SummaryBackgroundMost malaria deaths occur in rural areas. Rapid progression from illness to death can be interrupted by prompt, effective medication. Antimalarial treatment cannot rescue terminally ill patients but could be effective if given earlier. If patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate can be given before referral and acts rapidly on parasites. We investigated whether this intervention reduced mortality and permanent disability.MethodsIn Bangladesh, Ghana, and Tanzania, patients with suspected severe malaria who could not be treated orally were allocated randomly to a single artesunate (n=8954) or placebo (n=8872) suppository by taking the next numbered box, then referred to clinics at which injections could be given. Those with antimalarial injections or negative blood smears before randomisation were excluded, leaving 12 068 patients (6072 artesunate, 5996 placebo) for analysis. Primary endpoints were mortality, assessed 7–30 days later, and permanent disability, reassessed periodically. All investigators were masked to group assignment. Analysis was by intention to treat. This study is registered in all three countries, numbers ISRCTN83979018, 46343627, and 76987662.ResultsMortality was 154 of 6072 artesunate versus 177 of 5996 placebo (2·5% vs 3·0%, p=0·1). Two versus 13 (0·03% vs 0·22%, p=0·0020) were permanently disabled; total dead or disabled: 156 versus 190 (2·6% vs 3·2%, p=0·0484). There was no reduction in early mortality (56 vs 51 deaths within 6 h; median 2 h). In patients reaching clinic within 6 h (median 3 h), pre-referral artesunate had no significant effect on death after 6 h or permanent disability (71/4450 [1·6%] vs 82/4426 [1·9%], risk ratio 0·86 [95% CI 0·63–1·18], p=0·35). In patients still not in clinic after more than 6 h, however, half were still not there after more than 15 h, and pre-referral rectal artesunate significantly reduced death or permanent disability (29/1566 [1·9%] vs 57/1519 [3·8%], risk ratio 0·49 [95% CI 0·32–0·77], p=0·0013).InterpretationIf patients with severe malaria cannot be treated orally and access to injections will take several hours, a single inexpensive artesunate suppository at the time of referral substantially reduces the risk of death or permanent disability.FundingUNICEF/UNDP/World Bank Special Programme for Research and Training in Tropical Diseases (WHO/TDR); WHO Global Malaria Programme (WHO/GMP); Sall Family Foundation; the European Union (QLRT-2000-01430); the UK Medical Research Council; USAID; Irish Aid; the Karolinska Institute; and the University of Oxford Clinical Trial Service Unit (CTSU).

Summaryobjective WHO recommends artemisinin suppository formulations as pre-referral treatment for children who are unable to take oral medication and cannot rapidly reach a facility for parenteral treatment. We investigated factors influencing caretakers' adherence to referral advice following pre-referral treatment of their children with rectal artesunate suppositories.methods The study was nested within an intervention study that involved pre-referral treatment of all children who came to a community dispenser for treatment because they were unable to take oral medications because of repeated vomiting, lethargy, convulsions or altered consciousness. All patients who did not comply with referral advice were stratified by actions taken post-referral: taking their children to a drug shop, a traditional healer, or not seeking further treatment, and added to a random selection of patients who complied with referral advice. Caretakers of the children were interviewed about their socioeconomic status (SES), knowledge about malaria, referral advice given and actions they took following pre-referral treatment. Interview data for 587 caretakers were matched with symptoms of the children, the time of treatment, arrival at a health facility or other actions taken post-pre-referral treatment.results The majority (93.5%) of caretakers reported being given referral advice by the community drug dispenser. The odds of adherence with this advice were three times greater for children with altered consciousness and ⁄ or convulsions than for children with other symptoms [odds ratio (OR) 3.47, 95% confidence interval (CI) 2.32-5.17, P < 0.001]. When questioned, caretakers who remembered when (OR 2.19, 95% CI 1.48-3.23, P < 0.001) and why (OR 1.77, 95% CI 1.07-2.95, P = 0.026) they were advised to proceed to health facility -were more likely to follow referral advice. Cost did not influence adherence except within a catchment area of facilities that charged for services. In these areas, costs deterred adherence by four to five times for those who had previously paid for laboratory services (OR = 0.25, 95% CI: 0.09-0.67, P = 0.006) or consultation (OR 0.20, 95% CI: 0.06-0.61, P = 0.005) compared with those who had not.conclusion When given referral advice, caretakers of patients with life-threatening symptoms adhere to referral advice more readily than other caretakers. Health service charges deter adherence.

ObjectivesPreparatory to a community trial investigating how best to deliver rectal artesunate as pre-referral treatment for severe malaria; local understanding, perceptions of signs/symptoms of severe malaria and treatment-seeking patterns for and barriers to seeking biomedical treatment were investigated.Methodology/Principal Findings19 key informant interviews, 12 in-depth interviews and 14 focus group discussions targeting care-givers, opinion leaders, and formal and informal health care providers were conducted. Monthly fever episodes and danger signs or symptoms associated with severe malaria among under-fives were recorded. Respondents recognized convulsions, altered consciousness and coma, and were aware of their risks if not treated. But, these symptoms were perceived to be caused by supernatural forces, and traditional healers were identified as primary care providers. With some delay, mothers eventually visited a health facility when convulsions were part of the illness, despite pressures against this. Although vomiting and failure to eat/suck/drink were associated with malaria, they were not considered as indicators of danger signs unless combined with another more severe symptom. Study communities were familiar with rectal application of medicines.Conclusions/SignificanceCommunities' recognition and awareness of major symptoms of severe malaria could encourage action, but perceptions of their causes and poor discrimination of other danger signs – vomiting and failure to feed – might impede early treatment. An effective health education targeting parents/guardians, decision-makers/advisors, and formal and informal care providers might be a prerequisite for successful introduction of rectal artemisinins as an emergency treatment. Role of traditional healers in delivering such medication to the community should be explored.

We developed a test battery for use among children in Bangladesh, Ghana, and Tanzania, assessing general intelligence, executive functioning, and school achievement. The instruments were drawn from previously published materials and tests. The instruments were adapted and translated in a systematic way to meet the needs of the three assessment contexts. The instruments were administered by a total of 43 trained assessors to 786 children in Bangladesh, Ghana, and Tanzania with a mean age of about 13 years (range: 7-18 years). The battery provides a psychometrically solid basis for evaluating intervention studies in multiple settings. Within-group variation was adequate in each group. The expected positive correlations between test performance and age were found and reliability indices yielded adequate values. A confirmatory factor analysis (not including the literacy and numeracy tests) showed a good fit for a model, merging the intelligence and executive tests in a single factor labeled general intelligence. Measurement weights invariance was found, supporting conceptual equivalence across the three country groups, but not supporting full score comparability across the three countries.

Background. If malaria patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate prior to hospital referral can prevent death and disability. The goal is to reduce death from malaria by having rectal artesunate treatment available and used. How best to do this remains unknown.Methods. Villages remote from a health facility were randomized to different community-based treatment providers trained to provide rectal artesunate in Ghana, Guinea-Bissau, Tanzania, and Uganda. Prereferral rectal artesunate treatment was provided in 272 villages: 109 through community-based health workers (CHWs), 112 via trained mothers (MUMs), 25 via trained traditional healers (THs), and 26 through trained community-chosen personnel (COMs); episodes eligible for rectal artesunate were established through regular household surveys of febrile illnesses recording symptoms eligible for prereferral treatment. Differences in treatment coverage with rectal artesunate in children aged <5 years in MUM vs CHW (standard-of-care) villages were assessed using the odds ratio (OR); the predictive probability of treatment was derived from a logistic regression analysis, adjusting for heterogeneity between clusters (villages) using random effects.Results. Over 19 months, 54 013 children had 102 504 febrile episodes, of which 32% (31 817 episodes) had symptoms eligible for prereferral therapy; 14% (4460) children received treatment. Episodes with altered consciousness, coma, or convulsions constituted 36.6% of all episodes in treated children. The overall OR of treatment between MUM vs CHW villages, adjusting for country, was 1.84 (95% confidence interval [CI], 1.20–2.83; P = .005). Adjusting for heterogeneity, this translated into a 1.67 higher average probability of a child being treated in MUM vs CHW villages. Referral compliance was 81% and significantly higher with CHWs vs MUMs: 87% vs 82% (risk ratio [RR], 1.1 [95% CI, 1.0–1.1]; P < .0001). There were more deaths in the TH cluster than elsewhere (RR, 2.7 [95% CI, 1.4–5.6]; P = .0040).Conclusions. Prereferral episodes were almost one-third of all febrile episodes. More than one-third of patients treated had convulsions, altered consciousness, or coma. Mothers were effective in treating patients, and achieved higher coverage than other providers. Treatment access was low.Clinical Trials Registration. ISRCTN58046240.