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BACKGROUND: Artemisinin resistance in Plasmodium falciparum threatens global malaria elimination efforts. To contain and then eliminate artemisinin resistance in Eastern Myanmar a network of community-based malaria posts was instituted and targeted mass drug administration (MDA) with dihydroartemisinin-piperaquine (three rounds at monthly intervals) was conducted. The prevalence of artemisinin resistance during the elimination campaign (2013-2019) was characterized. METHODS: Throughout the six-year campaign Plasmodium falciparum positive blood samples from symptomatic patients and from cross-sectional surveys were genotyped for mutations in kelch-13-a molecular marker of artemisinin resistance. RESULT: The program resulted in near elimination of falciparum malaria. Of 5162 P. falciparum positive blood samples genotyped, 3281 (63.6%) had K13 mutations. The prevalence of K13 mutations was 73.9% in 2013 and 64.4% in 2019. Overall, there was a small but significant decline in the proportion of K13 mutants (p < 0.001). In the MDA villages there was no significant change in the K13 proportions before and after MDA. The distribution of different K13 mutations changed substantially; F446I and P441L mutations increased in both MDA and non-MDA villages, while most other K13 mutations decreased. The proportion of C580Y mutations fell from 9.2% (43/467) before MDA to 2.3% (19/813) after MDA (p < 0.001). Similar changes occurred in the 487 villages where MDA was not conducted. CONCLUSION: The malaria elimination program in Kayin state, eastern Myanmar, led to a substantial reduction in falciparum malaria. Despite the intense use of artemisinin-based combination therapies, both in treatment and MDA, this did not select for artemisinin resistance.
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Antimaláricos , Artemisininas , Resistência a Medicamentos , Malária Falciparum , Plasmodium falciparum , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Mianmar , Malária Falciparum/parasitologia , Malária Falciparum/epidemiologia , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Resistência a Medicamentos/genética , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Humanos , Estudos Transversais , Feminino , Masculino , Adolescente , Adulto , Administração Massiva de Medicamentos , Adulto Jovem , Mutação , Criança , Pré-Escolar , Pessoa de Meia-Idade , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Erradicação de Doenças/estatística & dados numéricos , PiperazinasRESUMO
Serum iron has long been thought to exhibit diurnal variation and is subsequently considered an unreliable biomarker of systemic iron status. Circadian regulation (endogenous ~24-h periodic oscillation of a biologic function) governs many critical physiologic processes. It is unknown whether serum iron levels are regulated by circadian machinery; likewise, the circadian nature of key players of iron homeostasis is unstudied. Here we show that serum iron, transferrin saturation (TSAT), hepatic transferrin receptor (TFR1) gene (Tfrc) expression, and erythropoietic activity exhibit circadian rhythms. Daily oscillations of serum iron, TSAT, hepatic Tfrc expression, and erythropoietic activity are maintained in mice housed in constant darkness, where oscillation reflects an endogenous circadian period. Oscillations of serum iron, TSAT, hepatic Tfrc, and erythropoietic activity were ablated when circadian machinery was disrupted in Bmal1 knockout mice. Interestingly, we find that circadian oscillations of erythropoietic activity and hepatic Tfrc expression are maintained in opposing phase, likely allowing for optimized usage and storage of serum iron whilst maintaining adequate serum levels and TSAT. This study provides the first confirmatory evidence that serum iron is circadian regulated, discerns circadian rhythms of TSAT, a widely used clinical marker of iron status, and uncovers liver-specific circadian regulation of TFR1, a major player in cellular iron uptake.
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BACKGROUND: Myanmar has a large majority of all malaria in the Greater Mekong Subregion. In the past decade, substantial progress was made in malaria control. The residual burden of malaria is in remote areas where currently recommended malaria elimination approaches are generally not feasible. In such hard-to-reach communities in Mon state, East Myanmar, Medical Action Myanmar introduced community health workers (CHWs) to deliver early diagnosis and treatment for malaria. We conducted a retrospective analysis to assess the impact of this intervention. METHODS AND FINDINGS: This retrospective analysis involved data collected routinely from a CHW programme in Mon state conducted between 2011 and 2018. A network of 172 CHWs serving a population of 236,340 was deployed. These CHWs carried out 260,201 malaria rapid diagnostic tests (RDTs) to investigate patients with acute febrile illness. The median blood examination rate was 1.33%; interquartile range (IQR) (0.38 to 3.48%); 95% CI [1.28%, 1.36%] per month. The changes in malaria incidence and prevalence in patients presenting with fever were assessed using negative binomial regression mixed effects models fitted to the observed data. The incidence of Plasmodium falciparum malaria (including mixed infections) declined by 70%; 95% CI [65%, 75%]; p < 0.001 for each year of CHW operation. The incidence of P. vivax malaria declined by 56%; 95% CI [50%, 62%]; p < 0.001 per year. Malaria RDT positivity rates for P. falciparum and P. vivax declined by 69%; 95% CI [62%, 75%]; p < 0.001 and 53%; 95% CI [47%, 59%]; p < 0.001 per year, respectively. Between 2017 and 2018, only 1 imported P. falciparum case was detected in 54,961 RDTs. The main limitations of the study are use of retrospective data with possible unidentified confounders and uncharacterised population movement. CONCLUSIONS: The introduction of CHWs providing community-based malaria diagnosis and treatment and basic health care services in remote communities in Mon state was associated with a substantial reduction in malaria. Within 6 years, P. falciparum was eliminated and the incidence of P. vivax fell markedly.
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Malária Falciparum , Malária Vivax , Malária , Humanos , Estudos Retrospectivos , Agentes Comunitários de Saúde , Mianmar/epidemiologia , Plasmodium falciparum , Malária Falciparum/diagnóstico , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Malária/epidemiologia , Malária Vivax/diagnóstico , Malária Vivax/epidemiologia , Malária Vivax/prevenção & controle , Febre , Plasmodium vivaxRESUMO
BACKGROUND: In Papua (Indonesia), infants with P. falciparum and/or P. vivax malaria are at risk of severe anaemia and death. We hypothesized that in an area of high malaria transmission, intermittent screening and treatment of infants with malaria (ISTi) will reduce morbidity compared to passive case detection (PCDi). METHODS: We conducted a cluster randomised, open label, superiority trial. A total of 21 clusters of village health posts (VHP) were randomised 1:1 to either IST for infants coinciding with 4 routine immunisation visits or PCDi. Healthy term infants born to consenting mothers enrolled into a maternal malaria cluster randomised trial were included in the study and followed for 12 months. Point of care malaria rapid diagnostic tests were used to detect peripheral parasitaemia at 2, 3, 4 and 9 months old in all infants in ISTi clusters and when symptomatic in PCDi clusters. Infants with detected peripheral parasitaemia were treated with dihydroartemisinin-piperaquine. The co-primary outcomes were the incidence rate of clinical malaria in the first year of life and the prevalence of parasitaemia at age 12 months. The incidence rate ratio and prevalence ratio between ISTi and PCDi were estimated using mixed-effects Poisson and log-binomial regression modelling (accounting for clustering at VHP level). RESULTS: Between May 2014 and February 2017, 757 infants were enrolled into the study, 313 into 10 ISTi clusters, and 444 into 11 PCDi clusters. Overall, 132 episodes of parasitaemia were detected, of whom 17 (12.9%) were in symptomatic infants. Over 12 months, the incidence rate (IR) of clinical malaria was 24 [95% CI, 10-50] per 1000 children-years at risk in the ISTi arm and 19 [95% CI, 8,38] per 1000 children-years in the PCDi arm (adjusted incidence rate ratio [aIRR] 1.77 [95% CI, 0.62-5.01]; p = 0.280). The prevalence of parasitaemia at 12 months was 13% (33/254) in the IST clusters and 15% (57/379) in the PCD clusters (adjusted prevalence ratio (aPR) = 0.92 (95% CI, 0.70-1.21), p = 0.55). There was no difference in the risk of anaemia between treatment arms. CONCLUSIONS: In high malaria transmission area outside of Africa, our study suggests that compared to PCDi, ISTi offers no significant benefit in reducing the risk of clinical malaria in infants born to women receiving effective protection from malaria during pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02001428 , registered on 20 Nov 2013.
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Anemia , Antimaláricos , Malária Falciparum , Malária Vivax , Malária , Anemia/epidemiologia , Antimaláricos/uso terapêutico , Criança , Feminino , Humanos , Indonésia/epidemiologia , Lactente , Malária/diagnóstico , Malária/epidemiologia , Malária/prevenção & controle , Malária Falciparum/diagnóstico , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Malária Vivax/diagnóstico , Malária Vivax/tratamento farmacológico , Malária Vivax/epidemiologia , Parasitemia/diagnóstico , Parasitemia/epidemiologia , Parasitemia/prevenção & controle , Gravidez , VacinaçãoRESUMO
BACKGROUND: The pathogenesis of malaria in pregnancy (MiP) involves accumulation of P. falciparum-infected red blood cells (pRBCs) in the placenta, contributing to poor pregnancy outcomes. Parasite accumulation is primarily mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1). Magnitude of IgG to pRBCs has been associated with reduced risk of MiP in some studies, but associations have been inconsistent. Further, antibody effector mechanisms are poorly understood, and the role of antibody complement interactions is unknown. METHODS: Studying a longitudinal cohort of pregnant women (n=302) from a malaria-endemic province in Papua New Guinea (PNG), we measured the ability of antibodies to fix and activate complement using placental binding pRBCs and PfEMP1 recombinant domains. We determined antibody-mediated complement inhibition of pRBC binding to the placental receptor, chondroitin sulfate A (CSA), and associations with protection against placental parasitemia. RESULTS: Some women acquired antibodies that effectively promoted complement fixation on placental-binding pRBCs. Complement fixation correlated with IgG1 and IgG3 antibodies, which dominated the response. There was, however, limited evidence for membrane attack complex activity or pRBC lysis or killing. Importantly, a higher magnitude of complement fixing antibodies was prospectively associated with reduced odds of placental infection at delivery. Using genetically modified P. falciparum and recombinant PfEMP1 domains, we found that complement-fixing antibodies primarily targeted a specific variant of PfEMP1 (known as VAR2CSA). Furthermore, complement enhanced the ability of antibodies to inhibit pRBC binding to CSA, which was primarily mediated by complement C1q protein. CONCLUSIONS: These findings provide new insights into mechanisms mediating immunity to MiP and reveal potential new strategies for developing malaria vaccines that harness antibody-complement interactions.
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Malária Falciparum , Complicações Parasitárias na Gravidez , Anticorpos Antiprotozoários , Antígenos de Protozoários , Eritrócitos , Feminino , Humanos , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Parasitemia , Placenta , Plasmodium falciparum , Gravidez , Resultado da Gravidez , GestantesRESUMO
BACKGROUND: Cryptococcal meningitis (CM) is a common HIV-associated opportunistic-infection worldwide. Existing literature focusses on hospital-based outcomes of induction treatment. This paper reviews outpatient management in integrated primary care clinics in Yangon. METHOD: This retrospective case note review analyses a Myanmar HIV-positive patient cohort managed using ambulatory induction-phase treatment with intravenous amphotericin-B-deoxycholate (0.7-1.0 mg/kg) and oral fluconazole (800 mg orally/day). RESULTS: Seventy-six patients were diagnosed between 2010 and 2017. The median age of patients diagnosed was 35 years, 63% were male and 33 (45%) were on concurrent treatment for tuberculosis. The median CD4 count was 60 at the time of diagnosis. Amphotericin-B-deoxycholate infusions precipitated 56 episodes of toxicity, namely hypokalaemia, nephrotoxicity, anaemia, febrile reactions, phlebitis, observed in 44 patients (58%). One-year survival (86%) was higher than existing hospital-based treatment studies. CONCLUSION: Ambulation of patients in this cohort saved 1029 hospital bed days and had better survival outcomes when compared to hospital-based studies in other resource constrained settings.
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Infecções Oportunistas Relacionadas com a AIDS/complicações , Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Cryptococcus neoformans/imunologia , Ácido Desoxicólico/administração & dosagem , Fluconazol/administração & dosagem , HIV , Meningite Criptocócica/complicações , Meningite Criptocócica/tratamento farmacológico , Atenção Primária à Saúde , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/virologia , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Anfotericina B/efeitos adversos , Antifúngicos/efeitos adversos , Cryptococcus neoformans/isolamento & purificação , Ácido Desoxicólico/efeitos adversos , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Fluconazol/efeitos adversos , Humanos , Masculino , Meningite Criptocócica/epidemiologia , Meningite Criptocócica/microbiologia , Pessoa de Meia-Idade , Mianmar/epidemiologia , Flebite/induzido quimicamente , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Community health workers (CHWs) can provide diagnosis and treatment of malaria in remote rural areas and are therefore key to the elimination of malaria. However, as incidence declines, uptake of their services could be compromised if they only treat malaria. METHODS: We conducted a retrospective analysis of 571,286 malaria rapid diagnostic tests conducted between 2011 and 2016 by 1335 CHWs supported by Medical Action Myanmar. We assessed rates of decline in Plasmodium falciparum and Plasmodium vivax incidence and rapid diagnostic test (RDT) positivity rates using negative binomial mixed effects models. We investigated whether broadening the CHW remit to provide a basic health care (BHC) package was associated with a change in malaria blood examination rates. RESULTS: Communities with CHWs providing malaria diagnosis and treatment experienced declines in P. falciparum and P. vivax malaria incidence of 70% (95% CI 66-73%) and 64% (59-68%) respectively each year of operation. RDT positivity rates declined similarly with declines of 70% (95% CI 66-73%) for P. falciparum and 65% (95% CI 61-69%) for P. vivax with each year of CHW operation. In four cohorts studied, adding a BHC package was associated with an immediate and sustained increase in blood examination rates (step-change rate ratios 2.3 (95% CI 2.0-2.6), 5.4 (95% CI 4.0-7.3), 1.7 (95% CI 1.4-2.1), and 1.1 (95% CI 1.0.1.3)). CONCLUSIONS: CHWs have overseen dramatic declines in P. falciparum and P. vivax malaria in rural Myanmar. Expanding their remit to general health care has sustained community uptake of malaria services. In similar settings, expanding health services offered by CHWs beyond malaria testing and treatment can improve rural health care while ensuring continued progress towards the elimination of malaria.
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Serviços de Saúde Comunitária/organização & administração , Atenção à Saúde/organização & administração , Pessoal de Saúde , Malária/epidemiologia , Serviços de Saúde Comunitária/métodos , Atenção à Saúde/métodos , Testes Diagnósticos de Rotina , Feminino , Humanos , Incidência , Análise de Séries Temporais Interrompida , Estudos Longitudinais , Malária/diagnóstico , Masculino , Pessoa de Meia-Idade , Mianmar/epidemiologia , Plasmodium falciparum , Plasmodium vivax , Estudos Retrospectivos , População RuralRESUMO
Background: Reductions in malaria transmission decrease naturally acquired immunity, which may influence the emergence of Plasmodium falciparum artemisinin-resistant phenotypes and genotypes over time. Methods: Antibodies specific for P. falciparum antigens were determined in uncomplicated hyperparasitemic malaria patients over a 10-year period of declining malaria transmission and emerging artemisinin resistance in northwestern Thailand. We investigated the association between antibody levels and both parasite clearance time (PCt½) and artemisinin resistance-associated kelch13 genotypes over time. Results: Immunity to P. falciparum declined prior to 2004, preceding the emergence of artemisinin resistance-associated genotypes and phenotypes (maximum mean change in antibody level per year: anti-MSP142 = -0.17; 95% confidence interval [CI] = -.31 to -.04; P = .01). In this period of declining immunity, and in the absence of kelch13 mutations, PCt½ increased. Between 2007 and 2011, levels of antibodies fluctuated, and higher antibody levels were associated with faster PCt½ (maximum yearly change in PCt½, in hours: EBA140rII = -0.39; 95% CI = -.61 to -.17; P < .001). Conclusions: Understanding the impact of changing transmission and immunity on the emergence of artemisinin resistance is important particularly as increased malaria control and elimination activities may enhance immunological conditions for the expansion of artemisinin-resistant P. falciparum.
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Artemisininas/uso terapêutico , Resistência a Medicamentos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/imunologia , Plasmodium falciparum/efeitos dos fármacos , Adolescente , Adulto , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/sangue , Antimaláricos/uso terapêutico , Criança , Pré-Escolar , DNA de Protozoário/genética , Feminino , Humanos , Modelos Lineares , Estudos Longitudinais , Malária Falciparum/transmissão , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tailândia , Adulto JovemRESUMO
INTRODUCTION: Approximately 40% of children aged 6-59 months worldwide are anaemic. Iron-containing multiple micronutrient powders (MNPs) and iron supplements (syrup/drops) are used to combat anaemia in children in different parts of the world. However, evidence for functional benefits of iron supplementation in children is scarce, and potential risks remain poorly defined, particularly concerning diarrhoea and malaria. This trial aims to determine if: (1) the efficacy of iron supplements or MNPs (containing iron) given with malaria chemoprevention is superior to malaria chemoprevention alone, or (2) if the efficacy of malaria chemoprevention alone is superior to placebo on child cognitive development. METHODS AND ANALYSIS: IRMA is a four-arm, parallel-group, double-blinded, placebo-controlled, triple-dummy, randomised trial in Southern Malawi. The study recruits 2168 infants aged 6 months, with an intervention period of 6 months and a post-intervention period of a further 6 months. Children are randomised into four arms: (1) No intervention (placebo); (2) malaria chemoprevention only; (3) MNPs and malaria chemoprevention; and (4) iron syrup and malaria chemoprevention. The primary outcome, cognitive development (Cognitive Composite Score (CogCS)), is measured at the end of the 6 months intervention. Secondary outcomes include CogCS at a further 6 months post-intervention, motor, language and behavioural development, physical growth and prevalence of anaemia and iron deficiency. Safety outcomes include incidence of malaria and other infections, and prevalence of malaria parasitaemia during and post-intervention period. ETHICS AND DISSEMINATION: The trial is approved by the National Health Sciences Research Committee (#19/01/2213) (Malawi) and the Human Research Ethics Committee (WEHI: 19/012) (Australia). Written informed consent in the local language is obtained from each participant before conducting any study-related procedure. Results will be shared with the local community and internationally with academic and policy stakeholders. TRIAL REGISTRATION NUMBER: ACTRN12620000386932.
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Anemia , Malária , Lactente , Humanos , Criança , Ferro/uso terapêutico , Malaui/epidemiologia , Malária/prevenção & controle , Malária/tratamento farmacológico , Anemia/tratamento farmacológico , Suplementos Nutricionais , Quimioprevenção , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como AssuntoRESUMO
Bilinear pooling (BLP) refers to a family of operations recently developed for fusing features from different modalities predominantly for visual question answering (VQA) models. Successive BLP techniques have yielded higher performance with lower computational expense, yet at the same time they have drifted further from the original motivational justification of bilinear models, instead becoming empirically motivated by task performance. Furthermore, despite significant success in text-image fusion in VQA, BLP has not yet gained such notoriety in video question answering (video-QA). Though BLP methods have continued to perform well on video tasks when fusing vision and non-textual features, BLP has recently been overshadowed by other vision and textual feature fusion techniques in video-QA. We aim to add a new perspective to the empirical and motivational drift in BLP. We take a step back and discuss the motivational origins of BLP, highlighting the often-overlooked parallels to neurological theories (Dual Coding Theory and The Two-Stream Model of Vision). We seek to carefully and experimentally ascertain the empirical strengths and limitations of BLP as a multimodal text-vision fusion technique in video-QA using two models (TVQA baseline and heterogeneous-memory-enchanced 'HME' model) and four datasets (TVQA, TGif-QA, MSVD-QA, and EgoVQA). We examine the impact of both simply replacing feature concatenation in the existing models with BLP, and a modified version of the TVQA baseline to accommodate BLP that we name the 'dual-stream' model. We find that our relatively simple integration of BLP does not increase, and mostly harms, performance on these video-QA benchmarks. Using our insights on recent work in BLP for video-QA results and recently proposed theoretical multimodal fusion taxonomies, we offer insight into why BLP-driven performance gain for video-QA benchmarks may be more difficult to achieve than in earlier VQA models. We share our perspective on, and suggest solutions for, the key issues we identify with BLP techniques for multimodal fusion in video-QA. We look beyond the empirical justification of BLP techniques and propose both alternatives and improvements to multimodal fusion by drawing neurological inspiration from Dual Coding Theory and the Two-Stream Model of Vision. We qualitatively highlight the potential for neurological inspirations in video-QA by identifying the relative abundance of psycholinguistically 'concrete' words in the vocabularies for each of the text components (e.g., questions and answers) of the four video-QA datasets we experiment with.
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Therapeutic efficacy in COVID-19 is dependent upon disease severity (treatment effect heterogeneity). Unfortunately, definitions of severity vary widely. This compromises the meta-analysis of randomised controlled trials (RCTs) and the therapeutic guidelines derived from them. The World Health Organisation 'living' guidelines for the treatment of COVID-19 are based on a network meta-analysis (NMA) of published RCTs. We reviewed the 81 studies included in the WHO COVID-19 living NMA and compared their severity classifications with the severity classifications employed by the international COVID-NMA initiative. The two were concordant in only 35% (24/68) of trials. Of the RCTs evaluated, 69% (55/77) were considered by the WHO group to include patients with a range of severities (12 mild-moderate; 3 mild-severe; 18 mild-critical; 5 moderate-severe; 8 moderate-critical; 10 severe-critical), but the distribution of disease severities within these groups usually could not be determined, and data on the duration of illness and/or oxygen saturation values were often missing. Where severity classifications were clear there was substantial overlap in mortality across trials in different severity strata. This imprecision in severity assessment compromises the validity of some therapeutic recommendations; notably extrapolation of "lack of therapeutic benefit" shown in hospitalised severely ill patients on respiratory support to ambulant mildly ill patients is not warranted. Both harmonised unambiguous definitions of severity and individual patient data (IPD) meta-analyses are needed to guide and improve therapeutic recommendations in COVID-19. Achieving this goal will require improved coordination of the main stakeholders developing treatment guidelines and medicine regulatory agencies. Open science, including prompt data sharing, should become the standard to allow IPD meta-analyses.
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BACKGROUND: Most antibiotic prescribing occurs in primary care. Even within the same health facility, there may be differences between prescribers in their tendency to prescribe antibiotics, which may be masked by summary data. We aimed to quantify prescriber variability in antibiotic prescription to patients with acute fever in primary care clinics in Myanmar. METHODS: We conducted a secondary analysis of prescribing data from 1090 patient consultations with 40 prescribing doctors from a trial investigating the effect of point-of-care C-reactive protein (CRP) tests on antibiotic prescription for acute fever. We used multilevel logistic regression models to assess inter-prescriber variability in the decision to prescribe antibiotics. RESULTS: The median odds ratio (MOR) in the unadjusted model was 1.82 (95% CI: 1.47-2.56) indicating that when two prescribers from this population are randomly selected then in half of these pairs the odds of prescription will be greater than 1.82-fold higher in one prescriber than the other. The estimated variability from this sample of prescribers corresponds to a population of prescribers where the top 25% of prescribers will prescribe antibiotics to over 41% of patients while the bottom 25% will prescribe antibiotics to less than 23% of patients. Inter-prescriber variation in antibiotic prescribing remained after adjustment for patient characteristics and CRP information (P < 0.001). CONCLUSIONS: Despite sharing the same management guidelines, there was substantial inter-prescriber variation in antibiotic prescription to patients with acute fever. This variation should be considered when designing trials and stewardship programmes aiming to reduce inappropriate antibiotic prescribing.
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Introduction: Pregnant women have an increased risk of P. falciparum infection, which is associated with low birth weight and preterm delivery. VAR2CSA, a variant surface antigen expressed on the parasitized erythrocyte surface, enables sequestration in the placenta. Few studies have prospectively examined relationships between antibody responses during pregnancy and subsequent adverse birth outcomes, and there are limited data outside Africa. Methods: Levels of IgG against VAR2CSA domains (DBL3; DBL5) and a VAR2CSA-expressing placental-binding P. falciparum isolate (PfCS2-IE) were measured in 301 women enrolled at their first visit to antenatal care which occurred mid-pregnancy (median = 26 weeks, lower and upper quartiles = 22, 28). Associations between antibody levels at enrolment and placental infection, birthweight and estimated gestational age at delivery were assessed by linear and logistic regression with adjustment for confounders. For all outcomes, effect modification by gravidity and peripheral blood P. falciparum infection at enrolment was assessed. Results: Among women who had acquired P. falciparum infection at enrolment, those with higher levels of VAR2CSA antibodies (75th percentile) had infants with higher mean birthweight (estimates varied from +35g to +149g depending on antibody response) and reduced adjusted odds of placental infection (aOR estimates varied from 0.17 to 0.80), relative to women with lower levels (25th percentile) of VAR2CSA antibodies. However, among women who had not acquired an infection at enrolment, higher VAR2CSA antibodies were associated with increased odds of placental infection (aOR estimates varied from 1.10 to 2.24). Conclusions: When infected by mid-pregnancy, a better immune response to VAR2CSA-expressing parasites may contribute to protecting against adverse pregnancy outcomes.
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Anticorpos Antiprotozoários , Antígenos de Protozoários , Peso ao Nascer/imunologia , Imunoglobulina G , Malária Falciparum , Doenças Placentárias , Plasmodium falciparum , Complicações Parasitárias na Gravidez , Adolescente , Adulto , Anticorpos Antiprotozoários/sangue , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/sangue , Antígenos de Protozoários/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Estudos Longitudinais , Malária Falciparum/sangue , Malária Falciparum/imunologia , Doenças Placentárias/sangue , Doenças Placentárias/imunologia , Plasmodium falciparum/imunologia , Plasmodium falciparum/metabolismo , Gravidez , Complicações Parasitárias na Gravidez/sangue , Complicações Parasitárias na Gravidez/imunologiaRESUMO
BACKGROUND: Scrub typhus is an acute febrile illness caused by intracellular bacteria from the genus Orientia. It is estimated that one billion people are at risk, with one million cases annually mainly affecting rural areas in Asia-Oceania. Relative to its burden, scrub typhus is understudied, and treatment recommendations vary with poor evidence base. These knowledge gaps could be addressed by establishing an individual participant-level data (IPD) platform, which would enable pooled, more detailed and statistically powered analyses to be conducted. This study aims to assess the characteristics of scrub typhus treatment studies and explore the feasibility and potential value of developing a scrub typhus IPD platform to address unanswered research questions. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a systematic literature review looking for prospective scrub typhus clinical treatment studies published from 1998 to 2020. Six electronic databases (Ovid Embase, Ovid Medline, Ovid Global Health, Cochrane Library, Scopus, Global Index Medicus), ClinicalTrials.gov, and WHO ICTRP were searched. We extracted data on study design, treatment tested, patient characteristics, diagnostic methods, geographical location, outcome measures, and statistical methodology. Among 3,100 articles screened, 127 were included in the analysis. 12,079 participants from 12 countries were enrolled in the identified studies. ELISA, PCR, and eschar presence were the most commonly used diagnostic methods. Doxycycline, azithromycin, and chloramphenicol were the most commonly administered antibiotics. Mortality, complications, adverse events, and clinical response were assessed in most studies. There was substantial heterogeneity in the diagnostic methods used, treatment administered (including dosing and duration), and outcome assessed across studies. There were few interventional studies and limited data collected on specific groups such as children and pregnant women. CONCLUSIONS/SIGNIFICANCE: There were a limited number of interventional trials, highlighting that scrub typhus remains a neglected disease. The heterogeneous nature of the available data reflects the absence of consensus in treatment and research methodologies and poses a significant barrier to aggregating information across available published data without access to the underlying IPD. There is likely to be a substantial amount of data available to address knowledge gaps. Therefore, there is value for an IPD platform that will facilitate pooling and harmonisation of currently scattered data and enable in-depth investigation of priority research questions that can, ultimately, inform clinical practice and improve health outcomes for scrub typhus patients.
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Antibacterianos/uso terapêutico , Tifo por Ácaros/tratamento farmacológico , Azitromicina/uso terapêutico , Doxiciclina/uso terapêutico , Estudos de Viabilidade , Feminino , Humanos , Masculino , Orientia tsutsugamushi/efeitos dos fármacos , Orientia tsutsugamushi/fisiologia , Tifo por Ácaros/diagnóstico , Tifo por Ácaros/microbiologiaRESUMO
BACKGROUND: To contain multidrug-resistant Plasmodium falciparum, malaria elimination in the Greater Mekong subregion needs to be accelerated while current antimalarials remain effective. We evaluated the safety, effectiveness, and potential resistance selection of dihydroartemisinin-piperaquine mass drug administration (MDA) in a region with artemisinin resistance in Myanmar. METHODS: We did a cluster-randomised controlled trial in rural community clusters in Kayin (Karen) state in southeast Myanmar. Malaria prevalence was assessed using ultrasensitive quantitative PCR (uPCR) in villages that were operationally suitable for MDA (villages with community willingness, no other malaria control campaigns, and a population of 50-1200). Villages were eligible to participate if the prevalence of malaria (all species) in adults was greater than 30% or P falciparum prevalence was greater than 10% (or both). Contiguous villages were combined into clusters. Eligible clusters were paired based on P falciparum prevalence (estimates within 10%) and proximity. Community health workers provided routine malaria case management and distributed long-lasting insecticidal bed-nets (LLINs) in all clusters. Randomisation of clusters (1:1) to the MDA intervention group or control group was by public coin-flip. Group allocations were not concealed. Three MDA rounds (3 days of supervised dihydroartemisinin-piperaquine [target total dose 7 mg/kg dihydroartemisinin and 55 mg/kg piperaquine] and single low-dose primaquine [target dose 0·25 mg base per kg]) were delivered to intervention clusters. Parasitaemia prevalence was assessed at 3, 5, 10, 15, 21, 27, and 33 months. The primary outcomes were P falciparum prevalence at months 3 and 10. All clusters were included in the primary analysis. Adverse events were monitored from the first MDA dose until 1 month after the final dose, or until resolution of any adverse event occurring during follow-up. This trial is registered with ClinicalTrials.gov, NCT01872702. FINDINGS: Baseline uPCR malaria surveys were done in January, 2015, in 43 villages that were operationally suitable for MDA (2671 individuals). 18 villages met the eligibility criteria. Three villages in close proximity were combined into one cluster because a border between them could not be defined. This gave a total of 16 clusters in eight pairs. In the intervention clusters, MDA was delivered from March 4 to March 17, from March 30 to April 10, and from April 27 to May 10, 2015. The weighted mean absolute difference in P falciparum prevalence in the MDA group relative to the control group was -10·6% (95% CI -15·1 to -6·1; p=0·0008) at month 3 and -4·5% (-10·9 to 1·9; p=0·14) at month 10. At month 3, the weighted P falciparum prevalence was 1·4% (0·6 to 3·6; 12 of 747) in the MDA group and 10·6% (7·0 to 15·6; 56 of 485) in the control group. Corresponding prevalences at month 10 were 3·2% (1·5 to 6·8; 34 of 1013) and 5·8% (2·5 to 12·9; 33 of 515). Adverse events were reported for 151 (3·6%) of 4173 treated individuals. The most common adverse events were dizziness (n=109) and rash or itching (n=20). No treatment-related deaths occurred. INTERPRETATION: In this low-transmission setting, the substantial reduction in P falciparum prevalence resulting from support of community case management was accelerated by MDA. In addition to supporting community health worker case management and LLIN distribution, malaria elimination programmes should consider using MDA to reduce P falciparum prevalence rapidly in foci of higher transmission. FUNDING: The Global Fund to Fight AIDS, Tuberculosis and Malaria.
Assuntos
Artemisininas/farmacologia , Artemisininas/uso terapêutico , Resistência a Medicamentos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Quinolinas/uso terapêutico , Adolescente , Adulto , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Artemisininas/administração & dosagem , Criança , Análise por Conglomerados , Erradicação de Doenças , Quimioterapia Combinada , Feminino , Humanos , Malária Falciparum/epidemiologia , Masculino , Administração Massiva de Medicamentos , Mianmar/epidemiologia , Primaquina/administração & dosagem , Primaquina/uso terapêutico , Quinolinas/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: Lower respiratory infections constitute a major disease burden worldwide. Treatment is usually empiric and targeted towards typical bacterial pathogens. Understanding the prevalence of pathogens not covered by empirical treatment is important to improve diagnostic and treatment algorithms. METHODS: A prospective observational study in peri-urban communities of Yangon, Myanmar was conducted between July 2018 and April 2019. Sputum specimens of 299 adults presenting with fever and productive cough were tested for Mycobacterium tuberculosis (microscopy and GeneXpert MTB/RIF [Mycobacterium tuberculosis/resistance to rifampicin]) and Burkholderia pseudomallei (Active Melioidosis Detect Lateral Flow Assay and culture). Nasopharyngeal swabs underwent respiratory virus (influenza A, B, respiratory syncytial virus) polymerase chain reaction testing. RESULTS: Among 299 patients, 32% (95% confidence interval [CI] 26 to 37) were diagnosed with tuberculosis (TB), including 9 rifampicin-resistant cases. TB patients presented with a longer duration of fever (median 14 d) and productive cough (median 30 d) than non-TB patients (median fever duration 6 d, cough 7 d). One case of melioidosis pneumonia was detected by rapid test and confirmed by culture. Respiratory viruses were detected in 16% (95% CI 12 to 21) of patients. CONCLUSIONS: TB was very common in this population, suggesting that microscopy and GeneXpert MTB/RIF on all sputum samples should be routinely included in diagnostic algorithms for fever and cough. Melioidosis was uncommon in this population.
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Melioidose , Mycobacterium tuberculosis , Infecções Respiratórias , Tuberculose Pulmonar , Tuberculose , Adulto , Farmacorresistência Bacteriana , Humanos , Melioidose/diagnóstico , Melioidose/tratamento farmacológico , Melioidose/epidemiologia , Mianmar/epidemiologia , Atenção Primária à Saúde , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/epidemiologia , Sensibilidade e Especificidade , Escarro , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/epidemiologiaRESUMO
BACKGROUND: Little research has been published on the prevalence of rickettsial infections in Myanmar. This study determined the seroprevalence of immunoglobulin G (IgG) antibodies to rickettsial species in different regions of Myanmar. METHODS: Seven hundred leftover blood samples from patients of all ages in primary care clinics and hospitals in seven regions of Myanmar were collected. Samples were screened for scrub typhus group (STG), typhus group (TG) and spotted fever group (SFG) IgG antibodies using enzyme-linked immunosorbent assays (ELISA). Immunofluorescence assays were performed for the same rickettsial groups to confirm seropositivity if ELISA optical density ≥0.5. RESULTS: Overall IgG seroprevalence was 19% [95% confidence interval (CI) 16-22%] for STG, 5% (95% CI 3-7%) for TG and 3% (95% CI: 2-5%) for SFG. The seroprevalence of STG was particularly high in northern and central Myanmar (59% and 19-33%, respectively). Increasing age was associated with higher odds of STG and TG seropositivity [per 10-year increase, adjusted odds ratio estimate 1.68 (p < 0.01) and 1.24 (p = 0.03), respectively]. CONCLUSION: Rickettsial infections are widespread in Myanmar, with particularly high seroprevalence of STG IgG antibodies in central and northern regions. Healthcare workers should consider rickettsial infections as common causes of fever in Myanmar.
Assuntos
Infecções por Rickettsia/epidemiologia , Adulto , Anticorpos Antibacterianos/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Mianmar/epidemiologia , Infecções por Rickettsia/imunologia , Estudos SoroepidemiológicosRESUMO
METHODS: A priority-setting process (PSP) was launched to define priorities for patient-centered antimicrobial resistance (AMR) surveillance and research in low- and middle-income countries (LMICs). A list of uncertainties related to AMR surveillance in human health was generated using an online survey of stakeholders in LMICs, which asked for unanswered questions about diagnosis, treatment, or prevention of antibiotic resistance. RESULTS: A total of 445 respondents generated 1076 questions that were mapped to a final shortlist of 107 questions. The most common theme was the treatment of drug-resistant infections, followed by diagnosis, then prevention, and requests for local AMR data. The most asked question was a request for local AMR data, revealing the lack of basic information in many LMICs to guide actions to tackle AMR. The steering group recommended three research areas to be prioritized for funding in the next five years: infection prevention and control in LMICs, improved electronic patient records, starting with laboratory information management systems, and sustainable behavior change among doctors and other health care professionals with a focus on diagnostic stewardship.
Assuntos
Resistência Microbiana a Medicamentos , Infecções/tratamento farmacológico , Adulto , Feminino , Pessoal de Saúde , Inquéritos Epidemiológicos , Humanos , Controle de Infecções , Infecções/diagnóstico , Masculino , Pessoa de Meia-Idade , Assistência Centrada no Paciente , Fatores Socioeconômicos , Adulto JovemRESUMO
Background: Since the coronavirus disease 2019 (COVID-19) outbreak was first reported in December 2019, many independent trials have been planned that aim to answer similar questions. Tools allowing researchers to review studies already underway can facilitate collaboration, cooperation and harmonisation. The Infectious Diseases Data Observatory (IDDO) has undertaken a living systematic review (LSR) to provide an open, accessible and frequently updated resource summarising characteristics of COVID-19 study registrations. Methods: Review of all eligible trial records identified by systematic searches as of 3 April 2020 and initial synthesis of clinical study characteristics were conducted. In partnership with Exaptive, an open access, cloud-based knowledge graph has been created using the results. Results: There were 728 study registrations which met eligibility criteria and were still active. Median (25 th, 75 th percentile) sample size was 130 (60, 400) for all studies and 134 (70, 300) for RCTs. Eight lower middle and low income countries were represented among the planned recruitment sites. Overall 109 pharmacological interventions or advanced therapy medicinal products covering 23 drug categories were studied. Majority (57%, 62/109) of them were planned only in one study arm, either alone or in combination with other interventions. There were 49 distinct combinations studied with 90% (44/49) of them administered in only one or two study arms. The data and interactive platform are available at https://iddo.cognitive.city/. Conclusions: Baseline review highlighted that the majority of investigations in the first three months of the outbreak were small studies with unique treatment arms, likely to be unpowered to provide solid evidence. The continued work of this LSR will allow a more dependable overview of interventions tested, predict the likely strength of evidence generated, allow fast and informative filtering of relevant trials for specific user groups and provide the rapid guidance needed by investigators and funders to avoid duplication of efforts.
RESUMO
AbstractPostpartum women may have an altered susceptibility to Plasmodium falciparum and Plasmodium vivax. The relationship between naturally acquired malarial immunity and susceptibility to malaria postpartum is yet to be determined. IgG levels were measured against P. falciparum and P. vivax antigens from delivery in 201 postpartum and 201 nonpregnant controls over 12 weeks. Associations between time-varying antibody levels and time to first microscopically confirmed species-specific infection were determined by Cox regression. Associations between antibody levels and prospective risk of Plasmodium infection were similar in postpartum and control women. A 2-fold increase in P. falciparum antibody levels was associated with increased prospective risk of P. falciparum infection (hazard ratio [HR] range = 1.37-1.94). Antibody levels against most P. vivax antigens displayed no association with prospective risk of P. vivax infection (HR range = 1.02-1.05) with the exception of PvMSP119 antibodies that were weakly associated with prospective risk of P. vivax infection (HR = 1.14 (95% confidence interval = 1.02, 1.28) per 2-fold increase in levels). Associations between antibody levels and prospective risk of infection attenuated when adjusted for documented retrospective exposure. Serology may be a useful tool to predict and monitor women at increased risk of P. falciparum infection postpartum, particularly in the absence of a detailed history of retrospective infections.