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1.  A methodological framework for the improved use of routine health system data to evaluate national malaria control programs: evidence from Zambia 
Population Health Metrics  2014;12(1):30.
Background
Due to challenges in laboratory confirmation, reporting completeness, timeliness, and health access, routine incidence data from health management information systems (HMIS) have rarely been used for the rigorous evaluation of malaria control program scale-up in Africa.
Methods
We used data from the Zambia HMIS for 2009–2011, a period of rapid diagnostic and reporting scale-up, to evaluate the association between insecticide-treated net (ITN) program intensity and district-level monthly confirmed outpatient malaria incidence using a dose–response national platform approach with district-time units as the unit of analysis. A Bayesian geostatistical model was employed to estimate longitudinal district-level ITN coverage from household survey and programmatic data, and a conditional autoregressive model (CAR) was used to impute missing HMIS data. The association between confirmed malaria case incidence and ITN program intensity was modeled while controlling for known confounding factors, including climate variability, reporting, testing, treatment-seeking, and access to health care, and additionally accounting for spatial and temporal autocorrelation.
Results
An increase in district level ITN coverage of one ITN per household was associated with an estimated 27% reduction in confirmed case incidence overall (incidence rate ratio (IRR): 0 · 73, 95% Bayesian Credible Interval (BCI): 0 · 65–0 · 81), and a 41% reduction in areas of lower malaria burden.
Conclusions
When improved through comprehensive parasitologically confirmed case reporting, HMIS data can become a valuable tool for evaluating malaria program scale-up. Using this approach we provide further evidence that increased ITN coverage is associated with decreased malaria morbidity and use of health services for malaria illness in Zambia. These methods and results are broadly relevant for malaria program evaluations currently ongoing in sub-Saharan Africa, especially as routine confirmed case data improve.
Electronic supplementary material
The online version of this article (doi:10.1186/s12963-014-0030-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12963-014-0030-0
PMCID: PMC4247605  PMID: 25435815
Malaria; Evaluation; Integrated Nested Laplace Approximation (INLA); Insecticide-treated nets; Health management information systems (HMIS)
3.  Monitoring, characterization and control of chronic, symptomatic malaria infections in rural Zambia through monthly household visits by paid community health workers 
Malaria Journal  2014;13:128.
Background
Active, population-wide mass screening and treatment (MSAT) for chronic Plasmodium falciparum carriage to eliminate infectious reservoirs of malaria transmission have proven difficult to apply on large national scales through trained clinicians from central health authorities.
Methodology
Fourteen population clusters of approximately 1,000 residents centred around health facilities (HF) in two rural Zambian districts were each provided with three modestly remunerated community health workers (CHWs) conducting active monthly household visits to screen and treat all consenting residents for malaria infection with rapid diagnostic tests (RDT). Both CHWs and HFs also conducted passive case detection among residents who self-reported for screening and treatment.
Results
Diagnostic positivity was higher among symptomatic patients self-reporting to CHWs (42.5%) and HFs (24%) than actively screened residents (20.3%), but spatial and temporal variations of diagnostic positivity were highly consistent across all three systems. However, most malaria infections (55.6%) were identified through active home visits by CHWs rather than self-reporting to CHWs or HFs. Most (62%) malaria infections detected actively by CHWs reported one or more symptoms of illness. Most reports of fever and vomiting, plus more than a quarter of history of fever, headache and diarrhoea, were attributable to malaria infection. The minority of residents who participated >12 times had lower rates of malaria infection and associated symptoms in later contacts but most residents were tested <4 times and high malaria diagnostic positivity (32%) in active surveys, as well as incidence (1.7 detected infections per person per year) persisted in the population. Per capita cost for active service delivery by CHWs was US$5.14 but this would rise to US$10.68 with full community compliance with monthly testing at current levels of transmission, and US$6.25 if pre-elimination transmission levels and negligible treatment costs were achieved.
Conclusion
Monthly active home visits by CHWs equipped with RDTs were insufficient to eliminate the human infection reservoir in this typical African setting, despite reasonably high LLIN/IRS coverage. However, dramatic impact upon infection and morbidity burden might be attainable and cost-effective if community participation in regular testing could be improved and the substantial, but not necessarily prohibitive, costs are affordable to national programmes.
doi:10.1186/1475-2875-13-128
PMCID: PMC4113135  PMID: 24678631
Malaria; Community health worker; Surveillance; Passive and active case detection; Treatment with ACT; Rapid diagnostic tests
4.  Declining malaria in Africa: improving the measurement of progress 
Malaria Journal  2014;13:39.
The dramatic escalation of malaria control activities in Africa since the year 2000 has increased the importance of accurate measurements of impact on malaria epidemiology and burden. This study presents a systematic review of the emerging published evidence base on trends in malaria risk in Africa and argues that more systematic, timely, and empirically-based approaches are urgently needed to track the rapidly evolving landscape of transmission.
doi:10.1186/1475-2875-13-39
PMCID: PMC3930350  PMID: 24479555
5.  Characterization of the Recombinant Exopeptidases PepX and PepN from Lactobacillus helveticus ATCC 12046 Important for Food Protein Hydrolysis 
PLoS ONE  2013;8(7):e70055.
The proline-specific X-prolyl dipeptidyl aminopeptidase (PepX; EC 3.4.14.11) and the general aminopeptidase N (PepN; EC 3.4.11.2) from Lactobacillus helveticus ATCC 12046 were produced recombinantly in E. coli BL21(DE3) via bioreactor cultivation. The maximum enzymatic activity obtained for PepX was 800 µkatH-Ala-Pro-pNA L−1, which is approx. 195-fold higher than values published previously. To the best of our knowledge, PepN was expressed in E. coli at high levels for the first time. The PepN activity reached 1,000 µkatH-Ala-pNA L−1. After an automated chromatographic purification, both peptidases were biochemically and kinetically characterized in detail. Substrate inhibition of PepN and product inhibition of both PepX and PepN were discovered for the first time. An apo-enzyme of the Zn2+-dependent PepN was generated, which could be reactivated by several metal ions in the order of Co2+>Zn2+>Mn2+>Ca2+>Mg2+. PepX and PepN exhibited a clear synergistic effect in casein hydrolysis studies. Here, the relative degree of hydrolysis (rDH) was increased by approx. 132%. Due to the remarkable temperature stability at 50°C and the complementary substrate specificities of both peptidases, a future application in food protein hydrolysis might be possible.
doi:10.1371/journal.pone.0070055
PMCID: PMC3716637  PMID: 23894590
6.  Planning long lasting insecticide treated net campaigns: should households’ existing nets be taken into account? 
Parasites & Vectors  2013;6:174.
Background
Mass distribution of long-lasting insecticide treated bed nets (LLINs) has led to large increases in LLIN coverage in many African countries. As LLIN ownership levels increase, planners of future mass distributions face the challenge of deciding whether to ignore the nets already owned by households or to take these into account and attempt to target individuals or households without nets. Taking existing nets into account would reduce commodity costs but require more sophisticated, and potentially more costly, distribution procedures. The decision may also have implications for the average age of nets in use and therefore on the maintenance of universal LLIN coverage over time.
Methods
A stochastic simulation model based on the NetCALC algorithm was used to determine the scenarios under which it would be cost saving to take existing nets into account, and the potential effects of doing so on the age profile of LLINs owned. The model accounted for variability in timing of distributions, concomitant use of continuous distribution systems, population growth, sampling error in pre-campaign coverage surveys, variable net ‘decay’ parameters and other factors including the feasibility and accuracy of identifying existing nets in the field.
Results
Results indicate that (i) where pre-campaign coverage is around 40% (of households owning at least 1 LLIN), accounting for existing nets in the campaign will have little effect on the mean age of the net population and (ii) even at pre-campaign coverage levels above 40%, an approach that reduces LLIN distribution requirements by taking existing nets into account may have only a small chance of being cost-saving overall, depending largely on the feasibility of identifying nets in the field. Based on existing literature the epidemiological implications of such a strategy is likely to vary by transmission setting, and the risks of leaving older nets in the field when accounting for existing nets must be considered.
Conclusions
Where pre-campaign coverage levels established by a household survey are below 40% we recommend that planners do not take such LLINs into account and instead plan a blanket mass distribution. At pre-campaign coverage levels above 40%, campaign planners should make explicit consideration of the cost and feasibility of accounting for existing LLINs before planning blanket mass distributions. Planners should also consider restricting the coverage estimates used for this decision to only include nets under two years of age in order to ensure that old and damaged nets do not compose too large a fraction of existing net coverage.
doi:10.1186/1756-3305-6-174
PMCID: PMC3689647  PMID: 23763773
Bed net; Long lasting insecticide treated bed net (LLIN); Malaria; Coverage; Mass campaign; Cost savings
7.  Measuring Coverage in MNCH: Accuracy of Measuring Diagnosis and Treatment of Childhood Malaria from Household Surveys in Zambia 
PLoS Medicine  2013;10(5):e1001417.
Background
To assess progress in the scale-up of rapid diagnostic tests and artemisinin-based combination therapies (ACTs) across Africa, malaria control programs have increasingly relied on standardized national household surveys to determine the proportion of children with a fever in the past 2 wk who received an effective antimalarial within 1–2 d of the onset of fever. Here, the validity of caregiver recall for measuring the primary coverage indicators for malaria diagnosis and treatment of children <5 y old is assessed.
Methods and Findings
A cross-sectional study was conducted in five public clinics in Kaoma District, Western Provence, Zambia, to estimate the sensitivity, specificity, and accuracy of caregivers' recall of malaria testing, diagnosis, and treatment, compared to a gold standard of direct observation at the health clinics. Compared to the gold standard of clinic observation, for recall for children with fever in the past 2 wk, the sensitivity for recalling that a finger/heel stick was done was 61.9%, with a specificity of 90.0%. The sensitivity and specificity of caregivers' recalling a positive malaria test result were 62.4% and 90.7%, respectively. The sensitivity and specificity of recalling that the child was given a malaria diagnosis, irrespective of whether a laboratory test was actually done, were 76.8% and 75.9%, respectively. The sensitivity and specificity for recalling that an ACT was given were 81.0% and 91.5%, respectively.
Conclusions
Based on these findings, results from household surveys should continue to be used for ascertaining the coverage of children with a fever in the past 2 wk that received an ACT. However, as recall of a malaria diagnosis remains suboptimal, its use in defining malaria treatment coverage is not recommended.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The World Health Organization estimates that there are over 200 million cases of malaria each year, with nearly 1 million deaths. The majority of these deaths are among children living in sub-Saharan Africa, and Plasmodium falciparum is the parasite responsible. Malaria transmission can be prevented by insect control measures, and current treatment regimens use antimalarial drugs. Recently, the use of highly effective artemisinin-based combination treatments (ACTs) has significantly reduced the deaths and disability caused by malaria. To avoid drug overuse and the development of parasite resistance to ACTs, the World Health Organization recommends that before treatment with ACTs, a laboratory test to confirm malaria should be performed. Rapid diagnostic tests (RDTs) allow health workers to diagnose malaria in settings lacking laboratory facilities, thus providing a method for improving malaria diagnosis and reducing the overuse of ACTs.
Why Was This Study Done?
The success of RDTs and ACTs across Africa in combating malaria is measured by standardized national household surveys. These surveys assess the proportion of children with a fever in the past two weeks who have received an antimalarial treatment within 1–2 days of the onset of fever. The surveys do not distinguish between treatment of a suspected malaria case and one that was laboratory confirmed. Due to the availability and scale-up of RDTs in many African countries, caregivers and mothers are also now asked in national surveys if the child was tested for malaria, but are not usually asked for the result of any malaria diagnostic test given. Knowing whether a child has been diagnosed with malaria is necessary to construct a better indicator of what proportion of children receive an effective and appropriate antimalarial within the appropriate treatment time frame. This indicator is important because it provides more insight into the current diagnosis and treatment policies in most African countries.
Biased coverage estimates for diagnosis and treatment may result from these types of surveys because survey questions to caregivers of children concerning fever in the past two weeks, treatment-seeking behavior, and malaria diagnosis and treatment can be particularly subject to sources of error and bias. Despite this possibility, these indicators and surveys have not been checked against direct observation of the children to assess the validity of caregivers' recall and household surveys to gauge appropriate treatment of malaria in children.
What Did the Researchers Do and Find?
In this study, the authors investigated the validity of caregiver recall of malaria diagnosis and treatment in children under five years old. The authors did a cross-sectional study of five public clinics in Kaoma District, Western Provence, Zambia, to estimate the sensitivity, specificity, and accuracy of caregivers' recall of malaria testing, malaria diagnosis, and antimalarial treatment, and compared the surveys to direct observation at the health clinics. The results from this study demonstrate low sensitivity of caregiver recall of malaria diagnostic use, test results, and malaria diagnosis among children who had a fever in the past two weeks. However, the accuracy of caregiver recall that a child received an ACT was relatively high in this setting. This suggests that the current indicator for measuring the coverage of children with a fever in the past two weeks who received an ACT can be applied in similar settings, and may be useful for estimating infection and treatment over time.
What Do These Findings Mean?
These findings suggest that results from household surveys are accurate for obtaining information about the coverage of children with a fever in the past two weeks that receive an ACT. However, as caregiver recall of a malaria diagnosis is not highly sensitive, the authors suggest that malaria diagnosis from caregiver recall in household surveys is not recommended for defining malaria treatment coverage.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001417.
More information about malaria is available from MedlinePlus, the World Health Organization, and the US Centers for Disease Control and Prevention
The Roll Back Malaria Partnership brings numerous organizations together to combat malaria around the globe
doi:10.1371/journal.pmed.1001417
PMCID: PMC3646207  PMID: 23667337
8.  Measuring Coverage in MNCH: Total Survey Error and the Interpretation of Intervention Coverage Estimates from Household Surveys 
PLoS Medicine  2013;10(5):e1001386.
In a PLOS Medicine Review, Thomas Eisele and colleagues discuss the importance of considering sampling and non-sampling errors when interpreting estimates of coverage of maternal, newborn, and child health interventions based on data from household surveys.
Nationally representative household surveys are increasingly relied upon to measure maternal, newborn, and child health (MNCH) intervention coverage at the population level in low- and middle-income countries. Surveys are the best tool we have for this purpose and are central to national and global decision making. However, all survey point estimates have a certain level of error (total survey error) comprising sampling and non-sampling error, both of which must be considered when interpreting survey results for decision making. In this review, we discuss the importance of considering these errors when interpreting MNCH intervention coverage estimates derived from household surveys, using relevant examples from national surveys to provide context. Sampling error is usually thought of as the precision of a point estimate and is represented by 95% confidence intervals, which are measurable. Confidence intervals can inform judgments about whether estimated parameters are likely to be different from the real value of a parameter. We recommend, therefore, that confidence intervals for key coverage indicators should always be provided in survey reports. By contrast, the direction and magnitude of non-sampling error is almost always unmeasurable, and therefore unknown. Information error and bias are the most common sources of non-sampling error in household survey estimates and we recommend that they should always be carefully considered when interpreting MNCH intervention coverage based on survey data. Overall, we recommend that future research on measuring MNCH intervention coverage should focus on refining and improving survey-based coverage estimates to develop a better understanding of how results should be interpreted and used.
doi:10.1371/journal.pmed.1001386
PMCID: PMC3646211  PMID: 23667331
9.  Travel history and malaria infection risk in a low-transmission setting in Ethiopia: a case control study 
Malaria Journal  2013;12:33.
Background
Malaria remains the leading communicable disease in Ethiopia, with around one million clinical cases of malaria reported annually. The country currently has plans for elimination for specific geographic areas of the country. Human movement may lead to the maintenance of reservoirs of infection, complicating attempts to eliminate malaria.
Methods
An unmatched case–control study was conducted with 560 adult patients at a Health Centre in central Ethiopia. Patients who received a malaria test were interviewed regarding their recent travel histories. Bivariate and multivariate analyses were conducted to determine if reported travel outside of the home village within the last month was related to malaria infection status.
Results
After adjusting for several known confounding factors, travel away from the home village in the last 30 days was a statistically significant risk factor for infection with Plasmodium falciparum (AOR 1.76; p=0.03) but not for infection with Plasmodium vivax (AOR 1.17; p=0.62). Male sex was strongly associated with any malaria infection (AOR 2.00; p=0.001).
Conclusions
Given the importance of identifying reservoir infections, consideration of human movement patterns should factor into decisions regarding elimination and disease prevention, especially when targeted areas are limited to regions within a country.
doi:10.1186/1475-2875-12-33
PMCID: PMC3570338  PMID: 23347703
Malaria; Travel; Human movement; Importation; Plasmodium vivax; Plasmodium falciparum; Ethiopia; Reservoir infection
10.  A quasi-experimental evaluation of an interpersonal communication intervention to increase insecticide-treated net use among children in Zambia 
Malaria Journal  2012;11:313.
Background
This paper presents results from an evaluation of the effect of a community health worker (CHW) –based, interpersonal communication campaign (IPC) for increasing insecticide-treated mosquito net (ITN) use among children in Luangwa District, Zambia, an area with near universal coverage of ITNs and moderate to low malaria parasite prevalence.
Methods
A quasi-experimental community randomized control trial was conducted from 2008 to 2010. CHWs were the unit of randomization. Cross-sectional data were collected from houses in both 2008 and 2010 using simple random sampling of a complete household enumeration of the district. A difference-in -differences approach was used to analyse the data.
Results
ITN use among children <5 years old in households with ≥1 ITN increased overall from 54% in 2008 to 81% in 2010 (χ2 = 96.3, p <0.01); however, there was no difference in increase between the treatment and control arms in 2010 (p >0.05). ITN use also increased among children five to 14 years old from 37% in 2008 to 68% in 2010. There was no indication that the CHW-based intervention activities had a significant effect on increasing ITN use in this context, over and above what is already being done to disseminate information on the importance of using an ITN to prevent malaria infection.
Discussion
ITN use increased dramatically in the district between 2008 and 2010. It is likely that IPC activities in general may have contributed to the observed increase in ITN use, as the increased observed in this study was far higher than the increase observed between 2008 and 2010 malaria indicator survey (MIS) estimates. Contamination across control communities, coupled with linear settlement patterns and subsequent behavioural norms related to communication in the area, likely contributed to the observed increase in net use and null effect in this study.
doi:10.1186/1475-2875-11-313
PMCID: PMC3459708  PMID: 22958441
Evaluation; Insecticide-treated net (ITN); Interpersonal communication campaign (IPC); Community health worker (CHW); Malaria; Zambia
11.  Reductions in Artemisinin-Based Combination Therapy Consumption after the Nationwide Scale up of Routine Malaria Rapid Diagnostic Testing in Zambia 
The National Malaria Control Center of Zambia introduced rapid diagnostic tests (RDTs) to detect Plasmodium falciparum as a pilot in some districts in 2005 and 2006; scale up at a national level was achieved in 2009. Data on RDT use, drug consumption, and diagnostic results were collected in three Zambian health districts to determine the impact RDTs had on malaria case management over the period 2004–2009. Reductions were seen in malaria diagnosis and antimalarial drug prescription (66.1 treatments per facility-month (95% confidence interval [CI] = 44.7–87.4) versus 26.6 treatments per facility-month (95% CI = 11.8–41.4)) pre- and post-RDT introduction. Results varied between districts, with significant reductions in low transmission areas but none in high areas. Rapid diagnostic tests may contribute to rationalization of treatment of febrile illness and reduce antimalarial drug consumption in Africa; however, their impact may be greater in lower transmission areas. National scale data will be necessary to confirm these findings.
doi:10.4269/ajtmh.2012.12-0127
PMCID: PMC3435345  PMID: 22848096
12.  Estimating Plasmodium falciparum Transmission Rates in Low-Endemic Settings Using a Combination of Community Prevalence and Health Facility Data 
PLoS ONE  2012;7(8):e42861.
As some malaria control programs shift focus from disease control to transmission reduction, there is a need for transmission data to monitor progress. At lower levels of transmission, it becomes increasingly more difficult to measure precisely, for example through entomological studies. Many programs conduct regular cross sectional parasite prevalence surveys, and have access to malaria treatment data routinely collected by ministries of health, often in health management information systems. However, by themselves, these data are poor measures of transmission. In this paper, we propose an approach for combining annual parasite incidence and treatment data with cross-sectional parasite prevalence and treatment seeking survey data to estimate the incidence of new infections in the human population, also known as the force of infection. The approach is based on extension of a reversible catalytic model. The accuracy of the estimates from this model appears to be highly dependent on levels of detectability and treatment in the community, indicating the importance of information on private sector treatment seeking and access to effective and appropriate treatment.
doi:10.1371/journal.pone.0042861
PMCID: PMC3425560  PMID: 22936995
13.  Production, active staining and gas chromatography assay analysis of recombinant aminopeptidase P from Lactococcus lactis ssp. lactis DSM 20481 
AMB Express  2012;2:39.
The aminopeptidase P (PepP, EC 3.4.11.9) gene from Lactococcus lactis ssp. lactis DSM 20481 was cloned, sequenced and expressed recombinantly in E. coli BL21 (DE3) for the first time. PepP is involved in the hydrolysis of proline-rich proteins and, thus, is important for the debittering of protein hydrolysates. For accurate determination of PepP activity, a novel gas chromatographic assay was established. The release of L-leucine during the hydrolysis of L-leucine-L-proline-L-proline (LPP) was examined for determination of PepP activity. Sufficient recombinant PepP production was achieved via bioreactor cultivation at 16 °C, resulting in PepP activity of 90 μkatLPP Lculture-1. After automated chromatographic purification by His-tag affinity chromatography followed by desalting, PepP activity of 73.8 μkatLPP Lculture-1 was achieved. This was approximately 700-fold higher compared to the purified native PepP produced by Lactococcus lactis ssp. lactis NCDO 763 as described in literature. The molecular weight of PepP was estimated to be ~ 40 kDa via native-PAGE together with a newly developed activity staining method and by SDS-PAGE. Furthermore, the kinetic parameters Km and Vmax were determined for PepP using three different tripeptide substrates. The purified enzyme showed a pH optimum between 7.0 and 7.5, was most active between 50°C and 60°C and exhibited reasonable stability at 0°C, 20°C and 37°C over 15 days. PepP activity could be increased 6-fold using 8.92 mM MnCl2 and was inhibited by 1,10-phenanthroline and EDTA.
doi:10.1186/2191-0855-2-39
PMCID: PMC3418211  PMID: 22853547
Lactococcus lactis; Aminopeptidase P; PepP; Gas chromatographic assay; Activity staining; LPP
14.  Household Possession and Use of Insecticide-Treated Mosquito Nets in Sierra Leone 6 Months after a National Mass-Distribution Campaign 
PLoS ONE  2012;7(5):e37927.
Background
In November 2010, Sierra Leone distributed over three million long-lasting insecticide-treated nets (LLINs) with the objective of providing protection from malaria to individuals in all households in the country.
Methods
We conducted a nationally representative survey six months after the mass distribution campaign to evaluate its impact on household insecticide-treated net (ITN) ownership and use. We examined factors associated with household ITN possession and use with logistic regression models.
Results
The survey included 4,620 households with equal representation in each of the 14 districts. Six months after the campaign, 87.6% of households own at least one ITN, which represents an increase of 137% over the most recent estimate of 37% in 2008. Thirty-six percent of households possess at least one ITN per two household members; rural households were more likely than urban households to have ≥1∶2 ITN to household members, but there was no difference by socio-economic status or household head education. Among individuals in households possessing ≥1 ITN, 76.5% slept under an ITN the night preceding the survey. Individuals in households where the household head had heard malaria messaging, had correct knowledge of malaria transmission, and where at least one ITN was hanging, were more likely to have slept under an ITN.
Conclusions
The mass distribution campaign was effective at achieving high coverage levels across the population, notably so among rural households where the malaria burden is higher. These important gains in equitable access to malaria prevention will need to be maintained to produce long-term reductions in the malaria burden.
doi:10.1371/journal.pone.0037927
PMCID: PMC3362537  PMID: 22666414
15.  Estimates of child deaths prevented from malaria prevention scale-up in Africa 2001-2010 
Malaria Journal  2012;11:93.
Background
Funding from external agencies for malaria control in Africa has increased dramatically over the past decade resulting in substantial increases in population coverage by effective malaria prevention interventions. This unprecedented effort to scale-up malaria interventions is likely improving child survival and will likely contribute to meeting Millennium Development Goal (MDG) 4 to reduce the < 5 mortality rate by two thirds between 1990 and 2015.
Methods
The Lives Saved Tool (LiST) model was used to quantify the likely impact that malaria prevention intervention scale-up has had on malaria mortality over the past decade (2001-2010) across 43 malaria endemic countries in sub-Saharan African. The likely impact of ITNs and malaria prevention interventions in pregnancy (intermittent preventive treatment [IPTp] and ITNs used during pregnancy) over this period was assessed.
Results
The LiST model conservatively estimates that malaria prevention intervention scale-up over the past decade has prevented 842,800 (uncertainty: 562,800-1,364,645) child deaths due to malaria across 43 malaria-endemic countries in Africa, compared to a baseline of the year 2000. Over the entire decade, this represents an 8.2% decrease in the number of malaria-caused child deaths that would have occurred over this period had malaria prevention coverage remained unchanged since 2000. The biggest impact occurred in 2010 with a 24.4% decrease in malaria-caused child deaths compared to what would have happened had malaria prevention interventions not been scaled-up beyond 2000 coverage levels. ITNs accounted for 99% of the lives saved.
Conclusions
The results suggest that funding for malaria prevention in Africa over the past decade has had a substantial impact on decreasing child deaths due to malaria. Rapidly achieving and then maintaining universal coverage of these interventions should be an urgent priority for malaria control programmes in the future. Successful scale-up in many African countries will likely contribute substantially to meeting MDG 4, as well as succeed in meeting MDG 6 (Target 1) to halt and reverse malaria incidence by 2015.
doi:10.1186/1475-2875-11-93
PMCID: PMC3350413  PMID: 22455864
16.  African Malaria Control Programs Deliver ITNs and Achieve What the Clinical Trials Predicted 
PLoS Medicine  2011;8(9):e1001088.
Thomas Eisele and Richard Steketee discuss new research in PLoS Medicine by Stephen Lim and colleagues that examined the association of insecticide-treated nets with the reduction of P. falciparum prevalence in children under 5 and all-cause post-neonatal mortality.
doi:10.1371/journal.pmed.1001088
PMCID: PMC3167796  PMID: 21909247
17.  Protective efficacy of malaria case management for preventing malaria mortality in children: a systematic review for the Lives Saved Tool 
BMC Public Health  2011;11(Suppl 3):S14.
Background
The Lives Saved Tool (LiST) model was developed to estimate the impact of the scale-up of child survival interventions on child mortality. New advances in antimalarials have improved their efficacy of treating uncomplicated and severe malaria. Artemisinin-based combination therapies (ACTs) for uncomplicated Plasmodium falciparum malaria and parenteral or rectal artemisinin or quinine for severe malaria syndromes have been shown to be very effective for the treatment of malaria in children. These interventions are now being considered for inclusion in the LiST model. However, for obvious ethical reasons, their protective efficacy (PE) compared to placebo is unknown and their impact on reducing malaria-attributable mortality has not been quantified.
Methods
We performed systematic literature reviews of published studies in P. falciparum endemic settings to determine the protective efficacy (PE) of ACT treatment against malaria deaths among children with uncomplicated malaria, as well as the PE of effective case management including parenteral quinine against malaria deaths among all hospitalized children. As no randomized placebo-controlled trials of malaria treatment have been conducted, we used multiple data sources to ascertain estimates of PE, including a previously performed Delphi estimate for treatment of uncomplicated malaria.
Results
Based on multiple data sources, we estimate the PE of ACT treatment of uncomplicated P. falciparum malaria on reducing malaria mortality in children 1–23 months to be 99% (range: 94-100%), and in children 24-59 months to be 97% (range: 86-99%). We estimate the PE of treatment of severe P. falciparum malaria with effective case management including intravenous quinine on reducing malaria mortality in children 1-59 months to be 82% (range: 63-94%) compared to no treatment.
Conclusions
This systematic review quantifies the PE of ACT used for treating uncomplicated malaria and effective case management including parenteral quinine for treating severe P. falciparum malaria for preventing malaria mortality in children <5. These data will be used in the Lives Saved Tool (LiST) model for estimating the impact of scaling-up these interventions against malaria. However, in order to estimate the reduction in child mortality due to scale-up of these interventions, it is imperative to develop standardized indicators to measure population coverage of these interventions.
doi:10.1186/1471-2458-11-S3-S14
PMCID: PMC3231887  PMID: 21501431
18.  Preventive zinc supplementation in developing countries: impact on mortality and morbidity due to diarrhea, pneumonia and malaria 
BMC Public Health  2011;11(Suppl 3):S23.
Background
Zinc deficiency is commonly prevalent in children in developing countries and plays a role in decreased immunity and increased risk of infection. Preventive zinc supplementation in healthy children can reduce mortality due to common causes like diarrhea, pneumonia and malaria. The main objective was to determine all-cause mortality and cause-specific mortality and morbidity in children under five in developing countries for preventive zinc supplementation.
Data sources/ review methods
A literature search was carried out on PubMed, the Cochrane Library and the WHO regional databases to identify RCTs on zinc supplementation for greater than 3 months in children less than 5 years of age in developing countries and its effect on mortality was analyzed.
Results
The effect of preventive zinc supplementation on mortality was given in eight trials, while cause specific mortality data was given in five of these eight trials. Zinc supplementation alone was associated with a statistically insignificant 9% (RR = 0.91; 95% CI: 0.82, 1.01) reduction in all cause mortality in the intervention group as compared to controls using a random effect model. The impact on diarrhea-specific mortality of zinc alone was a non-significant 18% reduction (RR = 0.82; 95% CI: 0.64, 1.05) and 15% for pneumonia-specific mortality (RR = 0.85; 95% CI: 0.65, 1.11). The incidence of diarrhea showed a 13% reduction with preventive zinc supplementation (RR = 0.87; 95% CI: 0.81, 0.94) and a 19% reduction in pneumonia morbidity (RR = 0.81; 95% CI: 0.73, 0.90). Keeping in mind the direction of effect of zinc supplementation in reducing diarrhea and pneumonia related morbidity and mortality; we considered all the outcomes for selection of effectiveness estimate for inclusion in the LiST model. After application of the CHERG rules with consideration to quality of evidence and rule # 6, we used the most conservative estimates as a surrogate for mortality. We, therefore, conclude that zinc supplementation in children is associated with a reduction in diarrhea mortality of 13% and pneumonia mortality of 15% for inclusion in the LiST tool. Preventive zinc supplementation had no effect on malaria specific mortality (RR = 0.90; 95% CI: 0.77, 1.06) or incidence of malaria (RR=0.92; 95 % CI 0.82-1.04)
Conclusion
Zinc supplementation results in reductions in diarrhea and pneumonia mortality.
doi:10.1186/1471-2458-11-S3-S23
PMCID: PMC3231897  PMID: 21501441
19.  Effectiveness of interventions to screen and manage infections during pregnancy on reducing stillbirths: a review 
BMC Public Health  2011;11(Suppl 3):S3.
Background
Infection is a well acknowledged cause of stillbirths and may account for about half of all perinatal deaths today, especially in developing countries. This review presents the impact of interventions targeting various important infections during pregnancy on stillbirth or perinatal mortality.
Methods
We undertook a systematic review including all relevant literature on interventions dealing with infections during pregnancy for assessment of effects on stillbirths or perinatal mortality. The quality of the evidence was assessed using the adapted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach by Child Health Epidemiology Reference Group (CHERG). For the outcome of interest, namely stillbirth, we applied the rules developed by CHERG to recommend a final estimate for reduction in stillbirth for input to the Lives Saved Tool (LiST) model.
Results
A total of 25 studies were included in the review. A random-effects meta-analysis of observational studies of detection and treatment of syphilis during pregnancy showed a significant 80% reduction in stillbirths [Relative risk (RR) = 0.20; 95% confidence interval (CI): 0.12 - 0.34) that is recommended for inclusion in the LiST model. Our meta-analysis showed the malaria prevention interventions i.e. intermittent preventive treatment (IPTp) and insecticide-treated mosquito nets (ITNs) can reduce stillbirths by 22%, however results were not statistically significant (RR = 0.78; 95% CI: 0.59 – 1.03). For human immunodeficiency virus infection, a pooled analysis of 6 radomized controlled trials (RCTs) failed to show a statistically significant reduction in stillbirth with the use of antiretroviral in pregnancy compared to placebo (RR = 0.93; 95% CI: 0.45 – 1.92). Similarly, pooled analysis combining four studies for the treatment of bacterial vaginosis (3 for oral and 1 for vaginal antibiotic) failed to yield a significant impact on perinatal mortality (OR = 0.88; 95% CI: 0.50 – 1.55).
Conclusions
The clearest evidence of impact in stillbirth reduction was found for adequate prevention and treatment of syphilis infection and possibly malaria. At present, large gaps exist in the growing list of stillbirth risk factors, especially those that are infection related. Potential causes of stillbirths including HIV and TORCH infections need to be investigated further to help establish the role of prevention/treatment and its subsequent impact on stillbirth reduction.
doi:10.1186/1471-2458-11-S3-S3
PMCID: PMC3231903  PMID: 21501448
20.  Comparison of Lives Saved Tool model child mortality estimates against measured data from vector control studies in sub-Saharan Africa 
BMC Public Health  2011;11(Suppl 3):S34.
Background
Insecticide-treated mosquito nets (ITNs) and indoor-residual spraying have been scaled-up across sub-Saharan Africa as part of international efforts to control malaria. These interventions have the potential to significantly impact child survival. The Lives Saved Tool (LiST) was developed to provide national and regional estimates of cause-specific mortality based on the extent of intervention coverage scale-up. We compared the percent reduction in all-cause child mortality estimated by LiST against measured reductions in all-cause child mortality from studies assessing the impact of vector control interventions in Africa.
Methods
We performed a literature search for appropriate studies and compared reductions in all-cause child mortality estimated by LiST to 4 studies that estimated changes in all-cause child mortality following the scale-up of vector control interventions. The following key parameters measured by each study were applied to available country projections: baseline all-cause child mortality rate, proportion of mortality due to malaria, and population coverage of vector control interventions at baseline and follow-up years.
Results
The percent reduction in all-cause child mortality estimated by the LiST model fell within the confidence intervals around the measured mortality reductions for all 4 studies. Two of the LiST estimates overestimated the mortality reductions by 6.1 and 4.2 percentage points (33% and 35% relative to the measured estimates), while two underestimated the mortality reductions by 4.7 and 6.2 percentage points (22% and 25% relative to the measured estimates).
Conclusions
The LiST model did not systematically under- or overestimate the impact of ITNs on all-cause child mortality. These results show the LiST model to perform reasonably well at estimating the effect of vector control scale-up on child mortality when compared against measured data from studies across a range of malaria transmission settings. The LiST model appears to be a useful tool in estimating the potential mortality reduction achieved from scaling-up malaria control interventions.
doi:10.1186/1471-2458-11-S3-S34
PMCID: PMC3231908  PMID: 21501453
21.  Claims about the Misuse of Insecticide-Treated Mosquito Nets: Are These Evidence-Based? 
PLoS Medicine  2011;8(4):e1001019.
Thomas Eisele and colleagues dispute reports in the media and elsewhere that insecticide-treated nets are not widely used, or are misused, and say that such misconceptions are not evidence-based and are damaging to malaria control efforts.
doi:10.1371/journal.pmed.1001019
PMCID: PMC3075220  PMID: 21532734
22.  Malaria Infection and Anemia Prevalence in Zambia's Luangwa District: An Area of Near-Universal Insecticide-Treated Mosquito Net Coverage 
We examined the relationship between insecticide-treated mosquito nets (ITNs), malaria parasite infection, and severe anemia prevalence in children in Luangwa District, Zambia, an area with near-universal ITN coverage, at the end of the 2008 and 2010 malaria transmission seasons. Malaria parasite infection prevalence among children < 5 years old was 9.7% (95% confidence interval [CI] = 8.0–11.4%) over both survey years. Prevalence of severe anemia among children 6–59 months old was 6.9% (95% CI = 5.4–8.5%) over both survey years. Within this context of near-universal ITN coverage, we were unable to detect a significant association between malaria parasite or severe anemia prevalence and ITNs (possession and use). In addition to maintaining universal ITN coverage, it will be essential for the malaria control program to achieve high ITN use and laboratory diagnosis and treatment of all fevers among all age groups to further reduce the malaria burden in this area.
doi:10.4269/ajtmh.2011.10-0287
PMCID: PMC3005497  PMID: 21212219
23.  Barriers to Insecticide-Treated Mosquito Net Possession 2 Years after a Mass Free Distribution Campaign in Luangwa District, Zambia 
PLoS ONE  2010;5(11):e13129.
Background and Methods
Roll Back Malaria set the goal of 100% of households in malaria endemic countries in Africa owning an insecticide-treated mosquito net (ITN) by 2010. Zambia has used mass free distribution campaigns and distribution through antenatal care (ANC) clinics to achieve high coverage.
Methodology and Principal Findings
We conducted a probability survey of 801 households in 2008 to assess factors associated with households that lacked an ITN after mass distribution. Community perceptions of barriers to ITN access were also obtained from in-depth interviews with household heads that reported not owning an ITN. Nearly 74% of households in Luangwa district reported owning ≥1 ITN. Logistic regression showed households without a child <5 years old during the ITN distribution campaigns were twice as likely to not have an ITN as those with a child <5 during distribution (Adjusted odds ratio (AOR)  = 2.43; 95% confidence interval (CI): 1.67–3.55). Households without a woman who attended an ANC in the past 2 years were more likely to be without ITNs compared to households with a woman who attended an ANC in the past 2 years (AOR  = 1.52; 95% CI: 1.04–2.21). In-depth interviews with heads of households without an ITN revealed that old age was a perceived barrier to receiving an ITN during distribution, and that ITNs wore out before they could be replaced.
Conclusions and Significance
Delivery of a large number of ITNs does not translate directly into 100% household coverage. Due to their design, current ITN distribution strategies may miss households occupied by the elderly and those without children or ANC access. ITN distribution strategies targeting the elderly, those with limited access to distribution points, and others most likely to be missed are necessary if 100% ITN coverage of households is to be achieved.
doi:10.1371/journal.pone.0013129
PMCID: PMC2978084  PMID: 21085711
24.  Protective efficacy of interventions for preventing malaria mortality in children in Plasmodium falciparum endemic areas 
International Journal of Epidemiology  2010;39(Suppl 1):i88-i101.
Background Insecticide-treated mosquito nets (ITNs) and indoor-residual spraying (IRS) are recommended strategies for preventing malaria in children. While their impact on all-cause child mortality is well documented, their impact on reducing malaria-attributable mortality has not been quantified. While the impact of intermittent preventive therapy in pregnant women (IPTp) and ITNs in pregnancy for improving birth outcomes is also well established, their impact on preventing neonatal or child mortality has not been quantified.
Methods We performed two systematic literature reviews in Plasmodium falciparum endemic settings; one to estimate the effect of ITNs and IRS on preventing malaria-attributable mortality in children 1–59 months, and another to estimate the effect of ITNs and IPTp on preventing neonatal and child mortality through improvements in birth outcomes.
Results We estimate the protective efficacy (PE) of ITNs and IRS on reducing malaria-attributable mortality 1–59 months to be 55%, with a range of 49–61%, in P. falciparum settings. We estimate malaria prevention interventions in pregnancy (IPTp and ITNs) to have a pooled PE of 35% (95% confidence interval: 23–45%) on reducing the prevalence of low birth weight (LBW) in the first or second pregnancy in areas of stable P. falciparum transmission.
Conclusion This systematic review quantifies the PE of ITNs for reducing malaria-attributable mortality in children, and the PE of IPTp and ITNs during pregnancy for reducing LBW. It is assumed the impact of IRS is equal to that of ITNs on reducing malaria-attributable mortality in children. These data will be used in the Lives Saved Tool (LiST) model for estimating the impact of malaria prevention interventions. These data support the continued scale-up of these malaria prevention interventions in endemic settings that will prevent a considerable number of child deaths due directly and indirectly to malaria.
doi:10.1093/ije/dyq026
PMCID: PMC2845865  PMID: 20348132
Systematic review; malaria prevention; child mortality; insecticide-treated mosquito nets; indoor-residual spraying; intermittent preventive therapy in pregnant women
25.  Is the Scale Up of Malaria Intervention Coverage Also Achieving Equity? 
PLoS ONE  2009;4(12):e8409.
Background and Methods
Malaria in Africa is most severe in young children and pregnant women, particularly in rural and poor households. In many countries, malaria intervention coverage rates have increased as a result of scale up; but this may mask limited coverage in these highest-risk populations. Reports were reviewed from nationally representative surveys in African malaria-endemic countries from 2006 through 2008 to understand how reported intervention coverage rates reflect access by the most at-risk populations.
Results
Reports were available from 27 Demographic and Health Surveys (DHSs), Multiple Indicator Cluster Surveys (MICSs), and Malaria Indicator Surveys (MISs) during this interval with data on household intervention coverage by urban or rural setting, wealth quintile, and sex. Household ownership of insecticide-treated mosquito nets (ITNs) varied from 5% to greater than 60%, and was equitable by urban/rural and wealth quintile status among 13 (52%) of 25 countries. Malaria treatment rates for febrile children under five years of age varied from less than 10% to greater than 70%, and while equitable coverage was achieved in 8 (30%) of 27 countries, rates were generally higher in urban and richest quintile households. Use of intermittent preventive treatment in pregnant women varied from 2% to more than 60%, and again tended to be higher in urban and richest quintile households. Across all countries, there were no significant male/female inequalities seen for children sleeping under ITNs or receiving antimalarial treatment for febrile illness. Parasitemia and anemia rates from eight national surveys showed predominance in poor and rural populations.
Conclusions/Significance
Recent efforts to scale up malaria intervention coverage have achieved equity in some countries (especially with ITNs), but delivery methods in other countries are not addressing the most at-risk populations. As countries seek universal malaria intervention coverage, their delivery systems must reach the rural and poor populations; this is not a small task, but it has been achieved in some countries.
doi:10.1371/journal.pone.0008409
PMCID: PMC2791860  PMID: 20027289

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