Summary Background Evidence suggests that the PfKelch13 mutations that confer artemisinin resistance in falciparum malaria have multiple independent origins across the Greater Mekong subregion, which ...has motivated a regional malaria elimination agenda. We aimed to use molecular genotyping to assess antimalarial drug resistance selection and spread in the Greater Mekong subregion. Methods In this observational study, we tested Plasmodium falciparum isolates from Myanmar, northeastern Thailand, southern Laos, and western Cambodia for PfKelch13 mutations and for Pfplasmepsin2 gene amplification (indicating piperaquine resistance). We collected blood spots from patients with microscopy or rapid test confirmed uncomplicated falciparum malaria. We used microsatellite genotyping to assess genetic relatedness. Findings As part of studies on the epidemiology of artemisinin-resistant malaria between Jan 1, 2008, and Dec 31, 2015, we collected 434 isolates. In 2014–15, a single long PfKelch13 C580Y haplotype (−50 to +31·5 kb) lineage, which emerged in western Cambodia in 2008, was detected in 65 of 88 isolates from northeastern Thailand, 86 of 111 isolates from southern Laos, and 14 of 14 isolates from western Cambodia, signifying a hard transnational selective sweep. Pfplasmepsin2 amplification occurred only within this lineage, and by 2015 these closely related parasites were found in ten of the 14 isolates from Cambodia and 15 of 15 isolates from northeastern Thailand. C580Y mutated parasites from Myanmar had a different genetic origin. Interpretation Our results suggest that the dominant artemisinin-resistant P falciparum C580Y lineage probably arose in western Cambodia and then spread to Thailand and Laos, outcompeting other parasites and acquiring piperaquine resistance. The emergence and spread of fit artemisinin-resistant P falciparum parasite lineages, which then acquire partner drug resistance across the Greater Mekong subregion, threatens regional malaria control and elimination goals. Elimination of falciparum malaria from this region should be accelerated while available antimalarial drugs still remain effective. Funding The Wellcome Trust and the Bill and Melinda Gates Foundation.
A multidrug-resistant co-lineage of Plasmodium falciparum malaria, named KEL1/PLA1, spread across Cambodia in 2008–13, causing high rates of treatment failure with the frontline combination therapy ...dihydroartemisinin-piperaquine. Here, we report on the evolution and spread of KEL1/PLA1 in subsequent years.
For this genomic epidemiology study, we analysed whole genome sequencing data from P falciparum clinical samples collected from patients with malaria between 2007 and 2018 from Cambodia, Laos, northeastern Thailand, and Vietnam, through the MalariaGEN P falciparum Community Project. Previously unpublished samples were provided by two large-scale multisite projects: the Tracking Artemisinin Resistance Collaboration II (TRAC2) and the Genetic Reconnaissance in the Greater Mekong Subregion (GenRe-Mekong) project. By investigating genome-wide relatedness between parasites, we inferred patterns of shared ancestry in the KEL1/PLA1 population.
We analysed 1673 whole genome sequences that passed quality filters, and determined KEL1/PLA1 status in 1615. Before 2009, KEL1/PLA1 was only found in western Cambodia; by 2016–17 its prevalence had risen to higher than 50% in all of the surveyed countries except for Laos. In northeastern Thailand and Vietnam, KEL1/PLA1 exceeded 80% of the most recent P falciparum parasites. KEL1/PLA1 parasites maintained high genetic relatedness and low diversity, reflecting a recent common origin. Several subgroups of highly related parasites have recently emerged within this co-lineage, with diverse geographical distributions. The three largest of these subgroups (n=84, n=79, and n=47) mostly emerged since 2016 and were all present in Cambodia, Laos, and Vietnam. These expanding subgroups carried new mutations in the crt gene, which arose on a specific genetic background comprising multiple genomic regions. Four newly emerging crt mutations were rare in the early period and became more prevalent by 2016–17 (Thr93Ser, rising to 19·8%; His97Tyr to 11·2%; Phe145Ile to 5·5%; and Ile218Phe to 11·1%).
After emerging and circulating for several years within Cambodia, the P falciparum KEL1/PLA1 co-lineage diversified into multiple subgroups and acquired new genetic features, including novel crt mutations. These subgroups have rapidly spread into neighbouring countries, suggesting enhanced fitness. These findings highlight the urgent need for elimination of this increasingly drug-resistant parasite co-lineage, and the importance of genetic surveillance in accelerating malaria elimination efforts.
Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and UK Department for International Development.
Plasmodium vivax infects an estimated 7 million people every year. Previously, vivax malaria was perceived as a benign condition, particularly when compared to falciparum malaria. Reports of the ...severe clinical impacts of vivax malaria have been increasing over the last decade.
We describe the main clinical impacts of vivax malaria, incorporating a rapid systematic review of severe disease with meta-analysis of data from studies with clearly defined denominators, stratified by hospitalization status. Severe anemia is a serious consequence of relapsing infections in children in endemic areas, in whom vivax malaria causes increased morbidity and mortality and impaired school performance. P. vivax infection in pregnancy is associated with maternal anemia, prematurity, fetal loss, and low birth weight. More than 11,658 patients with severe vivax malaria have been reported since 1929, with 15,954 manifestations of severe malaria, of which only 7,157 (45%) conformed to the World Health Organization (WHO) diagnostic criteria. Out of 423 articles, 311 (74%) were published since 2010. In a random-effects meta-analysis of 85 studies, 68 of which were in hospitalized patients with vivax malaria, we estimated the proportion of patients with WHO-defined severe disease as 0.7% 95% confidence interval (CI) 0.19% to 2.57% in all patients with vivax malaria and 7.11% 95% CI 4.30% to 11.55% in hospitalized patients. We estimated the mortality from vivax malaria as 0.01% 95% CI 0.00% to 0.07% in all patients and 0.56% 95% CI 0.35% to 0.92% in hospital settings. WHO-defined cerebral, respiratory, and renal severe complications were generally estimated to occur in fewer than 0.5% patients in all included studies. Limitations of this review include the observational nature and small size of most of the studies of severe vivax malaria, high heterogeneity of included studies which were predominantly in hospitalized patients (who were therefore more likely to be severely unwell), and high risk of bias including small study effects.
Young children and pregnant women are particularly vulnerable to adverse clinical impacts of vivax malaria, and preventing infections and relapse in this groups is a priority. Substantial evidence of severe presentations of vivax malaria has accrued over the last 10 years, but reporting is inconsistent. There are major knowledge gaps, for example, limited understanding of the underlying pathophysiology and the reason for the heterogenous geographical distribution of reported complications. An adapted case definition of severe vivax malaria would facilitate surveillance and future research to better understand this condition.
Dermatological services in Laos, South East Asia are limited mainly to the capital and patch testing is currently not available, so no data exists regarding the common cutaneous allergens in this ...population.
The aim of this study was to document common allergens in paediatric patients with atopic dermatitis attending the allergy clinic in the capital, Vientiane.
Fifty paediatric patients with atopic dermatitis were patch tested using TRUE Test® panels 1 to 3 (35 allergens). Readings were taken at Days 2 and 4.
Twenty-six positive patch tests were recorded on Day 4 in 15 children (30%). The most common allergens were: gold (18%), nickel (10%), formaldehyde (6%) and p-Phenylenediamine (6%). Other positive allergens were potassium dichromate (2%), cobalt dichloride (2%), Bronopol (2%), paraben mix (2%), fragrance mix 1 (2%) and neomycin (2%). The majority of the patients with positive reactions were female.
This study represents the first documented patch test results in the Lao population. It is hoped that these findings will help clinicians to advise the families of children with atopic dermatitis on common allergens to avoid and inform future work on contact dermatitis in this population.
Artemisinin resistance in Plasmodium falciparum threatens global efforts to control and eliminate malaria. Polymorphisms in the kelch domain–carrying protein K13 are associated with artemisinin ...resistance, but the underlying molecular mechanisms are unknown. We analyzed the in vivo transcriptomes of 1043 P. falciparum isolates from patients with acute malaria and found that artemisinin resistance is associated with increased expression of unfolded protein response (UPR) pathways involving the major PROSC and TRiC chaperone complexes. Artemisinin-resistant parasites also exhibit decelerated progression through the first part of the asexual intraerythrocytic development cycle. These findings suggest that artemisinin-resistant parasites remain in a state of decelerated development at the young ring stage, whereas their up-regulated UPR pathways mitigate protein damage caused by artemisinin. The expression profiles of UPR-related genes also associate with the geographical origin of parasite isolates, further suggesting their role in emerging artemisinin resistance in the Greater Mekong Subregion.
The Greater Mekong subregion is a recurrent source of antimalarial drug resistance in Plasmodium falciparum malaria. This study aimed to characterise the extent and spread of resistance across this ...entire region between 2007 and 2018.
P falciparum isolates from Myanmar, Thailand, Laos, and Cambodia were obtained from clinical trials and epidemiological studies done between Jan 1, 2007, and Dec 31, 2018, and were genotyped for molecular markers (pfkelch, pfcrt, pfplasmepsin2, and pfmdr1) of antimalarial drug resistance. Genetic relatedness was assessed using microsatellite and single nucleotide polymorphism typing of flanking sequences around target genes.
10 632 isolates were genotyped. A single long pfkelch Cys580Tyr haplotype (from −50 kb to +31·5 kb) conferring artemisinin resistance (PfPailin) now dominates across the eastern Greater Mekong subregion. Piperaquine resistance associated with pfplasmepsin2 gene amplification and mutations in pfcrt downstream of the Lys76Thr chloroquine resistance locus has also developed. On the Thailand–Myanmar border a different pfkelch Cys580Tyr lineage rose to high frequencies before it was eliminated. Elsewhere in Myanmar the Cys580Tyr allele remains widespread at low allele frequencies. Meanwhile a single artemisinin-resistant pfkelch Phe446Ile haplotype has spread across Myanmar. Despite intense use of dihydroartemisinin–piperaquine in Kayin state, eastern Myanmar, both in treatment and mass drug administrations, no selection of piperaquine resistance markers was observed. pfmdr1 amplification, a marker of resistance to mefloquine, remains at low prevalence across the entire region.
Artemisinin resistance in P falciparum is now prevalent across the Greater Mekong subregion. In the eastern Greater Mekong subregion a multidrug resistant P falciparum lineage (PfPailin) dominates. In Myanmar a long pfkelch Phe446Ile haplotype has spread widely but, by contrast with the eastern Greater Mekong subregion, there is no indication of artemisinin combination therapy (ACT) partner drug resistance from genotyping known markers, and no evidence of spread of ACT resistant P falciparum from the east to the west. There is still a window of opportunity to prevent global spread of ACT resistance.
Thailand Science Research and Innovation, Initiative 5%, Expertise France, Wellcome Trust.
Abstract
Thyroid disease, particularly hypothyroidism, has been reported in systemic sclerosis (SSc). Some clinical features of SSc can also present in hypothyroidism. Our aims were to determine the ...prevalence of, and describe clinical features associated with, hypothyroidism in SSc patients. We conducted a historical cohort study of adult SSc patients who underwent screening thyroid function tests at the Scleroderma Clinic, Khon Kaen University, Thailand, between 2009 and 2018. The patients who had any thyroid disorders before the onset of SSc and were diagnosed as an overlap syndrome were excluded. A total of 200 SSc were included according to sample size calculation, among whom the female to male ratio was 2:1. The majority of cases (137; 69.5%) were diffuse cutaneous SSc subset. The mean age was 55.8 ± 10.7 years and the median duration of disease 4.9 (IQR 1.6–9.9) years. Of the total, 9 had primary hypothyroidism (prevalence 4.5%; 95%CI 2.1–8.4) and 22 had subclinical hypothyroidism (prevalence 11%; 95%CI 7.0–16.2). Of the latter 22, 71% had dcSSc. Logistic regression analysis indicated that unexplained anemia was significantly associated with either subclinical hypothyroid or hypothyroidism (OR 2.74; 95% CI 1.17–6.47), whereas Raynaud’s phenomenon had a negative association (OR 0.28; 95% CI 0.11–0.66). Neither severity of skin tightness nor internal organ involvement were associated with hypothyroidism among SSc patients. Clinical-subclinical hypothyroidism is uncommon among SSc patients, it is frequently associated with anemia, and less so Raynaud’s phenomenon. Clinical-subclinical hypothyroidism should thus be considered in cases of unexplained anemia in SSc patients.
Evolving resistance to arte misi ni n-based compounds threatens to derail attempts to control malaria. Resistance has been confirmed in western Cambodia and has recently emerged in western Thailand, ...but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CRs) after treatment. We used a two-phase strategy to identify genome region(s) underlying this ongoing selective event. Geographical differentiation and haplotype structure at 6969 polymorphic single-nucleotide polymorphisms (SNPs) in 91 parasites from Cambodia, Thailand, and Laos identified 33 genome regions under strong selection. We screened SNPs and microsatellites within these regions in 715 parasites from Thailand, identifying a selective sweep on chromosome 13 that shows strong association (P = 10⁻⁶ to 10⁻¹²) with slow CRs, illustrating the efficacy of targeted association for identifying the genetic basis of adaptive traits.
Patch testing in Lao medical students Wootton, Catriona I; Soukavong, Mick; Kidoikhammouan, Sonexai ...
PloS one,
01/2020, Letnik:
15, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Dermatological services in Laos, South East Asia are limited to the capital and patch testing is currently not available, so no data exists regarding the common cutaneous allergens in this ...population.
The aim of this study was to document positive patch tests in medical students without evidence of contact dermatitis in Laos.
One hundred and fifty medical students were patch tested using TRUE Test® panels 1 to 3 (35 allergens). Readings were taken at Days 2 and 4.
Thirty-eight students (25.3%) had a positive reaction to at least one allergen, accounting for 52 reactions in total. The proportion of the students with positive patch test reading was significantly higher in the female 33/96 (34%) than in the male 5/54 (9%), p<0.001. The most common allergens were: nickel (10%), gold (6.6%), thiomersal (6.6%), cobalt dichloride (2%) and p-tert-Butylphenol formaldehyde resin (2%). Balsam of Peru (0.66%), black rubber mix (0.66%), Cl+Me-Isothiazolinone (0.66%), fragrance mix 1 (0.66%), quinolone mix (0.66%), methyldibromo glutaronitrile (0.66%), mercapto mix (0.66%), epoxy resin (0.66%), paraben mix (0.66%), thiuram (0.66%) and wool alcohols (0.66%) accounted for all of the other positive reactions.
This study represents the first documented patch test results in Lao medical students and in the adult Lao population. The results of this study will inform any future research into contact allergy in Laos and give an insight into the background level of contact sensitivity in this population.
Routine microbiology results are a valuable source of antimicrobial resistance (AMR) surveillance data in low- and middle-income countries (LMICs) as well as in high-income countries. Different ...approaches and strategies are used to generate AMR surveillance data.
We aimed to review strategies for AMR surveillance using routine microbiology results in LMICs and to highlight areas that need support to generate high-quality AMR data.
We searched PubMed for papers that used routine microbiology to describe the epidemiology of AMR and drug-resistant infections in LMICs. We also included papers that, from our perspective, were critical in highlighting the biases and challenges or employed specific strategies to overcome these in reporting AMR surveillance in LMICs.
Topics covered included strategies of identifying AMR cases (including case-finding based on isolates from routine diagnostic specimens and case-based surveillance of clinical syndromes), of collecting data (including cohort, point-prevalence survey, and case–control), of sampling AMR cases (including lot quality assurance surveys), and of processing and analysing data for AMR surveillance in LMICs.
The various AMR surveillance strategies warrant a thorough understanding of their limitations and potential biases to ensure maximum utilization and interpretation of local routine microbiology data across time and space. For instance, surveillance using case-finding based on results from clinical diagnostic specimens is relatively easy to implement and sustain in LMIC settings, but the estimates of incidence and proportion of AMR is at risk of biases due to underuse of microbiology. Case-based surveillance of clinical syndromes generates informative statistics that can be translated to clinical practices but needs financial and technical support as well as locally tailored trainings to sustain. Innovative AMR surveillance strategies that can easily be implemented and sustained with minimal costs will be useful for improving AMR data availability and quality in LMICs.
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