How can interventions that target forest-goers be tailored to accelerate malaria elimination in the Greater Mekong Subregion? A systematic review of the qualitative literature

Background Despite decreases in incidence and related mortality, malaria remains a major public health challenge in the Greater Mekong Sub-region (GMS). The emergence of artemisinin resistance threatens these gains and has prompted efforts to accelerate elimination in the region. In the GMS, transmission now clusters in hotspots along international borders and among high-risk populations, including forest-goers. To eliminate malaria in the region, interventions must target such hard-to-reach populations. This review provides a comprehensive overview of the qualitative research on behaviours and perceptions that influence uptake of and adherence to malaria interventions among forest-goers in the GMS. Methods A systematic search strategy was used to identify relevant sources, including database (OVID SP, PubMed, ISI Web of Knowledge) and bibliographic searches. Relevant findings from qualitative research methods were extracted and thematic analysis undertaken. Results Of 268 sources retrieved in searches twenty-two were reviewed. Most reported studies were conducted in Cambodia (n = 10), and were published after 2014 (n = 16). Four major themes emerged that are particularly relevant to the design of intervention packages targeted at forest-goers: (1) understanding of malaria and perceived risk; (2) preventive measures used when visiting the forest; (3) behaviours that put forest-goers at risk of infection; and, (4) malaria-related treatment seeking. There were notable differences across the reviewed articles that suggest the need for a locally tailored approach. Conclusion A more detailed characterization of forest activities is needed but research on this topic raises methodological challenges. Current vector control measures have limitations, with use of insecticidal-treated nets, hammocks and repellents influenced by the type of forest activities and the characteristics of these measures. In contrast, anti-malarial drugs, for example, as chemoprophylaxis, hold promise but require further evaluation

Activity of Ivermectin and Its Metabolites against Asexual Blood Stage Plasmodium falciparum and Its Interactions with Antimalarial Drugs

Ivermectin is an endectocide used widely to treat a variety of internal and external parasites. Field trials of ivermectin mass drug administration for malaria transmission control have demonstrated a reduction of Anopheles mosquito survival and human malaria incidence. Ivermectin will mostly be deployed together with artemisinin-based combination therapies (ACT), the first-line treatment of falciparum malaria. It has not been well established if ivermectin has activity against asexual stage Plasmodium falciparum or if it interacts with the parasiticidal activity of other antimalarial drugs. This study evaluated antimalarial activity of ivermectin and its metabolites in artemisinin-sensitive and artemisinin-resistant P. falciparum isolates and assessed in vitro drug-drug interaction with artemisinins and its partner drugs. The concentration of ivermectin causing half of the maximum inhibitory activity (IC50) on parasite survival was 0.81 μM with no significant difference between artemisinin-sensitive and artemisinin-resistant isolates (P = 0.574). The ivermectin metabolites were 2-fold to 4-fold less active than the ivermectin parent compound (P &lt; 0.001). Potential pharmacodynamic drug-drug interactions of ivermectin with artemisinins, ACT-partner drugs, and atovaquone were studied in vitro using mixture assays providing isobolograms and derived fractional inhibitory concentrations. There were no synergistic or antagonistic pharmacodynamic interactions when combining ivermectin and antimalarial drugs. In conclusion, ivermectin does not have clinically relevant activity against the asexual blood stages of P. falciparum. It also does not affect the in vitro antimalarial activity of artemisinins or ACT-partner drugs against asexual blood stages of P. falciparum.</p

Study protocol: an open-label individually randomised controlled trial to assess the efficacy of artemether-lumefantrine prophylaxis for malaria among forest goers in Cambodia

Introduction In the Greater Mekong Subregion, adults are at highest risk for malaria. The most relevant disease vectors bite during daytime and outdoors which makes forest work a high-risk activity for malaria. The absence of effective vector control strategies and limited periods of exposure during forest visits suggest that chemoprophylaxis could be an appropriate strategy to protect forest goers against malaria. Methods and analysis The protocol describes an open-label randomised controlled trial of artemether-lumefantrine (AL) versus multivitamin as prophylaxis against malaria among forest goers aged 16–65 years in rural northeast Cambodia. The primary objective is to compare the efficacy of the artemisinin combination therapy AL versus a multivitamin preparation as defined by the 28-day PCR parasite positivity rate and incidence of confirmed clinical malaria of any species. The sample size is 2200 patient-episodes of duration 1 month in each arm. The duration of follow-up and prophylaxis for each participant is 1, 2 or 3 consecutive 28-day periods, followed by a further 28 days of post-exposure prophylaxis, depending on whether they continue to visit the forest. Analysis will be done both by intention to treat and per protocol. Ethics and dissemination All participants will provide written, informed consent. Ethical approval was obtained from the Oxford Tropical Research Ethics Committee and the Cambodia National Ethics Committee for Health Research. Results will be disseminated by peer-reviewed open access publication together with open data

History of malaria treatment as a predictor of subsequent subclinical parasitaemia: A cross-sectional survey and malaria case records from three villages in Pailin, western Cambodia

Background: Treatment of the sub-clinical reservoir of malaria, which may maintain transmission, could be an important component of elimination strategies. The reliable detection of asymptomatic infections with low levels of parasitaemia requires high-volume quantitative polymerase chain reaction (uPCR), which is impractical to conduct on a large scale. It is unknown to what extent sub-clinical parasitaemias originate from recent or older clinical episodes. This study explored the association between clinical history of malaria and subsequent sub-clinical parasitaemia. Methods: In June 2013 a cross-sectional survey was conducted in three villages in Pailin, western Cambodia. Demographic and epidemiological data and blood samples were collected. Blood was tested for malaria by high-volume qP

Acceptability and feasibility of malaria prophylaxis for forest goers: findings from a qualitative study in Cambodia

Background: In the Greater Mekong Subregion, adults are at highest risk for malaria, particularly those who visit forests. The absence of effective vector control strategies and limited periods of exposure during forest visits suggest that chemoprophylaxis could be an appropriate strategy to protect forest goers against malaria. Methods: Alongside a clinical trial of anti-malarial chemoprophylaxis in northern Cambodia, qualitative research was conducted, including in-depth interviews and observation, to explore the acceptability of malaria prophylaxis for forest goers, the implementation opportunities, and challenges of this strategy. Results: Prophylaxis with artemether–lumefantrine for forest goers was found to be acceptable under trial conditions. Three factors played a major role: the community’s awareness and perception of the effectiveness of prophylaxis, their trust in the provider, and malaria as a local health concern. The findings highlight how uptake and adherence to prophylaxis are influenced by the perceived balance between benefits and burden of anti-malarials which are modulated by the seasonality of forest visits and its influence on malaria risk. Conclusions: The implementation of anti-malarial prophylaxis needs to consider how the preventive medication can be incorporated into existing vector-control measures, malaria testing and treatment services. The next step in the roll out of anti-malarial prophylaxis for forest visitors will require support from local health workers

Antimalarial Chemoprophylaxis for Forest Goers in Southeast Asia: An Open-Label, Individually Randomised Controlled Trial

Summary Background Malaria in the eastern Greater Mekong subregion has declined to historic lows. Countries in the Greater Mekong subregion are accelerating malaria elimination in the context of increasing antimalarial drug resistance. Infections are now increasingly concentrated in remote, forested foci. No intervention has yet shown satisfactory efficacy against forest-acquired malaria. The aim of this study was to assess the efficacy of malaria chemoprophylaxis among forest goers in Cambodia. Methods We conducted an open-label, individually randomized controlled trial in Cambodia, which recruited participants aged 16–65 years staying overnight in forests. Participants were randomly allocated 1:1 to antimalarial chemoprophylaxis, a 3-day course of twice-daily artemether–lumefantrine followed by the same daily dosing once a week while travelling in the forest and for a further 4 weeks after leaving the forest (four tablets per dose; 20 mg of artemether and 120 mg of lumefantrine per tablet), or a multivitamin with no antimalarial activity. Allocations were done according to a computer-generated randomization schedule, and randomization was in permuted blocks of size ten and stratified by village. Investigators and participants were not masked to drug allocation, but laboratory investigations were done without knowledge of allocation. The primary outcome was a composite endpoint of either clinical malaria with any Plasmodium species within 1–28, 29–56, or 57–84 days, or subclinical infection detected by PCR on days 28, 56, or 84 using complete-case analysis of the intention-to-treat population. Adherence to study drug was assessed primarily by self-reporting during follow-up visits. Adverse events were assessed in the intention-to-treat population as a secondary endpoint from self-reporting at any time, plus a physical examination and symptom questionnaire at follow-up. This trial is registered at ClinicalTrials.gov (NCT04041973) and is complete. Findings Between March 11 and November 20, 2020, 1,480 individuals were enrolled, of whom 738 were randomly assigned to artemether–lumefantrine and 742 to the multivitamin. 713 participants in the artemether–lumefantrine group and 714 in the multivitamin group had a PCR result or confirmed clinical malaria by rapid diagnostic test during follow-up. During follow-up, 19 (3%, 95% CI 2–4) of 713 participants had parasitaemia or clinical malaria in the artemether– lumefantrine group and 123 (17%, 15–20) of 714 in the multivitamin group (absolute risk difference 15%, 95% CI 12–18; p \u3c 0·0001). During follow-up, there were 166 malaria episodes caused by Plasmodium vivax, 14 by Plasmodium falciparum, and five with other or mixed species infections. The numbers of participants with P. vivax were 18 (3%, 95% CI 2–4) in the artemether–lumefantrine group versus 112 (16%, 13–19) in the multivitamin group (absolute risk difference 13%, 95% CI 10–16; p \u3c 0.0001). The numbers of participants with P. falciparum were two (0.3%, 95% CI 0.03–1.01) in the artemether–lumefantrine group versus 12 (1·7%, 0.9–2.9) in the multivitamin group (absolute risk difference 1·4%, 95% CI 0.4–2·4; p = 0.013). Overall reported adherence to the full course of medication was 97% (95% CI 96–98; 1,797 completed courses out of 1,854 courses started) in the artemether–lumefantrine group and 98% (97–98; 1,842 completed courses in 1,885 courses started) in the multivitamin group. Overall prevalence of adverse events was 1.9% (355 events in 18,806 doses) in the artemether–lumefantrine group and 1.1% (207 events in 19,132 doses) in the multivitamin group (p \u3c 0.0001). Interpretation Antimalarial chemoprophylaxis with artemether–lumefantrine was acceptable and well tolerated and substantially reduced the risk of malaria. Malaria chemoprophylaxis among high-risk groups such as forest workers could be a valuable tool for accelerating elimination in the Greater Mekong subregion

The feasibility of novel point-of-care diagnostics for febrile illnesses at health centres in Southeast Asia: a mixed-methods study

Background The decline of malaria in Southeast Asia means other causes of fever are increasingly relevant, but often undiagnosed. The objective of this study was to assess the feasibility of point-of-care tests to diagnose acute febrile illnesses in primary care settings. Methods A mixed-methods study was conducted at nine rural health centres in western Cambodia. Workshops introduced health workers to the STANDARD(TM) Q Dengue Duo, STANDARD(TM) Q Malaria/CRP Duo and a multiplex biosensor detecting antibodies and/or antigens of eight pathogens. Sixteen structured observation checklists assessed users’ performances and nine focus group discussions explored their opinions. Results All three point-of-care tests were performed well under assessment, but sample collection was difficult for the dengue test. Respondents expressed that the diagnostics were useful and could be integrated into routine clinical care, but were not as convenient to perform as standard malaria rapid tests. Health workers recommended that the most valued point-of-care tests would directly inform clinical management (e.g. a decision to refer a patient or to provide/withhold antibiotics). Conclusions Deployment of new point-of-care tests to health centres could be feasible and acceptable if they are user-friendly, selected for locally circulating pathogens and are accompanied by disease-specific education and simple management algorithms

Expanding the role of village malaria workers in Cambodia: Implementation and evaluation of four health education packages

Background: Early access to correct diagnosis and appropriate treatment is essential for malaria elimination, and in Cambodia this relies on village malaria workers (VMWs). Decreasing malaria transmission leave VMWs with diminished roles. Activities related to the control of other health conditions could keep these community health workers relevant. Methods: During 2022, 120 VMWs attended training at local health centres on four health education packages: 1. hygiene and sanitation; 2. disease surveillance; 3. management of mild illness; 4. vaccination and antenatal care. All training and evaluation sessions were documented through meeting minutes, and 19 focus group discussions (FGDs) were conducted among VMWs and health centre personnel. Audio-records of FGDs were transcribed and translated in English and underwent thematic analysis. Results: VMWs reported strong interest in the training and welcomed the expansion of their roles thus assuring their continued relevance. VMWs prioritized disease surveillance and management of mild illness among the available training packages because these topics were seen as most relevant. While training was considered comprehensible and important, the low literacy among VMWs was an impediment suggesting training materials need to be delivered visually. Since VMWs have limited resources, incentives could ensure that VMWs are motivated to undertake additional roles and responsibilities. Conclusions: The transformation of VMWs into community health workers with roles beyond malaria is a promising approach for sustaining health care provision in remote areas. Training needs to consider the low scientific literacy, time constraints and limited resources of VMWs

GENERAL CHARACTERISTICS OF PATIENTS WITH SHOULDER PROBLEMS

Amaç: Omuz ekleminden ve özellikle de eklem çevresindeki yumuşak dokulardan kökenalan problemler üst ekstremite ağrılarının en önemli nedenini oluşturur. Çalışmamızın amacıomuz ağrısı yakınması ile başvuran hastaların klinik özelliklerinin değerlendirilmesidir.Gereç ve yöntem: Omuz ağrısı yakınması ile başvuran 709 hastanın 744 omuzuretrospektif olarak değerlendirildi.Bulgular: Hastaların yaş ortalaması 55,16  10,88 yıl idi ve 395 hastada sağ, 279 hastadasol ve 35 hastada her iki omuz etkilenmişti. Vakaların %35,4'ünde travma öyküsü mevcuttu.Klinik ve radyolojik olarak yapılan değerlendirmelerde hastaların %45'inde subakromiyalsıkışma sendromu, %39,4'ünde rotator kaf rüptürü, %1,5'inde bisipital tendinit, %6,5'indeakromioklavikuler eklem dejenerasyonu, %2,2'sinde kalsifik tendinit, %5'inde donuk omuzve %0,4'ünde glenohumeral eklem artrozu saptandı. Subakromiyal sıkışma sendromu olanhastalar ile rotator kaf rüptürü olan hastaların karşılaştırılmasında rüptürü olan hastalarınyaş ortalamalarının daha yüksek ve "American Shoulder Elbow Score" (ASES) skorlarınındaha düşük olduğu ancak "Constant" skorları arasında herhangi bir fark olmadığı görüldü.Bu iki grup etiolojideki travma açısından değerlendirildiğinde rotator kaf rüptürü olan gruptatravma öyküsünün subakromiyal sıkışma sendromlu hastalara göre anlamlı olarak dahafazla olduğu ve travma öyküsünün rotator kafta rüptür riskini 2,9 kat arttırdığı görüldü.Sonuç: Omuz ağrısı nedenleri arasında rotator kaf sorunları çok önemli bir yer tutmaktadır.Travma ve yaş rotator kafta rüptür insidansını arttırmaktadır.Objective: Problems originating from the shoulder joint and periarticular soft tissues arethe most important causes of upper limb pain. The aim of this study was to investigate theclinical charactersitic patients.Material and method: Seven hundred forty-four shoulders 709 patients wereretrospectively studied.Results: The mean age of the patients was 55.16  10.88 years. Right shoulder wasinvolved in 395 patients, left in 279, and both shoulders in 35 patients. Thirty-five percenthad a history of trauma. According to clinical and radiological assessments, 45 % of patientswere diagnosed as subacromial impingement syndrome, 39.4 % roator cuff tears, 1.5 %bicipital tendinitis, 6.5 % degeneration of the acromioclavicular joint, 2.2 % calcific tendinitis,5 % frozen shoulder, and 0.4 % osteoarthritis of the glenohumeral joint. When the patientswith subacromial impingement syndrome were compared with the patients with rotator cuff tears, the mean age of the patients with rotator cuff tears was significantly higher andAmerican Shoulder Elbow Scores (ASES) were lower than the patients with subacromialimpingement syndrome. There were no significant differences between the Constant scores.Significantly more patients with rotator cuff tears had a history of trauma than patients withsubacromial impingement syndrome, and trauma increased the risk of rotator cuff tears 2.9times.Conclusion: Rotator cuff problems is one of the most common causes of shoulder painand functional limitations. Trauma and age are risk factors for rotator cuff rupture