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Author(s): Daniel A. Pfeffer, Benedikt Ley, Rosalind E. Howes, Patrick Adu, Mohammad Shafiul Alam, Pooja Bansil, Yap Boum, Marcelo Brito, Pimlak Charoenkwan, Archie Clements, Liwang Cui, Zeshuai Deng, Ochaka Julie [...]

Objective To study dengue vector breeding patterns under a variety of conditions in public and private spaces; to explore the ecological, biological and social (eco-bio-social) factors involved in vector breeding and viral transmission, and to define the main implications for vector control. Methods In each of six Asian cities or periurban areas, a team randomly selected urban clusters for conducting standardized household surveys, neighbourhood background surveys and entomological surveys. They collected information on vector breeding sites, people's knowledge, attitudes and practices surrounding dengue, and the characteristics of the study areas. AII premises were inspected; larval indices were used to quantify vector breeding sites, and pupal counts were used to identify productive water container types and as a proxy measure for adult vector abundance. Findings The most productive vector breeding sites were outdoor water containers, particularly if uncovered, beneath shrubbery and unused for at least one week. Peridomestic and intradomestic areas were much more important for pupal production than commercial and public spaces other than schools and religious facilities. A complex but non-significant association was found between water supply and pupal counts, and lack of waste disposal services was associated with higher vector abundance in only one site. Greater knowledge about dengue and its transmission was associated with lower mosquito breeding and production. Vector control measures (mainly larviciding in one site) substantially reduced larval and pupal counts and 'pushed' mosquito breeding to alternative containers. Conclusion Vector breeding and the production of adult Aedes aegypti are influenced by a complex interplay of factors. Thus, to achieve effective vector management, a public health response beyond routine larviciding or focal spraying is essential. Objectif Etudier les schemas de reproduction des vecteurs de la dengue dans diverses conditions et dans des espaces publics et prives, rechercher les facteurs ecologiques, biologiques et sociaux impliques dans la reproduction de ces vecteurs et la transmission virale et determiner les principales implications pour la lutte antivectorielle. Methodes Dans six grandes villes ou zones periurbaines d'Asie, une equipe a selectionne au hasard des groupes urbains pour mener des enquetes aupres des rnenages standardisees, des enquetes de voisinage et des enquetes entomologiques. Les equipes ont recueilli des informations sur les sites de reproduction des vecteurs, les connaissances des habitants, les attitudes et les pratiques a propos de la dengue et les caracteristiques des zones etudiees. Tous les lieux ont ete inspectes; les equipes ont utilise les indices larvaires pour evaluer sur le plan quantitatif les sites de reproduction vectorielle et le decompte des pupes pour identifier les types d'objets renfermant de l'eau les plus productifs et pour servir de mesure indirecte de l'abondance des vecteurs adultes. Resultats Les sites de reproduction les plus productifs etaient les objets renfermant de I'eau situes a I'exterieur, en particulier lorsqu'ils etaient depourvus de couvercle, sous des broussailles et inutilises pendant au moins une semaine. Les zones peridornestiques et intradornestiques jouaient un role beaucoup plus important dans la production de pupes que les espaces commerciaux et publics autres que les ecoles et les edifices religieux. Une association complexe, mais non significative, a ete relevee entre l'approvisionnement en eau et le nombre de pupes decomptees et on a constate un lien entre le manque de services d'elimination des dechets et une plus grande abondance des vecteurs sur un site seulement. La presence de meilleures connaissances sur la dengue et sa transmission chez les habitants etait egalement associee une reproduction et a une production plus limitees des vecteurs. Les mesures de lutte antivectorielle (principalement I'application de larvicide sur le site) ont permis de reduire substantiellement les nin de larves et de pupes eta <> la reproduction des moustiques vers d'autres recipients. Conclusion Un ensemble interactif complexe de facteurs influe sur la reproduction et la production de moustiques Aedes aegypti adultes. Ainsi, pour gerer efficacement les populations vectorielles, une reponse de sante publique globale, allant au-dela des traitements larvicides de routine ou de la pulverisation focale, est indispensable. Objetivo Estudiar las caracteristicas de la reproduccion del vector del dengue en diversas condiciones en espacios publicos y privados; investigar los aspectos ecologicos, biologicos y sociales (ecobiosociales) que intervienen en la reproduccion del vector y la transmision del virus, y determinar las principales implicaciones para la lucha antivectorial. Metodos En cada una de las seis zonas urbanas o periurbanas de Asia estudiadas, un equipo selecciono al azar conglomerados urbanos para realizar encuestas de hogares normalizadas, encuestas basales del vecindario y estudios entomologicos. Reunieron informacion sobre los criaderos de vectores, los conocimientos de la gente al respecto, las actitudes y practicas relacionadas con el dengue, y las caracteristicas de las zonas estudiadas. Se inspeccionaron todos los locales, y se usaron los indices larvarios para cuantificar los criaderos del vector, y el numero de pupas para distinguir el tipo de contenedores de agua productivos y como indicador sustitutivo de la abundancia de vectores adultos. Resultados Los criaderos de vectores mas productivos fueron los contenedores de agua situados al aire libre, sobre todo los que estaban sin cubrir o debajo de arbustos, y los que no habian sido utilizados por lo menos en una semana. Las areas peridomesticas e intradomesticas contribuian a la produccion de pupas mucho mas que los espacios comerciales y publicos, exceptuando las escuelas y los centros religiosos. Se observo una relacion compleja aunque no significativa entre el suministro de agua y el numero de pupas, y la falta de servicios de evacuacion de desechos se asocio a una mayor abundancia de vectores en un solo sitio. La posesion de mayores conocimientos sobre el dengue y su transmision se asocio a una menor reproduccion y produccion de'mosquitos. Las medidas de lucha antivectorial (principalmente la aplicacion de larvicidas en un sitio) lograron reducir sustancialmente el numero de larvas y pupas y los criaderos de mosquitos hacia otros contenedores. Conclusion La reproduccion del vector y la produccion de Aedes aegypti adulto dependen de una compleja interaccion de factores. En consecuencia, para lograr controlar eficazmente los vectores, es fundamental articular una respuesta de salud publica que no se limite a la aplicacion de larvicidas o el rociamiento localizado., Introduction Dengue, which is the fastest re-emerging arboviral disease in the world, imposes a heavy economic and health burden on countries, families and individual patients. (1,2) In the absence of [...]

Five human cases of infection with the simian malaria parasite Plasmodium knowlesi from Palawan, the Philippines, were confirmed by nested PCR. This study suggests that this zoonotic infection is found [...]

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. Daniel Pfeffer and coauthors report on the assessment of glucose-6-phosphate dehydrogenase activity, which is required for safe use of some malaria treatments. Author summary: Why was this study done?: Complete cure of vivax malaria, the most geographically widespread malaria species, requires the use of 8-aminoquinoline drugs to clear dormant liver stages of the parasite ('radical cure'); however, these drugs can cause severe haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Ultraviolet (UV) spectrophotometry is used as the reference test to measure G6PD activity, for validating new point-of-care diagnostics, and to determine population-specific definitions of G6PD deficiency. Currently, there is no universal threshold to define G6PD deficiency, and each laboratory must invest time and resources to derive site- and laboratory-specific definitions of G6PD deficiency. What did the researchers do and find?: We pooled measurements of G6PD activity from studies conducted across different countries and laboratories worldwide. We assessed the comparability of spectrophotometry results between these laboratories to see whether a universal definition and diagnostic cutoff for G6PD deficiency could be determined. There was substantial variation in the performance and absolute measurements of spectrophotometry conducted in different laboratories, hindering the definition of a universal cutoff for G6PD deficiency. What do these findings mean?: These findings highlight the importance of quality-control measures to minimise the influence of laboratory procedures on observed measurements. The data suggest that while a robust universal, assay-specific G6PD activity cutoff value can be established for diagnosis of severe G6PD deficiency (<30% normal enzyme activity), this approach is less robust for diagnosing intermediate G6PD deficiency. Newly developed diagnostic assays that are less sensitive to laboratory conditions and require less sample preparation are required and may help provide more standardised quantitative G6PD activity measurements across different contexts. [ABSTRACT FROM AUTHOR]

Background: To reduce the risk of drug-induced haemolysis, all patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) prior to prescribing primaquine (PQ)-based radical cure for the treatment of vivax malaria. This systematic review and individual patient meta-analysis assessed the utility of a qualitative lateral flow assay from Access Bio/CareStart (Somerset, NJ) (CareStart Screening test for G6PD deficiency) for the diagnosis of G6PDd compared to the gold standard spectrophotometry (International Prospective Register of Systematic Reviews [PROSPERO]: CRD42019110994).Methods and Findings: Articles published on PubMed between 1 January 2011 and 27 September 2019 were screened. Articles reporting performance of the standard CSG from venous or capillary blood samples collected prospectively and considering spectrophotometry as gold standard (using kits from Trinity Biotech PLC, Wicklow, Ireland) were included. Authors of articles fulfilling the inclusion criteria were contacted to contribute anonymized individual data. Minimal data requested were sex of the participant, CSG result, spectrophotometry result in U/gHb, and haemoglobin (Hb) reading. The adjusted male median (AMM) was calculated per site and defined as 100% G6PD activity. G6PDd was defined as an enzyme activity of less than 30%. Pooled estimates for sensitivity and specificity, unconditional negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) were calculated comparing CSG results to spectrophotometry using a random-effects bivariate model. Of 11 eligible published articles, individual data were available from 8 studies, 6 from Southeast Asia, 1 from Africa, and 1 from the Americas. A total of 5,815 individual participant data (IPD) were available, of which 5,777 results (99.3%) were considered for analysis, including data from 3,095 (53.6%) females. Overall, the CSG had a pooled sensitivity of 0.96 (95% CI 0.90-0.99) and a specificity of 0.95 (95% CI 0.92-0.96). When the prevalence of G6PDd was varied from 5% to 30%, the unconditional NPV was 0.99 (95% CI 0.94-1.00), with an LR+ and an LR- of 18.23 (95% CI 13.04-25.48) and 0.05 (95% CI 0.02-0.12), respectively. Performance was significantly better in males compared to females (p = 0.027) but did not differ significantly between samples collected from capillary or venous blood (p = 0.547). Limitations of the study include the lack of wide geographical representation of the included data and that the CSG results were generated under research conditions, and therefore may not reflect performance in routine settings.Conclusions: The CSG performed well at the 30% threshold. Its high NPV suggests that the test is suitable to guide PQ treatment, and the high LR+ and low LR- render the test suitable to confirm and exclude G6PDd. Further operational studies are needed to confirm the utility of the test in remote endemic settings. [ABSTRACT FROM AUTHOR]

Background: Primarily impacting poor, rural populations, the zoonotic malaria Plasmodium knowlesi is now the main cause of human malaria within Malaysian Borneo. While data is increasingly available on symptomatic cases, little is known about community-level patterns of exposure and infection. Understanding the true burden of disease and associated risk factors within endemic communities is critical for informing evidence-based control measures. Methodology/Principal findings: We conducted comprehensive surveys in three areas where P. knowlesi transmission is reported: Limbuak, Pulau Banggi and Matunggung, Kudat, Sabah, Malaysia and Bacungan, Palawan, the Philippines. Infection prevalence was low with parasites detected by PCR in only 0.2% (4/2503) of the population. P. knowlesi PkSERA3 ag1 antibody responses were detected in 7.1% (95% CI: 6.2–8.2%) of the population, compared with 16.1% (14.6–17.7%) and 12.6% (11.2–14.1%) for P. falciparum and P. vivax. Sero-prevalence was low in individuals <10 years old for P. falciparum and P. vivax consistent with decreased transmission of non-zoonotic malaria species. Results indicated marked heterogeneity in transmission intensity between sites and P. knowlesi exposure was associated with agricultural work (OR 1.63; 95% CI 1.07–2.48) and higher levels of forest cover (OR 2.40; 95% CI 1.29–4.46) and clearing (OR 2.14; 95% CI 1.35–3.40) around houses. Spatial patterns of P. knowlesi exposure differed from exposure to non-zoonotic malaria and P. knowlesi exposed individuals were younger on average than individuals exposed to non-zoonotic malaria. Conclusions/Significance: This is the first study to describe serological exposure to P. knowlesi and associated risk factors within endemic communities. Results indicate community–level patterns of infection and exposure differ markedly from demographics of reported cases, with higher levels of exposure among women and children. Further work is needed to understand these variations in risk across a wider population and spatial scale. [ABSTRACT FROM AUTHOR]

The emergence of drug-resistant Plasmodium vivax poses problems for malaria control and elimination in some parts of the world, especially in developing countries where individuals are routinely exposed to the infection. The aim of this study was to determine the single nucleotide polymorphisms (SNPs) in dihydropteroate synthase ( pvdhps ) and dihydrofolate reductase ( pvdhfr ) genes associated with sulfadoxine-pyrimethamine (SP) drug resistance among P . vivax isolates collected in Palawan, Philippines. Genetic polymorphisms of pvdhps and pvdhfr were analysed by nested PCR. Analysis at specific codons I 13 P 33 F 57 S 58 T 61 S 117 I 173 associated with pyrimethamine resistance in the pvdhfr gene revealed that most of the samples (66/87, 75.9%) carried double mutation at positions I 13 P 33 F 57 R 58 T 61 N 117 I 173 , while only 18.4% (16/87) of the isolates carried the wild-type haplotype (I 13 P 33 F 57 S 58 T 61 S 117 I 173 ). For the pvdhps gene, the codons involved in sulfadoxine resistance S 382 A 383 K 512 A 553 V 585 were investigated. Single mutation at position S 382 G 383 K 512 A 553 V 585 was most observed in 68.0% (68/100) of the samples, whereas wild-type haplotype was found in 26.0% (26/100) of samples. The pvdhps and pvdhfr combination S 382 A 383 K 512 A 553 V 585 /I 13 P 33 F 57 S 58 T 61 S 117 I 173 (wild-type), S 382 G 383 K 512 A 553 V 585 /I 13 P 33 F 57 R 58 T 61 N 117 I 173 , and S 382 A 383 K 512 A 553 V 585 -I 13 P 33 F 57 R 58 T 61 N 117 I 173 were the most frequently observed combination haplotypes from the three study sites. The information on molecular markers associated with antifolate drug-resistance could help better understanding ofthe molecular epidemiology and situation of SP resistant P. vivax malaria in the country. Continuous surveillance of these genetic markers is necessary to monitor the evolution of SP resistance in the Philippines. [ABSTRACT FROM AUTHOR]

Objective: We evaluated a battery of Glucose-6-Phosphate Dehydrogenase diagnostic point-of-care tests (PoC) to assess the most suitable product in terms of performance and operational characteristics for remote areas. Methods: Samples were collected in Puerto Princesa City, Palawan, Philippines and tested for G6PD deficiency with a fluorescent spot test (FST; Procedure 203, Trinity Biotech, Ireland), the semiquantitative WST8/1-methoxy PMS (WST; Dojindo, Japan) and the Carestart G6PD Rapid Diagnostic Test (CSG; AccessBio, USA). Results were compared to spectrophotometry (Procedure 345, Trinity Biotech, Ireland). Sensitivity and specificity were calculated for each test with cut-off activities of 10%, 20%, 30% and 60% of the adjusted male median. Results: The adjusted male median was 270.5 IU/1012 RBC. FST and WST were tested on 621 capillary blood samples, the CSG was tested on venous and capillary blood on 302 samples. At 30% G6PD activity, sensitivity for the FST was between 87.7% (95%CI: 76.8% to 93.9%) and 96.5% (95%CI: 87.9% to 99.5%) depending on definition of intermediate results; the WST was 84.2% (95%CI: 72.1% to 92.5%); and the CSG was between 68.8% (95%CI: 41.3% to 89.0%) and 93.8% (95%CI: 69.8% to 99.8%) when the test was performed on capillary or venous blood respectively. Sensitivity of FST and CSG (tested with venous blood) were comparable (p>0.05). The analysis of venous blood samples by the CSG yielded significantly higher results than FST and CSG performed on capillary blood (p<0.05). Sensitivity of the CSG varied depending on source of blood used (p<0.05). Conclusion: The operational characteristics of the CSG were superior to all other test formats. Performance and operational characteristics of the CSG performed on venous blood suggest the test to be a good alternative to the FST. [ABSTRACT FROM AUTHOR]

The only currently available drug that effectively removes malaria hypnozoites from the human host is primaquine. The use of 8-aminoquinolines is hampered by haemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Recently a number of qualitative and a quantitative rapid diagnostic test (RDT) format have been developed that provide an alternative to the current standard G6PD activity assays. The WHO has recently recommended routine testing of G6PD status prior to primaquine radical cure whenever possible. A workshop was held in the Philippines in early 2015 to discuss key challenges and knowledge gaps that hinder the introduction of routine G6PD testing. Two point-of-care (PoC) test formats for the measurement of G6PD activity are currently available: qualitative tests comparable to malaria RDT as well as biosensors that provide a quantitative reading. Qualitative G6PD PoC tests provide a binomial test result, are easy to use and some products are comparable in price to the widely used fluorescent spot test. Qualitative test results can accurately classify hemizygous males, heterozygous females, but may misclassify females with intermediate G6PD activity. Biosensors provide a more complex quantitative readout and are better suited to identify heterozygous females. While associated with higher costs per sample tested biosensors have the potential for broader use in other scenarios where knowledge of G6PD activity is relevant as well. The introduction of routine G6PD testing is associated with additional costs on top of routine treatment that will vary by setting and will need to be assessed prior to test introduction. Reliable G6PD PoC tests have the potential to play an essential role in future malaria elimination programmes, however require an improved understanding on how to best integrate routine G6PD testing into different health settings. [ABSTRACT FROM AUTHOR]

Background: Japanese encephalitis virus (JEV) is an important cause of encephalitis in most of Asia, with high case fatality rates and often significant neurologic sequelae among survivors. The epidemiology of JE in the Philippines is not well defined. To support consideration of JE vaccine for introduction into the national schedule in the Philippines, we conducted a systematic literature review and summarized JE surveillance data from 2011 to 2014. Methods: We conducted searches on Japanese encephalitis and the Philippines in four databases and one library. Data from acute encephalitis syndrome (AES) and JE surveillance and from the national reference laboratory from January 2011 to March 2014 were tabulated and mapped. Results: We identified 29 published reports and presentations on JE in the Philippines, including 5 serologic surveys, 18 reports of clinical cases, and 8 animal studies (including two with both clinical cases and animal data). The 18 clinical studies reported 257 cases of laboratory-confirmed JE from 1972 to 2013. JE virus (JEV) was the causative agent in 7% to 18% of cases of clinical meningitis and encephalitis combined, and 16% to 40% of clinical encephalitis cases. JE predominantly affected children under 15 years of age and 6% to 7% of cases resulted in death. Surveillance data from January 2011 to March 2014 identified 73 (15%) laboratory-confirmed JE cases out of 497 cases tested. Summary: This comprehensive review demonstrates the endemicity and extensive geographic range of JE in the Philippines, and supports the use of JE vaccine in the country. Continued and improved surveillance with laboratory confirmation is needed to systematically quantify the burden of JE, to provide information that can guide prioritization of high risk areas in the country and determination of appropriate age and schedule of vaccine introduction, and to measure the impact of preventive measures including immunization against this important public health threat. Author Summary: Japanese encephalitis virus (JEV) is an important cause of neurologic infections in Asia, resulting in substantial disability and deaths. Although believed to be endemic in the Philippines, little is known of the epidemiology and geographic distribution of this disease in the country. We reviewed data from clinical studies, prevalence surveys and animal studies since the 1950s. Based on this review, JEV is an important cause of encephalitis and febrile illness in all three major island groups of the country. The majority of cases were seen in children younger than 15 years and males were more often affected than females. The national laboratory initiated testing of referred cases in 2009 and surveillance for acute encephalitis syndrome (AES) with laboratory confirmation of a subset of cases was established in 2011. From 2011 to 2014, there were 1,032 cases of suspected JE. Of 497 cases with specimens tested, 73 (15%) had laboratory-confirmed JE. Our findings confirm that JE has an extensive geographic distribution in the Philippines. These findings support the introduction of JE vaccine into the country's routine immunization program. [ABSTRACT FROM AUTHOR]

Dengue virus infection is a leading cause of morbidity among children in the Philippines in recent years. In order to investigate the association of HLA Class I and II alleles and dengue disease severity in a cohort of Filipino children, we performed a case control study in 2 hospitals in Metro Manila from June 2008 to December 2009. A total of 250 laboratory confirmed dengue patients and 300 healthy individuals aged 5 to 15 years old were typed for HLA-A, B and DRB1 alleles. The frequency of HLA-A*33:01 was significantly decreased in severe dengue (DHF/ DSS; Pc = 0.0016)) and DSS (Pc = 0.0032) compared to the background population. These findings support a previous study that this allele may confer protection against the severe form of dengue and provide the first evidence of HLA association with dengue in the Philippines. Future studies should be directed in investigating the possible mechanisms of protection. [ABSTRACT FROM AUTHOR]

The diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency is a crucial aspect in the current phases of malaria control and elimination, which will require the wider use of 8-aminoquinolines for both reducing Plasmodium falciparum transmission and achieving the radical cure of Plasmodium vivax. 8-aminoquinolines, such as primaquine, can induce severe haemolysis in G6PD-deficient individuals, potentially creating significant morbidity and undermining confidence in 8-aminoquinoline prescription. On the other hand, erring on the side of safety and excluding large numbers of people with unconfirmed G6PD deficiency from treatment with 8-aminoquinolines will diminish the impact of these drugs. Estimating the remaining G6PD enzyme activity is the most direct, accessible, and reliable assessment of the phenotype and remains the gold standard for the diagnosis of patients who could be harmed by the administration of primaquine. Genotyping seems an unambiguous technique, but its use is limited by cost and the large range of recognized G6PD genotypes. A number of enzyme activity assays diagnose G6PD deficiency, but they require a cold chain, specialized equipment, and laboratory skills. These assays are impractical for care delivery where most patients with malaria live. Improvements to the diagnosis of G6PD deficiency are required for the broader and safer use of 8-aminoquinolines to kill hypnozoites, while lower doses of primaquine may be safely used to kill gametocytes without testing. The discussions and conclusions of a workshop conducted in Incheon, Korea in May 2012 to review key knowledge gaps in G6PD deficiency are reported here. [ABSTRACT FROM AUTHOR]

Background: Identifying fine-scale spatial patterns of disease is essential for effective disease control and elimination programmes. In low resource areas without formal addresses, novel strategies are needed to locate residences of individuals attending health facilities in order to efficiently map disease patterns. We aimed to assess the use of Android tablet-based applications containing high resolution maps to geolocate individual residences, whilst comparing the functionality, usability and cost of three software packages designed to collect spatial information. Results: Using Open Data Kit GeoODK, we designed and piloted an electronic questionnaire for rolling cross sectional surveys of health facility attendees as part of a malaria elimination campaign in two predominantly rural sites in the Rizal, Palawan, the Philippines and Kulon Progo Regency, Yogyakarta, Indonesia. The majority of health workers were able to use the tablets effectively, including locating participant households on electronic maps. For all households sampled (n = 603), health facility workers were able to retrospectively find the participant household using the Global Positioning System (GPS) coordinates and data collected by tablet computers. Median distance between actual house locations and points collected on the tablet was 116 m (IQR 42–368) in Rizal and 493 m (IQR 258–886) in Kulon Progo Regency. Accuracy varied between health facilities and decreased in less populated areas with fewer prominent landmarks. Conclusions: Results demonstrate the utility of this approach to develop real-time high-resolution maps of disease in resource-poor environments. This method provides an attractive approach for quickly obtaining spatial information on individuals presenting at health facilities in resource poor areas where formal addresses are unavailable and internet connectivity is limited. Further research is needed on how to integrate these with other health data management systems and implement in a wider operational context. [ABSTRACT FROM AUTHOR]

We previously reported, significantly higher levels of Chymase and Tryptase in early stage plasma of DSS patients prior to the occurrence of shock suggesting a possible role of mast cells in dengue pathogenesis. To further investigate, we analyzed CMA1 promoter SNP (rs1800875) and TPSAB1 gene alleles , which encode the Human Chymase and α- and β- tryptase 1 enzymes respectively, for susceptibility to Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) in patients from hospitals in Vietnam (Ho Chi Minh City and Vinh Long) and the Philippines. While the CMA1 promoter SNP (rs1800875) was not associated with DHF/DSS, the homozygous form of α-tryptase allele was associated with DSS patients in Vinh Long and the Philippines (OR = 3.52, p < 0.0001; OR = 3.37, p < 0.0001, respectively) and with DHF in Ho Chi Minh City (OR = 2.54, p = 0.0084). Also, a statistically significant association was observed when DHF and DSS were combined in Vinh Long (OR = 1.5, p = 0.034) and the Philippines (OR = 2.36, p = 0.0004); in Ho Chi Minh City when DHF and DSS were combine an association was observed, but it was not statistically significant (OR = 1.5, p = 0.0505). Therefore, the α-tryptase might have a possible effect on the susceptibility to severe form of Dengue infection. [ABSTRACT FROM AUTHOR]

Background: The Philippines reports a high prevalence of soil-transmitted helminth (STH) infections despite the implementation of nationwide mass drug administration since 2006. The spatial variation of STH infections in the Philippines was last described using the 2005-2007 national STH and schistosomiasis survey. This study aimed to identify sociodemographic and environmental factors that drive STH transmission and predict high-risk areas in the Philippines., Methods: Epidemiological data on STH for students aged 5-16 years were obtained from the 2015 Philippines National Prevalence survey, while environmental data were extracted from satellite images and publicly available sources. Model-based geostatistics, implemented in a Bayesian framework, was used to identify sociodemographic and environmental correlates and predict high-risk areas for STH across the Philippines. The best-fitting model with the lowest deviance information criterion (DIC) was used to interpret the findings of the model and predict STH infection risk for the entire country. Risk maps were developed for each STH infection using the posterior means derived from the model., Findings: The prevalence of Ascaris lumbricoides (20.0%) and Trichuris trichiura (29.3%) was higher in the Visayas Island than in the Luzon and Mindanao Islands. Hookworm prevalence was highest in Mindanao Island (1.3%). Risk of A. lumbricoides was positively associated with males (odds ratio [OR]: 1.197; 97.5% Credible Interval [CrI]: 1.114, 1.286) and temperature (OR: 1.148; 97.5% CrI: 1.033, 1.291), while normalized difference vegetation index (OR: 0.354; 97.5% CrI: 0.138, 0.930) and soil pH (OR: 0.606; 97.5% CrI: 0.338, 0.949) were negatively associated with the transmission. T. trichiura risk was positively associated with males (OR: 1.261; 97.5% CrI: 1.173, 1.341), temperature (OR: 1.153; 97.5% CrI: 1.001, 1.301), and rainfall (OR: 1.004; 97.5% CrI: 1.011, 1.069). Hookworm risk was positively associated with males (OR: 2.142; 97.5% CrI: 1.537, 2.998), while children aged ≤12 years (OR: 0.435; 97.5% CrI: 0.252, 0.753) had a negative association with risk compared to those over 12 years. Focal areas of high risk were identified for A. lumbricoides and T. trichiura in the Visayas Island, and hookworm in the Mindanao Island., Interpretation: The spatial distribution of all three STH infections has considerably decreased since a previous national risk-mapping exercise. The high-risk areas identified in the study can be used to strategically target deworming and health education activities to further reduce the burden of STH and support progress toward elimination., Funding: The Australian Centre for the Control and Elimination of Neglected Tropical Diseases and the Australian National Health and Medical Research Council., Competing Interests: Authors have nothing to declare., (© 2023 The Authors.)

This report describes the MalariaGEN Pv4 dataset, a new release of curated genome variation data on 1,895 samples of Plasmodium vivax collected at 88 worldwide locations between 2001 and 2017. It includes 1,370 new samples contributed by MalariaGEN and VivaxGEN partner studies in addition to previously published samples from these and other sources. We provide genotype calls at over 4.5 million variable positions including over 3 million single nucleotide polymorphisms (SNPs), as well as short indels and tandem duplications. This enlarged dataset highlights major compartments of parasite population structure, with clear differentiation between Africa, Latin America, Oceania, Western Asia and different parts of Southeast Asia. Each sample has been classified for drug resistance to sulfadoxine, pyrimethamine and mefloquine based on known markers at the dhfr , dhps and mdr1 loci. The prevalence of all of these resistance markers was much higher in Southeast Asia and Oceania than elsewhere. This open resource of analysis-ready genome variation data from the MalariaGEN and VivaxGEN networks is driven by our collective goal to advance research into the complex biology of P. vivax and to accelerate genomic surveillance for malaria control and elimination., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 MalariaGEN et al.)

Background: Antimalarial antibody measurements are useful because they reflect historical and recent exposure to malaria. As such, they may provide additional information to assess ongoing transmission in low endemic or pre-elimination settings where cases are rare. In addition, the absence of antibody responses in certain individuals can indicate the cessation of transmission. Commercial malaria enzyme-linked immunosorbent assays (ELISA) detect antimalarial antibodies and are commonly used to screen blood donations for possible malaria infection. However, there is no standardized test to detect antimalarial antibodies for epidemiological use. Here we compared five commercially available ELISA kits (Trinity Biotech, newbio, DiaPro, Cellabs, and NovaTec) in search of a standardized tool for supporting claims of absence of malaria transmission. For comparison, a research-based (RB) ELISA protocol was performed alongside the commercial kits. Results: The commercial kits were first compared using serum samples from known malaria-unexposed individuals ( n = 223) and Toxoplasma -infected individuals ( n = 191) to assess specificity and cross-reactivity against non-malaria infections. In addition, 134 samples from ≥10-year-olds collected in a hyperendemic region in the Gambia in the early 1990s were used to assess sensitivity. Three out of five kits showed high sensitivity (90-92%), high specificity (98-99%), low cross-reactivity (0-3%) and were considered user-friendly (Trinity Biotech, newbio and NovaTec). Two of these kits (Trinity Biotech and NovaTec) were taken forward for epidemiological evaluation and results were compared to those using the RB-ELISA. Samples from two pre-elimination settings (Praia, Cape Verde; n = 1,396, and Bataan, the Philippines; n = 1,824) were tested. Serological results from both the Trinity Biotech kit and the RB-ELISA concurred with recent passively detected case counts in both settings. Results from the Trinity Biotech kit reflected a significant decrease in the number of reported cases in Bataan in the 1990s better than the RB-ELISA. Results from the NovaTec kit did not reflect transmission patterns in either setting. Conclusion: The Trinity Biotech commercial ELISA kit was considered reliable for epidemiological use and accurately described transmission patterns in two (previously) malaria endemic settings. The use of this simple and standardized serological tool may aid national control and elimination programs by confirming that regions are free from malaria., (Copyright © 2020 van den Hoogen, Bareng, Alves, Reyes, Macalinao, Rodrigues, Fernandes, Goméz, Hall, Singh, Fornace, Luchavez, Kitchen, Chiodini, Espino, Tetteh, Stresman, Sepúlveda and Drakeley.)

Background: Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed "radical cure"). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax., Methods: This multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to <100,000 parasites per microliter) and normal glucose-6-phosphate dehydrogenase (G6PD) activity (with normal activity defined as ≥70% of the median value determined at each trial site among 36 healthy male volunteers who were otherwise not involved in the trial). All patients received a 3-day course of chloroquine (total dose of 1500 mg). In addition, patients were assigned to receive a single 300-mg dose of tafenoquine on day 1 or 2 (260 patients), placebo (133 patients), or a 15-mg dose of primaquine once daily for 14 days (129 patients). The primary outcome was the Kaplan-Meier estimated percentage of patients who were free from recurrence at 6 months, defined as P. vivax clearance without recurrent parasitemia., Results: In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P<0.001) and 0.26 (95% CI, 0.18 to 0.39) with primaquine as compared with placebo (P<0.001). Tafenoquine was associated with asymptomatic declines in hemoglobin levels, which resolved without intervention., Conclusions: Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167 .).

Background: Recent gains in reducing the global burden of malaria are threatened by the emergence of Plasmodium falciparum resistance to artemisinins. The discovery that mutations in portions of a P. falciparum gene encoding kelch (K13)-propeller domains are the major determinant of resistance has provided opportunities for monitoring such resistance on a global scale., Methods: We analyzed the K13-propeller sequence polymorphism in 14,037 samples collected in 59 countries in which malaria is endemic. Most of the samples (84.5%) were obtained from patients who were treated at sentinel sites used for nationwide surveillance of antimalarial resistance. We evaluated the emergence and dissemination of mutations by haplotyping neighboring loci., Results: We identified 108 nonsynonymous K13 mutations, which showed marked geographic disparity in their frequency and distribution. In Asia, 36.5% of the K13 mutations were distributed within two areas--one in Cambodia, Vietnam, and Laos and the other in western Thailand, Myanmar, and China--with no overlap. In Africa, we observed a broad array of rare nonsynonymous mutations that were not associated with delayed parasite clearance. The gene-edited Dd2 transgenic line with the A578S mutation, which expresses the most frequently observed African allele, was found to be susceptible to artemisinin in vitro on a ring-stage survival assay., Conclusions: No evidence of artemisinin resistance was found outside Southeast Asia and China, where resistance-associated K13 mutations were confined. The common African A578S allele was not associated with clinical or in vitro resistance to artemisinin, and many African mutations appear to be neutral. (Funded by Institut Pasteur Paris and others.).

We previously reported, significantly higher levels of Chymase and Tryptase in early stage plasma of DSS patients prior to the occurrence of shock suggesting a possible role of mast cells in dengue pathogenesis. To further investigate, we analyzed CMA1 promoter SNP (rs1800875) and TPSAB1 gene alleles, which encode the Human Chymase and α- and β- tryptase 1 enzymes respectively, for susceptibility to Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) in patients from hospitals in Vietnam (Ho Chi Minh City and Vinh Long) and the Philippines. While the CMA1 promoter SNP (rs1800875) was not associated with DHF/DSS, the homozygous form of α-tryptase allele was associated with DSS patients in Vinh Long and the Philippines (OR=3.52, p<0.0001; OR=3.37, p<0.0001, respectively) and with DHF in Ho Chi Minh City (OR=2.54, p=0.0084). Also, a statistically significant association was observed when DHF and DSS were combined in Vinh Long (OR=1.5, p=0.034) and the Philippines (OR=2.36, p=0.0004); in Ho Chi Minh City when DHF and DSS were combine an association was observed, but it was not statistically significant (OR=1.5, p=0.0505). Therefore, the α-tryptase might have a possible effect on the susceptibility to severe form of Dengue infection., (Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Dengue is the most important mosquito-borne disease in the Philippines, especially in Metropolitan Manila where communities are socially and economically diverse, and city governments struggle to provide basic services such as continuously available, piped water supply to residents. We examined responses to introducing water container management to control dengue vectors in two diverse communities in Masagana City: Village A (gated community) and Village B (informal settlers community). The roll out of the intervention was carried out by the study team, dengue control personnel and local health workers (BHWs). A behavioural change framework was used to describe the community responses to the introduction of a new vector control intervention - household water container management. Although, the desired outcome was not achieved during the study's timeline, observation on processes of behaviour change underscored the importance of understanding the social nature of the urban communities, often overlooked structures when dengue control program and researchers introduce new dengue control interventions.

Background: Research has shown that the classical Stegomyia indices (or "larval indices") of the dengue vector Aedes aegypti reflect the absence or presence of the vector but do not provide accurate measures of adult mosquito density. In contrast, pupal indices as collected in pupal productivity surveys are a much better proxy indicator for adult vector abundance. However, it is unknown when it is most optimal to conduct pupal productivity surveys, in the wet or in the dry season or in both, to inform control services about the most productive water container types and if this pattern varies among different ecological settings., Methods: A multi-country study in randomly selected twelve to twenty urban and peri-urban neighborhoods ("clusters") of six Asian countries, in which all water holding containers were examined for larvae and pupae of Aedes aegypti during the dry season and the wet season and their productivity was characterized by water container types. In addition, meteorological data and information on reported dengue cases were collected., Findings: The study reconfirmed the association between rainfall and dengue cases ("dengue season") and underlined the importance of determining through pupal productivity surveys the "most productive containers types", responsible for the majority (>70%) of adult dengue vectors. The variety of productive container types was greater during the wet than during the dry season, but included practically all container types productive in the dry season. Container types producing pupae were usually different from those infested by larvae indicating that containers with larval infestations do not necessarily foster pupal development and thus the production of adult Aedes mosquitoes., Conclusion: Pupal productivity surveys conducted during the wet season will identify almost all of the most productive container types for both the dry and wet seasons and will therefore facilitate cost-effective targeted interventions.

This review provides details on the role of Geographical Information Systems (GIS) in current dengue surveillance systems and focuses on the application of open access GIS technology to emphasize its importance in developing countries, where the dengue burden is greatest. It also advocates for increased international collaboration in transboundary disease surveillance to confront the emerging global challenge of dengue.

In endemic areas in the absence of microscopy, the WHO case definition of malaria is the presence or a history of fever without other obvious cause. Yet there is little empirical evidence on the accuracy, predictability and reliability of clinical signs and symptoms for diagnosing malaria within different endemic settings. Studying patients in endemic communities in the Philippines, we found that fever alone did not discriminate well for malaria. In contrast, a sequential occurrence of fever, chills and/or sweating, or a combination of all three symptoms was a good general predictor of the disease. However, the place of diagnosis and observation (home or clinic), age, and season affected the positive predictive values obtained. Specificities and positive predictive values were greatest (over 80%) for those at most risk--children under 9 years of age in highly endemic communities--and were most reliable when the diagnosis was made at home. Predictive values were also greatest during the season when childhood acute lower respiratory infections in the study area increase. The good predictability of clinical signs and symptoms for high-risk groups suggests that simple protocols can be developed for the management of malaria in endemic areas of the Philippines.