Model-informed target product profiles of long-acting-injectables for use as seasonal malaria prevention

Seasonal malaria chemoprevention (SMC) has proven highly efficacious in reducing malaria incidence. However, the continued success of SMC is threatened by the spread of resistance against one of its main preventive ingredients, Sulfadoxine-Pyrimethamine (SP), operational challenges in delivery, and incomplete adherence to the regimens. Via a simulation study with an individual-based model of malaria dynamics, we provide quantitative evidence to assess long-acting injectables (LAIs) as potential alternatives to SMC. We explored the predicted impact of a range of novel preventive LAIs as a seasonal prevention tool in children aged three months to five years old during late-stage clinical trials and at implementation. LAIs were co-administered with a blood-stage clearing drug once at the beginning of the transmission season. We found the establishment of non-inferiority of LAIs to standard 3 or 4 rounds of SMC with SP-amodiaquine was challenging in clinical trial stages due to high intervention deployment coverage. However, our analysis of implementation settings where the achievable SMC coverage was much lower, show LAIs with fewer visits per season are potential suitable replacements to SMC. Suitability as a replacement with higher impact is possible if the duration of protection of LAIs covered the duration of the transmission season. Furthermore, optimising LAIs coverage and protective efficacy half-life via simulation analysis in settings with an SMC coverage of 60% revealed important trade-offs between protective efficacy decay and deployment coverage. Our analysis additionally highlights that for seasonal deployment for LAIs, it will be necessary to investigate the protective efficacy decay as early as possible during clinical development to ensure a well-informed candidate selection process

Emulator-based Bayesian optimization for efficient multi-objective calibration of an individual-based model of malaria

Individual-based models have become important tools in the global battle against infectious diseases, yet model complexity can make calibration to biological and epidemiological data challenging. We propose using a Bayesian optimization framework employing Gaussian process or machine learning emulator functions to calibrate a complex malaria transmission simulator. We demonstrate our approach by optimizing over a high-dimensional parameter space with respect to a portfolio of multiple fitting objectives built from datasets capturing the natural history of malaria transmission and disease progression. Our approach quickly outperforms previous calibrations, yielding an improved final goodness of fit. Per-objective parameter importance and sensitivity diagnostics provided by our approach offer epidemiological insights and enhance trust in predictions through greater interpretability

Theory of reactive interventions in the elimination and control of malaria

Reactive case detection (RCD) is an integral part of many malaria control and elimination programmes and can be conceived of as a way of gradually decreasing transmission. However, it is unclear under what circumstances RCD may have a substantial impact on prevalence, how likely it is to lead to local elimination, or how effective it needs to be to prevent reintroduction after transmission has been interrupted.; Analyses and simulations of a discrete time compartmental susceptible-infectious-susceptible (SIS) model were used to understand the mechanisms of how RCD changes transmission dynamics and estimate the impact of RCD programmes in a range of settings with varying patterns of transmission potential and programme characteristics. Prevalence survey data from recent studies in Zambia were used to capture the effects of spatial clustering of patent infections.; RCD proved most effective at low prevalence. Increasing the number of index cases followed was more important than increasing the number of neighbours tested per index case. Elimination was achieved only in simulations of situations with very low transmission intensity and following many index cases. However, RCD appears to be helpful in maintaining the disease-free state after achieving malaria elimination (through other interventions).; RCD alone can eliminate malaria in only a very limited range of settings, where transmission potential is very low, and improving the coverage of RCD has little effect on this range. In other settings, it is likely to reduce disease burden. RCD may also help maintain the disease-free state in the face of imported infections. Prevalence survey data can be used to estimate a targeting ratio (the ratio of prevalence found through RCD to that in the general population) which is an important determinant of the effect of RCD

Implementing a multisector public-private partnership to improve urban hypertension management in low-and middle- income countries

BACKGROUND: Cardiovascular disease presents an increasing health burden to low- and middle-income countries. Although ample therapeutic options and care improvement frameworks exist to address its prime risk factor, hypertension, blood pressure control rates remain poor. We describe the results of an effectiveness study of a multisector urban population health initiative that targets hypertension in a real-world implementation setting in cities across three continents. The initiative followed the "CARDIO4Cities" approach (quality of Care, early Access, policy Reform, Data and digital technology, Intersectoral collaboration, and local Ownership). METHOD: The approach was applied in Ulaanbaatar in Mongolia, Dakar in Senegal, and Sao Paulo in Brazil. In each city, a portfolio of evidence-based practices was implemented, tailored to local priorities and available data. Outcomes were measured by extracting hypertension diagnosis, treatment and control rates from primary health records. Data from 18,997 patients with hypertension in primary health facilities were analyzed. RESULTS: Over one to two years of implementation, blood pressure control rates among enrolled patients receiving medication tripled in Sao Paulo (from 12.3% to 31.2%) and Dakar (from 6.7% to 19.4%) and increased six-fold in Ulaanbaatar (from 3.1% to 19.7%). CONCLUSIONS: This study provides first evidence that a multisectoral population health approach to implement known best-practices, supported by data and digital technologies, and relying on local buy-in and ownership, can improve hypertension control in high-burden urban primary care settings in low-and middle-income countries

Genotypic and phenotypic distinctness of restored and indigenous populations of Pimpinella saxifraga eight or more years after restoration

Formerly, non-local seed sourcing of naturally occurring herbaceous species was the main strategy for ecological restoration in Germany. Prices for non-local seeds were significantly lower and large quantities of local seeds were unavailable. We here tested whether the genetic composition of non-local seeds (R) of Pimpinella saxifraga L. (Apiaceae) of former restoration projects can still be detected several years after application and whether it differs from the species' regional gene pool (I). A comparative population genetic analysis (AFLP) was conducted. In a common garden experiment phenological and morphological differences were investigated. We further simulated mowing to investigate, if treatments affect indigenous (I) and restored (R) populations differently. The population genetic analysis resulted in two large and quite distinct and diverse cluster that separated I- and R-site individuals, with some signatures of introgression from R to I. Three generative fitness parameters featured significant differences between individuals of the R- and I-sites. The genotypic persistence reduces the availability of niches for the local genotype and may eventually lead to genotypic competition or introgression. We therefore recommend to retain from the introduction of the species' non-local genotypes in the region to avoid genotypic competition and recommend to use the genetically diverse local genotypes for restoration purposes. Data collection time: 2011.09.01 until 2013.11.30 In a comparative approach, we tested whether the genetic makeup of the former non-local seed source use of Pimpinella saxifraga L. (Apiaceae) in restoration projects at sites in Central Germany several years after application (restoration between 1994 and 2004) differs from the species' regional gene pool. In a comparative approach, we compared genetic diversities and differentiations by using amplified fragment length polymorphisms (AFLPs). Phenological and morphological differences were analyzed in a common garden experiment in which we cultivated plants from all sites. For that we sampled seed and plant material in autumn 2011 of seven populations per I- and R-site. Of each individual of each study site 60 seeds were sown in a common garden experiment at the Universities nursery in Giessen (Germany) in spring 2012. The data collections of generative and vegetative morphological variation were measured two times per week in 2013 throughout the season

Prevalence and characterization of hypoadrenocorticism in dogs with signs of chronic gastrointestinal disease – a multicenter study

Background Dogs with hypoadrenocorticism (HA) frequently show signs of gastrointestinal disease (SGD). The prevalence of dogs presented for chronic SGD with HA is unknown. Objectives The aims of this study were to determine the prevalence of HA in dogs with chronic SGD and to identify clinical and laboratory variables for HA in this population. Animals One hundred fifty‐one dogs with chronic SGD. Methods In this multicentered prevalence study a standardized workup was performed in prospectively enrolled dogs with SGD > 3 weeks duration. Basal serum cortisol concentration was measured in every dog with ACTH stimulation test (ACTHST) if basal serum cortisol concentration was <3 μg/dL. Results Basal serum cortisol concentration was <3 μg/dL in 80/151 (53%) dogs, <2 μg/dL in 42/151 (28%) dogs, and < 1 μg/dL in 9/151 (6%) dogs. In 6/151 dogs HA was diagnosed based on ACTHST (stimulated serum cortisol concentration < 2 μg/dL), a prevalence of 4%. There was no difference in history, physical examination, and laboratory variables between dogs with HA and those with other causes of chronic SGD. In 4/6 dogs with HA, there was melena or hematochezia indicating gastrointestinal blood loss. Hyperkalemia, hyponatremia, or both was not observed in any dog. Conclusion and Clinical Importance The prevalence of HA among dogs with chronic SGD is higher than in the general population. Based on these results, testing adrenal function should be performed as a standard screening test in dogs with chronic SGD to differentiate between HA and chronic enteropathies