. Conclusions -Patients with cystic fibrosis treated with rhDNase show an improvement in rheological properties and pulmonary function, one of the mechanisms being a reduction in the proportion of high molecular weight DNA.

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Abstract. The prophylactic antimalarial activity of atovaquone was determined in a randomized, double-blind, placebocontrolled study of healthy volunteers who were challenged by the bite of Plasmodium falciparum-infected Anopheles stephensi. Subjects were randomly assigned to one of three groups: six received seven daily doses of 750 mg of atovaquone, starting the day before challenge; six received a single dose of 250 mg of atovaquone the day before challenge; and four received placebo. Polymerase chain reaction-and culture-confirmed parasitemia developed in all four placebo recipients, but in none of the drug recipients, indicating that either of the atovaquone regimens provides effective prophylaxis (P ϭ 0.005). However, in low-dose recipients, the drug levels by day 6.5 were profoundly subtherapeutic, indicating that parasites were eliminated prior to the establishment of erythrocytic infection. Atovaquone thus protects non-immune subjects against mosquito-transmitted falciparum malaria, and has causal prophylactic activity.

Summary Background COBRA-BPS (Control of Blood Pressure and Risk Attenuation-Bangladesh, Pakistan, Sri Lanka), a multi-component hypertension management programme that is led by community health workers, has been shown to be efficacious at reducing systolic blood pressure in rural communities in Bangladesh, Pakistan, and Sri Lanka. In this study, we aimed to assess the budget required to scale up the programme and the incremental cost-effectiveness ratios. Methods In a cluster-randomised trial of COBRA-BPS, individuals aged 40 years or older with hypertension who lived in 30 rural communities in Bangladesh, Pakistan, and Sri Lanka were deemed eligible for inclusion. Costs were quantified prospectively at baseline and during 2 years of the trial. All costs, including labour, rental, materials and supplies, and contracted services were recorded, stratified by programme activity. Incremental costs of scaling up COBRA-BPS to all eligible adults in areas covered by community health workers were estimated from the health ministry (public payer) perspective. Findings Between April 1, 2016, and Feb 28, 2017, 11 510 individuals were screened and 2645 were enrolled and included in the study. Participants were examined between May 8, 2016, and March 31, 2019. The first-year per-participant costs for COBRA-BPS were US$10·65 for Bangladesh, $10·25 for Pakistan, and $6·42 for Sri Lanka. Per-capita costs were $0·63 for Bangladesh, $0·29 for Pakistan, and $1·03 for Sri Lanka. Incremental cost-effectiveness ratios were $3430 for Bangladesh, $2270 for Pakistan, and $4080 for Sri Lanka, per cardiovascular disability-adjusted life year averted, which showed COBRA-BPS to be cost-effective in all three countries relative to the WHO-CHOICE threshold of three times gross domestic product per capita in each country. Using this threshold, the cost-effectiveness acceptability curves predicted that the probability of COBRA-BPS being cost-effective is 79·3% in Bangladesh, 85·2% in Pakistan, and 99·8% in Sri Lanka. Interpretation The low cost of scale-up and the cost-effectiveness of COBRA-BPS suggest that this programme is a viable strategy for responding to the growing cardiovascular disease epidemic in rural communities in low-income and middle-income countries where community health workers are present, and that it should qualify as a priority intervention across rural settings in south Asia and in other countries with similar demographics and health systems to those examined in this study. Funding The UK Department of Health and Social Care, the UK Department for International Development, the Global Challenges Research Fund, the UK Medical Research Council, Wellcome Trust.

BackgroundGastro-esophageal reflux disease (GERD) predisposes to airway disease through a vagally-mediated esophago-bronchial reflex. This study investigates this vagal response to esophageal acid perfusion.Methods40 asthmatics with mild stable asthma participated. Each subject underwent spirometry and autonomic function testing (valsalva maneuver, heart rate response to deep breathing and to standing from supine position) four times: a) before intubation, b) after intubation, and then immediately after perfusion with, in random order, c) concentrated lime juice solution (pH 2–3) and d) 0.9% saline. Subjects were blinded to the solution perfused.ResultsAsthmatics were of mean (SD) age 34.3 years (1.3), and 67.5% of them were females. pH monitoring demonstrated that 20 subjects had abnormal reflux and 20 did not. In each group 10 subjects had a positive GERD symptom score. Following perfusion with acid compared to saline, all subjects showed significant decreases in FEV1 and PEFR and significant increases in the mean valsalva ratio and heart rate difference on deep breathing from baseline values, but no changes in FVC or heart rate ratio on standing. There were no significant differences in any of the parameters between subjects with and without reflux.ConclusionsAcid stimulation of the distal esophagus results in increased parasympathetic activity and concomitant broncho-constriction in asthmatics irrespective of their reflux state. This strengthens the hypothesis that GER triggers asthma-like symptoms through a vagally mediated esophago-bronchial reflex and encourages a possible role for anti-cholinergic drugs in the treatment of reflux-associated asthma.

ObjectiveTo determinate the prevalence and correlates of cardiometabolic multimorbidity (CMM), and their cross-country variation among individuals with hypertension residing in rural communities in South Asia.DesignA cross-sectional study.SettingRural communities in Bangladesh, Pakistan and Sri Lanka.ParticipantsA total of 2288 individuals with hypertension aged ≥40 years from the ongoing Control of Blood Pressure and Risk Attenuation- Bangladesh, Pakistan and Sri Lanka clinical trial.Main outcome measuresCMM was defined as the presence of ≥2 of the conditions: diabetes, chronic kidney disease, heart disease and stroke. Logistic regression was done to evaluate the correlates of CMM.ResultsAbout 25.4% (95% CI 23.6% to 27.2%) of the hypertensive individuals had CMM. Factors positively associated with CMM included residing in Bangladesh (OR 3.42, 95% CI 2.52 to 4.65) or Sri Lankan (3.73, 95% CI 2.48 to 5.61) versus in Pakistan, advancing age (2.33, 95% CI 1.59 to 3.40 for 70 years and over vs 40–49 years), higher waist circumference (2.15, 95% CI 1.42 to 3.25) for Q2–Q3 and 2.14, 95% CI 1.50 to 3.06 for Q3 and above), statin use (2.43, 95% CI 1.84 to 3.22), and higher levels of triglyceride (1.01, 95% CI 1.01 to 1.02 per 5 mg/dL increase). A lower odds of CMM was associated with being physically active (0.75, 95% CI 0.57 to 0.97). A weak inverted J-shaped association between International Wealth Index and CMM was found (p for non-linear=0.058), suggesting higher risk in the middle than higher or lower socioeconomic strata.ConclusionsCMM is highly prevalent in rural South Asians affecting one in four individuals with hypertension. There is an urgent need for strategies to concomitantly manage hypertension, cardiometabolic comorbid conditions and associated determinants in South Asia.