Assessment of molecular markers for anti-malarial drug resistance after the introduction and scale-up of malaria control interventions in western Kenya

Background Although it is well known that drug pressure selects for drug-resistant parasites, the role of transmission reduction by insecticide-treated bed nets (ITNs) on drug resistance remains unclear. In this study, the drug resistance profile of current and previous first-line anti-malarials in Kenya was assessed within the context of drug policy change and scale-up of ITNs. National first-line treatment changed from chloroquine (CQ) to sulphadoxine-pyrimethamine (SP) in 1998 and to artemether-lumefantrine (AL) in 2004. ITN use was scaled-up in the Asembo, Gem and Karemo areas of western Kenya in 1997, 1999 and 2006, respectively. Methods Smear-positive samples (N = 253) collected from a 2007 cross-sectional survey among children in Asembo, Gem and Karemo were genotyped for mutations in pfcrt and pfmdr1 (CQ), dhfr and dhps (SP), and at pfmdr-N86 and the gene copy number in pfmdr1 (lumefantrine). Results were compared among the three geographic areas in 2007 and to retrospective molecular data from children in Asembo in 2001. Results In 2007, 69 and 85% of samples harboured the pfmdr1-86Y mutation and dhfr/dhps quintuple mutant, respectively, with no significant differences by study area. However, the prevalence of the pfcrt-76T mutation differed significantly among areas (p <0.02), between 76 and 94%, with the highest prevalence in Asembo. Several 2007 samples carried mutations at dhfr-164L, dhps-436A, or dhps-613T. From 2001 to 2007, there were significant increases in the pfcrt-76T mutation from 82 to 94% (p <0.03), dhfr/dhps quintuple mutant from 62 to 82% (p <0.03), and an increase in the septuple CQ and SP combined mutant haplotype, K 76 Y 86 I 51 R 59 N 108 G 437 E 540 , from 28 to 39%. The prevalence of the pfmdr1-86Y mutation remained unchanged. All samples were single copy for pfmdr1. Conclusions Molecular markers associated with lumefantrine resistance were not detected in 2007. More recent samples will be needed to detect any selective effects by AL. The prevalence of CQ and SP resistance markers increased from 2001 to 2007 in the absence of changes in transmission intensity. In 2007, only the prevalence of pfcrt-76T mutation differed among study areas of varying transmission intensity. Resistant parasites were most likely selected by sustained drug pressure from the continued use of CQ, SP, and mechanistically similar drugs, such as amodiaquine and cotrimoxazole. There was no clear evidence that differences in transmission intensity, as a result of ITN scale-up, influenced the prevalence of drug resistance molecular markers

Genetic diversity of Plasmodium falciparum parasite by microsatellite markers after scale-up of insecticide-treated bed nets in western Kenya

Background: An initial study of genetic diversity of Plasmodium falciparum in Asembo, western Kenya showed that the parasite maintained overall genetic stability 5 years after insecticide-treated bed net (ITN) introduction in 1997. This study investigates further the genetic diversity of P. falciparum 10 years after initial ITN introduction in the same study area and compares this with two other neighbouring areas, where ITNs were introduced in 1998 (Gem) and 2004 (Karemo). Methods: From a cross-sectional survey conducted in 2007, 235 smear-positive blood samples collected from children ≤15-year-old in the original study area and two comparison areas were genotyped employing eight neutral microsatellites. Differences in multiple infections, allele frequency, parasite genetic diversity and parasite population structure between the three areas were assessed. Further, molecular data reported previously (1996 and 2001) were compared to the 2007 results in the original study area Asembo. Results: Overall proportion of multiple infections (M A ) declined with time in the original study area Asembo (from 95.9 %-2001 to 87.7 %-2007). In the neighbouring areas, M A was lower in the site where ITNs were introduced in 1998 (Gem 83.7 %) compared to where they were introduced in 2004 (Karemo 96.7 %) in 2007. Overall mean allele count (M AC ~ 2.65) and overall unbiased heterozygosity (H e ~ 0.77) remained unchanged in 1996, 2001 and 2007 in Asembo and was the same level across the two neighbouring areas in 2007. Overall parasite population differentiation remained low over time and in the three areas at F ST < 0.04. Both pairwise and multilocus linkage disequilibrium showed limited to no significant association between alleles in Asembo (1996, 2001 and 2007) and between three areas. Conclusions: This study showed the P. falciparum high genetic diversity and parasite population resilience on samples collected 10 years apart and in different areas in western Kenya. The results highlight the need for long-term molecular monitoring after implementation and use of combined and intensive prevention and intervention measures in the region

Modelling the relationship between malaria prevalence as a measure of transmission and mortality across age groups

Parasite prevalence has been used widely as a measure of malaria transmission, especially in malaria endemic areas. However, its contribution and relationship to malaria mortality across different age groups has not been well investigated. Previous studies in a health and demographic surveillance systems (HDSS) platform in western Kenya quantified the contribution of incidence and entomological inoculation rates (EIR) to mortality. The study assessed the relationship between outcomes of malaria parasitaemia surveys and mortality across age groups.; Parasitological data from annual cross-sectional surveys from the Kisumu HDSS between 2007 and 2015 were used to determine malaria parasite prevalence (PP) and clinical malaria (parasites plus reported fever within 24 h or temperature above 37.5 °C). Household surveys and verbal autopsy (VA) were used to obtain data on all-cause and malaria-specific mortality. Bayesian negative binomial geo-statistical regression models were used to investigate the association of PP/clinical malaria with mortality across different age groups. Estimates based on yearly data were compared with those from aggregated data over 4 to 5-year periods, which is the typical period that mortality data are available from national demographic and health surveys.; Using 5-year aggregated data, associations were established between parasite prevalence and malaria-specific mortality in the whole population (RR; malaria; = 1.66; 95% Bayesian Credible Intervals: 1.07-2.54) and children 1-4 years (RR; malaria; = 2.29; 1.17-4.29). While clinical malaria was associated with both all-cause and malaria-specific mortality in combined ages (RR; all-cause; = 1.32; 1.01-1.74); (RR; malaria; = 2.50; 1.27-4.81), children 1-4 years (RR; all-cause; = 1.89; 1.00-3.51); (RR; malaria; = 3.37; 1.23-8.93) and in older children 5-14 years (RR; all-cause; = 3.94; 1.34-11.10); (RR; malaria; = 7.56; 1.20-39.54), no association was found among neonates, adults (15-59 years) and the elderly (60+ years). Distance to health facilities, socioeconomic status, elevation and survey year were important factors for all-cause and malaria-specific mortality.; Malaria parasitaemia from cross-sectional surveys was associated with mortality across age groups over 4 to 5 year periods with clinical malaria more strongly associated with mortality than parasite prevalence. This effect was stronger in children 5-14 years compared to other age-groups. Further analyses of data from other HDSS sites or similar platforms would be useful in investigating the relationship between malaria and mortality across different endemicity levels

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Voltage Controller for Radial Distribution Networks with Distributed Generation

Abstract- This paper presents a coordinated network controller whose objective is to maintain an optimal voltage profile across radial distribution networks with distributed generation. This is done by varying the output of the distributed generators. The controller was modeled as an optimization problem which was solved using Particle Swarm Optimization. The IEEE 33-bus and 69-bus test networks are then used to verify the effectiveness of the controller. The results obtained show that this controller can improve the voltage profile of a power network. Index Terms- radial distribution networks, particle swarm optimization, modified backward-forward sweep I

Trends of non-vaccination, under-vaccination and missed opportunities for vaccination (2003-2014) amongst children 0-23 months in Kenya.

Vaccines are effective and cost-effective. Non-vaccination, under-vaccination, and missed opportunities for vaccination (MOV), have contributed to incomplete vaccination coverage in Kenya. Analyzing their trends is essential for targeting interventions and improvement strategies. This study aimed to assess trends of non-vaccination, under-vaccination, and MOV among children aged 0-23 months in Kenya using data obtained from the Kenya Demographic and Health Surveys (KDHS) conducted in 2003, 2008/09, and 2014. A two-stage, multi-stage, and stratified sampling technique was used. Weighted analysis was conducted to ensure generalizability to the full population. Using the KDHS sample size estimation process, the sample size was estimated for each indicator, with varying standard error estimates, level of coverage and estimated response rates. Final sample size was 2380 (2003), 2237 (2008/09) and 7380 (2014). To determine the level of non-vaccination, under-vaccination and MOV among children aged 0-23 months, a weighted descriptive analysis was used to estimate their prevalence, with 95% confidence intervals (CI) for each year. MOV was defined using an algorithm as a binary variable. Data coding and recoding were done using Stata (version 14; College Station, TX: StataCorp LP). Trends in proportions of non-vaccination, under-vaccination and MOV were compared between 2003, 2008/09, and 2014 using the Cochrane-Armitage trend test. All results with P≤0.05 were considered statistically significant. Trends in proportion of non-vaccination among children aged 0-23 months in Kenya was 13.2%, 6.1% and 3.2% in 2003, 2008/09 and 2014, respectively (P = 0.0001). Trends in proportion of under-vaccination among children aged 0-23 months in Kenya was 54.3%, 50% and 51.3% in 2003, 2008/09 and 2014, respectively (P = 0.0109). The trends in proportion of children who experienced MOV was 22.7% in 2003, 31.9% in 2008/09 and 37.6% in 2014 (P = 0.0001). In the study duration, non-vaccination decreased by 10%, under-vaccination remained relatively stable, and MOV increased by ~15%. There is need for the Government and partners to implement initiatives that improve vaccine access and coverage, particularly in regions with low coverage rates, and to address missed opportunities for vaccination