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EY Lukianova-Hleb et al. Hemozoin-generated vapor nanobubbles for transdermal reagent- and needle-free detection of malaria. Proc Natl Acad Sci U S A
Successful diagnosis, screening, and elimination of malaria critically depend on rapid and sensitive detection of this dangerous infection, preferably transdermally and without sophisticated reagents or blood drawing. . . .
KJ Vogel et al. Phylogenetic investigation of Peptide hormone and growth factor receptors in five dipteran genomes. Front Endocrinol (Lausanne)
Peptide hormones and growth factors bind to membrane receptors and regulate a myriad of processes in insects and other metazoans. . . .
J Rydzak et al. Human erythrocyte glycophorin C as the receptor for EBA-140 Plasmodium falciparum merozoite ligand. Postepy Hig Med Dosw (Online)
Erythrocyte invasion by the blood-stage Plasmodium falciparum parasites is a multistep process involving specific interactions between parasites and red blood cells. . . .
R Sundararajan et al. Barriers to Malaria Control among Marginalized Tribal Communities: A Qualitative Study. PLoS One
Malaria infection accounts for over one million deaths worldwide annually. . . .
DV Canyon et al. Insights in public health: systems thinking: basic constructs, application challenges, misuse in health, and how public health leaders can pave the way forward. Hawaii J Med Public Health
The strengthening of health systems is fundamental to improving health outcomes, crisis preparedness, and our capacity to meet global challenges, such as accelerating progress towards the Millennium Development Goals, reducing maternal and child mortality, combating HIV, malaria and other diseases, limiting the effects of a new influenza pandemic, and responding appropriately to climate change. . . .
F Carlini et al. HLA-G UTR Haplotype Conservation in the Malian Population: Association with Soluble HLA-G. PLoS One
The HLA-G molecule plays an important role in immunomodulation. . . .
Modelling recurrent events: comparison of statistical models with continuous and discontinuous risk intervals on recurrent malaria episodes data
Background: Recurrent events data analysis is common in biomedicine. Literature review indicates that most statistical models used for such data are often based on time to the first event or consider events within a subject as independent. Even when taking into account the non-independence of recurrent events within subjects, data analyses are mostly done with continuous risk interval models, which may not be appropriate for treatments with sustained effects (e.g., drug treatments of malaria patients). Furthermore, results can be biased in cases of a confounding factor implying different risk exposure, e.g. in malaria transmission: if subjects are located at zones showing different environmental factors implying different risk exposures. Methods: This work aimed to compare four different approaches by analysing recurrent malaria episodes from a clinical trial assessing the effectiveness of three malaria treatments [artesunate + amodiaquine (AS + AQ), artesunate + sulphadoxine-pyrimethamine (AS + SP) or artemether-lumefantrine (AL)], with continuous and discontinuous risk intervals: Andersen-Gill counting process (AG-CP), Prentice-Williams-Peterson counting process (PWP-CP), a shared gamma frailty model, and Generalized Estimating Equations model (GEE) using Poisson distribution. Simulations were also made to analyse the impact of the addition of a confounding factor on malaria recurrent episodes. Results: Using the discontinuous interval analysis, AG-CP and Shared gamma frailty models provided similar estimations of treatment effect on malaria recurrent episodes when adjusted on age category. The patients had significant decreased risk of recurrent malaria episodes when treated with AS + AQ or AS + SP arms compared to AL arm; Relative Risks were: 0.75 (95% CI (Confidence Interval): 0.62-0.89), 0.74 (95% CI: 0.62-0.88) respectively for AG-CP model and 0.76 (95% CI: 0.64-0.89), 0.74 (95% CI: 0.62-0.87) for the Shared gamma frailty model.With both discontinuous and continuous risk intervals analysis, GEE Poisson distribution models failed to detect the effect of AS + AQ arm compared to AL arm when adjusted for age category. The discontinuous risk interval analysis was found to be the more appropriate approach. Conclusion: Repeated event in infectious diseases such as malaria can be analysed with appropriate existing models that account for the correlation between multiple events within subjects with common statistical software packages, after properly setting up the data structures.
Background: Accurate early diagnosis and prompt treatment is one of the key strategies to control and prevent malaria in Ethiopia where both Plasmodium falciparum and Plasmodium vivax are sympatric and require different treatment regimens. Microscopy is the standard for malaria diagnosis at the health centres and hospitals whereas rapid diagnostic tests are used at community-level health posts. The current study was designed to assess malaria microscopy capacity of health facilities in Oromia Regional State and Dire Dawa Administrative City, Ethiopia. Methods: A descriptive cross-sectional study was conducted from February to April 2011 in 122 health facilities, where health professionals were interviewed using a pre-tested, standardized assessment tool and facilities' laboratory practices were assessed by direct observation. Results: Of the 122 assessed facilities, 104 (85%) were health centres and 18 (15%) were hospitals. Out of 94 health facilities reportedly performing blood films, only 34 (36%) used both thin and thick smears for malaria diagnosis. The quality of stained slides was graded in 66 health facilities as excellent, good and poor quality in 11(17%), 31 (47%) and 24 (36%) respectively. Quality assurance guidelines and malaria microscopy standard operating procedures were found in only 13 (11%) facilities and 12 (10%) had involved in external quality assessment activities, and 32 (26%) had supportive supervision within six months of the survey. Only seven (6%) facilities reported at least one staff's participation in malaria microscopy refresher training during the previous 12 months. Although most facilities, 96 (79%), had binocular microscopes, only eight (7%) had the necessary reagents and supplies to perform malaria microscopy. Treatment guidelines for malaria were available in only 38 (31%) of the surveyed facilities. Febrile patients with negative malaria laboratory test results were managed with artemether-lumefantrine or chloroquine in 51% (53/104) of assessed health facilities. Conclusions: The current study indicated that most of the health facilities had basic infrastructure and equipment to perform malaria laboratory diagnosis but with significant gaps in continuous laboratory supplies and reagents, and lack of training and supportive supervision. Overcoming these gaps will be critical to ensure that malaria laboratory diagnosis is of high-quality for better patient management.
While significant advances have been made in the prevention and treatment of malaria in recent years, these successes continue to fall short of the World Health Organization (WHO) goals for malaria control and elimination. For elimination strategies to be effective, limited disease transmission, achieved through rapid reduction in the infectious parasite reservoir and decreased gametocyte carriage, will be critical. Artemisinin-based combination therapy (ACT) forms the cornerstone of WHO-recommended treatment for uncomplicated Plasmodium falciparum malaria, and in combination with other effective interventions will undoubtedly play a vital role in elimination programmes. The gametocytocidal properties of artemisinins are a bonus attribute; there is epidemiological evidence of reductions in malaria incidence and transmission in African regions since the introduction of these agents. Many studies and analyses have specifically investigated the effects of the ACT, artemether-lumefantrine (AL) on gametocyte carriage. In this systematic review of 62 articles published between 1998 and January 2014, the effects of AL on gametocyte carriage and malaria transmission are compared with other artemisinin-based anti-malarials and non-ACT. The impact of AL treatment of asymptomatic carriers on population gametocyte carriage, and the potential future role of AL in malaria elimination initiatives are also considered. Despite the inherent difficulties in comparing data from a range of different studies that also utilized different diagnostic approaches to assess baseline gametocyte counts, the gametocytocidal effect of AL was proportionately consistent across the studies reviewed, suggesting that AL will continue to play a vital role in the treatment of malaria and contribute to clearing the path towards malaria elimination. However, the specific place of AL is the subject of much ongoing research and will undoubtedly be dependent on different demographic and geographical scenarios. Utilizing ACT, such as AL, within malaria elimination strategies is also associated with a number of other challenges, such as balancing potential increased use of ACT (e g, treatment of asymptomatic carriers and home-based treatment) with rational use and avoidance of drug resistance development.
Access to artemisinin-based combination therapy (ACT) and quinine in malaria holoendemic regions of western Kenya
Background: Artemisinin-based combination therapy (ACT) has been adopted as the most effective treatment against malaria in many endemic countries like Kenya while quinine has remained the second line. The objective of the current study was to assess access to Kenya's policy recommended anti-malarials, ACT and quinine in the public, private and not-for-profit drug outlets in western Kenya. Methods: A cross-sectional survey using purposive sampling of 288 outlets (126 public, 96 private, 66 not-for-profit) was conducted in western Kenya in two regions with varying Plasmodium falciparum endemicities. Information on access (availability, price, affordability) on ACT and quinine was collected using the WHO and Healthcare Associated Infection (HAI) standardized methodologies for availability, prices and affordability of drugs. From a Ministry of Health database, the following were included in the analyses: one (1) main public hospital, followed by random selection of five hospitals under this main facility. Eight other public outlets under each of the hospitals were selected, to a total of 96. Matching number of private outlets (n = 96), all (66) not-for-profit outlets and additional 30 public health facilities were sampled to get the required sample size of 288. Results: More public 76 (60.3%) and not-for-profit 27 (40.9%) outlets stocked subsidized ACT (artemether-lumefantrine, AL). Other artemisinin-based combinations were widely available for both children 93 (96.9%) and adults 82 (85.0%) in private outlets. Frequent stock-outs were in public in 106 (84%), reporting three times or more stock-outs in three months. Subsidized ACT (AL) was sold at median price of USD 0.94 and 0.75 in private and not-for-profit outlets respectively. The costs was higher than recommended price of USD 0.5 and requiring up to 0.20-0.25 days of disposable income for households in lowest economic status. Conclusion: There is low availability of subsidized ACT (AL) and higher frequency of stock-outs in government facilities, while private sector sells AL at higher prices, thus making it less affordable to many households. These factors determine the adherence to the dosing schedules during the treatment course and thus the evaluation of the subsidy policy, its implementation and role in malaria burden in this region is compulsory.
Background: Blood group O protects African children against severe malaria and has reached high prevalence in malarious regions. However, its role in malaria in pregnancy is ambiguous. In 839 delivering Ghanaian women, associations of ABO blood groups with Plasmodium falciparum infection were examined. Methods: Plasmodium falciparum infection was diagnosed in placental blood samples by microscopy and PCR assays. Present or past infection was defined as the detection of parasitaemia or haemozoin by microscopy, or a positive PCR result. Blood groups were inferred from genotyping rs8176719 (indicating the O allele) and rs8176746/rs8176747 (distinguishing the B allele from the A allele). Results: The majority of women had blood group O (55.4%); present or past P. falciparum infection was seen in 62.3% of all women. Among multiparae, the blood groups had no influence on P. falciparum infection. In contrast, primiparae with blood group O had significantly less present or past infection than women with non-O blood groups (61.5 vs 76.2%, P = 0.007). In multivariate analysis, the odds of present or past placental P. falciparum infection were reduced by 45% in blood group O primiparae (aOR, 0.55 [95% CI, 0.33-0.94]). Conclusions: The present study shows a clear protective effect of blood group O against malaria in primiparae. This accords with findings in severe malaria and in vitro results. The data underline the relevance of host genetic protection among primiparae, i.e. the high-risk group for malaria in pregnancy, and contribute to the understanding of high O allele frequencies in Africa.
Measurement of parasitological data by quantitative real-time PCR from controlled human malaria infection trials at the Walter Reed Army Institute of Research
Background: The use of quantitative real-time PCR (qPCR) has allowed for precise quantification of parasites in the prepatent period and greatly improved the reproducibility and statistical power of controlled human malaria infection (CHMI) trials. Parasitological data presented here are from non-immunized, control-challenged subjects who participated in two CHMI trials conducted at the Walter Reed Army Institute of Research (WRAIR). Methods: Standardized sporozoite challenge was achieved through the bite of five Anopheles stephensi mosquitoes infected with the 3D7clone of the NF54 strain of Plasmodium falciparum. Blood smears were scored positive when two unambiguous parasites were found. Analysis of parasitological PCR data was performed on log-transformed data using an independent sample t-test when comparing the two studies. The multiplication rate of blood-stage parasites was estimated using the linear model. Results: On average, parasites were detected 4.91 days (95% CI = 4.190 to 5.627) before smears. The earliest parasites were detected within 120 hours (5.01 days) after challenge. Parasite densities showed consistent cyclic patterns of blood-stage parasite growth in all volunteers. The parasite multiplication rates for both studies was 8.18 (95% CI = 6.162 to 10.20). Data showed that at low parasite densities, a combination of sequestration and stochastic effects of low copy number DNA may impact qPCR detection and the parasite detection limit. Conclusion: Smear positive is an endpoint which antimalarial rescue is imperative whereas early detection of parasitological data by qPCR can allow for better anticipation of the endpoint. This would allow for early treatment to reduce clinical illness and risk for study participants. To use qPCR as the primary endpoint in CHMI trials, an algorithm of two positives by qPCR where one of the positives must have parasite density of at least 2 parasites/muL is proposed.
"You're losing your Ghanaianess": understanding malaria decision-making among Africans visiting friends and relatives in the UK
Background: In the UK, the majority of imported malaria infections occur in the London area among UK residents of African origin who travel to Africa visiting friends and relatives (VFRs). Effective malaria prevention measures are available but there is little understanding of the factors that enhance and constrain their use among VFRs. Methods: Semi-structured interviews were undertaken with Africans resident in London who visited friends and relatives in Nigeria and Ghana (n = 20) and with African VFRs recently treated for malaria (n = 6). Data collection took place between December 2007 and February 2011. Information on migration patterns and travel of respondents was collected and the data were analysed using a framework analysis approach. Results: Knowledge of the link between mosquitoes and malaria was high. Factors influencing the use of mosquito avoidance methods included knowledge about the local environment, perceptions of the inevitability of contracting malaria, and a desire to fit with the norms of host families. Previous experience of bed nets, and the belief that more modern ways of preventing mosquito bites were available deterred people from using them. Chemoprophylaxis use was varied and influenced by: perceptions about continuing immunity to malaria; previous experiences of malaria illness; the cost of chemoprophylaxis; beliefs about the likely severity of malaria infections; the influence of friends in the UK; and, the way malaria is perceived and managed in Nigeria and Ghana. Malaria treatment was considered by many to be superior in Nigeria and Ghana than in the UK. A conceptual framework was developed to illustrate the manner in which these factors interact to affect malaria decisions. Conclusions: The use of malaria prevention among VFRs needs to be understood not only in terms of individual risk factors but also in relation to the context in which decisions are made. For VFRs, malaria decisions are undertaken across two distinct social and environmental contexts and within the structural constraints associated with each. Strategies for reducing the burden of malaria among VFRs that ignore this complexity are likely to face challenges. New approaches that take account of contextual as well as individual factors are required.
The challenge of artemisinin resistance can only be met by eliminating Plasmodium falciparum malaria across the Greater Mekong subregion
Artemisinin-based combinations are currently the most effective anti-malarials and, in addition to vector control, have led to significant declines in malaria morbidity and mortality. However, foci of artemisinin drug resistance have been identified in the Greater Mekong subregion (GMS) of the Asia Pacific, threatening the major gains made in malaria control and potentially creating a parasite pool that is more difficult to treat and eliminate. Efforts are underway to halt the spread of artemisinin resistance, including coordination of activities and funding, and identification of areas of suspected artemisinin resistance, now using a newly identified molecular marker. However, targeting resources to the containment of resistant parasites is likely inefficient and monitoring impact is challenging. A more sustainable solution is the rapid elimination of all Plasmodium falciparum parasites from the GMS. This strategy is more efficient for several reasons. First, a subregional strategy is in line with current commitment to elimination and will build upon the existing national political support for elimination as well as enhancing collaboration among countries. Second, the challenge of human mobility in the GMS is subregional in scope and requires a harmonized elimination strategy. Third, countries will need to improve and intensify malaria operations to reach elimination, and this will be a singular goal across the subregion. Rallying around the goal of P. falciparum elimination will not only utilize existing regional bodies to catalyze political and funding support, but will also leverage the funding already in place to achieve this subregional goal.
Background: Haemolytic conditions may contribute to disease pathogenesis and severe clinical manifestations through the liberation of free haemoglobin (Hb) and production of toxic free haem. Thus, free Hb and haem should be associated with altered MetHb and COHb levels in malaria as in other conditions. Methods: This study comprises data collected at three different sites: (i) a retrospective analysis of the first arterial blood gas result (ABGS) of any patient during 2010 at the University Hospital in Lisbon; (ii) a retrospective analysis of ABGS from patients with severe malaria admitted to the intensive care unit in Berlin, Germany; and (iii) a prospective study of non-invasive MetHb measurements in children with and without malaria in Lambarene, Gabon. Results: In Lisbon, the mean MetHb level was 1.4% (SD: 0.5) in a total of 17,834 ABGS. Only 11 of 98 samples with a MetHb level of >3.0 referred to infections. COHb levels showed no particular association with clinical conditions, including sepsis. In 13 patients with severe malaria in Berlin, the mean MetHb levels on admission was 1.29%, with 1.36% for cerebral malaria and 1.14% for non-cerebral malaria (P > 0.05). All COHb measurements were below 2.3%. In Lambarene, Gabon, 132 healthy children had a mean MetHb level of 1.57%, as compared to 150 children with malaria, with a value of 1.77% and 2.05% in uncomplicated and complicated cases, respectively (P < 0.01). Conclusions: The data appears consistent with the methaemoglobin/haem hypothesis in malaria and sepsis pathogenesis. However, although MetHb was significantly different between healthy controls and children with malaria in Africa, the difference was rather small, also when compared to previous studies. Still, non-invasive bedside MetHb testing may warrant further evaluation as it could be a simple adjuvant tool for prognosis in resource poor settings.
Background: Anti-malarial drug resistance in Plasmodium falciparum in India has historically travelled from northeast India along the Myanmar border. The treatment policy for P. falciparum in the region was, therefore, changed from chloroquine to artesunate (AS) plus sulphadoxine-pyrimethamine (SP) in selected areas in 2005 and in 2008 it became the first-line treatment. Recognizing that resistance to the partner drug can limit the useful life of this combination therapy, routine in vivo and molecular monitoring of anti-malarial drug efficacy through sentinel sites was initiated in 2009. Methods: Between May and October 2012, 190 subjects with acute uncomplicated falciparum malaria were enrolled in therapeutic efficacy studies in the states of Arunachal Pradesh, Tripura, and Mizoram. Clinical and parasitological assessments were conducted over 42 days of follow-up. Multivariate analysis was used to determine risk factors associated with treatment failure. Genotyping was done to distinguish re-infection from recrudescence as well as to determine the prevalence of molecular markers of antifolate resistance among isolates. Results: A total of 169 patients completed 42 days of follow-up at three sites. The crude and PCR-corrected Kaplan-Meier survival estimates of AS + SP were 60.8% (95% CI: 48.0-71.4) and 76.6% (95% CI: 64.1-85.2) in Gomati, Tripura; 74.6% (95% CI: 62.0-83.6) and 81.7% (95% CI: 69.4-89.5) in Lunglei, Mizoram; and, 59.5% (95% CI: 42.0-73.2) and 82.3% (95% CI: 64.6-91.6) in Changlang, Arunachal Pradesh. Most patients with P. falciparum cleared parasitaemia within 24 hours of treatment, but eight, including three patients who failed treatment, remained parasitaemic on day 3. Risk factors associated with treatment failure included age < five years, fever at the time of enrolment and AS under dosing. No adverse events were reported. Presence of dhfr plus dhps quintuple mutation was observed predominantly in treatment failure samples. Conclusion: AS + SP treatment failure was widespread in northeast India and exceeded the threshold for changing drug policy. Based on these results, in January 2013 the expert committee of the National Vector Borne Disease Control Programme formulated the first subnational drug policy for India and selected artemether plus lumefantrine as the new first-line treatment in the northeast. Continued monitoring of anti-malarial drug efficacy is essential for effective malaria control.
Plasmodium falciparum parasites lacking histidine-rich protein 2 and 3: a review and recommendations for accurate reporting
Malaria rapid diagnostic tests (RDTs) play a critical role in malaria case management, surveillance and case investigations. Test performance is largely determined by design and quality characteristics, such as detection sensitivity, specificity, and thermal stability. However, parasite characteristics such as variable or absent expression of antigens targeted by RDTs can also affect RDT performance. Plasmodium falciparum parasites lacking the PfHRP2 protein, the most common target antigen for detection of P. falciparum, have been reported in some regions. Therefore, accurately mapping the presence and prevalence of P. falciparum parasites lacking pfhrp2 would be an important step so that RDTs targeting alternative antigens, or microscopy, can be preferentially selected for use in such regions. Herein the available evidence and molecular basis for identifying malaria parasites lacking PfHRP2 is reviewed, and a set of recommended procedures to apply for future investigations for parasites lacking PfHRP2, is proposed.
Evaluation of community-based systems for the surveillance of day three-positive Plasmodium falciparum cases in Western Cambodia
Background: Delayed clearance of Plasmodium falciparum parasites is used as an operational indicator of potential artemisinin resistance. Effective community-based systems to detect P. falciparum cases remaining positive 72 hours after initiating treatment would be valuable for guiding case follow-up in areas of known resistance risk and for detecting areas of emerging resistance. Methods: Systems incorporating existing networks of village malaria workers (VMWs) to monitor day three-positive P. falciparum cases were piloted in three provinces in western Cambodia. Quantitative and qualitative data were used to evaluate the wider feasibility and sustainability of community-based surveillance of day three-positive P. falciparum cases. Results: Of 294 day-three blood slides obtained across all sites (from 297 day-0 positives), 63 were positive for P. falciparum, an overall day-three positivity rate of 21%. There were significant variations in the systems implemented by different partners. Full engagement of VMWs and health centre staff is critical. VMWs are responsible for a range of individual tasks including preparing blood slides on day-0, completing forms, administering directly observed therapy (DOT) on days 0-2, obtaining follow-up slides on day-three and transporting slides and paperwork to their supervising health centre. When suitably motivated, unsalaried VMWs are willing and able to produce good quality blood smears and achieve very high rates of DOT and day-three follow-up. Conclusions: Community-based surveillance of day-three P. falciparum cases is feasible, but highly intensive, and as such needs strong and continuous support, particularly supervision and training. The purpose and role of community-based day-three surveillance should be assessed in the light of resource requirements; scaling-up would need to be systematic and targeted, based on clearly defined epidemiological criteria. To be truly comprehensive, the system would need to be extended beyond VMWs to other public and private health providers.
Pharmacokinetic evaluation of intravenous artesunate in adults with uncomplicated falciparum malaria in Kenya: a phase II study
Background: Alternatives to treatment for malaria treatment of travellers are needed in the USA and in Europe for travellers who return with severe malaria infections. The objective of this study is to show the pharmacokinetic (PK) profile of intravenous artesunate (AS), which was manufactured under good manufacturing practice (GMP) conditions, in adults with uncomplicated falciparum malaria in Kenya. Methods: The PK parameters of intravenous AS manufactured under current cGMP were evaluated after a single dose of drug at 2.4 mg/kg infused over 2 min in 28 adults with uncomplicated Plasmodium falciparum malaria. Plasma concentrations of AS and dihydroartemisinin (DHA) were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) methodology. Pharmacokinetic data were analysed with a compartmental analysis for AS and DHA. Results: The results suggest there were no drug-related adverse events in any of the patients. After intravenous infusion, the concentration of the parent drug rapidly declined, and the AS was converted to DHA. AS and DHA showed mean elimination half-lives of 0.17 hours and 1.30 hours, respectively. The high mean peak concentration (Cmax) of AS was shown to be 28,558 ng/mL while the Cmax of DHA was determined to be 2,932 ng/mL. Significant variability was noted in the PK profiles of the 28 patients tested. For example, Cmax values of AS were calculated to range from 3,362 to 55,873 ng/mL, and the Cmax value of DHA was noted to vary from 1,493 to 5,569 ng/mL. The mean area under the curve (AUC) of AS was shown to be approximately half that of DHA (1,878 ng.h/mL vs 3,543 ng.h/mL). The DHA/AS ratio observed was 1.94 during the one-day single treatment, and the AUC and half- life measured for DHA were significantly larger and longer than for AS. Conclusions: Intravenous AS can provide much higher peak concentrations of AS when compared to concentrations achieved with oral therapy; this may be crucial for the rapid elimination of parasites in patients with severe malaria. Given the much longer half-life of DHA compared to the short half-life of AS, DHA also plays a significant role in treatment of severe malaria.