Current Fluid Management Practice in Critically Ill Adults on Continuous Renal Replacement Therapy: A Binational, Observational Study.

INTRODUCTION: In critically ill patients undergoing continuous renal replacement therapy (CRRT), a positive fluid balance (FB) is associated with adverse outcomes. However, current FB management practices in CRRT patients are poorly understood. We aimed to study FB and its components in British and Australian CRRT patients to inform future trials. METHODS: We obtained detailed electronic health record data on all fluid-related variables during CRRT and hourly FB for the first 7 days of treatment. RESULTS: We studied 1,616 patients from three tertiary intensive care units (ICUs) in two countries. After the start of CRRT, the mean cumulative FB became negative at 31 h and remained negative over 7 days to a mean nadir of -4.1 L (95% confidence interval (CI) of -4.6 to -3.5). The net ultrafiltration (NUF) rate was the dominant fluid variable (-67.7 mL/h; standard deviation (SD): 75.7); however, residual urine output (-34.7 mL/h; SD: 54.5), crystalloid administration (48.1 mL/h; SD: 44.6), and nutritional input (36.4 mL/h; SD: 29.7) significantly contributed to FB. Patients with a positive FB after 72 h of CRRT were more severely ill, required high-dose vasopressors, and had high lactate concentrations (5.0 mmol/L; interquartile range: 2.3-10.5). A positive FB was independently associated with increased hospital mortality (odds ratio: 1.70; 95% CI; p = 0.004). CONCLUSION: In the study ICUs, most CRRT patients achieved a predominantly NUF-dependent negative FB. Patients with a positive FB at 72 h had greater illness severity and haemodynamic instability. Achieving equipoise for conducting trials that target a negative early FB in such patients may be difficult.

Cytochrome P450 2D6 profiles and anti-relapse efficacy of tafenoquine against Plasmodium vivax in Australian Defence Force personnel.

Plasmodium vivax infections and relapses remain a major health problem for malaria-endemic countries, deployed military personnel, and travelers. Presumptive anti-relapse therapy and radical cure using the 8-aminoquinoline drugs primaquine and tafenoquine are necessary to prevent relapses. Although it has been demonstrated that the efficacy of primaquine is associated with Cytochrome P450 2D6 (CYP2D6) activity, there is insufficient data on the role of CYP2D6 in the anti-relapse efficacy of tafenoquine. We investigated the relationship between CYP2D6 activity status and tafenoquine efficacy in preventing P. vivax relapses retrospectively using plasma samples collected from Australian Defence Force personnel deployed to Papua New Guinea and Timor-Leste who participated in clinical trials of tafenoquine during 1999-2001. The CYP2D6 gene was amplified from plasma samples and fully sequenced from 92 participant samples, comprised of relapse (n = 31) and non-relapse (n = 61) samples, revealing 14 different alleles. CYP2D6 phenotypes deduced from combinations of CYP2D6 alleles predicted that among 92 participants 67, 15, and 10 were normal, intermediate, and poor metabolizers, respectively. The deduced CYP2D6 phenotype did not correlate with the corresponding participant's plasma tafenoquine concentrations that were determined in the early 2000s by high-performance liquid chromatography or liquid chromatography-mass spectrometry. Furthermore, the deduced CYP2D6 phenotype did not associate with P. vivax relapse outcomes. Our results indicate that CYP2D6 does not affect plasma tafenoquine concentrations and the efficacy of tafenoquine in preventing P. vivax relapses in the assessed Australian Defence Force personnel.

A 5-year review of prevalence, temporal trends and characteristics of individuals experiencing moderate and severe food insecurity in 34 high income countries.

BACKGROUND: Due to the relatively low numbers of households in high income countries experiencing food insecurity most studies conflate the levels of severity, which masks between- and within-country differences. This study aims to describe the characteristics of individuals living in high income countries who were moderately or severely food insecure and investigates temporal trends in prevalence. It assesses these characteristics in comparison to those who were food secure. METHODS: This is a secondary analysis of data collected by the FAO Voices of the Hungry between 2014-2018. The data were collected during the annual Gallup World Polls of nationally representative samples using the Food Insecurity Experience Scale. Data from 34 highly developed, wealthy countries were analysed. The age, gender, income, education, area of residence and household structure of individuals experiencing moderate/severe food insecurity (FI), and severe FI, were compared using ANOVA, Welch's F, Pearson's Chi-square, and Linear-by-Linear Association, dependent on the variable of interest. Hierarchical cluster analysis was used to group countries according to their prevalence of moderate/severe FI, and severe FI. RESULTS: Overall, 6.5% of the weighted sample were moderately/severely food insecure (M-SFI), while 1.6% were severely food insecure. M-SFI individuals were present in all 34 countries, in all years and across all education levels and income quintiles. The proportion of individuals experiencing moderate/severe FI varied between years and countries. Fifteen countries showed a significant downward temporal trend in prevalence of moderate/severe FI (p < 0.001), while three countries demonstrated an increasing temporal trend driven by increasing prevalence in those aged 65 years or less (p < 0.001). Comparing individuals experiencing moderate versus severe FI showed over-representation of males, single adult households and lower household income in the severe FI group. CONCLUSIONS: Individuals across all income, education and age categories living in high income countries are experiencing moderate/severe food insecurity, but with higher prevalence in those experiencing more disadvantage. Over the study period some countries experienced escalating while others demonstrated decreasing moderate/severe FI trends. This comparison of countries with similar economic and human development indices highlights an opportunity to investigate subtle variations in social, economic and education policy that could have profound impacts on food insecurity.

Mapping the risk of respiratory infections using suburban district areas in a large city in Colombia.

BACKGROUND: Acute respiratory infections (ARI) in Cúcuta -Colombia, have a comparatively high burden of disease associated with high public health costs. However, little is known about the epidemiology of these diseases in the city and its distribution within suburban areas. This study addresses this gap by estimating and mapping the risk of ARI in Cúcuta and identifying the most relevant risk factors. METHODS: A spatial epidemiological analysis was designed to investigate the association of sociodemographic and environmental risk factors with the rate of ambulatory consultations of ARI in urban sections of Cúcuta, 2018. The ARI rate was calculated using a method for spatial estimation of disease rates. A Bayesian spatial model was implemented using the Integrated Nested Laplace Approximation approach and the Besag-York-Mollié specification. The risk of ARI per urban section and the hotspots of higher risk were also estimated and mapped. RESULTS: A higher risk of IRA was found in central, south, north and west areas of Cúcuta after adjusting for sociodemographic and environmental factors, and taking into consideration the spatial distribution of the city's urban sections. An increase of one unit in the percentage of population younger than 15 years; the Index of Multidimensional Poverty and the rate of ARI in the migrant population was associated with a 1.08 (1.06-1.1); 1.04 (1.01-1.08) and 1.25 (1.22-1.27) increase of the ARI rate, respectively. Twenty-four urban sections were identified as hotspots of risk in central, south, north and west areas in Cucuta. CONCLUSION: Sociodemographic factors and their spatial patterns are determinants of acute respiratory infections in Cúcuta. Bayesian spatial hierarchical models can be used to estimate and map the risk of these infections in suburban areas of large cities in Colombia. The methods of this study can be used globally to identify suburban areas and or specific communities at risk to support the implementation of prevention strategies and decision-making in the public and private health sectors.

The in-vivo dynamics of Plasmodium falciparum HRP2: implications for the use of rapid diagnostic tests in malaria elimination.

BACKGROUND: Rapid diagnostic tests (RDTs) that rely on the detection of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) have become key tools for diagnosing P. falciparum infection. The utility of RDTs can be limited by PfHRP2 persistence, however it can be a potential benefit in low transmission settings where detection of persistent PfHRP2 using newer ultra-sensitive PfHRP2 based RDTs can serve as a surveillance tool to identify recent exposure. Better understanding of the dynamics of PfHRP2 over the course of a malaria infection can inform optimal use of RDTs. METHODS: A previously published mathematical model was refined to mimic the production and decay of PfHRP2 during a malaria infection. Data from 15 individuals from volunteer infection studies were used to update the original model and estimate key model parameters. The refined model was applied to a cohort of patients from Namibia who received treatment for clinical malaria infection for whom longitudinal PfHRP2 concentrations were measured. RESULTS: The refinement of the PfHRP2 dynamic model indicated that in malaria naïve hosts, P. falciparum parasites of the 3D7 strain produce 33.6 × 10-15 g (95% CI 25.0-42.1 × 10-15 g) of PfHRP2 in vivo per parasite replication cycle, with an elimination half-life of 1.67 days (95% CI 1.11-3.40 days). The refined model included these updated parameters and incorporated individualized body fluid volume calculations, which improved predictive accuracy when compared to the original model. The performance of the model in predicting clearance of PfHRP2 post treatment in clinical samples from six adults with P. falciparum infection in Namibia improved when using a longer elimination half-life of 4.5 days, with 14% to 67% of observations for each individual within the predicted range. CONCLUSIONS: The updated mathematical model can predict the growth and clearance of PfHRP2 during the production and decay of a mono-infection with P. falciparum, increasing the understanding of PfHRP2 antigen dynamics. This model can guide the optimal use of PfHRP2-based RDTs for reliable diagnosis of P. falciparum infection and re-infection in endemic settings, but also for malaria surveillance and elimination programmes in low transmission areas.

Dormant Plasmodium falciparum Parasites in Human Infections Following Artesunate Therapy.

BACKGROUND: Artemisinin monotherapy of Plasmodium falciparum infection is frequently ineffective due to recrudescence. Artemisinin-induced dormancy, shown in vitro and in animal models, provides a plausible explanation. To date, direct evidence of artemisinin-induced dormancy in humans is lacking. METHODS: Blood samples were collected from Plasmodium falciparum 3D7- or K13-infected participants before and 48-72 hours after single-dose artesunate (AS) treatment. Parasite morphology, molecular signature of dormancy, capability and dynamics of seeding in vitro cultures, and genetic mutations in the K13 gene were investigated. RESULTS: Dormant parasites were observed in post-AS blood samples of 3D7- and K13-infected participants. The molecular signature of dormancy, an up-regulation of acetyl CoA carboxylase, was detected in 3D7 and K13 samples post-AS, but not in pre-AS samples. Posttreatment samples successfully seeded in vitro cultures, with a significant delay in time to reach 2% parasitemia compared to pretreatment samples. CONCLUSIONS: This study provides strong evidence for the presence of artemisinin-induced dormant parasites in P. falciparum infections. These parasites are a likely reservoir for recrudescent infection following artemisinin monotherapy and artemisinin combination therapy (ACT). Combination regimens that target dormant parasites or remain at therapeutic levels for a sufficient time to kill recovering parasites will likely improve efficacy of ACTs.

A comparative evaluation of mobile medical APPS (MMAS) for reading and interpreting malaria rapid diagnostic tests.

BACKGROUND: The World Health Organization recommends confirmatory diagnosis by microscopy or malaria rapid diagnostic test (RDT) in patients with suspected malaria. In recent years, mobile medical applications (MMAs), which can interpret RDT test results have entered the market. To evaluate the performance of commercially available MMAs, an evaluation was conducted by comparing RDT results read by MMAs to RDT results read by the human eye. METHODS: Five different MMAs were evaluated on six different RDT products using cultured Plasmodium falciparum blood samples at five dilutions ranging from 20 to 1000 parasites (p)/microlitre (µl) and malaria negative blood samples. The RDTs were performed in a controlled, laboratory setting by a trained operator who visually read the RDT results. A second trained operator then used the MMAs to read the RDT results. Sensitivity (Sn) and specificity (Sp) for the RDTs were calculated in a Bayesian framework using mixed models. RESULTS: The RDT Sn of the P. falciparum (Pf) test line, when read by the trained human eye was significantly higher compared to when read by MMAs (74% vs. average 47%) at samples of 20 p/µl. In higher density samples, the Sn was comparable to the human eye (97%) for three MMAs. The RDT Sn of test lines that detect all Plasmodium species (Pan line), when read by the trained human eye was significantly higher compared to when read by MMAs (79% vs. average 56%) across all densities. The RDT Sp, when read by the human eye or MMAs was 99% for both the Pf and Pan test lines across all densities. CONCLUSIONS: The study results show that in a laboratory setting, most MMAs produced similar results interpreting the Pf test line of RDTs at parasite densities typically found in patients that experience malaria symptoms (> 100 p/µl) compared to the human eye. At low parasite densities for the Pf line and across all parasite densities for the Pan line, MMAs were less accurate than the human eye. Future efforts should focus on improving the band/line detection at lower band intensities and evaluating additional MMA functionalities like the ability to identify and classify RDT errors or anomalies.

Climate variability, socio-ecological factors and dengue transmission in tropical Queensland, Australia: A Bayesian spatial analysis.

BACKGROUND: Dengue is a wide-spread mosquito-borne disease globally with a likelihood of becoming endemic in tropical Queensland, Australia. The aim of this study was to analyse the spatial variation of dengue notifications in relation to climate variability and socio-ecological factors in the tropical climate zone of Queensland, Australia. METHODS: Data on the number of dengue cases and climate variables including minimum temperature, maximum temperature and rainfall for the period of January 1st, 2010 to December 31st, 2015 were obtained for each Statistical Local Area (SLA) from Queensland Health and Australian Bureau of Meteorology, respectively. Socio-ecological data including estimated resident population, percentage of Indigenous population, housing structure (specifically terrace house), socio-economic index and land use types for each SLA were obtained from Australian Bureau of Statistics, and Australian Bureau of Agricultural and Resource Economics and Sciences, respectively. To quantify the relationship between dengue, climate and socio-ecological factors, multivariate Poisson regression models in a Bayesian framework were developed with a conditional autoregressive prior structure. Posterior parameters were estimated using Bayesian Markov Chain Monte Carlo simulation with Gibbs sampling. RESULTS: In the tropical climate zone of Queensland, the estimated number of dengue cases was predicted to increase by 85% [95% Credible Interval (CrI): 25%, 186%] and 7% (95% CrI: 0.1%, 14%) for a 1-mm increase in average annual rainfall and 1% increase in the proportion of terrace houses, respectively. The estimated spatial variation (structured random effects) was small compared to the remaining unstructured variation, suggesting that the inclusion of covariates resulted in no residual spatial autocorrelation in dengue data. CONCLUSIONS: Climate and socio-ecological factors explained much of the heterogeneity of dengue transmission dynamics in the tropical climate zone of Queensland. Results will help to further understand the risk factors of dengue transmission and will provide scientific evidence in designing effective local dengue control programs in the most needed areas.

Impact of Plasmodium falciparum gene deletions on malaria rapid diagnostic test performance.

BACKGROUND: Malaria rapid diagnostic tests (RDTs) have greatly improved access to diagnosis in endemic countries. Most RDTs detect Plasmodium falciparum histidine-rich protein 2 (HRP2), but their sensitivity is seriously threatened by the emergence of pfhrp2-deleted parasites. RDTs detecting P. falciparum or pan-lactate dehydrogenase (Pf- or pan-LDH) provide alternatives. The objective of this study was to systematically assess the performance of malaria RDTs against well-characterized pfhrp2-deleted P. falciparum parasites. METHODS: Thirty-two RDTs were tested against 100 wild-type clinical isolates (200 parasites/µL), and 40 samples from 10 culture-adapted and clinical isolates of pfhrp2-deleted parasites. Wild-type and pfhrp2-deleted parasites had comparable Pf-LDH concentrations. Pf-LDH-detecting RDTs were also tested against 18 clinical isolates at higher density (2,000 parasites/µL) lacking both pfhrp2 and pfhrp3. RESULTS: RDT positivity against pfhrp2-deleted parasites was highest (> 94%) for the two pan-LDH-only RDTs. The positivity rate for the nine Pf-LDH-detecting RDTs varied widely, with similar median positivity between double-deleted (pfhrp2/3 negative; 63.9%) and single-deleted (pfhrp2-negative/pfhrp3-positive; 59.1%) parasites, both lower than against wild-type P. falciparum (93.8%). Median positivity for HRP2-detecting RDTs against 22 single-deleted parasites was 69.9 and 35.2% for HRP2-only and HRP2-combination RDTs, respectively, compared to 96.0 and 92.5% for wild-type parasites. Eight of nine Pf-LDH RDTs detected all clinical, double-deleted samples at 2,000 parasites/µL. CONCLUSIONS: The pan-LDH-only RDTs evaluated performed well. Performance of Pf-LDH-detecting RDTs against wild-type P. falciparum does not necessarily predict performance against pfhrp2-deleted parasites. Furthermore, many, but not all HRP2-based RDTs, detect pfhrp2-negative/pfhrp3-positive samples, with implications for the HRP2-based RDT screening approach for detection and surveillance of HRP2-negative parasites.

Towards harmonization of microscopy methods for malaria clinical research studies.

Microscopy performed on stained films of peripheral blood for detection, identification and quantification of malaria parasites is an essential reference standard for clinical trials of drugs, vaccines and diagnostic tests for malaria. The value of data from such research is greatly enhanced if this reference standard is consistent across time and geography. Adherence to common standards and practices is a prerequisite to achieve this. The rationale for proposed research standards and procedures for the preparation, staining and microscopic examination of blood films for malaria parasites is presented here with the aim of improving the consistency and reliability of malaria microscopy performed in such studies. These standards constitute the core of a quality management system for clinical research studies employing microscopy as a reference standard. They can be used as the basis for the design of training and proficiency testing programmes as well as for procedures and quality assurance of malaria microscopy in clinical research.

Different responses of dengue to weather variability across climate zones in Queensland, Australia.

BACKGROUND: Dengue is a significant public health concern in northern Queensland, Australia. This study compared the epidemic features of dengue transmission among different climate zones and explored the threshold of weather variability for climate zones in relation to dengue in Queensland, Australia. METHODS: Daily data on dengue cases and weather variables including minimum temperature, maximum temperature and rainfall for the period of January 1, 2010 to December 31, 2015 were obtained from Queensland Health and Australian Bureau of Meteorology, respectively. Climate zones shape file for Australia was also obtained from Australian Bureau of Meteorology. Kruskal-Wallis test was performed to check whether the distribution of dengue significantly differed between climate zones. Time series regression tree model was used to estimate the threshold effects of the monthly weather variables on dengue in different climate zones. RESULTS: During the study period, the highest dengue incidence rate was found in the tropical climate zone (15.09/10,000) with the second highest in the grassland climate zone (3.49/10,000). Dengue responded differently to weather variability in different climate zones. In every climate zone, temperature was the primary predictor of dengue. However, the threshold values, type of temperature (e.g. maximum, minimum, or mean), and lag time for dengue varied between climate zones. Monthly mean temperature above 27°C at a lag of two months and monthly minimum temperature above 22°C at a lag of one month was found to be the most favourable weather condition for dengue in the tropical and subtropical climate zone, respectively. However, in the grassland climate zone, maximum temperature above 38°C at a lag of five months was found to be the ideal condition for dengue. Monthly rainfall with threshold value of 1.7 mm was found to be a significant contributor to dengue only in the tropical climate zone. CONCLUSIONS: The temperature threshold for dengue was lower in both tropical and subtropical climate zones than in the grassland climate zone. The different temperature threshold between climate zones suggests that an early warning system would need to be developed based on local socio-ecological conditions of the climate zone to manage dengue control and intervention programs effectively.

Cytochrome P450 2D6 profiles and their relationship with outcomes of primaquine anti-relapse therapy in Australian Defence Force personnel deployed to Papua New Guinea and East Timor.

BACKGROUND: Primaquine, an 8-aminoquinoline with anti-hypnozoite activity against Plasmodium vivax, is metabolized by human cytochrome P450 2D6 (CYP2D6) to its active metabolite. Human CYP2D6 activities may influence the metabolism of primaquine and the risk of experiencing Plasmodium relapses following primaquine anti-relapse therapies (PART). In this study, the CYP2D6 profile and its relationship with outcomes of PART in Australian Defence Force (ADF) personnel is retrospectively investigated. METHODS: Genomic DNA was isolated from stored and de-identified serum or blood samples from ADF personnel deployed on peacekeeping duties to Papua New Guinea (PNG) (1999) and East Timor (1999-2000) who received PART before returning to Australia and after experiencing relapses. CYP2D6 allelic type was determined by PCR and Sanger sequencing. CYP2D6 allele frequency, predicted phenotypes and activity scores were compared among personnel who did not experience P. vivax (ADF-NR, n = 48) and those who experience at least one (ADF-R, n = 109) relapse, as well as between those who experienced 1 (n = 79), 2 (n = 21) and 3-5 (n = 9) relapses within the ADF-R group. RESULTS: 16 CYP2D6 alleles were observed in 157 ADF personnel. Alleles *1, *4, *2 and *41 were major alleles (> 5%). The CYP2D6 allele frequency profile in the ADF-NR group matched that of a European population. There was an increased proportion of non-functional CYP2D6 alleles in the ADF-R group compared to the European population and ADF-NR group. However, frequencies of predicted CYP2D6 phenotype and activity score were not different between the ADF-R and ADF-NR groups, nor among sub-groups experiencing multiple relapses within the ADF-R group. CONCLUSIONS: CYP2D6 phenotype or activity score based on the allele classification was not a major contributor to P. vivax relapse in this ADF cohort. Other factors such as adherence and/or parasite tolerance to primaquine are likely contributing factors to P. vivax relapses in this cohort.

A review of the WHO malaria rapid diagnostic test product testing programme (2008-2018): performance, procurement and policy.

Malaria rapid diagnostic tests (RDTs) emerged in the early 1990s into largely unregulated markets, and uncertain field performance was a major concern for the acceptance of tests for malaria case management. This, combined with the need to guide procurement decisions of UN agencies and WHO Member States, led to the creation of an independent, internationally coordinated RDT evaluation programme aiming to provide comparative performance data of commercially available RDTs. Products were assessed against Plasmodium falciparum and Plasmodium vivax samples diluted to two densities, along with malaria-negative samples from healthy individuals, and from people with immunological abnormalities or non-malarial infections. Three measures were established as indicators of performance, (i) panel detection score (PDS) determined against low density panels prepared from P. falciparum and P. vivax wild-type samples, (ii) false positive rate, and (iii) invalid rate, and minimum criteria defined. Over eight rounds of the programme, 332 products were tested. Between Rounds 1 and 8, substantial improvements were seen in all performance measures. The number of products meeting all criteria increased from 26.8% (11/41) in Round 1, to 79.4% (27/34) in Round 8. While products submitted to further evaluation rounds under compulsory re-testing did not show improvement, those voluntarily resubmitted showed significant increases in P. falciparum (p = 0.002) and P. vivax PDS (p < 0.001), with more products meeting the criteria upon re-testing. Through this programme, the differentiation of products based on comparative performance, combined with policy changes has been influential in the acceptance of malaria RDTs as a case-management tool, enabling a policy of parasite-based diagnosis prior to treatment. Publication of product testing results has produced a transparent market allowing users and procurers to clearly identify appropriate products for their situation, and could form a model for introduction of other, broad-scale diagnostics.

Major Threat to Malaria Control Programs by Plasmodium falciparum Lacking Histidine-Rich Protein 2, Eritrea.

False-negative results for Plasmodium falciparum histidine-rich protein (HRP) 2-based rapid diagnostic tests (RDTs) are increasing in Eritrea. We investigated HRP gene 2/3 (pfhrp2/pfhrp3) status in 50 infected patients at 2 hospitals. We showed that 80.8% (21/26) of patients at Ghindae Hospital and 41.7% (10/24) at Massawa Hospital were infected with pfhrp2-negative parasites and 92.3% (24/26) of patients at Ghindae Hospital and 70.8% (17/24) at Massawa Hospital were infected with pfhrp3-negative parasites. Parasite densities between pfhrp2-positive and pfhrp2-negative patients were comparable. All pfhrp2-negative samples had no detectable HRP2/3 antigen and showed negative results for HRP2-based RDTs. pfhrp2-negative parasites were genetically less diverse and formed 2 clusters with no close relationships to parasites from Peru. These parasites probably emerged independently by selection in Eritrea. High prevalence of pfhrp2-negative parasites caused a high rate of false-negative results for RDTs. Determining prevalence of pfhrp2-negative parasites is urgently needed in neighboring countries to assist case management policies.

Implications of Parasites Lacking Plasmodium falciparum Histidine-Rich Protein 2 on Malaria Morbidity and Control When Rapid Diagnostic Tests Are Used for Diagnosis.

Background: Rapid diagnostic tests (RDTs) are an important tool for malaria diagnosis, with most using antibodies against Plasmodium falciparum histidine-rich protein 2 (PfHRP2). Reports of P. falciparum lacking this protein are increasing, creating a problem for diagnosis of falciparum malaria in locations without quality-assured microscopy. Methods: An agent-based stochastic simulation model of P. falciparum transmission was used to investigate the selective pressure exerted on parasite populations by use of RDTs for diagnosis of symptomatic cases. The model considered parasites with normal, reduced, or no PfHRP2, and diagnosis using PfHRP2-only or combination RDTs. Results: Use of PfHRP2-only RDTs in communities where a PfHRP2-negative parasite was introduced during the simulation resulted in transmission of the parasite in >80% of cases, compared with <30% for normal or PfHRP2-reduced parasites. Using PfHRP2-only RDTs in the presence of PfHRP2-negative parasites caused an increase in prevalence, reduced RDT positivity within symptomatic patients but no change in the number of antimalarial treatments due to false-negative RDT results. Diagnosis with PfHRP2/Pf-Plasmodium lactate dehydrogenase combination RDTs did not select for PfHRP2-negative parasites. Conclusions: The use of PfHRP2-only RDTs is sufficient to select P. falciparum parasites lacking this protein, thus posing a significant public health problem, which could be moderated by using PfHRP2/Pf-Plasmodium lactate dehydrogenase combination RDTs.

'Work it out': evaluation of a chronic condition self-management program for urban Aboriginal and Torres Strait Islander people, with or at risk of cardiovascular disease.

BACKGROUND: Chronic diseases disproportionately burden Aboriginal and Torres Strait Islander people in Australia, with cardiovascular (CV) diseases being the greatest contributor. To improve quality of life and life expectancy for people living with CV disease, secondary prevention strategies such as rehabilitation and self-management programs are critical. However, there is no published evidence examining the effect of chronic condition self-management (CCSM) group programs for Aboriginal and Torres Strait Islander people who have, or are at risk of, CV disease specifically. This study evaluates the Work It Out program for its effect on clinical outcome measures in urban Aboriginal and Torres Strait Islander participants with or at risk of CV disease. METHODS: This study was underpinned by a conceptual framework based on Aboriginal and Torres Strait Islander community control. Participants had at least one diagnosed CV disease, or at least one CV disease risk factor. Short-term changes in clinical outcome measures over (approximately) 12 weeks were evaluated with a quasi-experimental, pre-post test design, using paired t-tests. Factors contributing to positive changes were tested using general linear models. The outcome measures included blood pressure (mmHg), weight (kg), body mass index (kg/m2), waist and hip circumference (cm), waist to hip ratio (waist cm/hip cm) and six minute walk test (6MWT). RESULTS: Changes in several clinical outcome measures were detected, either within the entire group (n = 85) or within specific participant sub-groups. Participant's 6MWT distance improved by an average 0.053 km (95% CI: 0.01-0.07 km). The change in distance travelled was influenced by number of social and emotional wellbeing conditions participants presented with. The weight of participants classified with extreme obesity decreased on average by 1.6 kg (95% CI: 0.1-3.0 kg). Participants with high baseline systolic blood pressure demonstrated a mean decrease of 11 mmHg (95% CI: 3.2-18.8 mmHg). Change in blood pressure was influenced by the number of cardiovascular conditions participants experienced. CONCLUSIONS: Short-term improvements seen in some measures could indicate a trend for improvement in other indicators over the longer term. These results suggest the Work It Out program could be a useful model for cardiovascular rehabilitation and prevention for other urban Aboriginal and Torres Strait Islander populations.

Temporal patterns and predictors of bullying roles among adolescents in Vietnam: a school-based cohort study.

Although many cross-sectional studies have examined bullying experiences and correlated factors among adolescents in schools, relatively little is known about the extent to which bullying roles are stable or fluid over time. This short-term quantitative longitudinal study in Vietnam examined temporal patterns and predictors of bullying roles over an academic year. A total of 1424 middle and high school students aged 12-17 years completed two anonymous, self-administered questionnaires six months apart in 2014 and 2015. Young people were classified into different bullying roles as follow: not-involved (38.9%), victims only (24%), bullies only (6.6%), and bully-victims (40.4%) across the two times. About 60% of all surveyed students experienced bullying either as victim, bully, or bully-victim during the year. Of these students, nearly three in four indicated unstable bullying roles over time. Multivariate multinomial logistic regressions indicated factors ranging from individual (age, gender, and mental health) to family (social support, parental supervision and monitoring, witnessing parental violence, and conflict with siblings), school (perceived social support, teachers' attempt to stop bullying at school), and peers (social support, students' attempt to stop bullying at school) have significant associations with levels of bullying involvement. Implications for bullying prevention programs nationally and internationally are discussed.

Development and evaluation of a spatial decision support system for malaria elimination in Bhutan.

BACKGROUND: Bhutan has reduced its malaria incidence significantly in the last 5 years, and is aiming for malaria elimination by 2016. To assist with the management of the Bhutanese malaria elimination programme a spatial decision support system (SDSS) was developed. The current study aims to describe SDSS development and evaluate SDSS utility and acceptability through informant interviews. METHODS: The SDSS was developed based on the open-source Quantum geographical information system (QGIS) and piloted to support the distribution of long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) in the two sub-districts of Samdrup Jongkhar District. It was subsequently used to support reactive case detection (RACD) in the two sub-districts of Samdrup Jongkhar and two additional sub-districts in Sarpang District. Interviews were conducted to ascertain perceptions on utility and acceptability of 11 informants using the SDSS, including programme and district managers, and field workers. RESULTS: A total of 1502 households with a population of 7165 were enumerated in the four sub-districts, and a total of 3491 LLINs were distributed with one LLIN per 1.7 persons. A total of 279 households representing 728 residents were involved with RACD. Informants considered that the SDSS was an improvement on previous methods for organizing LLIN distribution, IRS and RACD, and could be easily integrated into routine malaria and other vector-borne disease surveillance systems. Informants identified some challenges at the programme and field level, including the need for more skilled personnel to manage the SDSS, and more training to improve the effectiveness of SDSS implementation and use of hardware. CONCLUSIONS: The SDSS was well accepted and informants expected its use to be extended to other malaria reporting districts and other vector-borne diseases. Challenges associated with efficient SDSS use included adequate skills and knowledge, access to training and support, and availability of hardware including computers and global positioning system receivers.

Mitochondrial Membrane Potential in a Small Subset of Artemisinin-Induced Dormant Plasmodium falciparum Parasites In Vitro.

Artemisinin-induced dormancy is a proposed mechanism for failures of monotherapy and is linked with artemisinin resistance in Plasmodium falciparum. The biological characterization and dynamics of dormant parasites are not well understood. Here we report that after dihydroartemisinin treatment in vitro, a small subset of morphologically dormant parasites was stained with rhodamine 123 (RH), a mitochondrial membrane potential marker, and persisted to recovery. RH-positive parasites sorted with fluorescence-activated cell sorting resumed growth at 10,000/well whereas RH-negative parasites failed to recover at 5 million/well. Furthermore, transcriptional activity for mitochondrial enzymes was detected only in RH-positive dormant parasites. Importantly, after treatment of dormant parasites with different concentrations of atovaquone, a mitochondrial inhibitor, the recovery of dormant parasites was delayed or stopped. This demonstrates that mitochondrial activity is critical for survival and regrowth of dormant parasites and that RH staining provides a means of identifying these parasites. These findings provide novel paths for studying and eradicating this dormant stage.

A simulation model of the within-host dynamics of Plasmodium vivax infection.

BACKGROUND: The benign reputation of Plasmodium vivax is at odds with the burden and severity of the disease. This reputation, combined with restricted in vitro techniques, has slowed efforts to gain an understanding of the parasite biology and interaction with its human host. METHODS: A simulation model of the within-host dynamics of P. vivax infection is described, incorporating distinctive characteristics of the parasite such as the preferential invasion of reticulocytes and hypnozoite production. The developed model is fitted using digitized time-series' from historic neurosyphilis studies, and subsequently validated against summary statistics from a larger study of the same population. The Chesson relapse pattern was used to demonstrate the impact of released hypnozoites. RESULTS: The typical pattern for dynamics of the parasite population is a rapid exponential increase in the first 10 days, followed by a gradual decline. Gametocyte counts follow a similar trend, but are approximately two orders of magnitude lower. The model predicts that, on average, an infected naïve host in the absence of treatment becomes infectious 7.9 days post patency and is infectious for a mean of 34.4 days. In the absence of treatment, the effect of hypnozoite release was not apparent as newly released parasites were obscured by the existing infection. CONCLUSIONS: The results from the model provides useful insights into the dynamics of P. vivax infection in human hosts, in particular the timing of host infectiousness and the role of the hypnozoite in perpetuating infection.