From efficacy to effectiveness: a comprehensive framework for monitoring, evaluating and optimizing seasonal malaria chemoprevention programmes.

BACKGROUND: Seasonal Malaria Chemoprevention (SMC) is a highly effective intervention for preventing malaria, particularly in areas with highly seasonal transmission. Monitoring and evaluating (M&E) SMC programmes are complex due to the scale, time-sensitive delivery of the programme, and influence of external factors. This paper describes the process followed to develop a comprehensive M&E framework tailored specifically for the SMC context. METHODS: The Framework was developed through a literature and programme review, and stakeholder dialogues across three implementing countries-Burkina Faso, Chad, and Nigeria. Expert consultation further refined the Framework through an iterative approach drawing upon data collected through the three sources. The Framework was designed using the Logical Framework Approach incorporating external factors and intentionally aligned with global malaria M&E standards. RESULTS: An overall aim and seven programme objectives were developed measured by 70 indicators. The indicators also capture the causal links between the implementation and results of the programme. The Framework leverages the use of current data sources and existing mechanisms, ensuring efficient data use without requiring a significant increase in resources for overall programme optimization. It also promotes the use of data triangulation, and stratification for a more nuanced understanding of factors affecting programme performance and timely data informed decision-making. CONCLUSIONS: The SMC M&E Framework presented here provides a standardized approach for programme implementers to enhance decision-making for optimal programme performance. This is an essential tool as the scope of SMC programmes expands to new geographies and target age groups.

Eliminating Plasmodium falciparum malaria: results from tailoring active case detection approaches to remote populations in forested border areas in north-eastern Cambodia.

BACKGROUND: Remaining Plasmodium falciparum cases in Cambodia are concentrated in forested border areas and in remote populations who are hard to reach through passive case detection. A key approach to reach these populations is active case detection by mobile malaria workers (MMWs). However, this is operationally challenging because of changing movement patterns of the target population moving into less accessible areas. From January 2018 to December 2020, a tailored package of active case detection approaches was implemented in forested border areas of three provinces in north-eastern Cambodia to reach remote populations and support the elimination of falciparum malaria. METHODS: Key elements of this project were to tailor approaches to local populations, use responsive monitoring systems, maintain operational flexibility, build strong relationships with local communities, and implement close supervision practices. MMWs were recruited from local communities. Proactive case detection approaches included mobile malaria posts positioned at frequented locations around and within forests, and locally informed outreach activities targeting more remote locations. Reactive case detection was conducted among co-travellers of confirmed cases. Testing for malaria was conducted independent of fever symptoms. Routine monitoring of programmatic data informed tactical adaptations, while supervision exercises ensured service quality. RESULTS: Despite operational challenges, service delivery sites were able to maintain consistently high testing rates throughout the implementation period, with each of 45 sites testing a monthly average of 64 (SD 6) people in 2020. In 2020, project MMWs detected only 32 P. falciparum cases. Over the project period, the P. falciparum/P. vivax ratio steadily inversed. Including data from neighbouring health centres and village malaria workers, 45% (80,988/180,732) of all people tested and 39% (1280/3243) of P. falciparum cases detected in the area can be attributed to project MMWs. Remaining challenges of the last elimination phase include maintaining intensified elimination efforts, addressing the issue of detecting low parasitaemia cases and shifting focus to P. vivax malaria. CONCLUSIONS: Reaching remote populations through active case detection should remain a key strategy to eliminate P. falciparum malaria. This case study presented a successful approach combining tailored proactive and reactive strategies that could be transferred to similar settings in other areas of the Greater Mekong Subregion.

Development of weight and age-based dosing of daily primaquine for radical cure of vivax malaria.

BACKGROUND: In many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients of all ages. However, for many anti-malarial drugs, including primaquine, there is evidence that children have lower exposures than adults for the same weight-adjusted dose. The aim of the study was to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax. METHODS: The recommended adult target dose of 0.5 mg/kg/day (30 mg in a 60 kg patient) is highly efficacious against tropical P. vivax and was assumed to produce optimal drug exposure. Primaquine doses were calculated using allometric scaling to derive a weight-based primaquine regimen over a weight range from 5 to 100 kg. Growth curves were constructed from an anthropometric database of 53,467 individuals from the Greater Mekong Subregion (GMS) to define weight-for-age relationships. The median age associated with each weight was used to derive an age-based dosing regimen from the weight-based regimen. RESULTS: The proposed weight-based regimen has 5 dosing bands: (i) 5-7 kg, 5 mg, resulting in 0.71-1.0 mg/kg/day; (ii) 8-16 kg, 7.5 mg, 0.47-0.94 mg/kg/day; (iii) 17-40 kg, 15 mg, 0.38-0.88 mg/kg/day; (iv) 41-80 kg, 30 mg, 0.37-0.73 mg/kg/day; and (v) 81-100 kg, 45 mg, 0.45-0.56 mg/kg/day. The corresponding age-based regimen had 4 dosing bands: 6-11 months, 5 mg, 0.43-1.0 mg/kg/day; (ii) 1-5 years, 7.5 mg, 0.35-1.25 mg/kg/day; (iii) 6-14 years, 15 mg, 0.30-1.36 mg/kg/day; and (iv) ≥ 15 years, 30 mg, 0.35-1.07 mg/kg/day. CONCLUSION: The proposed weight-based regimen showed less variability around the primaquine dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands for both regimens. The age-based regimen might not be applicable to regions outside the GMS, which must be based on local anthropometric data. Pharmacokinetic data in small children are needed urgently to inform the proposed regimens.

Correction: Quantification of glucose-6-phosphate dehydrogenase activity by spectrophotometry: A systematic review and meta-analysis.

[This corrects the article DOI: 10.1371/journal.pmed.1003084.].

Quantification of glucose-6-phosphate dehydrogenase activity by spectrophotometry: A systematic review and meta-analysis.

BACKGROUND: The radical cure of Plasmodium vivax and P. ovale requires treatment with primaquine or tafenoquine to clear dormant liver stages. Either drug can induce haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, necessitating screening. The reference diagnostic method for G6PD activity is ultraviolet (UV) spectrophotometry; however, a universal G6PD activity threshold above which these drugs can be safely administered is not yet defined. Our study aimed to quantify assay-based variation in G6PD spectrophotometry and to explore the diagnostic implications of applying a universal threshold. METHODS AND FINDINGS: Individual-level data were pooled from studies that used G6PD spectrophotometry. Studies were identified via PubMed search (25 April 2018) and unpublished contributions from contacted authors (PROSPERO: CRD42019121414). Studies were excluded if they assessed only individuals with known haematological conditions, were family studies, or had insufficient details. Studies of malaria patients were included but analysed separately. Included studies were assessed for risk of bias using an adapted form of the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Repeatability and intra- and interlaboratory variability in G6PD activity measurements were compared between studies and pooled across the dataset. A universal threshold for G6PD deficiency was derived, and its diagnostic performance was compared to site-specific thresholds. Study participants (n = 15,811) were aged between 0 and 86 years, and 44.4% (7,083) were women. Median (range) activity of G6PD normal (G6PDn) control samples was 10.0 U/g Hb (6.3-14.0) for the Trinity assay and 8.3 U/g Hb (6.8-15.6) for the Randox assay. G6PD activity distributions varied significantly between studies. For the 13 studies that used the Trinity assay, the adjusted male median (AMM; a standardised metric of 100% G6PD activity) varied from 5.7 to 12.6 U/g Hb (p < 0.001). Assay precision varied between laboratories, as assessed by variance in control measurements (from 0.1 to 1.5 U/g Hb; p < 0.001) and study-wise mean coefficient of variation (CV) of replicate measures (from 1.6% to 14.9%; p < 0.001). A universal threshold of 100% G6PD activity was defined as 9.4 U/g Hb, yielding diagnostic thresholds of 6.6 U/g Hb (70% activity) and 2.8 U/g Hb (30% activity). These thresholds diagnosed individuals with less than 30% G6PD activity with study-wise sensitivity from 89% (95% CI: 81%-94%) to 100% (95% CI: 96%-100%) and specificity from 96% (95% CI: 89%-99%) to 100% (100%-100%). However, when considering intermediate deficiency (<70% G6PD activity), sensitivity fell to a minimum of 64% (95% CI: 52%-75%) and specificity to 35% (95% CI: 24%-46%). Our ability to identify underlying factors associated with study-level heterogeneity was limited by the lack of availability of covariate data and diverse study contexts and methodologies. CONCLUSIONS: Our findings indicate that there is substantial variation in G6PD measurements by spectrophotometry between sites. This is likely due to variability in laboratory methods, with possible contribution of unmeasured population factors. While an assay-specific, universal quantitative threshold offers robust diagnosis at the 30% level, inter-study variability impedes performance of universal thresholds at the 70% level. Caution is advised in comparing findings based on absolute G6PD activity measurements across studies. Novel handheld quantitative G6PD diagnostics may allow greater standardisation in the future.

The tolerability of single low dose primaquine in glucose-6-phosphate deficient and normal falciparum-infected Cambodians.

BACKGROUND: The WHO recommends single low-dose primaquine (SLDPQ, 0.25 mg/kg body weight) in falciparum-infected patients to block malaria transmission and contribute to eliminating multidrug resistant Plasmodium falciparum from the Greater Mekong Sub region (GMS). However, the anxiety regarding PQ-induced acute haemolytic anaemia in glucose-6-phosphate dehydrogenase deficiency (G6PDd) has hindered its use. Therefore, we assessed the tolerability of SLDPQ in Cambodia to inform national policy. METHODS: This open randomised trial of dihydroartemisinin-piperaquine (DHAPP) + SLDPQ vs. DHAPP alone recruited Cambodians aged ≥1 year with acute uncomplicated P. falciparum. Randomisation was 4:1 DHAPP+SLDPQ: DHAPP for G6PDd patients and 1:1 for G6PDn patients, according to the results of the qualitative fluorescent spot test. Definitive G6PD status was determined by genotyping. Day (D) 7 haemoglobin (Hb) concentration was the primary outcome measure. RESULTS: One hundred nine patients (88 males, 21 females), aged 4-76 years (median 23) were enrolled; 12 were G6PDd Viangchan (9 hemizygous males, 3 heterozygous females). Mean nadir Hb occurred on D7 [11.6 (range 6.4 ─ 15.6) g/dL] and was significantly lower (p = 0.040) in G6PDd (n = 9) vs. G6PDn (n = 46) DHAPP+SLDPQ recipients: 10.9 vs. 12.05 g/dL, Δ = -1.15 (95% CI: -2.24 ─ -0.05) g/dL. Three G6PDn patients had D7 Hb concentrations < 8 g/dL; D7-D0 Hbs were 6.4 ─ 6.9, 7.4 ─ 7.4, and 7.5 ─ 8.2 g/dL. For all patients, mean (range) D7-D0 Hb decline was -1.45 (-4.8 ─ 2.4) g/dL, associated significantly with higher D0 Hb, higher D0 parasitaemia, and receiving DHAPP; G6PDd was not a factor. No patient required a blood transfusion. CONCLUSIONS: DHAPP+SLDPQ was associated with modest Hb declines in G6PD Viangchan, a moderately severe variant. Our data augment growing evidence that SLDPQ in SE Asia is well tolerated and appears safe in G6PDd patients. Cambodia is now deploying SLDPQ and this should encourage other GMS countries to follow suit. TRIAL REGISTRATION: The clinicaltrials.gov reference number is NCT02434952 .

Acceptability of insecticide-treated clothing for malaria prevention among migrant rubber tappers in Myanmar: a cluster-randomized non-inferiority crossover trial.

BACKGROUND: Insecticide-treated clothing (ITC) has long been used for military and outdoor recreational purposes and there is substantial evidence to show that it can protect against arthropod biting. As a complementary vector control measure, ITC could be used to address outdoor transmission of malaria, particularly among mobile and migrant populations and night-time workers such as rubber tappers, who may be beyond the reach of core interventions. However, more information is required on acceptability and preferences of target groups towards ITC to understand whether it could be a viable strategy in Myanmar. METHODS: A cluster-randomized, double-blind, non-inferiority crossover trial was performed to determine acceptability of ITC versus identical, untreated clothing (NTC) among migrant rubber tappers. The study took place between January and May 2015 with 234 participants in 16 clusters in Thanbyuzayat Township, Mon State, Myanmar. Participants were randomly assigned to the order of clothing distribution and followed up at 2, 4 and 6 week intervals. Acceptability was assessed through structured questionnaires, focus group discussions and in-depth interviews. A cluster-level non-inferiority analysis was conducted using STATA, while qualitative data were digitally recorded, transcribed and content-analysed to identify patterns and themes, and managed thematically in Excel 2010®. RESULTS: Acceptability of both types of clothing was high. ITC was deduced to be non-inferior to NTC for seven out of eight indicators regarding perceptions (looks nice, is durable, is pleasant to wear for nighttime work, reduces mosquito bites, would recommend the clothing, would buy the clothing, like the clothing overall). A high proportion of respondents reported that the clothing reduced mosquito bites (ITC-98%; NTC-94%). Clothing was worn regularly (about 11 times in the previous two weeks). The most common reasons for not wearing the clothing every night were that it was being washed or dried, or the participant did not go to work. CONCLUSIONS: The high level of acceptability suggests that ITC could be an appropriate strategy for personal protection amongst migrant rubber tappers in outdoor transmission settings in Myanmar. However, more research is needed into the feasibility and protective efficacy of ITC before it can be considered for wider roll-out. Trial registration Clinical trials ACTRN12615000432516.

Positive deviance as a novel tool in malaria control and elimination: methodology, qualitative assessment and future potential.

BACKGROUND: Positive deviance (PD) is an asset-based, community-driven approach to behaviour change that has successfully been applied to address many health and social problems. It is yet to have been assessed for malaria control but may represent a promising tool for malaria elimination given its suitability in targeting small and remote population groups, apparent sustainability and ability to instil a high amount of community mobilisation. Here, the PD methodology as applied to malaria is explained, with focus upon and qualitative assessment of a proof of concept study in Cambodia. METHODS: Three villages in Battambang, northwestern Cambodia were selected for the intervention, with an estimated population of 5036 including both residents and migrant workers. In August 2010, field teams conducted a 1 week PD process to sensitise and mobilise the community, establish normative behaviours in relation to malaria control and prevention, identify positive deviant behaviours from within the community, and identify PD volunteers. Until March 2011, PD volunteers were supported by field teams via monthly meetings to conduct activities in their respective communities to increase practice of PD behaviours. In February 2012, 1 year following the end of external support, evaluative interviews were conducted with community members to qualitatively assess community acceptance and interpretation of the PD intervention, perceived behaviour changes, and perceived positive outcomes. RESULTS: Qualitative data from focus group discussions and in-depth interviews showed that the PD approach was well-accepted into the communities and created a strong sense of community empowerment. Positive behaviour change was linked to the PD intervention, including greater usage of nets by forest goers, and use of public health facilities for malaria diagnosis and treatment. One year following the end of external assistance, PD volunteers were still conducting activities in their respective communities. CONCLUSIONS: PD offers a promising tool in malaria control and elimination settings. Work is ongoing to quantitatively measure impact of PD on behaviours and malaria transmission and once gathered, national malaria control programmes should be encouraged to look at including PD as part of their national strategies. Feasibility of scale-up, cost-effectiveness, and applicability to other settings and diseases is also currently being explored.

Evaluation of intensified behaviour change communication strategies in an artemisinin resistance setting.

BACKGROUND: In Cambodia, behaviour change communication (BCC) represents an integral component of malaria efforts aimed at fighting artemisinin resistant parasites and achieving elimination. The multi-pronged BCC interventions include interpersonal communication through village health volunteers (VHVs) and village malaria workers (VMWs), broadcasting malaria prevention, diagnosis and treatment messages via TV, radio and mobile broadcasting units (MBUs), distributing information education and communication (IEC) materials and introducing mobile malaria workers (MMWs) in endemic villages. METHODS: This was a cross sectional household survey using a stratified multi-stage cluster sampling approach, conducted in December 2012. A stratified multi-stage cluster sampling approach was used; 30 villages were selected (15 in each stratum) and a total of 774 households were interviewed. This survey aimed to assess the potential added effect of 'intense' BCC interventions in three Western provinces. Conducted 2 years after start of these efforts, 'non-intense' BCC (niBBC) interventions (e.g., radio or TV) were compared to "intense" BCC (iBBC) implemented through a set of interpersonal communication strategies such as VMWs, VHVs, mobile broadcasting units and listener viewer clubs. RESULTS: In both groups, the knowledge of the mode of malaria transmission was high (96.9 vs 97.2 %; p = 0.83), as well as of fever as a symptom (91.5 vs 93.5 %; p = 0.38). Knowledge of local risk factors, such as staying in the forest (39.7 vs 30.7 %; p = 0.17) or the farm (7.1 vs 5.1 %; p = 0.40) was low in both groups. Few respondents in either group knew that they must get tested if they suspected malaria (0.3 vs 0.1; p = 0.69). However, iBBC increased the discussions about malaria in the family (51.7 vs 35.8 %; p = 0.002) and reported prompt access to treatment in case of fever (77.1 vs 59.4 %; p < 0.01). CONCLUSION: The use of iBCC supported positive improvements in both attitudes and behaviours among the population with regard to malaria compared to mass media (niBCC) only. The significantly increase in people seeking treatment for fever in iBCC villages supports Objective Five of the Strategic Plan in the Cambodia Malaria Elimination Action Framework (2016-2020). Therefore, this study provides evidence for the planning and implementation of future BCC interventions to achieve the elimination of artemisinin resistant Plasmodium falciparum malaria.

Reactive case-detection of malaria in Pailin Province, Western Cambodia: lessons from a year-long evaluation in a pre-elimination setting.

BACKGROUND: As momentum towards malaria elimination grows, strategies are being developed for scale-up in elimination settings. One prominent strategy, reactive case detection (RACD), involves screening and treating individuals living in close proximity to passively detected, or "index" cases. This study aims to use RACD to quantify Plasmodium parasitaemia in households of index cases, and identify risk factors for infection; these data could inform reactive screening approaches and identify target risk groups. METHODS: This study was conducted in the Western Cambodian province of Pailin between May 2013 and March 2014 among 440 households. Index participants/index cases (n = 270) and surrounding households (n = 110) were screened for Plasmodium infection with rapid diagnostic tests (RDT), microscopy and real-time polymerase chain reaction (PCR). Participants were interviewed to identify risk factors. A comparison group of 60 randomly-selected households was also screened, to compare infection levels of RACD and non-RACD households. In order to identify potential risk factors that would inform screening approaches and identify risk groups, multivariate logistic regression models were applied. RESULTS: Nine infections were identified in households of index cases (RACD approach) through RDT screening of 1898 individuals (seven Plasmodium vivax, two Plasmodium falciparum); seven were afebrile. Seventeen infections were identified through PCR screening of 1596 individuals (15 P. vivax, and 22 % P. falciparum/P. vivax mixed infections). In the control group, 25 P. falciparum infections were identified through PCR screening of 237 individuals, and no P. vivax was found. Plasmodium falciparum infection was associated with fever (p = 0.013), being a member of a control household (p ≤ 0.001), having a history of malaria infection (p = 0.041), and sleeping without a mosquito net (p = 0.011). Significant predictors of P. vivax infection, as diagnosed by PCR, were fever (p = 0.058, borderline significant) and history of malaria infection (p ≤ 0.001). CONCLUSION: This study found that RACD identified very few secondary infections when targeting index and neighbouring households for screening. The results suggest RACD is not appropriate, where exposure to malaria occurs away from the community, and there is a high level of treatment-seeking from the private sector. Piloting RACD in a range of transmission settings would help to identify the ideal environment for feasible and effective reactive screening methods.

Malaria and the mobile and migrant population in Cambodia: a population movement framework to inform strategies for malaria control and elimination.

BACKGROUND: The relationships between human population movement (HPM) and health are a concern at global level. In the case of malaria, those links are crucial in relation to the spread of drug resistant parasites and to the elimination of malaria in the Greater Mekong sub-Region (GMS) and beyond. The mobile and migrant populations (MMP) who are involved in forest related activities are both at high risk of being infected with malaria and at risk of receiving late and sub-standard treatment due to poor access to health services. In Cambodia, in 2012, the National Malaria Control Programme (NMCP) identified, as a key objective, the development of a specific strategy for MMPs in order to address these challenges. A population movement framework (PMF) for malaria was developed and operationalized in order to contribute to this strategy. METHODS: A review of the published and unpublished literature was conducted. Based on a synthesis of the results, information was presented and discussed with experienced researchers and programme managers in the Cambodian NMCP and led to the development and refinement of a PMF for malaria. The framework was "tested" for face and content validity with national experts through a workshop approach. RESULTS: In the literature, HPM has been described using various spatial and temporal dimensions both in the context of the spread of anti-malarial drug resistance, and in the context of malaria elimination and previous classifications have categorized MMPs in Cambodia and the GMS through using a number of different criteria. Building on these previous models, the PMF was developed and then refined and populated with in-depth information relevant to Cambodia collected from social science research and field experiences in Cambodia. The framework comprises of the PMF itself, MMP activity profiles and a Malaria Risk Index which is a summation of three related indices: a vulnerability index, an exposure index and an access index which allow a qualitative ranking of malaria risk in the MMP population. Application of currently available data to the framework illustrates that the highest risk population are those highly mobile populations engaged in forest work. CONCLUSION: This paper describes the process of defining MMPs in Cambodia, identifying the different activities and related risks to appropriately target and tailor interventions to the highest risk groups. The framework has been used to develop more targeted behaviour change and outreach interventions for MMPs in Cambodia and its utility and effectiveness will be evaluated as part of those interventions.

Novel approaches to risk stratification to support malaria elimination: an example from Cambodia.

BACKGROUND: Accurate malaria stratification is essential for effective targeting of interventions but represents a particular challenge in pre-elimination settings. In these settings transmission is typically sufficiently low and spatially heterogeneous to warrant a need for estimates of malaria risk at sub-district or village level but is also likely to be sufficiently high to render the type of decision support systems appropriate to the final stages of malaria elimination impractical. In such a scenario it is arguably more feasible to strengthen existing passive malaria surveillance systems so that routinely generated case data can provide an effective basis for stratifying malaria risk. This paper explores the utility of routine malaria surveillance data for the stratification of malaria risk in Cambodia, where the target is malaria elimination by 2025. METHODS: A malaria information system (MIS) was developed to generate timely, routine data on temporal and spatial variations in malaria cases reported through public health facilities and village malaria workers (VMWs). The MIS was implemented across all malaria endemic districts in the country during 2010-11. In 2012 MIS data were extracted and assessed on the basis of coverage and completeness. Village-level incidence estimates for 2011 were generated using predefined data inclusion criteria. RESULTS: In 2011, the MIS covered 681 health facilities and 1,489 VMW villages; the overall completeness of monthly reporting was 82& and 97& for health facilities and VMWs respectively. Using these data it was possible to estimate malaria incidence for 89& of villages covered by the MIS. The resulting stratification highlights the highly heterogeneous nature of malaria transmission in Cambodia and underlines the importance of village-level data for effective targeting of interventions, including VMWs. Challenges associated with implementing the MIS and the implications of these for developing viable and sustainable MIS in Cambodia and elsewhere are discussed. CONCLUSIONS: This study demonstrates the operational feasibility of introducing a system to routinely generate village level malaria case data in Cambodia. Although resulting incidence estimates are subject to various limitations and biases the data provide an objective, repeatable basis for a dynamic system of stratification which is appropriate for guiding the transition between malaria pre-elimination and elimination phases.

Improving the Quality and Use of Malaria Surveillance Data: Results from Evaluating an Integrated Malaria Information Storage System at the Health Facility Level in Selected Districts in Mozambique.

Mozambique addressed critical malaria surveillance system challenges by rolling out an integrated malaria information storage system (iMISS) at the district level in February 2021. The iMISS integrates malaria data from existing systems across thematic program areas to improve data availability and use. In seven districts, the platform was extended to health facilities (HFs), allowing HFs to access iMISS and use tablets to submit monthly malaria reports to a central database, eliminating the need for paper-based reporting to districts. A structured evaluation of the iMISS rollout to HFs was carried out in February-July 2021. The four evaluation areas were data quality (reporting rate, timeliness, and fidelity) of monthly malaria reports electronically submitted to the iMISS, adoption of the iMISS for data-informed decision-making, system maintenance, and acceptability of the iMISS among target users. All 94 HFs in the seven targeted districts were assessed. Over the 6-month period, 86.1% of reported cases on the iMISS were consistent with cases recorded in paper-based reports, allowing for up to 10% discrepancy. In addition, 69.0% of expected monthly district meetings were held, and information from iMISS was discussed during 58.6% of these meetings. Maintenance issues, mostly related to tablet access and internet connectivity, were experienced by 74.5% of HFs; 33.7% of issues were resolved within 1 month. The iMISS and electronic submission of malaria reports were well accepted by HF- and district-level users. Continued political commitment and timely execution of issue management workflows are crucial to ensure trust in the new platform and facilitate higher levels of data use.

Optimizing Routine Malaria Surveillance Data in Urban Environments: A Case Study in Maputo City, Mozambique.

In urban settings in malaria-endemic countries, malaria incidence is not well characterized and assumed to be typically very low and consisting largely of imported infections. In such contexts, surveillance systems should adapt to ensure that data are of sufficient spatial and temporal resolution to inform appropriate programmatic interventions. The aim of this research was to 1) assess spatial and temporal trends in reported malaria cases in Maputo City, Mozambique, using an expanded case notification form and 2) to determine how malaria surveillance can be optimized to characterize the local epidemiological context, which can then be used to inform targeted entomological investigations and guide implementation of localized malaria responses. This study took place in all six health facilities of KaMavota District in Maputo City, Mozambique. A questionnaire was administered to all confirmed cases from November 2019 to August 2021. Households of cases were retrospectively geolocated using local landmarks as reference. Overall, 2,380 malaria cases were reported, with the majority being uncomplicated (97.7%) and a median age of 21 years; 70.8% of cases had reported traveling outside the city in the past month with nine reporting traveling internationally. Maps of the 1,314 malaria cases that were geolocated showed distinct spatial patterns. The expanded case notification form enables a more granular overview of the malaria epidemiology in Maputo City; the geolocation data clearly show the areas where endemic transmission is likely, thus informing where resources should be prioritized. As urbanization is rapidly increasing in malaria endemic areas, identifying systems and key variables to collect ensures an operational way to characterize urban malaria through optimization of routine data to inform decision-making.

Surveillance as a Core Intervention to Strengthen Malaria Control Programs in Moderate to High Transmission Settings.

New tools are needed for malaria control, and recent improvements in malaria surveillance have opened the possibility of transforming surveillance into a core intervention. Implementing this strategy can be challenging in moderate to high transmission settings. However, there is a wealth of practical experience among national malaria control programs and partners working to improve and use malaria surveillance data to guide programming. Granular and timely data are critical to understanding geographic heterogeneity, appropriately defining and targeting interventions packages, and enabling timely decision-making at the operational level. Resources to be targeted based on surveillance data include vector control, case management commodities, outbreak responses, quality improvement interventions, and human resources, including community health workers, as they contribute to a more refined granularity of the surveillance system. Effectively transforming malaria surveillance into a core intervention will require strong global and national leadership, empowerment of subnational and local leaders, collaboration among development partners, and global coordination. Ensuring that national health systems include community health work can contribute to a successful transformation. It will require a strong supply chain to ensure that all suspected cases can be diagnosed and data reporting tools including appropriate electronic devices to provide timely data. Regular data quality audits, decentralized implementation, supportive supervision, data-informed decision-making processes, and harnessing technology for data analysis and visualization are needed to improve the capacity for data-driven decision-making at all levels. Finally, resources must be available to respond programmatically to these decisions.

Lack of decline in childhood malaria, Malawi, 2001-2010.

In some areas of Africa, health facility data have indicated declines in malaria that might have resulted from increasingly effective control programs. Most such reports have been from countries where malaria transmission is highly seasonal or of modest intensity. In Malawi, perennial malaria transmission is intense, and malaria control measures have been scaled up during the past decade. We examined health facility data for children seen as outpatients and parasitemia-positive children hospitalized with cerebral malaria in a large national hospital. The proportion of Plasmodium falciparum-positive slides among febrile children at the hospital declined early in the decade, but no further reductions were observed after 2005. The number of admissions for cerebral malaria did not differ significantly by year. Continued surveillance for malaria is needed to evaluate the effects of the increased malaria control efforts.

Impact of seasonal malaria chemoprevention on prevalence of malaria infection in malaria indicator surveys in Burkina Faso and Nigeria.

BACKGROUND: In 2012, the WHO issued a policy recommendation for the use of seasonal malaria chemoprevention (SMC) to children 3-59 months in areas of highly seasonal malaria transmission. Clinical trials have found SMC to prevent around 75% of clinical malaria. Impact under routine programmatic conditions has been assessed during research studies but there is a need to identify sustainable methods to monitor impact using routinely collected data. METHODS: Data from Demographic Health Surveys were merged with rainfall, geographical and programme data in Burkina Faso (2010, 2014, 2017) and Nigeria (2010, 2015, 2018) to assess impact of SMC. We conducted mixed-effects logistic regression to predict presence of malaria infection in children aged 6-59 months (rapid diagnostic test (RDT) and microscopy, separately). RESULTS: We found strong evidence that SMC administration decreases odds of malaria measured by RDT during SMC programmes, after controlling for seasonal factors, age, sex, net use and other variables (Burkina Faso OR 0.28, 95% CI 0.21 to 0.37, p<0.001; Nigeria OR 0.40, 95% CI 0.30 to 0.55, p<0.001). The odds of malaria were lower up to 2 months post-SMC in Burkina Faso (1-month post-SMC: OR 0.29, 95% CI 0.12 to 0.72, p=0.01; 2 months post-SMC: OR: 0.33, 95% CI 0.17 to 0.64, p<0.001). The odds of malaria were lower up to 1 month post-SMC in Nigeria but was not statistically significant (1-month post-SMC 0.49, 95% CI 0.23 to 1.05, p=0.07). A similar but weaker effect was seen for microscopy (Burkina Faso OR 0.38, 95% CI 0.29 to 0.52, p<0.001; Nigeria OR 0.53, 95% CI 0.38 to 0.76, p<0.001). CONCLUSIONS: Impact of SMC can be detected in reduced prevalence of malaria from data collected through household surveys if conducted during SMC administration or within 2 months afterwards. Such evidence could contribute to broader evaluation of impact of SMC programmes.

Prospective surveillance study to detect antimalarial drug resistance, gene deletions of diagnostic relevance and genetic diversity of Plasmodium falciparum in Mozambique: protocol.

INTRODUCTION: Genomic data constitute a valuable adjunct to routine surveillance that can guide programmatic decisions to reduce the burden of infectious diseases. However, genomic capacities remain low in Africa. This study aims to operationalise a functional malaria molecular surveillance system in Mozambique for guiding malaria control and elimination. METHODS AND ANALYSES: This prospective surveillance study seeks to generate Plasmodium falciparum genetic data to (1) monitor molecular markers of drug resistance and deletions in rapid diagnostic test targets; (2) characterise transmission sources in low transmission settings and (3) quantify transmission levels and the effectiveness of antimalarial interventions. The study will take place across 19 districts in nine provinces (Maputo city, Maputo, Gaza, Inhambane, Niassa, Manica, Nampula, Zambézia and Sofala) which span a range of transmission strata, geographies and malaria intervention types. Dried blood spot samples and rapid diagnostic tests will be collected across the study districts in 2022 and 2023 through a combination of dense (all malaria clinical cases) and targeted (a selection of malaria clinical cases) sampling. Pregnant women attending their first antenatal care visit will also be included to assess their value for molecular surveillance. We will use a multiplex amplicon-based next-generation sequencing approach targeting informative single nucleotide polymorphisms, gene deletions and microhaplotypes. Genetic data will be incorporated into epidemiological and transmission models to identify the most informative relationship between genetic features, sources of malaria transmission and programmatic effectiveness of new malaria interventions. Strategic genomic information will be ultimately integrated into the national malaria information and surveillance system to improve the use of the genetic information for programmatic decision-making. ETHICS AND DISSEMINATION: The protocol was reviewed and approved by the institutional (CISM) and national ethics committees of Mozambique (Comité Nacional de Bioética para Saúde) and Spain (Hospital Clinic of Barcelona). Project results will be presented to all stakeholders and published in open-access journals. TRIAL REGISTRATION NUMBER: NCT05306067.

Feasibility, Acceptability, and Protective Efficacy of Seasonal Malaria Chemoprevention Implementation in Nampula Province, Mozambique: Protocol for a Hybrid Effectiveness-Implementation Study.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a highly effective community-based intervention to prevent malaria infections in areas where the malaria burden is high and transmission occurs mainly during the rainy season. In Africa, so far, SMC has been implemented in the Sahel region. Mozambique contributes 4% of the global malaria cases, and malaria is responsible for one-quarter of all deaths in the country. Based on recommendations in the Malaria Strategic Plan, the Malaria Consortium, in partnership with the National Malaria Control Programme in Mozambique, initiated a phased SMC implementation study in the northern province of Nampula. The first phase of this 2-year implementation study was conducted in 2020-2021 and focused on the feasibility and acceptability of SMC. The second phase will focus on demonstrating impact. This paper describes phase 2 of the implementation study. OBJECTIVE: Specific objectives include the following: (1) to determine the effectiveness of SMC in terms of its reduction in incidence of malaria infection among children aged 3 to 59 months; (2) to determine the chemoprevention efficacy of sulfadoxine-pyrimethamine plus amodiaquine (SP+AQ) when used for SMC in Nampula Province, Mozambique, and the extent to which efficacy is impacted by drug resistance and drug concentrations; (3) to investigate the presence and change in SP+AQ- and piperaquine-resistance markers over time as a result of SMC implementation; and (4) to understand the impact of the SMC implementation model, determining the process and acceptability outcomes for the intervention. METHODS: This type 2, hybrid, effectiveness-implementation study uses a convergent mixed methods approach. SMC will be implemented in four monthly cycles between December 2021 and March 2022 in four districts of Nampula Province. Phase 2 will include four components: (1) a cluster randomized controlled trial to establish confirmed malaria cases, (2) a prospective cohort to determine the chemoprevention efficacy of the antimalarials used for SMC and whether drug concentrations or resistance influence the duration of protection, (3) a resistance marker study in children aged 3 to 59 months to describe changes in resistance marker prevalence over time, and (4) a process evaluation to determine feasibility and acceptability of SMC. RESULTS: Data collection began in mid-January 2022, and data analysis is expected to be completed by October 2022. CONCLUSIONS: This is the first effectiveness trial of SMC implemented in Mozambique. The findings from this trial will be crucial to policy change and program expansion to other suitable geographies outside of the Sahel. The chemoprevention efficacy cohort study is a unique opportunity to better understand SMC drug efficacy in this new SMC environment. TRIAL REGISTRATION: ClinicalTrials.gov NCT05186363; https://clinicaltrials.gov/ct2/show/NCT05186363. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36403.

Genetic Variants of Glucose-6-Phosphate Dehydrogenase and Their Associated Enzyme Activity: A Systematic Review and Meta-Analysis.

Low glucose-6-phosphate dehydrogenase enzyme (G6PD) activity is a key determinant of drug-induced haemolysis. More than 230 clinically relevant genetic variants have been described. We investigated the variation in G6PD activity within and between different genetic variants. In this systematic review, individual patient data from studies reporting G6PD activity measured by spectrophotometry and corresponding the G6PD genotype were pooled (PROSPERO: CRD42020207448). G6PD activity was converted into percent normal activity applying study-specific definitions of 100%. In total, 4320 individuals from 17 studies across 10 countries were included, where 1738 (40.2%) had one of the 24 confirmed G6PD mutations, and 61 observations (3.5%) were identified as outliers. The median activity of the hemi-/homozygotes with A-(c.202G>A/c.376A>G) was 29.0% (range: 1.7% to 76.6%), 10.2% (range: 0.0% to 32.5%) for Mahidol, 16.9% (range 3.3% to 21.3%) for Mediterranean, 9.0% (range: 2.9% to 23.2%) for Vanua Lava, and 7.5% (range: 0.0% to 18.3%) for Viangchan. The median activity in heterozygotes was 72.1% (range: 16.4% to 127.1%) for A-(c.202G>A/c.376A>G), 54.5% (range: 0.0% to 112.8%) for Mahidol, 37.9% (range: 20.7% to 80.5%) for Mediterranean, 53.8% (range: 10.9% to 82.5%) for Vanua Lava, and 52.3% (range: 4.8% to 78.6%) for Viangchan. A total of 99.5% of hemi/homozygotes with the Mahidol mutation and 100% of those with the Mediterranean, Vanua Lava, and Viangchan mutations had <30% activity. For A-(c.202G>A/c.376A>G), 55% of hemi/homozygotes had <30% activity. The G6PD activity for each variant spanned the current classification thresholds used to define clinically relevant categories of enzymatic deficiency.