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BackgroundGood hand hygiene compliance amongst healthcare workers is critical for patient safety and plays a central role in preventing healthcare-associated infections. The World Health Organization (WHO) recommends a multimodal strategy to improve healthcare worker hand hygiene. We aimed to evaluate the effectiveness of this strategy in a middle-income country using a stepped-wedge cluster randomized trial.MethodsThe trial was conducted between 2013 and 2015 in 58 wards in a 1000-bed hospital in Thailand. The intervention was adapted from the WHO’s Hand Hygiene Improvement Strategy and implemented by the hospital’s infection control team. The primary outcome was observed hand hygiene compliance among healthcare workers in the study wards. This study was registered atClinicalTrials.gov(NCT01933087).FindingsDuring 4,230 observation sessions, 54,073 hand hygiene opportunities were identified. Hand hygiene compliance increased from 10.0% (2,660/26,482) to 11.0% (3,048/27,591) after the intervention (odds ratio [OR] 1.12; 95% CI: 1.01-1.24). Among the five moments for hand hygiene, the greatest improvement in compliance was observed in hand hygiene before patient contact (OR 1.52; 95% CI: 1.21, 1.91).InterpretationWhile hand hygiene compliance improved slightly, the intervention failed to achieve the substantial improvements that were needed. There is a need for new strategies to ensure that all hospitals in low and middle-income countries can achieve and maintain acceptable levels of hand hygiene.FundingOak Foundation, MRC

Malaria outbreaks are an important public health concern in endemic regions approaching elimination. Genetic surveillance of malaria parasites can elucidate the population dynamics of an outbreak, and help identify its causes. We investigated the epidemiology of a Plasmodium falciparum outbreak in Attapeu Province, Laos, during the 2020-2021 season. An analysis of 249 samples, collected by routine genetic surveillance during the outbreak, revealed a massive loss of genetic diversity in the parasite population, primarily caused by the rapid expansion of a multidrug resistant strain, named LAA1. This strain carried the kelch13 R539T mutation and expanded clonally, replacing the previously dominant kelch13 C580Y mutants (KEL1/PLA1) resistant to dihydroartemisinin-piperaquine. Identity by descent (IBD) patterns showed that LAA1 was a recombinant that inherited 60% of its genome from a strain first sampled in Cambodia over a decade ago. A less common outbreak strain (LAA2) carried the kelch13 C580Y allele, but was distinct from KEL1/PLA1, its genome essentially identical to that of a Cambodian parasite from 2009. A third, low-frequency strain (LAA7) was a recombinant of KEL1/PLA1 with a R539T mutant, the latter providing the kelch13 variant. These results strongly suggest that the outbreak was driven by a selective sweep, possibly associated with drug-resistant phenotypes of the outbreak strains. The observation that new variants of established multidrug resistant populations can overwhelm previously dominant strains so rapidly has implications for elimination of malaria. Genetic surveillance provides the tools for characterizing outbreaks, and for monitoring the evolution and spread of the populations involved.

Background Understanding the effect of immunity on Plasmodium falciparum clearance is essential for interpreting therapeutic efficacy studies designed to monitor emergence of artemisinin drug resistance. In low-transmission areas of Southeast Asia, where resistance has emerged, P. falciparum antibodies confound parasite clearance measures. However, variation in naturally acquired antibodies across Asian and sub-Saharan African epidemiological contexts and their impact on parasite clearance re yet to be quantified. Methods In an artemisinin therapeutic efficacy study, antibodies to 12 pre-erythrocytic and erythrocytic P. falciparum antigens were measured in 118 children with uncomplicated P. falciparum malaria in the Democratic Republic of Congo (DRC) and compared with responses in patients from Asian sites, described elsewhere. Results Parasite clearance half-life was shorter in DRC patients (median, 2 hours) compared with most Asian sites (median, 2–7 hours), but P. falciparum antibody levels and seroprevalences were similar. There was no evidence for an association between antibody seropositivity and parasite clearance half-life (mean difference between seronegative and seropositive, −0.14 to +0.40 hour) in DRC patients. Conclusions In DRC, where artemisinin remains highly effective, the substantially shorter parasite clearance time compared with Asia was not explained by differences in the P. falciparum antibody responses studied.

Despite long-standing availability of an effective vaccine, tetanus remains a significant problem in many countries. Outcome depends on access to mechanical ventilation and intensive care facilities and in settings where these are limited, mortality remains high. Administration of tetanus antitoxin by the intramuscular route is recommended treatment for tetanus, but as the tetanus toxin acts within the central nervous system, it has been suggested that intrathecal administration of antitoxin may be beneficial. Previous studies have indicated benefit, but with the exception of one small trial no blinded studies have been performed. The objective of this study is to establish whether the addition of intrathecal tetanus antitoxin reduces the need for mechanical ventilation in patients with tetanus. Secondary objectives: to determine whether the addition of intrathecal tetanus antitoxin reduces autonomic nervous system dysfunction and length of hospital/ intensive care unit stay; whether the addition of intrathecal tetanus antitoxin in the treatment of tetanus is safe and cost-effective; to provide data to inform recommendation of human rather than equine antitoxin. This study will enroll adult patients (≥16 years old) with tetanus admitted to the Hospital for Tropical Diseases, Ho Chi Minh City. The study is a 2x2 factorial blinded randomized controlled trial. Eligible patients will be randomized in a 1:1:1:1 manner to the four treatment arms (intrathecal treatment and human intramuscular treatment, intrathecal treatment and equine intramuscular treatment, sham procedure and human intramuscular treatment, sham procedure and equine intramuscular treatment). Primary outcome measure will be requirement for mechanical ventilation. Secondary outcome measures: duration of hospital/ intensive care unit stay, duration of mechanical ventilation, in-hospital and 240-day mortality and disability, new antibiotic prescription, incidence of ventilator associated pneumonia and autonomic nervous system dysfunction, total dose of benzodiazepines and pipecuronium, and incidence of adverse events. Trial registration: ClinicalTrials.gov NCT02999815 Registration date: 21 December 2016

Background: Village Malaria Workers (VMWs) are lay people trained to provide a valuable role in frontline testing and treatment of malaria in rural villages in Cambodia. Emergence of artemisinin-resistant malaria highlights the essential role of such VMWs in surveillance and early treatment of malaria. Smartphone technology offers huge potential to support VMWs in isolated and resource-poor settings. Methods: We investigated the feasibility of issuing established VMWs with a smartphone, bespoke Android application and solar charger to support their role. 27 VMWs in Kampong Cham and Kratie provinces participated. Results: 26/27 of the smartphones deployed were working well at study completion twelve months later. Interviews with VMWs using quantitative and qualitative methods revealed pride, ease of use and reports of faster communication with the smartphone. VMWs also expressed a strong wish to help people presenting with non-malarial fever, for which further potential supportive smartphone applications are increasingly available. Conclusions: As a result of this pilot study, two smartphone based reporting systems for malaria have been developed at the Cambodian National Malaria Center, and the programme is now being extended nationwide. The full code for the smartphone application is made available to other researchers and healthcare providers with this article. Smartphones represent a feasible platform for developing the VMW role to include other health conditions, thus maintaining the relevance of these important community health workers.

Activation of vascular endothelium and blood cells can result in the formation of microparticles (MPs), which are membrane vesicles with a diameter1 microm which can play a pathogenetic role in a variety of infectious and other diseases. In this study, we validated a modified quantitative method called "flow rate based calibration", to measure circulating MPs in plasma of healthy subjects and malaria patients using FACSCalibur flow cytometry. MPs counts obtained from "flow rate based calibration" correlated closely with the standard method (R2 = 0.9, p = 0.001). The median (range) number of MPs in healthy subjects was 163/microl (81-375/microl). We demonstrated a flow rate based calibration for the quantitation of MPs in P. falciparum malaria-infected patients. The median (range) number of MPs was 2,051/microl (222-6,432/microl), n = 28 in patients with falciparum malaria. The number of MPs in plasma from patients with severe falciparum malaria was significantly higher than in uncomplicated falciparum malaria (2,567/microl (366-6,432/microl), n = 18 versus [1,947/microl (222-4,107/microl), n = 10, p0.01]. Cellular origin of MPs in malaria patients were mainly derived from red blood cells (35%), platelets (10%), and endothelial cells (5%). There was no significant correlation between the total number of MPs and parasitemia. Flow rate based calibration is a simple, reliable, reproducible method and more affordable to quantitate MPs.

In falciparum malaria, the deformability of the entire erythrocyte population is reduced in proportion to disease severity, and this compromises microcirculatory blood flow through vessels partially obstructed by cytoadherent parasitized erythrocytes. The cause of rigidity of uninfected erythrocytes in not known but could be mediated by malaria heme products. In this study, we show that red blood cell deformability (RBC-D), measured by laser-assisted optical rotational cell analyzer, decreased in a dose-dependent manner after incubation with hemin and hydrogen peroxide but not with hemoglobin or beta-hematin. Hemin also reduced mean red cell volume. Albumin decreased and N-acetylcysteine (NAC) both prevented and reversed rigidity induced by hemin. Hemin-induced oxidative damage of the membrane seems to be a more important contributor to pathology than cell shrinkage because the antioxidant NAC restored RBC-D but not red blood cell volume. The findings suggest novel approaches to the treatment of potentially lethal malaria.

A serologic survey of adults resident in Myanmar was conducted to define the presence of antibodies to Burkholderia pseudomallei, the cause of melioidosis. Antibodies were detectable by indirect hemagglutination assay (IHA) in 757 (78%) of 968 adults, of whom 69 (7%) had an IHA titeror =1:160.