Molecular markers of artemisinin resistance during falciparum malaria elimination in Eastern Myanmar.

BACKGROUND: Artemisinin resistance in Plasmodium falciparum threatens global malaria elimination efforts. To contain and then eliminate artemisinin resistance in Eastern Myanmar a network of community-based malaria posts was instituted and targeted mass drug administration (MDA) with dihydroartemisinin-piperaquine (three rounds at monthly intervals) was conducted. The prevalence of artemisinin resistance during the elimination campaign (2013-2019) was characterized. METHODS: Throughout the six-year campaign Plasmodium falciparum positive blood samples from symptomatic patients and from cross-sectional surveys were genotyped for mutations in kelch-13-a molecular marker of artemisinin resistance. RESULT: The program resulted in near elimination of falciparum malaria. Of 5162 P. falciparum positive blood samples genotyped, 3281 (63.6%) had K13 mutations. The prevalence of K13 mutations was 73.9% in 2013 and 64.4% in 2019. Overall, there was a small but significant decline in the proportion of K13 mutants (p < 0.001). In the MDA villages there was no significant change in the K13 proportions before and after MDA. The distribution of different K13 mutations changed substantially; F446I and P441L mutations increased in both MDA and non-MDA villages, while most other K13 mutations decreased. The proportion of C580Y mutations fell from 9.2% (43/467) before MDA to 2.3% (19/813) after MDA (p < 0.001). Similar changes occurred in the 487 villages where MDA was not conducted. CONCLUSION: The malaria elimination program in Kayin state, eastern Myanmar, led to a substantial reduction in falciparum malaria. Despite the intense use of artemisinin-based combination therapies, both in treatment and MDA, this did not select for artemisinin resistance.

Postoperative Magnetic Resonance Imaging after Anterior Cruciate Ligament Reconstruction: An Overview and Practical Step-by-step Guide.

Anterior cruciate ligament (ACL) rupture is a frequently encountered injury among athletes, often requiring surgical intervention to restore knee stability. Magnetic resonance imaging (MRI) after ACL reconstruction is common, especially in the evaluation of clinical complications leading to knee instability, decreased range of motion, or pain. This article provides a detailed overview of normal and abnormal postoperative findings including a practical step-by-step guide for MRI assessment. MRI findings must be correlated with surgical technique, time interval from surgery to imaging, and clinical examination.

Uptake and challenges with daily oral pre-exposure prophylaxis among men who have sex with men and transgender women, suburban Yangon, Myanmar.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is effective for human immunodeficiency virus (HIV) prevention in risk groups. We assessed PrEP uptake and 12-month retention among men who have sex with men (MSM) and transgender women (TGW) in Myanmar during the coronavirus disease 2019 pandemic and a political crisis. METHODS: Using prospectively collected data, we assessed the proportion of persons eligible, initiated and retained 12 months on PrEP. We calculated HIV and syphilis incidence among those initiated on PrEP. Predictors of compliance to scheduled visits were assessed with fractional logistic regression. RESULTS: Among 652 persons screened between July and December 2020, 85.3% were eligible and 38.8% initiated PrEP. The daily pill burden was the main reason (86.5%) for refusing PrEP. A history of HIV post-exposure prophylaxis (PEP) and having an HIV-positive partner not on anti-retroviral therapy (ART) was associated with PrEP uptake (p<0.05). The 12-month retention among those initiating PrEP was 43.0%. Age ≥25 y, a history of PEP and having an HIV-positive partner not on ART predicted better compliance with scheduled visits (p<0.05). HIV incidence among PrEP initiators was 3.1 per 100 person-years (95% confidence interval [CI] 1.3 to 7.4) and syphilis incidence was 17.6 per 100 person-years (95% CI 12.3 to 25.1). CONCLUSIONS: A PrEP program for MSM and TGW in Myanmar was implemented successfully under difficult circumstances. Alternative strategies are needed addressing PrEP uptake and retention.

Accelerated IVIM-corrected DTI in acute hamstring injury: towards a clinically feasible acquisition time.

BACKGROUND: Intravoxel incoherent motion (IVIM)-corrected diffusion tensor imaging (DTI) potentially enhances return-to-play (RTP) prediction after hamstring injuries. However, the long scan times hamper clinical implementation. We assessed accelerated IVIM-corrected DTI approaches in acute hamstring injuries and explore the sensitivity of the perfusion fraction (f) to acute muscle damage. METHODS: Athletes with acute hamstring injury received DTI scans of both thighs < 7 days after injury and at RTP. For a subset, DTI scans were repeated with multiband (MB) acceleration. Data from standard and MB-accelerated scans were fitted with standard and accelerated IVIM-corrected DTI approach using high b-values only. Segmentations of the injury and contralateral healthy muscles were contoured. The fitting methods as well as the standard and MB-accelerated scan were compared using linear regression analysis. For sensitivity to injury, Δ(injured minus healthy) DTI parameters between the methods and the differences between injured and healthy muscles were compared (Wilcoxon signed-rank test). RESULTS: The baseline dataset consisted of 109 athletes (16 with MB acceleration); 64 of them received an RTP scan (8 with MB acceleration). Linear regression of the standard and high-b DTI fitting showed excellent agreement. With both fitting methods, standard and MB-accelerated scans were comparable. Δ(injured minus healthy) was similar between standard and accelerated methods. For all methods, all IVIM-DTI parameters except f were significantly different between injured and healthy muscles. CONCLUSIONS: High-b DTI fitting with MB acceleration reduced the scan time from 11:08 to 3:40 min:s while maintaining sensitivity to hamstring injuries; f was not different between healthy and injured muscles. RELEVANCE STATEMENT: The accelerated IVIM-corrected DTI protocol, using fewer b-values and MB acceleration, reduced the scan time to under 4 min without affecting the sensitivity of the quantitative outcome parameters to hamstring injuries. This allows for routine clinical monitoring of hamstring injuries, which could directly benefit injury treatment and monitoring. KEY POINTS: • Combining high-b DTI-fitting and multiband-acceleration dramatically reduced by two thirds the scan time. • The accelerated IVIM-corrected DTI approaches maintained the sensitivity to hamstring injuries. • The IVIM-derived perfusion fraction was not sensitive to hamstring injuries.

Reporting of Morphology, Location, and Size in the Treatment of Osteochondral Lesions of the Talus in 11,785 Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: Uniformity of reporting is a requisite to be able to compare results of clinical studies on the treatment of osteochondral lesions of the talus (OLT). The primary aim of this study was to evaluate the frequency and quality of reporting of size, morphology, and location of OLTs. DESIGN: A literature search was performed from 1996 to 2023 to identify clinical studies on surgical treatment of OLTs. Screening was performed by 2 reviewers, who subsequently graded the quality using the methodological index for non-randomized studies (MINORS). The primary outcome was the frequency and qualitative assessment of reporting of size, morphology, and location. RESULTS: Of 3,074 articles, 262 articles were included. This comprised a total of 11,785 patients. Size was reported in 248 (95%) of the articles and was described with a measure for surface area in 83%, however, in 56%, definition of measurement is unknown. Intraclass coefficient (ICC) value for the reliability of size measurement was 0.94 for computed tomography (CT) scan and 0.87 for MRI scan. Morphology was reported in 172 (66%) of the articles and using a classification system in 23% of the studies. Location was reported in 220 (84%) of the studies. CONCLUSION: No consensus was found on the reporting of morphology, with non-validated classification systems and different terminologies used. For location, reporting in 9 zones is underreported. Size was well reported and measurements are more reliable for CT compared with MRI. As these prognostic factors guide clinical decision-making, we advocate the development of a standardized and validated OLT classification to reach uniform reporting in literature. LEVEL OF EVIDENCE: Level III, systematic review.

A systematic review of neglected tropical diseases (NTDs) in Myanmar.

BACKGROUND: Neglected tropical diseases (NTDs) affect most impoverished communities in developing countries, like Myanmar in Southeast Asia. NTDs have been understudied and underreported in Myanmar. METHODS: A systematic review of published and grey literature (1900-2023) on neglected tropical diseases (NTDs) in Myanmar was conducted. The literature search included five international databases: PubMed, EMBASE, Ovid Global Health, and Web of Science Core Collection and one national database: the Myanmar Central Biomedical Library (locally published papers and grey literature). The selection criteria included articles with all types of study designs of current or previous infections conducted in humans, that reported NTDs, recognised by WHO, US CDC, and listed in PLoS NTDs. We included melioidosis and rickettsioses which we consider also meet the definition of an NTD. RESULTS: A total of 5941 records were retrieved and screened, of which, 672 (11%) met the selection criteria and were included in this review. Of the included articles, 449 (65%) were published after 2000 and 369 (55%) were from two regions (Yangon and Mandalay) of Myanmar. Of the included articles, 238 (35%) reported bacterial NTDs, 212 (32%) viral NTDs, 153 (23%) helminth NTDs, 25 (4%) protozoal NTDs and 39 (6%) reported more than one aetiology. Based on reported frequency in descending order, the bacterial NTDs were leprosy, Escherichia coli enteritis, salmonellosis, cholera, shigellosis, melioidosis, leptospirosis and rickettsioses; the viral NTDs were dengue, chikungunya and Japanese encephalitis virus (JEV) infection; the protozoal NTDs were amoebiasis, giardiasis and leishmaniasis, and the helminth NTDs were ascariasis, trichuriasis, hookworm disease, filariasis and strongyloidiasis. CONCLUSION: This review summarises NTDs reported in Myanmar over the past 100 years. The findings suggest that most NTDs are likely to be under reported, especially from the majority of the country which is far from academic centres. Research capacity building together with strengthening of laboratory systems would lead to better understanding of the true burden of NTDs in Myanmar. TRIAL REGISTRATION: PROSPERO registration ID: CRD42018092627.

Successful elimination of falciparum malaria following the introduction of community-based health workers in Eastern Myanmar: A retrospective analysis.

BACKGROUND: Myanmar has a large majority of all malaria in the Greater Mekong Subregion. In the past decade, substantial progress was made in malaria control. The residual burden of malaria is in remote areas where currently recommended malaria elimination approaches are generally not feasible. In such hard-to-reach communities in Mon state, East Myanmar, Medical Action Myanmar introduced community health workers (CHWs) to deliver early diagnosis and treatment for malaria. We conducted a retrospective analysis to assess the impact of this intervention. METHODS AND FINDINGS: This retrospective analysis involved data collected routinely from a CHW programme in Mon state conducted between 2011 and 2018. A network of 172 CHWs serving a population of 236,340 was deployed. These CHWs carried out 260,201 malaria rapid diagnostic tests (RDTs) to investigate patients with acute febrile illness. The median blood examination rate was 1.33%; interquartile range (IQR) (0.38 to 3.48%); 95% CI [1.28%, 1.36%] per month. The changes in malaria incidence and prevalence in patients presenting with fever were assessed using negative binomial regression mixed effects models fitted to the observed data. The incidence of Plasmodium falciparum malaria (including mixed infections) declined by 70%; 95% CI [65%, 75%]; p < 0.001 for each year of CHW operation. The incidence of P. vivax malaria declined by 56%; 95% CI [50%, 62%]; p < 0.001 per year. Malaria RDT positivity rates for P. falciparum and P. vivax declined by 69%; 95% CI [62%, 75%]; p < 0.001 and 53%; 95% CI [47%, 59%]; p < 0.001 per year, respectively. Between 2017 and 2018, only 1 imported P. falciparum case was detected in 54,961 RDTs. The main limitations of the study are use of retrospective data with possible unidentified confounders and uncharacterised population movement. CONCLUSIONS: The introduction of CHWs providing community-based malaria diagnosis and treatment and basic health care services in remote communities in Mon state was associated with a substantial reduction in malaria. Within 6 years, P. falciparum was eliminated and the incidence of P. vivax fell markedly.

Don't Miss Me: Midfoot Sprains, A Point-of-Care Review.

Athletes practicing high-contact sports are exposed to an increased risk of midfoot injuries, namely midtarsal sprains. The complexity of reaching an accurate diagnosis is clearly depicted in the reported incidence of midtarsal sprains, ranging from 5% to 33% of ankle inversion injuries. Because the focus of the treating physician and physical therapist is on lateral stabilizing structures, midtarsal sprains are missed at initial evaluation in up to 41% of patients, with delayed treatment as a result.Detecting acute midtarsal sprains requires a high degree of clinical awareness. Radiologists must become familiar with the characteristic imaging findings of normal and pathologic midfoot anatomy to avoid adverse outcomes such as pain and instability. In this article we describe Chopart joint anatomy, mechanisms of midtarsal sprains, clinical importance, and key imaging findings with a focus on magnetic resonance imaging. A team effort is essential to provide optimal care for the injured athlete.

Near point-of-care HIV viral load testing: Cascade after high viral load in suburban Yangon, Myanmar.

INTRODUCTION: HIV viral load (VL) testing in resource-limited settings is often centralised, limiting access. In Myanmar, we assessed outcomes according to VL access and the VL cascade (case management after a first high VL result) before and after near point-of-care (POC) VL was introduced. METHODS: Routine programme data from people living with HIV (PLHIV) on antiretroviral therapy (ART) were used. We assessed the odds of getting a VL test done by year. Attrition and mortality two years after ART initiation were compared between three groups of PLHIV with different access to VL testing using Kaplan-Meier analysis. We compared VL cascades in those with a first VL result before and after near POC VL testing became available. With logistic regression, predictors of confirmed virological failure after a first high VL in the POC era were explored. RESULTS: Among 4291 PLHIV who started ART between July 2009 and June 2018, 794 (18.5%) became eligible for VL testing when it was not available, 2388 (55.7%) when centralised laboratory-based VL testing was available, and 1109 (25.8%) when near POC VL testing was available. Between 2010 and 2019, the odds of getting a VL test among those eligible increased with each year (OR: 5.21 [95% CI: 4.95-5.48]). Attrition and mortality were not different in the three groups. When comparing PLHIV with a first VL result before and after implementation of the near POC VL testing, in the latter, more had a first VL test (92% versus 15%, p<0.001), less had a first high VL result (5% versus 14%, p<0.001), and more had confirmed virological failure (67% versus 47%, p = 0.013). Having a first VL ≥5000 copies/mL after near POC implementation was associated with confirmed virological failure (adjusted OR: 2.61 [95% CI: 1.02-6.65]). CONCLUSION: Near POC VL testing enabled rapid increase of VL coverage and a well-managed VL cascade in Myanmar.

Correction: The 20-minute whole blood clotting test (20WBCT) for snakebite coagulopathy-A systematic review and meta-analysis of diagnostic test accuracy.

[This corrects the article DOI: 10.1371/journal.pntd.0009657.].

[18F]Fluoride PET provides distinct information on disease activity in ankylosing spondylitis as compared to MRI and conventional radiography.

PURPOSE: To relate [18F]fluoride uptake on PET with abnormalities on magnetic resonance imaging (MRI) and conventional radiography (CR) in ankylosing spondylitis (AS) patients. METHODS: Ten clinically active AS patients (female 6/10, age 38 ± 11 years) were included, and both spine and SI-joints were examined. PET scans were dichotomously scored for enhanced [18F]fluoride uptake, MRI scans were scored for fatty lesions, erosions, ankylosis, and bone marrow edema (BME), and CR was scored for erosions, syndesmophytes, and ankylosis. The overlap of lesions across all modalities was evaluated through univariate and multivariate analyses using a generalized mixed model. RESULTS: In the spine, 69 lesions with enhanced [18F]fluoride uptake, 257 MRI lesions, and 88 CR lesions were observed. PET lesions were mostly located in costovertebral and facet joints, outside the field of view (FOV) of the MRI and CR. However, PET lesions inside the FOV of MRI and CR partially showed no abnormality on MRI and CR. In lesions with abnormalities on multiple modalities, both univariate and multivariate analysis showed that PET activity had the strongest association with BME on MRI and ankylosis on CR. In the SI joints, 15 lesions (75%) with PET uptake were found, with 87% showing abnormalities on MRI and CR. CONCLUSION: [18F]fluoride PET lesions are often found outside the scope of MRI and CR, and even in the same location show only partial overlap with abnormalities on MRI (especially BME) and CR (especially ankylosis). This suggests that [18F]fluoride PET partially visualizes aspects of AS separate from MRI and CR, providing novel information. CLINICAL TRIAL REGISTRATION: NL43223.029.13 registered at 02-05-2013.  https://www.toetsingonline.nl/to/ccmo_search.nsf/fABRpop?readform&unids=C1257BA2002CC066C1257B4E0049A65A.

The impact of C-reactive protein testing on treatment-seeking behavior and patients' attitudes toward their care in Myanmar and Thailand.

C-reactive protein (CRP) point-of-care testing can reduce antibiotic prescribing in primary care patients with febrile and respiratory illness, yet little is known about its effects on treatment-seeking behavior. If patients go on to source antibiotics elsewhere, the impact of CRP testing will be limited. A randomized controlled trial assessed the impact of CRP testing on antibiotic prescriptions in Myanmar and Thai primary care patients with a febrile illness. Here we report patients' treatment-seeking behavior before and during the two-week study period. Self-reported antibiotic use is compared against urine antibacterial activity. Patients' opinions towards CRP testing were evaluated. Antibiotic use before study enrolment was reported by 5.4% while antimicrobial activity was detected in 20.8% of samples tested. During the study period, 14.8% of the patients sought additional healthcare, and 4.3% sourced their own antibiotics. Neither were affected by CRP testing. Overall, patients' satisfaction with their care and CRP testing was high. CRP testing did not affect patients' treatment-seeking behavior during the study period whilst modestly reducing antibiotic prescriptions. CRP testing appears to be acceptable to patients and their caregivers.

Ultrasound and MR muscle imaging in new onset idiopathic inflammatory myopathies at diagnosis and after treatment: a comparative pilot study.

OBJECTIVES: To prospectively compare ultrasound (US) and whole-body MRI for detection of muscle abnormalities compatible with idiopathic inflammatory myopathies (IIM). METHODS: Newly diagnosed IIM patients underwent US (14 muscles) and MRI (36 muscles) at diagnosis and after nine weeks monotherapy with intravenous immunoglobulin. Muscles were compatible with IIM when quantitative US echo-intensity (EI) z scores was ≥1.5, semi-quantitative US Heckmatt score was ≥2, qualitative US was abnormal, or when MRI showed oedema on T2-weighted images. At patient level, findings were classified as abnormal when quantitative US EI z scores was >1.5 (n = 3 muscles), >2.5 (n = 2 muscles) or >3.5 (n = 1 muscle), or if ≥3 muscles showed abnormalities as described above for the other diagnostic methods. RESULTS: At diagnosis, in 18 patients US of 252 muscles revealed abnormalities in 36 muscles (14%) with quantitative, in 153 (61%) with semi-quantitative and in 168 (67%) with qualitative analysis. MRI showed oedema in 476 out of 623 muscles (76%). Five patients (28%) reached abnormal classification with quantitative US, 16 (89%) with semi-quantitative and qualitative US, and all patients (100%) with MRI. Nine-week follow-up of 12 patients showed no change over time with quantitative US or MRI, and a decrease in abnormalities with semi-quantitative US (P <0.01), and qualitative US (P <0.01). CONCLUSION: At diagnosis, MRI was more sensitive than US to detect muscle abnormalities compatible with IIM. Semi-quantitative US and qualitative US detected abnormalities in the majority of the patients while evaluating fewer muscles than MRI and showed change over time after nine weeks of treatment.

Artemisinin resistance in the malaria parasite, Plasmodium falciparum, originates from its initial transcriptional response.

The emergence and spread of artemisinin-resistant Plasmodium falciparum, first in the Greater Mekong Subregion (GMS), and now in East Africa, is a major threat to global malaria elimination ambitions. To investigate the artemisinin resistance mechanism, transcriptome analysis was conducted of 577 P. falciparum isolates collected in the GMS between 2016-2018. A specific artemisinin resistance-associated transcriptional profile was identified that involves a broad but discrete set of biological functions related to proteotoxic stress, host cytoplasm remodelling, and REDOX metabolism. The artemisinin resistance-associated transcriptional profile evolved from initial transcriptional responses of susceptible parasites to artemisinin. The genetic basis for this adapted response is likely to be complex.

Ulnar variance and triangular fibrocartilage thickness in adolescents: a cross-sectional MRI study of healthy participants.

Skeletally immature wrists are considered at risk of injury due to increased axial loading through a relatively shorter ulna. The aim of this study was to determine whether triangular fibrocartilage thickness relates to ulnar variance and age in adolescents. The radiographs and MRIs of 24 healthy adolescents were retrospectively assessed. Four observers assessed bone age and ulnar variance on radiographs and measured triangular fibrocartilage thickness on MRIs. Median calendar and bone age was 13 years and ulnar variance was -0.7 mm. Median triangular fibrocartilage thickness was 1.4 mm, with excellent inter-observer agreement (r = 0.86). It was moderately correlated with ulnar variance (ρ = -0.46) as well as with bone age (ρ = -0.49). Both variables were statistically significant predictors in a multivariate analysis. This suggests that triangular fibrocartilage thickness changes during skeletal maturation, which might influence axial load distribution in skeletally immature wrists.

Proximal hamstring tendon avulsions: comparable clinical outcomes of operative and non-operative treatment at 1-year follow-up using a shared decision-making model.

OBJECTIVE: To prospectively evaluate 1-year clinical and radiological outcomes after operative and non-operative treatment of proximal hamstring tendon avulsions. METHODS: Patients with an MRI-confirmed proximal hamstring tendon avulsion were included. Operative or non-operative treatment was selected by a shared decision-making process. The primary outcome was the Perth Hamstring Assessment Tool (PHAT) score. Secondary outcome scores were Proximal Hamstring Injury Questionnaire, EQ-5D-3L, Tegner Activity Scale, return to sports, hamstring flexibility, isometric hamstring strength and MRI findings including proximal continuity. RESULTS: Twenty-six operative and 33 non-operative patients with a median age of 51 (IQR: 37-57) and 49 (IQR: 45-56) years were included. Median time between injury and initial visit was 12 (IQR 6-19) days for operative and 21 (IQR 12-48) days for non-operative patients (p=0.004). Baseline PHAT scores were significantly lower in the operative group (32±16 vs 45±17, p=0.003). There was no difference in mean PHAT score between groups at 1 year follow-up (80±19 vs 80±17, p=0.97). Mean PHAT score improved by 47 (95% CI 39 to 55, p<0.001) after operative and 34 (95% CI 27 to 41, p<0.001) after non-operative treatment. There were no relevant differences in secondary clinical outcome measures. Proximal continuity on MRI was present in 20 (95%, 1 recurrence) operative and 14 (52%, no recurrences) non-operative patients (p=0.008). CONCLUSION: In a shared decision-making model of care, both operative and non-operative treatment of proximal hamstring tendon avulsions resulted in comparable clinical outcome at 1-year follow-up. Operative patients had lower pretreatment PHAT scores but improved substantially to reach comparable PHAT scores as non-operative patients. We recommend using this shared decision model of care until evidence-based indications in favour of either treatment option are available from high-level clinical trials.

Spend wisely to eliminate malaria.

The countries of the Greater Mekong subregion-Myanmar, Thailand, Laos, Cambodia, and Vietnam-have set a target of eliminating all Plasmodium falciparum malaria by 2025. Generous funding has been provided, principally by The Global Fund to Fight AIDS, Tuberculosis, and Malaria, to achieve this objective and thereby prevent the spread of artemisinin-resistant Plasmodium falciparum to India and Africa. As the remaining time to reach agreed targets is limited and future external funding is uncertain, it is important to be realistic about the future and spend what remaining funding is left, wisely. New, labour intensive, vertical approaches to malaria elimination (such as the 1-3-7 approach) should not be promoted as these are unproven, likely to be ineffective, costly, and unlikely to be sustainable in the most remote areas where malaria prevalence is highest. Instead, the focus should be on reducing the malaria burden more rapidly in the remaining localised high transmission foci with proven effective interventions, including mass drug administration. Well supported community-based health workers are the key operatives in controlling malaria, but their remit should be broadened to sustain the uptake of their services as malaria declines. This strategy is a sustainable evolution, which will improve rural health care while ensuring progress towards malaria elimination.

OptimisAtion of Diagnostic Accuracy in idioPathic inflammaTory myopathies (ADAPT study): a protocol for a prospective diagnostic accuracy study of multimodality testing in patients suspected of a treatable idiopathic inflammatory myopathy.

INTRODUCTION: Idiopathic inflammatory myopathies (IIMs) excluding inclusion body myositis (IBM) are a group of heterogeneous autoimmune disorders characterised by subacute-onset and progressive proximal muscle weakness, which are frequently part of a multisystem autoimmune disorder. Reaching the diagnosis can be challenging, and no gold standard for the diagnosis of IIM exists. Diagnostic modalities include serum creatine kinase activity, muscle imaging (MRI or ultrasound (US)), electromyography (EMG), myositis autoantibody testing and muscle biopsy. Several diagnostic criteria have been developed for IIMs, varying in reported sensitivity and specificity. HYPOTHESIS: We hypothesise that an evidence-based diagnostic strategy, using fewer and preferably the least invasive diagnostic modalities, can achieve the accuracy of a complete panel of diagnostic tests, including MRI, US, EMG, myositis-specific autoantibody testing and muscle biopsy. METHODS AND ANALYSIS: The OptimizAtion of Diagnostic Accuracy in idioPathic inflammaTory myopathies study is a prospective diagnostic accuracy study with an over-complete study design. 100 patients suspected of an IIM excluding IBM will be included. A reference diagnosis will be assigned by an expert panel using all clinical information and all results of all ancillary tests available, including 6 months of follow-up. Several predefined diagnostic strategies will be compared against the reference diagnosis to find the optimal diagnostic strategy. ETHICS AND DISSEMINATION: Ethical approval was obtained from the medical ethics committee of the Academic Medical Centre, University of Amsterdam, The Netherlands (2019-814). The results will be distributed through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: Netherlands trial register; NL8764.

Development of weight and age-based dosing of daily primaquine for radical cure of vivax malaria.

BACKGROUND: In many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients of all ages. However, for many anti-malarial drugs, including primaquine, there is evidence that children have lower exposures than adults for the same weight-adjusted dose. The aim of the study was to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax. METHODS: The recommended adult target dose of 0.5 mg/kg/day (30 mg in a 60 kg patient) is highly efficacious against tropical P. vivax and was assumed to produce optimal drug exposure. Primaquine doses were calculated using allometric scaling to derive a weight-based primaquine regimen over a weight range from 5 to 100 kg. Growth curves were constructed from an anthropometric database of 53,467 individuals from the Greater Mekong Subregion (GMS) to define weight-for-age relationships. The median age associated with each weight was used to derive an age-based dosing regimen from the weight-based regimen. RESULTS: The proposed weight-based regimen has 5 dosing bands: (i) 5-7 kg, 5 mg, resulting in 0.71-1.0 mg/kg/day; (ii) 8-16 kg, 7.5 mg, 0.47-0.94 mg/kg/day; (iii) 17-40 kg, 15 mg, 0.38-0.88 mg/kg/day; (iv) 41-80 kg, 30 mg, 0.37-0.73 mg/kg/day; and (v) 81-100 kg, 45 mg, 0.45-0.56 mg/kg/day. The corresponding age-based regimen had 4 dosing bands: 6-11 months, 5 mg, 0.43-1.0 mg/kg/day; (ii) 1-5 years, 7.5 mg, 0.35-1.25 mg/kg/day; (iii) 6-14 years, 15 mg, 0.30-1.36 mg/kg/day; and (iv) ≥ 15 years, 30 mg, 0.35-1.07 mg/kg/day. CONCLUSION: The proposed weight-based regimen showed less variability around the primaquine dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands for both regimens. The age-based regimen might not be applicable to regions outside the GMS, which must be based on local anthropometric data. Pharmacokinetic data in small children are needed urgently to inform the proposed regimens.