BACKGROUND: Global progress on malaria control has stalled recently, partly due to challenges in universal access to malaria diagnosis and treatment. Community health workers (CHWs) can play a key role in improving access to malaria care for children under 5 years (CU5), but national policies rarely permit them to treat older individuals. We conducted a two-arm cluster randomized trial in rural Madagascar to assess the impact of expanding malaria community case management (mCCM) to all ages on health care access and use. METHODS: Thirty health centers and their associated CHWs in Farafangana District were randomized 1:1 to mCCM for all ages (intervention) or mCCM for CU5 only (control). Both arms were supported with CHW trainings on malaria case management, community sensitization on free malaria care, monthly supervision of CHWs, and reinforcement of the malaria supply chain. Cross-sectional household surveys in approximately 1600 households were conducted at baseline (Nov-Dec 2019) and endline (Nov-Dec 2021). Monthly data were collected from health center and CHW registers for 36 months (2019-2021). Intervention impact was assessed via difference-in-differences analyses for survey data and interrupted time-series analyses for health system data. RESULTS: Rates of care-seeking for fever and malaria diagnosis nearly tripled in both arms (from less than 25% to over 60%), driven mostly by increases in CHW care. Age-expanded mCCM yielded additional improvements for individuals over 5 years in the intervention arm (rate ratio for RDTs done in 6-13-year-olds, RR(RDT6-13 years) = 1.65; 95% CIs 1.45-1.87), but increases were significant only in health system data analyses. Age-expanded mCCM was associated with larger increases for populations living further from health centers (RR(RDT6-13 years) = 1.21 per km; 95% CIs 1.19-1.23). CONCLUSIONS: Expanding mCCM to all ages can improve universal access to malaria diagnosis and treatment. In addition, strengthening supply chain systems can achieve significant improvements even in the absence of age-expanded mCCM. TRIAL REGISTRATION: The trial was registered at the Pan-African Clinical Trials Registry (#PACTR202001907367187).

BACKGROUND: Malaria in pregnancy (MIP) increases the risk of poor maternal and infant outcomes. To reduce these risks, WHO recommends insecticide-treated net (ITN) use, intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP), and prompt case management. However, uptake of these interventions remains sub-optimal in Madagascar. A scoping review was conducted to determine the breadth and depth of information available during 2010-2021 about Madagascar's MIP activities and to identify barriers and facilitators to MIP interventions uptake. METHODS: PubMed, Google Scholar, and USAID's files (Development Experience Catalog) were searched using the terms "Madagascar AND pregnancy AND malaria," and reports and materials from stakeholders were collected. Documents in English and French from 2010 to 2021 with data regarding MIP were included. Documents were systematically reviewed and summarized; results were captured in an Excel database. RESULTS: Of 91 project reports, surveys and published articles, 23 (25%) fell within the stated time period and contained relevant data on MIP activities in Madagascar and were categorized accordingly: eight (35%) quality of care, including health facility readiness, provider knowledge and commodity availability; nine (39%) care-seeking behaviour; and, six (26%) prevention of MIP. Key barriers were identified: nine articles mentioned SP stockouts; seven found limitations of provider knowledge, attitudes, and behaviours (KAB) regarding MIP treatment and prevention; and, one reported limited supervision. MIP care seeking and prevention barriers and facilitators included women's KAB regarding MIP treatment and prevention, distance, wait times, poor service quality, cost, and/or unwelcoming providers. A 2015 survey of 52 health facilities revealed limited client access to antenatal care due to financial and geographic barriers; two 2018 surveys revealed similar findings. Self-treatment and care-seeking delays were reported even when distance was not a barrier. CONCLUSION: Among the studies and reports on MIP in Madagascar, the scoping review frequently noted barriers that could be mitigated by reducing stockouts, improving provider knowledge and attitudes, refining MIP communication, and improving service access. There is a need for coordinated efforts to address the identified barriers is the key implication of the findings.

BACKGROUND: Malaria remains a leading cause of morbidity and mortality worldwide, with progress in malaria control stalling in recent years. Proactive community case management (pro-CCM) has been shown to increase access to diagnosis and treatment and reduce malaria burden. However, lack of experimental evidence may hinder the wider adoption of this intervention. We conducted a cluster randomized community intervention trial to assess the efficacy of pro-CCM at decreasing malaria prevalence in rural endemic areas of Madagascar. METHODS: Twenty-two fokontany (smallest administrative unit) of the Mananjary district in southeast Madagascar were selected and randomized 1:1 to pro-CCM (intervention) or conventional integrated community case management (iCCM). Residents of all ages in the intervention arm were visited by a community health worker every 2 weeks from March to October 2017 and screened for fever; those with fever were tested by a rapid diagnostic test (RDT) and treated if positive. Malaria prevalence was assessed using RDTs on all consenting study area residents prior to and following the intervention. Hemoglobin was measured among women of reproductive age. Intervention impact was assessed via difference-in-differences analyses using logistic regressions in generalized estimating equations. RESULTS: A total of 27,087 and 20,475 individuals participated at baseline and endline, respectively. Malaria prevalence decreased from 8.0 to 5.4% in the intervention arm for individuals of all ages and from 6.8 to 5.7% in the control arm. Pro-CCM was associated with a significant reduction in the odds of malaria positivity in children less than 15 years (OR = 0.59; 95% CI [0.38-0.91]), but not in older age groups. There was no impact on anemia among women of reproductive age. CONCLUSION: This trial suggests that pro-CCM approaches could help reduce malaria burden in rural endemic areas of low- and middle-income countries, but their impact may be limited to younger age groups with the highest malaria burden. TRIAL REGISTRATION: NCT05223933. Registered on February 4, 2022.

BACKGROUND: Prompt diagnosis and treatment of malaria contributes to reduced morbidity, particularly among children and pregnant women; however, in Madagascar, care-seeking for febrile illness is often delayed. To describe factors influencing decisions for prompt care-seeking among caregivers of children aged < 15 years and pregnant women, a mixed-methods assessment was conducted with providers (HP), community health volunteers (CHV) and community members. METHODS: One health district from each of eight malaria-endemic zones of Madagascar were purposefully selected based on reported higher malaria transmission. Within districts, one urban and one rural community were randomly selected for participation. In-depth interviews (IDI) and focus group discussions (FGD) were conducted with caregivers, pregnant women, CHVs and HPs in these 16 communities to describe practices and, for HPs, system characteristics that support or inhibit care-seeking. Knowledge tests on malaria case management guidelines were administered to HPs, and logistics management systems were reviewed. RESULTS: Participants from eight rural and eight urban communities included 31 HPs from 10 public and 8 private Health Facilities (HF), five CHVs, 102 caregivers and 90 pregnant women. All participants in FGDs and IDIs reported that care-seeking for fever is frequently delayed until the ill person does not respond to home treatment or symptoms become more severe. Key care-seeking determinants for caregivers and pregnant women included cost, travel time and distance, and perception that the quality of care in HFs was poor. HPs felt that lack of commodities and heavy workloads hindered their ability to provide quality malaria care services. Malaria commodities were generally more available in public versus private HFs. CHVs were generally not consulted for malaria care and had limited commodities. CONCLUSIONS: Reducing cost and travel time to care and improving the quality of care may increase prompt care-seeking among vulnerable populations experiencing febrile illness. For patients, perceptions and quality of care could be improved with more reliable supplies, extended HF operating hours and staffing, supportive demeanors of HPs and seeking care with CHVs. For providers, malaria services could be improved by increasing the reliability of supply chains and providing additional staffing. CHVs may be an under-utilized resource for sick children.

BACKGROUND: Since 2005, artemisinin-based combination therapy (ACT) has been recommended to treat uncomplicated falciparum malaria in Madagascar. Artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are the first- and second-line treatments, respectively. A therapeutic efficacy study was conducted to assess ACT efficacy and molecular markers of anti-malarial resistance. METHODS: Children aged six months to 14 years with uncomplicated falciparum malaria and a parasitaemia of 1000-100,000 parasites/µl determined by microscopy were enrolled from May-September 2018 in a 28-day in vivo trial using the 2009 World Health Organization protocol for monitoring anti-malarial efficacy. Participants from two communes, Ankazomborona (tropical, northwest) and Matanga (equatorial, southeast), were randomly assigned to ASAQ or AL arms at their respective sites. PCR correction was achieved by genotyping seven neutral microsatellites in paired pre- and post-treatment samples. Genotyping assays for molecular markers of resistance in the pfk13, pfcrt and pfmdr1 genes were conducted. RESULTS: Of 344 patients enrolled, 167/172 (97%) receiving ASAQ and 168/172 (98%) receiving AL completed the study. For ASAQ, the day-28 cumulative PCR-uncorrected efficacy was 100% (95% CI 100-100) and 95% (95% CI 91-100) for Ankazomborona and Matanga, respectively; for AL, it was 99% (95% CI 97-100) in Ankazomborona and 83% (95% CI 76-92) in Matanga. The day-28 cumulative PCR-corrected efficacy for ASAQ was 100% (95% CI 100-100) and 98% (95% CI 95-100) for Ankazomborona and Matanga, respectively; for AL, it was 100% (95% CI 99-100) in Ankazomborona and 95% (95% CI 91-100) in Matanga. Of 83 successfully sequenced samples for pfk13, no mutation associated with artemisinin resistance was observed. A majority of successfully sequenced samples for pfmdr1 carried either the NFD or NYD haplotypes corresponding to codons 86, 184 and 1246. Of 82 successfully sequenced samples for pfcrt, all were wild type at codons 72-76. CONCLUSION: PCR-corrected analysis indicated that ASAQ and AL have therapeutic efficacies above the 90% WHO acceptable cut-off. No genetic evidence of resistance to artemisinin was observed, which is consistent with the clinical outcome data. However, the most common pfmdr1 haplotypes were NYD and NFD, previously associated with tolerance to lumefantrine.

Approximately 20% of Shigella isolates tested in New York City, New York, USA, during 2013-2015 displayed decreased azithromycin susceptibility. Case-patients were older and more frequently male and HIV infected than those with azithromycin-susceptible Shigella infection; 90% identified as men who have sex with men. Clinical interpretation guidelines for azithromycin resistance and outcome studies are needed.

Human Brucella canis infection incidence is unknown. Most identified cases are associated with pet dogs. Laboratory-acquired infections can occur following contact with Brucella spp. We identified a paediatric B. canis case, the source and other exposed persons. A 3-year-old New York City child with fever and dyspnoea was hospitalized for 48 h for bronchiolitis. After her admission, blood culture grew B. canis, she was prescribed anti-microbials and recovered. B. canis was also isolated from blood of the child's pet dog; these isolates were genetically similar. The dog originated from an Iowa breeding facility which was quarantined after identification of the dog's infection. Additionally, 31 laboratory workers were exposed and subsequently monitored for symptoms; 15 completed post-exposure prophylaxis. To our knowledge, this is the first report strongly suggesting B. canis zoonotic transmission to a child in the United States, and highlights the need for coordinated control policies to minimize human illness.

BACKGROUND: The duration of protection in children and adults (including health care workers) resulting from the hepatitis B vaccine primary series is unknown. METHODS: To determine the protection afforded by hepatitis B vaccine, Alaska Native persons who had received plasma-derived hepatitis B vaccine when they were >6 months of age were tested for antibody to hepatitis B surface antigen (anti-HBs) 22 years later. Those with levels <10 mIU/mL received 1 dose of recombinant hepatitis B vaccine and were evaluated on the basis of anti-HBs measurements at 10-14 days, 30-60 days, and 1 year. RESULTS: Of 493 participants, 60% (298) had an anti-HBs level 10 mIU/mL. A booster dose was administered to 164 persons, and 77% responded with an anti-HBs level 10 mIU/mL at 10-14 days, reaching 81% by 60 days. Response to a booster dose was positively correlated with younger age, peak anti-HBs response after primary vaccination, and the presence of detectable anti-HBs before boosting. Considering persons with an anti-HBs level 10 mIU/mL at 22 years and those who responded to the booster dose, protection was demonstrated in 87% of the participants. No new acute or chronic hepatitis B virus infections were identified. CONCLUSIONS: The protection afforded by primary immunization with plasma-derived hepatitis B vaccine during childhood and adulthood lasts at least 22 years. Booster doses are not needed.

BACKGROUND: Vaccination with conjugate vaccines stimulates T cell-dependent immunity, whereas vaccination with polysaccharide vaccines does not. Thus, vaccination with the 7-valent pneumococcal conjugate vaccine (PCV7) followed by the 23-valent pneumococcal polysaccharide vaccine (PPV23) may offer better protection against invasive pneumococcal disease for older adults than does vaccination with PPV23 alone, which is what is currently recommended. METHODS: Alaska Native adults 55-70 years of age with no previous pneumococcal vaccination were randomized to receive (1) PPV23, (2) PCV7 followed 2 months later by PPV23, or (3) PCV7 followed 6 months later by PPV23. Participants recorded reactions after each vaccination. Serum samples collected during the period from May 2002 through February 2003 were tested for serotype-specific immunoglobulin G (IgG) and for opsonophagocytic activity (OPA) against serotypes 1, 4, 6B, 14, and 19F. RESULTS: Vaccination with PCV7 was well tolerated, but persons receiving PCV7 followed by PPV23 reported more local reactions than those receiving only PPV23. All reactions resolved spontaneously within 72 h of receiving vaccine. The geometric mean IgG concentrations of and the median OPA titers to serotypes 4, 6B, 14, and 19F increased in all groups after 1 dose of either PCV7 or PPV23. Serotype-specific geometric mean IgG concentrations and median OPA titers did not differ between any of the groups after vaccination with PPV23, regardless of whether they had previously received PCV7. CONCLUSIONS: In this study, PCV7 given 2 or 6 months before PPV23 was well tolerated but did not improve immune response to PPV23 in older Alaska Native adults.