Surveillance to achieve malaria elimination in eastern Myanmar: a 7-year observational study.

BACKGROUND: The collection and utilization of surveillance data is essential in monitoring progress towards achieving malaria elimination, in the timely response to increases in malaria case numbers and in the assessment of programme functioning. This paper describes the surveillance activities used by the malaria elimination task force (METF) programme which operates in eastern Myanmar, and provides an analysis of data collected from weekly surveillance, case investigations, and monitoring and evaluation of programme performance. METHODS: This retrospective analysis was conducted using data collected from a network of 1250 malaria posts operational between 2014 and 2021. To investigate changes in data completeness, malaria post performance, malaria case numbers, and the demographic details of malaria cases, summary statistics were used to compare data collected over space and time. RESULTS: In the first 3 years of the METF programme, improvements in data transmission routes resulted in a 18.9% reduction in late reporting, allowing for near real-time analysis of data collected at the malaria posts. In 2020, travel restrictions were in place across Karen State in response to COVID-19, and from February 2021 the military coup in Myanmar resulted in widescale population displacement. However, over that period there has been no decline in malaria post attendance, and the majority of consultations continue to occur within 48 h of fever onset. Case investigations found that 43.8% of cases travelled away from their resident village in the 3 weeks prior to diagnosis and 36.3% reported never using a bed net whilst sleeping in their resident village, which increased to 72.2% when sleeping away from their resident village. Malaria post assessments performed in 82.3% of the METF malaria posts found malaria posts generally performed to a high standard. CONCLUSIONS: Surveillance data collected by the METF programme demonstrate that despite significant changes in the context in which the programme operates, malaria posts have remained accessible and continue to provide early diagnosis and treatment contributing to an 89.3% decrease in Plasmodium falciparum incidence between 2014 and 2021.

Factors That Inform Individual Decision Making Between Active Surveillance, Hemithyroidectomy and Total Thyroidectomy for Low-Risk Thyroid Cancer: A Scoping Review.

Background: Due to the excellent prognosis and relatively high incidence of small low-risk thyroid cancers, more conservative management strategies such as active surveillance (AS) or hemithyroidectomy (HT) may be preferable to total thyroidectomy (TT) for patients seeking to balance long-term survival rates with the potential adverse effects of overtreatment. The aim of this review was to synthesize key factors or variables that inform patient decision making about treatment for low-risk thyroid cancer, from current primary investigations that presented participants with information facilitating this choice. Methods: Studies were identified from the Medline, Cochrane, and Embase databases up until March 2022. Study characteristics were extracted into a pre-piloted form. Factors were hypothesized to include treatment-related risks and possible outcomes and identified from a review of studies with consensus by discussion. Results: The search identified 444 unique studies: 397 were excluded on review of abstract and title with 47 studies undergoing a full text review and 6 studies identified to be eligible. Four were cross-sectional: one a prospective cohort study and one a mixed-methods study with both a prospective observational and qualitative component. The decisions addressed included: the choice between AS versus surgery (HT and/or TT) and HT versus TT and enrolled participants ranging from healthy volunteers to thyroid cancer patients. Treatment choice was the primary outcome in five studies. Across the studies, participants who were given the option of AS or surgery predominately chose the more conservative pathway, with a range of 70-84%. The major factors represented by information provision in the studies were risk of cancer recurrence or spread, need for hormone replacement therapy, and voice change. Conclusions: A framework of key factors informing patient treatment choice may be derived from current studies involving information provision for low-risk thyroid cancer management. Further research evaluating the efficacy and optimal timing for decision support interventions would help inform the design and clinical use of these tools to promote shared decision making.

Tumour volume is a predictor of lymphovascular invasion in differentiated small thyroid cancer.

Objectives: For small thyroid cancers (≤2 cm), tumour volume may better predict aggressive disease, defined by lymphovascular invasion (LVI) than a traditional single measurement of diameter. We aimed to investigate the relationship between tumour diameter, volume and associated LVI. Methods: Differentiated thyroid cancers (DTC) ≤ 2 cm surgically resected between 2007 and 2016 were analysed. Volume was calculated using the formula for an ellipsoid shape from pathological dimensions. A 'larger volume' cut-off was established by receiver operating characteristic (ROC) analysis using the presence of lateral cervical lymph node metastasis (N1b). Logistic regression was performed to compare the 'larger volume' cut-off to traditional measurements of diameter in the prediction. Results: During the study period, 2405 DTCs were surgically treated and 523 met the inclusion criteria. The variance of tumour volume relative to diameter increased exponentially with increasing tumour size; the interquartile ranges for the volumes of 10, 15 and 20 mm diameter tumours were 126, 491 and 1225 mm3, respectively. ROC analysis using volume to predict N1b disease established an optimal volume cut-off of 350 mm3 (area under curve = 0.59, P = 0.02) as 'larger volume'. 'Larger volume' DTC was an independent predictor for LVI in multivariate analysis (odds ratio (OR) = 1.7, P = 0.02), whereas tumour diameter > 1 cm was not (OR = 1.5, P = 0.13). Both the volume > 350 mm3 and dimension > 1 cm were associated with greater than five lymph node metastasis and extrathyroidal extension. Conclusion: In this study for small DTCs ≤ 2 cm, the volume of >350 mm3 was a better predictor of LVI than greatest dimension > 1 cm.

Longitudinal trends in malaria testing rates in the face of elimination in eastern Myanmar: a 7-year observational study.

BACKGROUND: Providing at-risk communities with uninterrupted access to early diagnosis and treatment is a key component in reducing malaria transmission and achieving elimination. As programmes approach malaria elimination targets it is critical that each case is tested and treated early, which may present a challenge when the burden of malaria is reduced. In this paper we investigate whether malaria testing rates decline over time and assess the impacts of integrating malaria and non-malaria services on testing rates in the malaria elimination task force (METF) programme in the Kayin state of Myanmar. METHODS: A retrospective analysis was conducted using weekly collected data on testing rates from a network of more than 1200 malaria posts during the period from 2014 to 2020. To determine whether monthly testing rates changed over the years of programme operations, and whether integrating malaria and non-malaria services impacted these testing rates, we fitted negative binomial mixed-effects regression models to aggregate monthly data, accounting for malaria seasonal variation. RESULTS: In the first year of malaria post operation, testing rates declined, correlating with a decline in attendance by people from outside the malaria post catchment area, but then remained fairly constant (the Rate Ratio (RR) for 2nd versus 1st year open ranged from 0.68 to 0.84 across the four townships included in the analysis, the RR for 3rd to 6th year versus 1st year open were similar, ranging from 0.59-0.78). The implementation of a training programme, which was intended to expand the role of the malaria post workers, had minimal impact on testing rates up to 24 months after training was delivered (RR for integrated versus malaria-only services ranged from 1.00 to 1.07 across METF townships). CONCLUSION: Despite the decline in malaria incidence from 2014 to 2020, there has been no decline in the malaria testing rate in the METF programme after the establishment of the complete malaria post network in 2016. While the integration of malaria posts with other health services provides benefits to the population, our evaluation questions the necessity of integrated services in maintaining malaria testing rates in areas approaching elimination of malaria.

Mass drug administrations with dihydroartemisinin-piperaquine and single low dose primaquine to eliminate Plasmodium falciparum have only a transient impact on Plasmodium vivax: Findings from randomised controlled trials.

BACKGROUND: Mass administrations of antimalarial drugs (MDA) have reduced the incidence and prevalence of P. falciparum infections in a trial in the Greater Mekong Subregion. Here we assess the impact of the MDA on P. vivax infections. METHODS: Between May 2013 and July 2017, four villages in each Myanmar, Vietnam, Cambodia and Lao PDR were selected based on high prevalence of P. falciparum infections. Eight of the 16 villages were randomly assigned to receive MDA consisting of three-monthly rounds of three-day courses of dihydroartemisinin-piperaquine and, except in Cambodia, a single low-dose of primaquine. Cross-sectional surveys were conducted at quarterly intervals to detect Plasmodium infections using ultrasensitive qPCR. The difference in the cumulative incidence between the groups was assessed through a discrete time survival approach, the difference in prevalence through a difference-in-difference analysis, and the difference in the number of participants with a recurrence of P. vivax infection through a mixed-effect logistic regression. RESULTS: 3,790 (86%) residents in the intervention villages participated in at least one MDA round, of whom 2,520 (57%) participated in three rounds. The prevalence of P. vivax infections fell from 9.31% to 0.89% at month 3 but rebounded by six months to 5.81%. There was no evidence that the intervention reduced the cumulative incidence of P.vivax infections (95% confidence interval [CI] Odds ratio (OR): 0.29 to 1.36). Similarly, there was no evidence of MDA related reduction in the number of participants with at least one recurrent infection (OR: 0.34; 95% CI: 0.08 to 1.42). CONCLUSION: MDA with schizontocidal drugs had a lasting effect on P. falciparum infections but only a transient effect on the prevalence of P. vivax infections. Radical cure with an 8-aminoquinoline will be needed for the rapid elimination of vivax malaria.

Potential herd protection against Plasmodium falciparum infections conferred by mass antimalarial drug administrations.

The global malaria burden has decreased over the last decade and many nations are attempting elimination. Asymptomatic malaria infections are not normally diagnosed or treated, posing a major hurdle for elimination efforts. One solution to this problem is mass drug administration (MDA), with success depending on adequate population participation. Here, we present a detailed spatial and temporal analysis of malaria episodes and asymptomatic infections in four villages undergoing MDA in Myanmar. In this study, individuals from neighborhoods with low MDA adherence had 2.85 times the odds of having a malaria episode post-MDA in comparison to those from high adherence neighborhoods, regardless of individual participation, suggesting a herd effect. High mosquito biting rates, living in a house with someone else with malaria, or having an asymptomatic malaria infection were also predictors of clinical episodes. Spatial clustering of non-adherence to MDA, even in villages with high overall participation, may frustrate elimination efforts.

Community engagement, social context and coverage of mass anti-malarial administration: Comparative findings from multi-site research in the Greater Mekong sub-Region.

BACKGROUND: Between 2013 and 2017, targeted malaria elimination (TME), a package of interventions that includes mass drug administration (MDA)-was piloted in communities with reservoirs of asymptomatic P. falciparum across the Greater Mekong sub-Region (GMS). Coverage in target communities is a key determinant of the effectiveness of MDA. Drawing on mixed methods research conducted alongside TME pilot studies, this article examines the impact of the community engagement, local social context and study design on MDA coverage. METHODS AND FINDINGS: Qualitative and quantitative data were collected using questionnaire-based surveys, semi-structured and in-depth interviews, focus group discussions, informal conversations, and observations of study activities. Over 1500 respondents were interviewed in Myanmar, Vietnam, Cambodia and Laos. Interview topics included attitudes to malaria and experiences of MDA. Overall coverage of mass anti-malarial administration was high, particularly participation in at least a single round (85%). Familiarity with and concern about malaria prompted participation in MDA; as did awareness of MDA and familiarity with the aim of eliminating malaria. Fear of adverse events and blood draws discouraged people. Hence, community engagement activities sought to address these concerns but their impact was mediated by the trust relationships that study staff could engender in communities. In contexts of weak healthcare infrastructure and (cash) poverty, communities valued the study's ancillary care and the financial compensation. However, coverage did not necessarily decrease in the absence of cash compensation. Community dynamics, affected by politics, village conformity, and household decision-making also affected coverage. CONCLUSIONS: The experimental nature of TME presented particular challenges to achieving high coverage. Nonetheless, the findings reflect those from studies of MDA under implementation conditions and offer useful guidance for potential regional roll-out of MDA: it is key to understand target communities and provide appropriate information in tailored ways, using community engagement that engenders trust.

The role of monitoring and evaluation to ensure functional access to community-based early diagnosis and treatment in a malaria elimination programme in Eastern Myanmar.

BACKGROUND: Improving access to early diagnosis and treatment (EDT) has increasingly proven to be a major contributor to decreasing malaria incidence in low-transmission settings. The Malaria Elimination Task Force (METF) has deployed malaria posts set up in Eastern Myanmar, providing free uninterrupted community-based access to EDT in more than 1200 villages. Ensuring high quality services are provided by these malaria posts is essential to reaching elimination targets. The present study aimed to determine the functionality of the malaria posts in the METF programme. METHODS: This report analysed routinely collected data (weekly reports, individual consultation, diagnostic test quality control) and data collected specifically during monitoring and evaluation visits using descriptive statistics and univariate logistic regression. The presence of major dysfunctions (stock-outs and reported closing; likely to impair the ability of the population to access EDT) or minor dysfunctions (no formal METF training, lack of regular salary, forms and manual not on-site, and low frequency of supervisor visits) and the ability to anticipate dysfunctions through analysis of weekly reports were assessed. RESULTS: A total of 65% of malaria posts had no major dysfunction identified during monitoring and evaluation visits, while 86% of malaria posts were fully stocked with tests and medicines used for treatment. Diagnosis was correctly conducted with few false positives and rare mis-speciation of results. Malaria post worker knowledge of malaria treatments showed few gaps, mostly in the treatment of more complex presentations. Malaria posts were well utilized in the population, with 94% of consultations occurring within the first 3 days of fever. In the regression analysis, reported stock-outs and delayed weekly reports were associated with observed major and minor dysfunctions in monitoring and evaluation visits, emphasizing the need to reinforce support to malaria post supervisors, who were responsible for the local logistics of supply and data transmission and day-to-day supervision. CONCLUSION: The malaria posts operating under the METF programme perform to a high standard, with the majority offering uninterrupted access to diagnosis and treatment, and high service uptake in the villages serviced by the programme. However, programme operations can be strengthened by increasing malaria post supervisor visits and re-training malaria post workers.

The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: A cluster randomised trial.

BACKGROUND: The emergence and spread of multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion (GMS) threatens global malaria elimination efforts. Mass drug administration (MDA), the presumptive antimalarial treatment of an entire population to clear the subclinical parasite reservoir, is a strategy to accelerate malaria elimination. We report a cluster randomised trial to assess the effectiveness of dihydroartemisinin-piperaquine (DP) MDA in reducing falciparum malaria incidence and prevalence in 16 remote village populations in Myanmar, Vietnam, Cambodia, and the Lao People's Democratic Republic, where artemisinin resistance is prevalent. METHODS AND FINDINGS: After establishing vector control and community-based case management and following intensive community engagement, we used restricted randomisation within village pairs to select 8 villages to receive early DP MDA and 8 villages as controls for 12 months, after which the control villages received deferred DP MDA. The MDA comprised 3 monthly rounds of 3 daily doses of DP and, except in Cambodia, a single low dose of primaquine. We conducted exhaustive cross-sectional surveys of the entire population of each village at quarterly intervals using ultrasensitive quantitative PCR to detect Plasmodium infections. The study was conducted between May 2013 and July 2017. The investigators randomised 16 villages that had a total of 8,445 residents at the start of the study. Of these 8,445 residents, 4,135 (49%) residents living in 8 villages, plus an additional 288 newcomers to the villages, were randomised to receive early MDA; 3,790 out of the 4,423 (86%) participated in at least 1 MDA round, and 2,520 out of the 4,423 (57%) participated in all 3 rounds. The primary outcome, P. falciparum prevalence by month 3 (M3), fell by 92% (from 5.1% [171/3,340] to 0.4% [12/2,828]) in early MDA villages and by 29% (from 7.2% [246/3,405] to 5.1% [155/3,057]) in control villages. Over the following 9 months, the P. falciparum prevalence increased to 3.3% (96/2,881) in early MDA villages and to 6.1% (128/2,101) in control villages (adjusted incidence rate ratio 0.41 [95% CI 0.20 to 0.84]; p = 0.015). Individual protection was proportional to the number of completed MDA rounds. Of 221 participants with subclinical P. falciparum infections who participated in MDA and could be followed up, 207 (94%) cleared their infections, including 9 of 10 with artemisinin- and piperaquine-resistant infections. The DP MDAs were well tolerated; 6 severe adverse events were detected during the follow-up period, but none was attributable to the intervention. CONCLUSIONS: Added to community-based basic malaria control measures, 3 monthly rounds of DP MDA reduced the incidence and prevalence of falciparum malaria over a 1-year period in areas affected by artemisinin resistance. P. falciparum infections returned during the follow-up period as the remaining infections spread and malaria was reintroduced from surrounding areas. Limitations of this study include a relatively small sample of villages, heterogeneity between villages, and mobility of villagers that may have limited the impact of the intervention. These results suggest that, if used as part of a comprehensive, well-organised, and well-resourced elimination programme, DP MDA can be a useful additional tool to accelerate malaria elimination. TRIAL REGISTRATION: ClinicalTrials.gov NCT01872702.

Contribution of Asymptomatic Plasmodium Infections to the Transmission of Malaria in Kayin State, Myanmar.

BACKGROUND: The objective of mass antimalarial drug administration (MDA) is to eliminate malaria rapidly by eliminating the asymptomatic malaria parasite reservoirs and interrupting transmission. In the Greater Mekong Subregion, where artemisinin-resistant Plasmodium falciparum is now widespread, MDA has been proposed as an elimination accelerator, but the contribution of asymptomatic infections to malaria transmission has been questioned. The impact of MDA on entomological indices has not been characterized previously. METHODS: MDA was conducted in 4 villages in Kayin State (Myanmar). Malaria mosquito vectors were captured 3 months before, during, and 3 months after MDA, and their Plasmodium infections were detected by polymerase chain reaction (PCR) analysis. The relationship between the entomological inoculation rate, the malaria prevalence in humans determined by ultrasensitive PCR, and MDA was characterized by generalized estimating equation regression. RESULTS: Asymptomatic P. falciparum and Plasmodium vivax infections were cleared by MDA. The P. vivax entomological inoculation rate was reduced by 12.5-fold (95% confidence interval [CI], 1.6-100-fold), but the reservoir of asymptomatic P. vivax infections was reconstituted within 3 months, presumably because of relapses. This was coincident with a 5.3-fold (95% CI, 4.8-6.0-fold) increase in the vector infection rate. CONCLUSION: Asymptomatic infections are a major source of malaria transmission in Southeast Asia.

Sonographic Volumetric Assessment Is a More Accurate Measure Than Maximum Diameter Alone in Papillary Thyroid Cancer.

BACKGROUND: Tumor size is an important prognostic factor in papillary thyroid cancer (PTC). Management guidelines, staging systems, and pathological definitions use maximum diameter (Dmax) as a surrogate marker of tumor size. However, PTC nodules are three-dimensional (3D) structures, with behavior reflective of tumor cell count, which is directly proportional to volume. We explored the relationship between sonographically determined Dmax, volume, and lymph node status (LNS) in a cohort of patients with PTC. METHODS: All patients treated for PTC between 2003 and 2015 in our institution who had sonographic 3D nodule measurements available were evaluated. We examined the relationship between diameter, volume, and LNS. RESULTS: A total of 159 nodules in 153 patients met the inclusion criteria. Mean nodule dimensions were 2.4 × 1.9 × 1.5 cm, giving "ideal" nodule dimensions of y × 0.78y × 0.62y, where y is the Dmax. Observed volumes differed from predicted nodule volumes by an average of 26.2%. For PTC ≤2 cm, the coefficient of variation was 26.7%. Dmax did not correlate with the presence of lymph node metastases (Pearson coefficient 0.08), whereas volume very weakly correlated with LNS (Pearson coefficient 0.22). However, both Dmax and volume correlated very strongly with the number of nodal metastases (Pearson coefficients 0.93 and 0.89, respectively). CONCLUSIONS: PTC nodules demonstrated significant volume heterogeneity, rendering Dmax an inaccurate marker of true tumor size. Although there was little difference between Dmax and volume in predicting nodal status or nodal disease burden, we propose that a prospective, randomized trial might demonstrate a clear clinical advantage of 3D sonographic nodule measurement over Dmax alone.

Operational Performance of a Plasmodium falciparum Ultrasensitive Rapid Diagnostic Test for Detection of Asymptomatic Infections in Eastern Myanmar.

In the Greater Mekong Subregion in Southeast Asia, malaria elimination strategies need to target all Plasmodium falciparum parasites, including those carried asymptomatically. More than 70% of asymptomatic carriers are not detected by current rapid diagnostic tests (RDTs) or microscopy. An HRP2-based ultrasensitive RDT (uRDT) developed to improve the detection of low-density infections was evaluated during prevalence surveys within a malaria elimination program in a low-transmission area of eastern Myanmar. Surveys were conducted to identify high-prevalence villages. Two-milliliter venous blood samples were collected from asymptomatic adult volunteers and transported to the laboratory. Plasmodium parasites were detected by RDT, uRDT, microscopy, ultrasensitive qPCR (uPCR), and multiplex enzyme-linked immunosorbent assay (ELISA). The sensitivity, specificity, and predictive positive and negative values of RDT and uRDT were calculated compared to uPCR and ELISA. Parasite and antigen concentrations detected by each test were defined using uPCR and ELISA, respectively. A total of 1,509 samples, including 208 P. falciparum-positive samples were analyzed with all tests. The sensitivity of the uRDT was twofold higher than that of RDT, 51.4% versus 25.2%, with minor specificity loss, 99.5% versus 99.9%, against the combined reference (uPCR plus ELISA). The geometric mean parasitemia detected by uRDT in P. falciparum monospecific infections was 3,019 parasites per ml (95% confidence interval [95% CI], 1,790 to 5,094; n = 79) compared to 11,352 parasites per ml (95% CI, 5,643 to 22,837; n = 38) by RDT. The sensitivities of uRDT and RDT dropped to 34.6% and 15.1%, respectively, for the matched tests performed in the field. The uRDT performed consistently better than RDT and microscopy at low parasitemias. It shows promising characteristics for the identification of high-prevalence communities and warrants further evaluation in mass screening and treatment interventions.

"Nine Dimensions": A multidisciplinary approach for community engagement in a complex postwar border region as part of the targeted malaria elimination in Karen/Kayin State, Myanmar.

Background: In light of growing antimalarial drug resistance in Southeast Asia, control programmes have become increasingly focused on malaria elimination, composed of mass drug administration coupled with prompt diagnosis and treatment of symptomatic cases. The key to a successful elimination programme centres on high participation rates in targeted communities, often enhanced by community engagement (CE) efforts. Social science research was conducted to develop a conceptual framework used for CE activities in the Targeted Malaria Elimination programme, as a cross-border operation in Karen/Kayin State, Myanmar. Methods: Data was collected from three main sources: (1) participant observation and semi-structured interviews of CE team members; (2) participant observation and semi-structured interviews with villagers; and (3) records of CE workshops with CE workers conducted as part of the TME programme. Results: Interviews were conducted with 17 CE team members, with 10 participant observations and interviews conducted with villagers and a total of 3 workshops conducted over the course of this pilot programme in 4 villages (November 2013 to October 2014). Thematic analysis was used to construct the nine dimensions for CE in this complex, post-war region: i) history of the people; ii) space; iii) work; iv) knowledge about the world; v) intriguing obstacle (rumour); vi) relationship with the health care system; vii) migration; viii) logic of capitalism influencing openness; and ix) power relations. Conclusions: Conducting CE for the Targeted Malaria Elimination programme was immensely complicated in Karen/Kayin State because of three key realities: heterogeneous terrains, a post-war atmosphere and cross-border operations. These three key realities constituted the nine dimensions, which proved integral to health worker success in conducting CE. Summary of this approach can aid in infectious disease control programmes, such as those using mass drug administration, to engender high rates of community participation.

Safety and effectiveness of mass drug administration to accelerate elimination of artemisinin-resistant falciparum malaria: A pilot trial in four villages of Eastern Myanmar.

Background: Artemisinin and partner drug-resistant falciparum malaria is expanding over the Greater Mekong Sub-region (GMS). Eliminating falciparum malaria in the GMS while drugs still retain enough efficacy could prevent global spread of antimalarial resistance. Eliminating malaria rapidly requires targeting the reservoir of asymptomatic parasite carriers. This pilot trial aimed to evaluate the acceptability, safety, feasibility and effectiveness of mass-drug administration (MDA) in reducing malaria in four villages in Eastern Myanmar. Methods: Villages with ≥30% malaria prevalence were selected. Long-lasting insecticidal bednets (LLINs) and access to malaria early diagnosis and treatment (EDT) were provided. Two villages received MDA immediately and two were followed for nine months pre-MDA. MDA consisted of a 3-day supervised course of  dihydroartemisinin-piperaquine and single low-dose primaquine administered monthly for three months. Adverse events (AE) were monitored by interviews and consultations. Malaria prevalence was assessed by ultrasensitive PCR quarterly for 24 months. Symptomatic malaria incidence,entomological indices, and antimalarial resistance markers were monitored. Results: MDA was well tolerated. There were no serious AE and mild to moderate AE were reported in 5.6%(212/3931) interviews. In the smaller villages, participation to three MDA courses was 61% and 57%, compared to 28% and 29% in the larger villages. Baseline prevalence was higher in intervention than in control villages (18.7% (95%CI=16.1-21.6) versus 6.8%(5.2-8.7), p<0.0001) whereas three months after starting MDA, prevalence was lower in intervention villages (0.4%(0.04-1.3) versus 2.7%(1.7-4.1), p=0.0014). After nine months the difference was no longer significant (2.0%(1.0-3.5) versus 0.9%(0.04-1.8), p=0.10). M0-M9 symptomatic falciparum incidence was similar between intervention and control. Before/after MDA comparisons showed that asymptomatic P. falciparum carriage and anopheline vector positivity decreased significantly whereas prevalence of the artemisinin-resistance molecular marker remained stable. Conclusions: This MDA was safe and feasible, and, could accelerate elimination of P. falciparum in addition to EDT and LLINs when community participation was sufficient.

Community engagement for the rapid elimination of malaria: the case of Kayin State, Myanmar.

BACKGROUND:  Currently, malaria elimination efforts are ongoing in several locations across Southeast Asia,  including in Kayin State (also known as Karen State), Myanmar . This paper describes the community engagement efforts for a pilot malaria elimination project, the challenges encountered and lessons learnt. METHODS:  Between May 2013 and June 2015, a study on targeted malaria elimination (TME) that included mass drug administration was conducted in four villages (TPN, TOT, KNH, and HKT) of Kayin State. Community engagement efforts included workshops, meetings and house-to-house visits with community members.  Exhibitions related to malaria and fun activities were organized for children. In addition, we provided primary care, small individual incentives and village-level incentives. This paper is based on our analysis of data extracted from meeting minutes, field notes, feedback sessions among staff and with community members as well as our own reflections. RESULTS:  Average participation across three rounds of MDA were 84.4%, 57.4%, 88.6% and 59.3% for TPN, TOT, KNH and HKT, respectively. Community engagement was fraught with practical challenges such as seasonal tasks of the villagers. There were challenges in explaining difficult concepts like drug resistance and submicroscopic infection. Another was understanding and navigating the politics of these villages, which are located in politically contested areas.  Managing expectations of villagers was difficult as they assumed that the community team must know everything related to health. CONCLUSIONS:  In the TME project, many different community engagement strategies were employed. We encountered many challenges which included logistical, scientific and political difficulties.  An approach that is tailored to the local population is key.

Accelerated Training of Skilled Birth Attendants in a Marginalized Population on the Thai-Myanmar Border: A Multiple Methods Program Evaluation.

BACKGROUND: To evaluate a skilled birth attendant (SBA) training program in a neglected population on the Thai-Myanmar border, we used multiple methods to show that refugee and migrant health workers can be given effective training in their own environment to become SBAs and teachers of SBAs. The loss of SBAs through resettlement to third countries necessitated urgent training of available workers to meet local needs. METHODS AND FINDINGS: All results were obtained from student records of theory grades and clinical log books. Qualitative evaluation of both the SBA and teacher programs was obtained using semi-structured interviews with supervisors and teachers. We also reviewed perinatal indicators over an eight-year period, starting prior to the first training program until after the graduation of the fourth cohort of SBAs. RESULTS: Four SBA training programs scheduled between 2009 and 2015 resulted in 79/88 (90%) of students successfully completing a training program of 250 theory hours and 625 supervised clinical hours. All 79 students were able to: achieve pass grades on theory examination (median 80%, range [70-89]); obtain the required clinical experience within twelve months; achieve clinical competence to provide safe care during childbirth. In 2010-2011, five experienced SBAs completed a train-the-trainer (TOT) program and went on to facilitate further training programs. Perinatal indicators within Shoklo Malaria Research Unit (SMRU), such as place of birth, maternal and newborn outcomes, showed no significant differences before and after introduction of training or following graduate deployment in the local maternity units. Confidence, competence and teamwork emerged from qualitative evaluation by senior SBAs working with and supervising students in the clinics. CONCLUSIONS: We demonstrate that in resource-limited settings or in marginalized populations, it is possible to accelerate training of skilled birth attendants to provide safe maternity care. Education needs to be tailored to local needs to ensure evidence-based care of women and their families.

The acceptability of mass administrations of anti-malarial drugs as part of targeted malaria elimination in villages along the Thai-Myanmar border.

BACKGROUND: A targeted malaria elimination project, including mass drug administrations (MDA) of dihydroartemisinin/piperaquine plus a single low dose primaquine is underway in villages along the Thailand Myanmar border. The intervention has multiple components but the success of the project will depend on the participation of the entire communities. Quantitative surveys were conducted to study reasons for participation or non-participation in the campaign with the aim to identify factors associated with the acceptance and participation in the mass drug administrations. METHODS: The household heads in four study villages in which MDAs had taken place previously were interviewed between January 2014 and July 2015. RESULTS: 174/378 respondents (46 %) completed three rounds of three drug doses each, 313/378 (83 %) took at least three consecutive doses and 56/378 (15 %) did not participate at all in the MDA. The respondents from the two villages (KNH and TPN) were much more likely to participate in the MDA than respondents from the other two villages (HKT and TOT). The more compliant villages KNH and TPN had both an appearance of cohesive communities with similar demographic and ethnic backgrounds. By contrast the villages with low participation were unique. One village was fragmented following years of armed conflict and many respondents gave little inclination to cooperate with outsiders. The other village with low MDA coverage was characterised by a high percentage of short-term residents with little interest in community interventions. A universal reason for non-participation in the MDA applicable to all villages was an inadequate understanding of the intervention. CONCLUSIONS: It is unlikely that community engagement can unite fragmented communities in participating in an intervention, which benefits the community. Understanding the purpose and the reasons underlying the intervention is an important pre-condition for participation. In the absence of direct benefits and a complete understanding of the indirect benefits trust in the investigators is critical for participation.

Single Low Dose Primaquine (0.25 mg/kg) Does Not Cause Clinically Significant Haemolysis in G6PD Deficient Subjects.

BACKGROUND: Primaquine is the only drug consistently effective against mature gametocytes of Plasmodium falciparum. The transmission blocking dose of primaquine previously recommended was 0.75 mg/kg (adult dose 45 mg) but its deployment was limited because of concerns over haemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is an inherited X-linked enzymatic defect that affects an estimated 400 million people around the world with high frequencies (15-20%) in populations living in malarious areas. To reduce transmission in low transmission settings and facilitate elimination of P. falciparum, the World Health Organization now recommends adding a single dose of 0.25 mg/kg (adult dose 15 mg) to Artemisinin-based Combination Therapies (ACTs) without G6PD testing. Direct evidence of the safety of this low dose is lacking. Adverse events and haemoglobin variations after this treatment were assessed in both G6PD normal and deficient subjects in the context of targeted malaria elimination in a malaria endemic area on the North-Western Myanmar-Thailand border where prevalence of G6PD deficiency (Mahidol variant) approximates 15%. METHODS AND FINDINGS: The tolerability and safety of primaquine (single dose 0.25 mg base/kg) combined with dihydroartemisinin-piperaquine (DHA-PPQ) given three times at monthly intervals was assessed in 819 subjects. Haemoglobin concentrations were estimated over the six months preceding the ACT + primaquine rounds of mass drug administration. G6PD deficiency was assessed with a phenotypic test and genotyping was performed in male subjects with deficient phenotypes and in all females. Fractional haemoglobin changes in relation to G6PD phenotype and genotype and primaquine round were assessed using linear mixed-effects models. No adverse events related to primaquine were reported during the trial. Mean fractional haemoglobin changes after each primaquine treatment in G6PD deficient subjects (-5.0%, -4.2% and -4.7%) were greater than in G6PD normal subjects (0.3%, -0.8 and -1.7%) but were clinically insignificant. Fractional drops in haemoglobin concentration larger than 25% following single dose primaquine were observed in 1.8% of the population but were asymptomatic. CONCLUSIONS: The single low dose (0.25mg/kg) of primaquine is clinically well tolerated and can be used safely without prior G6PD testing in populations with high prevalence of G6PD deficiency. The present evidence supports a broader use of low dose primaquine without G6PD testing for the treatment and elimination of falciparum malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT01872702.