Neonatal mortality in East Africa and West Africa: a geographic analysis of district-level demographic and health survey data.

Under-five child mortality declined 47% since 2000 following the implementation of the United Nation's (UN) Millennium Development Goals. To further reduce under-five child mortality, the UN's Sustainable Development Goals (SDGs) will focus on interventions to address neonatal mortality, a major contributor of under-five mortality. The African region has the highest neonatal mortality rate (28.0 per 1000 live births), followed by that of the Eastern Mediterranean (26.6) and South-East Asia (24.3). This study used the Demographic and Health Survey Birth Recode data (http://dhsprogram.com/data/File-Types-and-Names.cfm) to identify high-risk districts and countries for neonatal mortality in two sub-regions of Africa - East Africa and West Africa. Geographically weighted Poisson regression models were estimated to capture the spatially varying relationships between neonatal mortality and dimensions of potential need i) care around the time of delivery, ii) maternal education, and iii) women's empowerment. In East Africa, neonatal mortality was significantly associated with home births, mothers without an education and mothers whose husbands decided on contraceptive practices, controlling for rural residency. In West Africa, neonatal mortality was also significantly associated with home births, mothers with a primary education and mothers who did not want or plan their last child. Importantly, neonatal mortality associated with home deliveries were explained by maternal exposure to unprotected water sources in East Africa and older maternal age and female sex of infants in West Africa. Future SDG-interventions may target these dimensions of need in priority high-risk districts and countries, to further reduce the burden of neonatal mortality in Africa.

Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK).

The UK Refractory Asthma Stratification Programme (RASP-UK) will explore novel biomarker stratification strategies in severe asthma to improve clinical management and accelerate development of new therapies. Prior asthma mechanistic studies have not stratified on inflammatory phenotype and the understanding of pathophysiological mechanisms in asthma without Type 2 cytokine inflammation is limited. RASP-UK will objectively assess adherence to corticosteroids (CS) and examine a novel composite biomarker strategy to optimise CS dose; this will also address what proportion of patients with severe asthma have persistent symptoms without eosinophilic airways inflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.

Hypothalamic-pituitary-adrenal axis function after inhaled corticosteroids: unreliability of urinary free cortisol estimation.

Free cortisol in the urine (UFC) is frequently measured in clinical research to assess whether inhaled corticosteroids (ICS) cause suppression of the hypothalamic-pituitary-adrenal axis. Thirteen healthy male subjects received single inhaled doses (of molar equivalence) of fluticasone propionate (FP), triamcinolone acetonide (TAA), budesonide (BUD), and placebo in this single blind, randomized, cross-over study. UFC output was measured using four commercial immunoassays in samples collected in 12-h aliquots over 24 h. The cortisol production rate was assessed from the outputs of cortisol metabolites. UFC showed a 100% increase over placebo levels in the Abbott TDX assay after the administration of BUD. The other assays detected variable suppression (ranging from 29-61% suppression for FP, 30-62% suppression for TAA, and 25% suppression to 100% stimulation for BUD). Suppression was more pronounced in the first 12 h after TAA and in the second 12 h after FP. Similar suppression was found in each 12-h period after BUD. UFC estimation based on immunoassays after ICS may be an unreliable surrogate marker of adrenal suppression. Many of the published studies describing or comparing the safety of different ICS should be reevaluated, and some should be interpreted with caution.

Bioavailability and metabolism of mometasone furoate: pharmacology versus methodology.

The degree of systemic exposure ofter inhalation of corticosteroids is of great clinical concern. For optimum outcome, the pulmonary deposition should be sufficiently high to produce the desired anti-inflammatory effect in the lungs, whereas the plasma concentrations due to the absorption of the corticosteroid from the lung and the gut should be minimal. Recently, it has been reported that inhaled mometasone furoate has a systemic bioavailability of less than 1%, which is much lower than other corticosteroids currently available. However, critical evaluation of the study methodology and results does not support this finding. A major shortfall of the study was an insufficient analytical sensitivity, resulting in a calculated average plasma concentration profile that was entirely below the limit of quantification. These numbers were generated by replacing all concentrations below the limit of quantification byzero and then calculating an average value. This procedure can lead to erroneous results and misinterpretation. Furthermore, the potential contribution of active metabolites needs to be adequately addressed in comparisons of inhaled corticosteroids. Reliable estimates of systemic drug exposure are critical in evaluating the real safety profiles and therapeutic index for inhaled corticosteroids that are effective in treating chronic asthma.