Increasing coverage of pediatric diarrhea treatment in high-burden countries.

BACKGROUND: Diarrhea is the second leading cause of infectious deaths in children under-five globally. Oral rehydration salts (ORS) and zinc could avert an estimated 93% of deaths, but progress to increase coverage of these interventions has been largely stagnant over the past several decades. The Clinton Health Access Initiative (CHAI), along with donors and country governments in India, Kenya, Nigeria, and Uganda, implemented programs to scale-up ORS and zinc coverage from 2012 to 2016. The programs sought to demonstrate that increases in pediatric diarrhea treatment rates are possible at scale in high-burden settings through a holistic approach addressing both supply and demand barriers. We describe the overall program model and the activities undertaken in each country. The overall goal of the paper is to share the program results and lessons learned to inform other countries aiming to scale-up ORS and zinc. METHODS: We used a triangulation approach, using population-based household surveys, public facility audits, and private outlet surveys, to evaluate the program model. We used pre- and post-program population-based household survey data to estimate the changes in coverage of ORS and zinc for treatment of diarrhea cases in children under-five in program areas. We also conducted secondary analysis of Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS) surveys in surrounding regions and compared annual coverage changes in the CHAI-supported program geographies to the surrounding regions. RESULTS: Across CHAI-supported focal geographies, the average ORS coverage across the program areas increased from 35% to 48% and combined ORS and zinc coverage increased from 1% to 24%. ORS coverage increases were statistically significant in the program states in India, from 22% (95% confidence interval CI = 21-23%) to 48% (95% CI = 47-50%) and program states in Nigeria, from 38% (95% CI = 32-40%) to 55% (95% CI = 51-58%). For combined ORS and zinc, coverage increases were statistically significant in all program geographies. Compared to surrounding regions, the estimated annual changes in combined ORS and zinc coverage were greater in program geographies. Using the Lives Saved Tool and based on the coverage changes during the program period, we estimated 76 090 diarrheal deaths were averted in the program geographies. CONCLUSIONS: Increasing ORS and zinc coverage at scale in high-burden countries and states is possible through a comprehensive approach that targets both demand and supply barriers, including pricing, optimal product qualities, provider dispensing practices, stocking rates, and consumer demand.

Salmonella employs multiple mechanisms to subvert the TLR-inducible zinc-mediated antimicrobial response of human macrophages.

We aimed to characterize antimicrobial zinc trafficking within macrophages and to determine whether the professional intramacrophage pathogen Salmonella enterica serovar Typhimurium (S Typhimurium) subverts this pathway. Using both Escherichia coli and S Typhimurium, we show that TLR signaling promotes the accumulation of vesicular zinc within primary human macrophages. Vesicular zinc is delivered to E. coli to promote microbial clearance, whereas S. Typhimurium evades this response via Salmonella pathogenicity island (SPI)-1. Even in the absence of SPI-1 and the zinc exporter ZntA, S Typhimurium resists the innate immune zinc stress response, implying the existence of additional host subversion mechanisms. We also demonstrate the combinatorial antimicrobial effects of zinc and copper, a pathway that S. Typhimurium again evades. Our use of complementary tools and approaches, including confocal microscopy, direct assessment of intramacrophage bacterial zinc stress responses, specific E. coli and S Typhimurium mutants, and inductively coupled plasma mass spectroscopy, has enabled carefully controlled characterization of this novel innate immune antimicrobial pathway. In summary, our study provides new insights at the cellular level into the well-documented effects of zinc in promoting host defense against infectious disease, as well as the complex host subversion strategies employed by S Typhimurium to combat this pathway.-Kapetanovic, R., Bokil, N. J., Achard, M. E. S., Ong, C.-L. Y., Peters, K. M., Stocks, C. J., Phan, M.-D., Monteleone, M., Schroder, K., Irvine, K. M., Saunders, B. M., Walker, M. J., Stacey, K. J., McEwan, A. G., Schembri, M. A., Sweet, M. J. Salmonella employs multiple mechanisms to subvert the TLR-inducible zinc-mediated antimicrobial response of human macrophages.

Mechanisms of unconventional secretion of IL-1 family cytokines.

One of the most poorly understood processes in cell biology is the peculiar ability of specific leaderless proteins to be secreted via ER/Golgi-independent mechanisms ('unconventional protein secretion'). One such leaderless protein is the major immune-activating cytokine, interleukin-1ß (IL-1ß). Unusual amongst cytokines, IL-1ß is expressed in the cytosol as an inactive precursor protein. It requires maturation by the caspase-1 protease, which itself requires activation upon immune cell sensing of infection or cell stress. Despite 25 years of intensive research into IL-1ß secretory mechanisms, how it exits the cell is still not well understood. Here we will review the various mechanisms by which macrophages have been proposed to secrete IL-1 family cytokines, and the potential involvement of caspase-1 therein. Since aberrant IL-1ß production drives inherited and acquired human diseases (e.g. autoinflammatory diseases, arthritic diseases, gout, Alzheimer's disease), elucidation of the IL-1ß secretory pathway may offer new therapeutic opportunities for treatment across this wide range of human conditions.

Bottlenecks, barriers, and solutions: results from multicountry consultations focused on reduction of childhood pneumonia and diarrhoea deaths.

Millions of children still die unnecessarily from pneumonia and diarrhoea, mainly in resource-poor settings. A series of collaborative consultations and workshops involving several hundred academic, public health, governmental and private sector stakeholders were convened to identify the key barriers to progress and to issue recommendations. Bottlenecks impairing access to commodities included antiquated supply management systems, insufficient funding for drugs, inadequate knowledge about interventions by clients and providers, health worker shortages, poor support for training or retention of health workers, and a failure to convert national policies into action plans. Key programmatic barriers included an absence of effective programme coordination between and within partner organisations, scarce financial resources, inadequate training and support for health workers, sporadic availability of key commodities, and suboptimal programme management. However, these problems are solvable. Advocacy could help to mobilise needed resources, raise awareness, and prioritise childhood pneumonia and diarrhoea deaths in the coming decade.