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In 1995, journalist Gary Taubes published an article in Science titled “Epidemiology faces its limits,” which questioned the utility of nonrandomized epidemiologic research and has since been cited more than 1000 times. He highlighted numerous examples of research topics he viewed as having questionable merit. Studies have since accumulated for these associations. We systematically evaluated current evidence of 53 example associations discussed in the article. Approximately one-quarter of those presented as doubtful are now widely viewed as causal based on current evaluations of the public health consensus. They include associations between alcohol consumption and breast cancer, residential radon exposure and lung cancer, and the use of tanning devices and melanoma. This history should inform current debates about the reproducibility of epidemiologic research results.

Background Studies evaluating mass drug administration (MDA) in malarious areas have shown reductions in malaria immediately following the intervention. However, these effects vary by endemicity and are not sustained. Since the 2013 version of this Cochrane Review on this topic, additional studies have been published. Objectives Primary objectives To assess the sustained effect of MDA with antimalarial drugs on: ‐ the reduction in malaria transmission in moderate‐ to high‐transmission settings; ‐ the interruption of transmission in very low‐ to low‐transmission settings. Secondary objective To summarize the risk of drug‐associated adverse effects following MDA. Search methods We searched several trial registries, citation databases, conference proceedings, and reference lists for relevant articles up to 11 February 2021. We also communicated with researchers to identify additional published and unpublished studies. Selection criteria Randomized controlled trials (RCTs) and non‐randomized studies comparing MDA to no MDA with balanced co‐interventions across study arms and at least two geographically distinct sites per study arm. Data collection and analysis Two review authors independently assessed trials for eligibility and extracted data. We calculated relative risk (RR) and rate ratios with corresponding 95% confidence intervals (CIs) to compare prevalence and incidence, respectively, in MDA compared to no‐MDA groups. We stratified analyses by malaria transmission and by malaria species. For cluster‐randomized controlled trials (cRCTs), we adjusted standard errors using the intracluster correlation coefficient. We assessed the certainty of the evidence using the GRADE approach. For non‐randomized controlled before‐and‐after (CBA) studies, we summarized the data using difference‐in‐differences (DiD) analyses. Main results Thirteen studies met our criteria for inclusion. Ten were cRCTs and three were CBAs. Cluster‐randomized controlled trials Moderate‐ to high‐endemicity areas (prevalence ≥ 10%) We included data from two studies conducted in The Gambia and Zambia. At one to three months after MDA, the Plasmodium falciparum (hereafter, P falciparum) parasitaemia prevalence estimates may be higher compared to control but the CIs included no effect (RR 1.76, 95% CI 0.58 to 5.36; Zambia study; low‐certainty evidence); parasitaemia incidence was probably lower (RR 0.61, 95% CI 0.40 to 0.92; The Gambia study; moderate‐certainty evidence); and confirmed malaria illness incidence may be substantially lower, but the CIs included no effect (rate ratio 0.41, 95% CI 0.04 to 4.42; Zambia study; low‐certainty evidence). At four to six months after MDA, MDA showed little or no effect on P falciparum parasitaemia prevalence (RR 1.18, 95% CI 0.89 to 1.56; The Gambia study; moderate‐certainty evidence) and, no persisting effect was demonstrated with parasitaemia incidence (rate ratio 0.91, 95% CI 0.55 to 1.50; The Gambia study). Very low‐ to low‐endemicity areas (prevalence < 10%) Seven studies from Cambodia, Laos, Myanmar (two studies), Vietnam, Zambia, and Zanzibar evaluated the effects of multiple rounds of MDA on P falciparum. Immediately following MDA (less than one month after MDA), parasitaemia prevalence was reduced (RR 0.12, 95% CI 0.03 to 0.52; one study; low‐certainty evidence). At one to three months after MDA, there was a reduction in both parasitaemia incidence (rate ratio 0.37, 95% CI 0.21 to 0.55; 1 study; moderate‐certainty evidence) and prevalence (RR 0.25, 95% CI 0.15 to 0.41; 7 studies; low‐certainty evidence). For confirmed malaria incidence, absolute rates were low, and it is uncertain whether MDA had an effect on this outcome (rate ratio 0.58, 95% CI 0.12 to 2.73; 2 studies; very low‐certainty evidence). For P falciparum prevalence, the relative differences declined over time, from RR 0.63 (95% CI 0.36 to 1.12; 4 studies) at four to six months after MDA, to RR 0.86 (95% CI 0.55 to 1.36; 5 studies) at 7 to 12 months after MDA. Longer‐term prevalence estimates showed overall low absolute risks, and relative effect estimates of the effect of MDA on prevalence varied from RR 0.82 (95% CI 0.20 to 3.34) at 13 to 18 months after MDA, to RR 1.25 (95% CI 0.25 to 6.31) at 31 to 36 months after MDA in one study. Five studies from Cambodia, Laos, Myanmar (2 studies), and Vietnam evaluated the effect of MDA on Plasmodium vivax (hereafter, P vivax). One month following MDA, P vivax prevalence was lower (RR 0.18, 95% CI 0.08 to 0.40; 1 study; low‐certainty evidence). At one to three months after MDA, there was a reduction in P vivax prevalence (RR 0.15, 95% CI 0.10 to 0.24; 5 studies; low‐certainty evidence). The immediate reduction on P vivax prevalence was not sustained over time, from RR 0.78 (95% CI 0.63 to 0.95; 4 studies) at four to six months after MDA, to RR 1.12 (95% CI 0.94 to 1.32; 5 studies) at 7 to 12 months after MDA. One of the studies in Myanmar provided estimates of longer‐term effects, where overall absolute risks were low, ranging from RR 0.81 (95% CI 0.44 to 1.48) at 13 to 18 months after MDA, to RR 1.20 (95% CI 0.44 to 3.29) at 31 to 36 months after MDA. Non‐randomized studies Three CBA studies were conducted in moderate‐ to high‐transmission areas in Burkina Faso, Kenya, and Nigeria. There was a reduction in P falciparum parasitaemia prevalence in MDA groups compared to control groups during MDA (DiD range: ‐15.8 to ‐61.4 percentage points), but the effect varied at one to three months after MDA (DiD range: 14.9 to ‐41.1 percentage points). Authors' conclusions In moderate‐ to high‐transmission settings, no studies reported important effects on P falciparum parasitaemia prevalence within six months after MDA. In very low‐ to low‐transmission settings, parasitaemia prevalence and incidence were reduced initially for up to three months for both P falciparum and P vivax; longer‐term data did not demonstrate an effect after four months, but absolute risks in both intervention and control groups were low. No studies provided evidence of interruption of malaria transmission., Plain language summary Administration of antimalarial drugs to whole populations for reducing malaria What is mass drug administration (MDA) for malaria? MDA for malaria consists of giving a full treatment course of antimalarial medicine (even to persons with no symptoms of malaria and regardless of whether malaria is present) to every member of a defined population or every person living in a defined geographical area (except to those for whom the medicine could be harmful) at approximately the same time and often at repeated intervals. How can MDA reduce malaria transmission in a population? The life cycle of the malaria parasite consists of human liver, human blood, and mosquito stages. Malaria infection begins with the bite of an Anopheles species mosquito carrying the malaria parasite. During the bite, the infective mosquito injects the malaria parasite into the human host. After initially replicating in the liver, the parasites are released into the bloodstream. During the blood stage, parasites multiply in red blood cells, sometimes causing fever and other symptoms characteristic of malaria. Some of these parasites become a form which is infectious to mosquitoes. When the infected person is bitten again, the mosquito ingests blood containing the parasites, which then restarts the transmission cycle. MDA with antimalarial drugs temporarily prevents new and clears existing malaria infections in the population. Depending on the characteristics of the antimalarial drug used, MDA targets parasites at different stages, which can lead to reduced disease burden and transmission in the population. Whether MDA can successfully reduce or interrupt malaria transmission may depend on how much malaria there is in the area; the use of other tools to control malaria, including preventing mosquito bites; the proportion of the population who receive at least one round of MDA; population movement; and when MDA rounds occur in relation to the peak malaria transmission season. What was the aim of the review? To guide policy‐making and future research for malaria control and elimination, the aim of this review was to update the evidence evaluating the effect of MDA compared to no MDA on malaria outcomes in moderate‐ to high‐transmission settings and very low‐ to low‐transmission settings. Our search of relevant published and unpublished literature identified 13 studies that met our inclusion criteria. What are the main findings of the review? Malaria burden was compared in people receiving MDA and those who did not receive MDA, at different time points. The findings differed by malaria transmission setting. In areas with malaria prevalence of 10% or higher (moderate‐ to high‐transmission areas), based on one trial, MDA did not reduce malaria in the population (low‐certainty evidence). In areas with malaria prevalence under 10% (very low‐ to low‐endemicity areas), evidence from seven trials indicates that MDA reduced malaria in the population immediately after MDA has stopped (low‐certainty evidence), but we are uncertain if the decline continues long‐term because the number of malaria cases in both intervention and control groups were low (very low‐certainty evidence). In all settings of malaria transmission, the type of antimalarial drug used for MDA, co‐interventions such as mosquito control, coverage of MDA, and risk of re‐introduction may have an impact on the effect of MDA compared to no MDA. However, we were unable to explore these factors due to the limited number of studies. How up to date is the review? We included studies available up to 11 February 2021.

The use of mobile technologies in medicine, or mHealth, holds promise to improve health worker (HW) performance, but evidence is mixed. We conducted a cluster-randomized controlled trial to evaluate the effect of text message reminders to HWs in outpatient health facilities (HFs) on quality of care for malaria, pneumonia, and diarrhea in Malawi. After a baseline HF survey (2,360 patients) in January 2015, 105 HFs were randomized to three arms: 1) text messages to HWs on malaria case management; 2) text messages to HWs on malaria, pneumonia, and diarrhea case management (latter two for children < 5 years); and 3) control arm (no messages). Messages were sent beginning April 2015 twice daily for 6 months, followed by an endline HF survey (2,536 patients) in November 2015. An intention-to-treat analysis with difference-in-differences binomial regression modeling was performed. The proportion of patients with uncomplicated malaria managed correctly increased from 42.8% to 59.6% in the control arm, from 43.7% to 55.8% in arm 1 (effect size −4.7%-points, 95% confidence interval (CI): −18.2, 8.9, P = 0.50) and from 30.2% to 50.9% in arm 2 (effect size 3.9%-points, 95% CI: −14.1, 22.0, P = 0.67). Prescription of first-line antibiotics to children < 5 years with clinically defined pneumonia increased in all arms, but decreased in arm 2 (effect size −4.1%-points, 95% CI: −42.0, 33.8, P = 0.83). Prescription of oral rehydration solution to children with diarrhea declined slightly in all arms. We found no significant improvements in malaria, pneumonia, or diarrhea treatment after HW reminders, illustrating the importance of rigorously testing new interventions before adoption.

Despite substantial declines since the 1960's, heart disease remains the leading cause of death in the United States (US) and geographic disparities in heart disease mortality have grown. State-level socioeconomic factors might be important contributors to geographic differences in heart disease mortality. This study examined the association between state-level minimum wage increases above the federal minimum wage and heart disease death rates from 1980 to 2015 among ‘working age’ individuals aged 35–64 years in the US. Annual, inflation-adjusted state and federal minimum wage data were extracted from legal databases and annual state-level heart disease death rates were obtained from CDC Wonder. Although most minimum wage and health studies to date use conventional regression models, we employed marginal structural models to account for possible time-varying confounding. Quasi-experimental, marginal structural models accounting for state, year, and state × year fixed effects estimated the association between increases in the state-level minimum wage above the federal minimum wage and heart disease death rates. In models of ‘working age’ adults (35–64 years old), a $1 increase in the state-level minimum wage above the federal minimum wage was on average associated with ~6 fewer heart disease deaths per 100,000 (95% CI: −10.4, −1.99), or a state-level heart disease death rate that was 3.5% lower per year. In contrast, for older adults (65+ years old) a $1 increase was on average associated with a 1.1% lower state-level heart disease death rate per year (b = −28.9 per 100,000, 95% CI: −71.1, 13.3). State-level economic policies are important targets for population health research.

Pneumonia and diarrhea are leading causes of child deaths in Malawi. Guidelines to manage childhood illnesses in resource-poor settings exist, but studies have reported low health-care worker (HCW) adherence to guidelines. We conducted a health facility survey from January to March 2015 to assess HCW management of pneumonia and diarrhea in children < 5 years of age in southern Malawi, and to determine factors associated with case management quality. Descriptive statistics and multivariable logistic regression models examined patient, HCW, and health facility factors associated with recommended pneumonia and diarrhea management, using Malawi's national guidelines as the gold standard. Of 694 surveyed children 2–59 months of age at 95 health facilities, 132 (19.0%) met survey criteria for pneumonia; HCWs gave recommended antibiotic treatment to 90 (68.2%). Of 723 children < 5 years of age, 222 (30.7%) had uncomplicated diarrhea; HCWs provided recommended treatment to 94 (42.3%). In multivariable analyses, caregivers' spontaneous report of children's symptoms was associated with recommended treatment of both pneumonia (odds ratio [OR]: 2.8, 95% confidence interval [CI]: 1.2–6.8, P = 0.023) and diarrhea (OR: 24.2, 95% CI: 6.0–97.0, P < 0001). Malaria diagnosis was negatively associated with recommended treatment (OR for pneumonia: 0.5, 95% CI: 0.2–1.0, P = 0.046; OR for diarrhea: 0.3, 95% CI: 0.1–0.6, P = 0.003). To improve quality of care, children should be assessed systematically, even when malaria is suspected. Renewed efforts to invigorate such a systematic approach, including HCW training, regular follow-up supervision, and monitoring HCW performance, are needed in Malawi.

Background Measuring the physical condition of long-lasting insecticidal nets (LLINs) under field conditions is of great importance for malaria control programmes to guide decisions on how frequently to replace LLINs. Current guidelines by the World Health Organization Pesticide Evaluation Scheme (WHOPES) propose a proportionate hole index (pHI) for assessing LLIN condition by counting the number of holes the size of a thumb, fist, head, and larger than a head. However, this method does not account for irregular hole shapes or exact hole sizes which could result in inaccurate decisions about when to replace LLINs. Methods LLINs were collected during a 2013 health facility-based malaria case control study in Machinga District, Malawi. To evaluate the accuracy of the pHI, the physical condition of 277 LLINs was estimated by the WHOPES method and then compared with two more thorough measurement methods: image analysis of digital photographs of each LLIN side; and for 10 nets, ruler measurements of the length, width, and location of each hole. Total hole counts and areas per net were estimated by each method, and detailed results of hole shapes and composite pictures of hole locations were generated using image analysis. Results The WHOPES method and image analysis resulted in similar estimates of total hole counts, each with a median of 10 (inter-quartile range (IQR) 4–24 and 4–23, respectively; p = 0.004); however, estimated hole areas were significantly larger using the WHOPES method (median 162 cm2, IQR 28–793) than image analysis (median 13 cm2, IQR 3–101; p

Background Long-lasting insecticidal nets (LLINs) are a cornerstone of malaria prevention. Holes develop in LLINs over time and compromise their physical integrity, but how holes affect malaria transmission risk is not well known. Methods After a nationwide mass LLIN distribution in July 2012, a study was conducted to assess the relationship between LLIN damage and malaria. From March to September 2013, febrile children ages 6–59 months who consistently slept under LLINs (every night for 2 weeks before illness onset) were enrolled in a case–control study at Machinga District Hospital outpatient department. Cases were positive for Plasmodium falciparum asexual parasites by microscopy while controls were negative. Digital photographs of participants’ LLINs were analysed using an image-processing programme to measure holes. Total hole area was classified by quartiles and according to the World Health Organization’s proportionate hole index (pHI) cut-offs [ 790 cm2 (too torn)]. Number of holes by location and size, and total hole area, were compared between case and control LLINs using non-parametric analyses and logistic regression. Results Of 248 LLINs analysed, 97 (39%) were from cases. Overall, 86% of LLINs had at least one hole. The median number of holes of any size was 9 [interquartile range (IQR) 3, 22], and most holes were located in the lower halves of the nets [median 7 (IQR 2, 16)]. There were no differences in number or location of holes between LLINs used by cases and controls. The median total hole area was 10 cm2 (IQR 2, 125) for control LLINs and 8 cm2 (IQR 2, 47) for case LLINs (p = 0.10). Based on pHI, 109 (72%) control LLINs and 83 (86%) case LLINs were in “good” condition. Multivariable modeling showed no association between total hole area and malaria, controlling for child age, caregiver education, and iron versus thatched roof houses. Conclusions LLIN holes were not associated with increased odds of malaria in this study. However, most of the LLINs were in relatively good condition 1 year after distribution. Future studies should examine associations between LLIN holes and malaria risk with more damaged nets. Electronic supplementary material The online version of this article (doi:10.1186/s12936-017-2033-3) contains supplementary material, which is available to authorized users.

Background Academic achievement is influenced by factors at the student, school, and community levels. We estimated the effect of cardiorespiratory fitness performance on academic performance at the school level in Georgia elementary schools and examined effect modification by sociodemographic factors. Methods This study is a repeat cross-sectional analysis of Georgia elementary schools between 2011 and 2014 (approximately 1138 schools per year). Multivariable beta regression estimated the effect of the proportion of 4th and 5th graders meeting cardiorespiratory fitness standards on the proportion of 5th graders passing standardized tests for Reading, English and Language Arts, Mathematics, Science, and Social Studies and considered potential interaction by school-level socioeconomic status (SES), racial composition, and urbanity. Results There was a 0.15 higher estimated odds (OR: 1.15 (1.09, 1.22)) of passing the mathematics standardized test for every 10-percentage-point increase in school-level cardiorespiratory fitness among high-SES schools and 0.04 higher odds (OR: 1.04 (1.02, 1.05)) for low-SES schools. This pattern was similar for other academic subjects. No effect modification by racial composition or urbanity was observed for any academic subject. Conclusions Promoting physical fitness may be effective in improving academic performance among high-SES schools, but additional strategies may be needed among lower-SES schools.

Background With 71% of Malawians living on

A malaria cohort study was conducted among young children in Machinga District, Malawi, following distribution of insecticide-treated bednets (ITNs) in May 2012. To assess ITN use, two independently sampled subsets of children (211 during survey 1 [December 2012–January 2013] and 325 during survey 2 [September–October 2013]) were randomly selected to compare the proportions of positive and negative agreement between caregiver verbal reports at monthly interviews with visual observation of the ITN at home visits. Caregiver-reported ITN use was consistently high during both surveys (98.1% and 96.0%, respectively; P = 0.17). Home visit-based ITN use fell significantly (P < 0.001) from survey 1 (98.6%) to survey 2 (88.6%). The proportions of positive agreement between caregiver report and home visit in the first and second surveys were 98.8% (95% confidence interval [CI] 97.6–99.8%) and 93.3% (95% CI 91.2–95.3%), respectively. The proportions of negative agreement in the first and second surveys were 28.6% (95% CI 0–75.0%) and 20.0% (95% CI 0.1–35.0%), respectively. ITN use by children was high in Machinga District, and caregiver reports and home visits with visual confirmation of the net demonstrated a high level of agreement for use of ITNs, but a low level of agreement when ITNs were not used.

Background The escalating level of mosquito resistance to pyrethroid insecticides threatens the effectiveness of insecticide-treated nets (ITNs) for malaria control in Malawi. An evaluation of the effectiveness of ITNs for preventing malaria in children aged 6–59 months old, after 1 year of mass distribution of LLINs was conducted in Machinga District, Malawi, an area of moderate pyrethroid resistance. Methods A facility-based, case–control study among children 6–59 months was conducted in an area of pyrethroid resistance between March and September 2013 in Machinga District. Cases and controls were children with fever who sought care from the same hospital and tested positive and negative, respectively, for malaria parasites by microscopy. Results A high proportion of both cases (354 of 404 or 87.6 %) and controls (660 of 778 or 84.8 %) slept under an ITN the night before the survey. In univariable logistic regression, older age (24–59 months versus 6–23 months, p

Despite the clear public health benefit of insecticide-treated bednets (ITNs), the impact of malaria transmission-reduction by vector control on the spread of drug resistance is not well understood. In the present study, the effect of sustained transmission reduction by ITNs on the prevalence of Plasmodium falciparum gene mutations associated with resistance to the antimalarial drugs sulfadoxine-pyrimethamine (SP) and chloroquine (CQ) in children under the age of five years was investigated during an ITN trial in Asembo area, western Kenya. During the ITN trial, the national first line antimalarial treatment changed from CQ to SP. Smear-positive samples collected from cross sectional surveys prior to ITN introduction (baseline, n = 250) and five years post-ITN intervention (year 5 survey, n = 242) were genotyped for single nucleotide polymorphisms (SNPs) at dhfr-51, 59, 108, 164 and dhps-437, 540 (SP resistance), and pfcrt-76 and pfmdr1-86 (CQ resistance). The association between the drug resistance mutations and epidemiological variables was evaluated. There were significant increases in the prevalence of SP dhps mutations and the dhfr/dhps quintuple mutant, and a significant reduction in the proportion of mixed infections detected at dhfr-51, 59 and dhps-437, 540 SNPs from baseline to the year 5 survey. There was no change in the high prevalence of pfcrt-76 and pfmdr1-86 mutations. Multivariable regression analysis further showed that current antifolate use and year of survey were significantly associated with more SP drug resistance mutations. These results suggest that increased antifolate drug use due to drug policy change likely led to the high prevalence of SP mutations 5 years post-ITN intervention and reduced transmission had no apparent effect on the existing high prevalence of CQ mutations. There is no evidence from the current study that sustained transmission reduction by ITNs reduces the prevalence of genes associated with malaria drug resistance.

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 (MA) declined with time in the original study area Asembo (from 95.9 %-2001 to 87.7 %-2007). In the neighbouring areas, MA 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 (MAC ~ 2.65) and overall unbiased heterozygosity (He ~ 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 FST

Background Severe malaria has a case fatality rate of 10-20 %; however, few studies have addressed the quality of severe malaria case management. This study evaluated the diagnostic and treatment practices of malaria patients admitted to inpatient health facilities (HF) in Malawi. Methods In July–August 2012, a nationwide, cross-sectional survey of severe malaria management was conducted in 36 HFs selected with equal probability from all eligible public sector HFs in Malawi. Patient records from all admissions during October 2011 and April 2012 (low and high season, respectively) were screened for an admission diagnosis of malaria or prescription of any anti-malarial. Eligible records were stratified by age (

Background Insecticide-treated bed nets (ITNs) are the cornerstone of malaria control in sub-Saharan Africa but their effectiveness may be compromised by the spread of pyrethroid resistance among malaria vectors. The objective of this investigation was to assess the effectiveness of ITNs to prevent malaria in an area of Malawi with moderate pyrethroid resistance. Methods One deltamethrin ITN was distributed in the study area for every two individuals in each household plus one extra ITN for households with an odd number of residents. A fixed cohort of 1,199 children aged six to 59 months was seen monthly for one year and at sick visits to measure malaria infection and use of ITNs. Insecticide resistance among malaria vectors was measured. The effect of ITN use on malaria incidence was assessed, adjusting for potential confounders using generalized estimating equations accounting for repeated measures. Results There were 1,909 infections with Plasmodium falciparum over 905 person-years at risk (PYAR), resulting in an observed incidence of 2.1 infections per person-year (iPPY). ITNs were used during 97% of the PYAR. The main vector was Anopheles funestus: mortality in WHO tube assays after exposure to 0.05% deltamethrin was 38% (95% confidence interval (CI) 29–47), and resistance was due to elevated oxidase enzymes. After adjusting for potential confounders, the incidence of malaria infection among ITN users was 1.7 iPPY (95% CI 1.5-2.1) and among non-bed net users was 2.6 iPPY (95% CI 2.0-3.3). Use of ITNs reduced the incidence of malaria infection by 30% (rate ratio 0.7; 95% CI, 0.5-0.8) compared to no bed nets. Conclusion ITNs significantly reduced the incidence of malaria infection in children in an area with moderate levels of pyrethroid resistance and considerable malaria transmission. This is the first study to show that ITNs provide protection in areas where pyrethroid-resistant An. funestus is the major malaria vector. Malaria control programmes should continue to distribute and promote ITNs in areas with low to moderate pyrethroid resistance; however, insecticide resistance may intensify further and it is not known whether ITNs will remain effective at higher levels of resistance. There is an urgent need to identify or develop new insecticides and technologies to limit the vulnerability of ITNs to insecticide resistance.

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. 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. 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

Background Resistance to sulphadoxine-pyrimethamine (SP) in Plasmodium falciparum parasites is associated with mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes and has spread worldwide. SP remains the recommended drug for intermittent preventive treatment for malaria in pregnancy (IPTp) and information on population prevalence of the SP resistance molecular markers in pregnant women is limited. Methods Temporal trends of SP resistance molecular markers were investigated in 489 parasite samples collected from pregnant women at delivery from three different observational studies between 1996 and 2009 in Kenya, where SP was adopted for both IPTp and case treatment policies in 1998. Using real-time polymerase chain reaction, pyrosequencing and direct sequencing, 10 single-nucleotide polymorphisms (SNPs) of SP resistance molecular markers were assayed. Results The prevalence of quintuple mutant (dhfr N51I/C59R/S108N and dhps A437G/K540E combined genotype) increased from 7 % in the first study (1996–2000) to 88 % in the third study (2008–2009). When further stratified by sample collection year and adoption of IPTp policy, the prevalence of the quintuple mutant increased from 2.4 % in 1998 to 44.4 % three years after IPTp policy adoption, seemingly in parallel with the increase in percentage of SP use in pregnancy. However, in the 1996–2000 study, more mutations in the combined dhfr/dhps genotype were associated with SP use during pregnancy only in univariable analysis and no associations were detected in the 2002–2008 and 2008–2009 studies. In addition, in the 2008–2009 study, 5.3 % of the parasite samples carried the dhps triple mutant (A437G/K540E/A581G). There were no differences in the prevalence of SP mutant genotypes between the parasite samples from HIV + and HIV- women over time and between paired peripheral and placental samples. Conclusions There was a significant increase in dhfr/dhps quintuple mutant and the emergence of new genotype containing dhps 581 in the parasites from pregnant women in western Kenya over 13 years. IPTp adoption and SP use in pregnancy only played a minor role in the increased drug-resistant parasites in the pregnant women over time. Most likely, other major factors, such as the high prevalence of resistant parasites selected by the use of SP for case management in large non-pregnant population, might have contributed to the temporally increased prevalence of SP resistant parasites in pregnant women. Further investigations are needed to determine the linkage between SP drug resistance markers and efficacy of IPTp-SP.