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On 21 June 2017, the Cambodia Oxford Medical Research Unit (COMRU) and Angkor Hospital for Children (AHC) hosted the kick-off meeting for the multi-country Real-time Tracking of Neglected Bacterial Infectious Diseases Resistance Patterns Asia (TuNDRA) study.
Case Report: Genetic evolution of Burkholderia pseudomallei during treatment leading to antibiotic resistance and disease relapse.
Background Melioidosis is a significant yet neglected cause of sepsis in tropical regions, particularly in southeast Asia, with poor clinical outcomes. It is a growing threat with an expanding global footprint. The causative organism, Burkholderia pseudomallei, is intrinsically resistant to most first-line empiric antibiotic regimens, but acquired resistance to recommended antibiotics for this infection is uncommon. Nonetheless, the genetic determinants of resistance in this species remain poorly elucidated. Case presentation A 60-year-old farmer presented in septic shock to a hospital in Laos, and B. pseudomallei was grown from blood cultures. Following initial antibiotic treatment with meropenem and co-trimoxazole, his infection relapsed. Several subsequent B. pseudomallei isolates from the patient were resistant to multiple antibiotics, and whole genome sequencing demonstrated that this phenotype was associated with a novel 54-kb genomic deletion. This deletion, on chromosome 1, includes the 5’ end of amrR – which encodes a regulator of an efflux pump known to be important in conferring meropenem resistance – as well as 46 other genes, some of which have not been characterised. Treatment was targeted to the new antibiogram, requiring a further prolonged intravenous course and second-line oral eradication therapy. The patient made a full recovery. Conclusions Mutations in Burkholderia pseudomallei lead to increased virulence and drug resistance. Repeat microbiological sampling of patients who do not make clinical improvement as anticipated is essential, with repeat full antimicrobial susceptibility testing on subsequent isolates. Characterisation of drug-resistant mutants is required to understand mechanisms of resistance and to predict phenotypes from whole genome sequencing.
Microhaplotype deep sequencing assays to capture Plasmodium vivax infection lineages.
Plasmodium vivax elimination is challenged by dormant liver stages (hypnozoites) that can reactivate months after initial infection resulting in relapses. Relapsing infections confound antimalarial clinical efficacy trials due to the inability to distinguish between recurrences arising from blood-stage treatment failure (recrudescence), reinfection or relapse. Genetic relatedness of paired parasite isolates, measured by identity-by-descent (IBD), can provide important information on whether individuals have had single or multiple mosquito inoculations, thus informing on recurrence origin. We developed a high-throughput amplicon sequencing assay comprising 93 multi-SNP (microhaplotype) markers to determine IBD between P. vivax clinical isolates. The assay was evaluated in 745 global infections, including 128 infection pairs from a randomized controlled trial (RCT) (ClinicalTrials.gov NCT01680406). Simulations demonstrate low error in pairwise IBD estimation at the panel (RMSE
Climate-driven marmot-plague dynamics in Mongolia and China.
The incidence of plague has rebounded in the Americas, Asia, and Africa alongside rapid globalization and climate change. Previous studies have shown local climate to have significant nonlinear effects on plague dynamics among rodent communities. We analyzed an 18-year database of plague, spanning 1998 to 2015, in the foci of Mongolia and China to trace the associations between marmot plague and climate factors. Our results suggested a density-dependent effect of precipitation and a geographic location-dependent effect of temperature on marmot plague. That is, a significantly positive relationship was evident between risk of plague and precipitation only when the marmot density exceeded a certain threshold. The geographical heterogeneity of the temperature effect and the contrasting slopes of influence for the Qinghai-Tibet Plateau (QTP) and other regions in the study (nQTP) were primarily related to diversity of climate and landscape types.
Infection and risk factors of human and avian influenza in pigs in south China.
The coinfection of swine influenza (SI) strains and avian/human-source influenza strains in piggeries can contribute to the evolution of new influenza viruses with pandemic potential. This study analyzed surveillance data on SI in south China and explored the spatial predictor variables associated with different influenza infection scenarios in counties within the study area. Blood samples were collected from 7670 pigs from 534 pig farms from 2015 to 2017 and tested for evidence of infection with influenza strains from swine, human and avian sources. The herd prevalences for EA H1N1, H1N1pdm09, classic H1N1, HS-like H3N2, seasonal human H1N1 and avian influenza H9N2 were 88.5, 64.5, 60.3, 57.8, 12.9 and 10.3 %, respectively. Anthropogenic factors including detection frequency, chicken density, duck density, pig density and human population density were found to be better predictor variables for three influenza infection scenarios (infection with human strains, infection with avian strains, and coinfection with H9N2 avian strain and at least one swine strain) than were meteorological and geographical factors. Predictive risk maps generated for the four provinces in south China highlighted that the areas with a higher risk of the three infection scenarios were predominantly clustered in the delta area of the Pearl River in Guangdong province and counties surrounding Poyang Lake in Jiangxi province. Identification of higher risk areas can inform targeted surveillance for influenza in humans and pigs, helping public health authorities in designing risk-based SI control strategies to address the pandemic influenza threat in south China.
Impact and mitigation of near infrared absorption in quantitative Transmission Raman Spectroscopy.
Transmission Raman Spectroscopy is an analytical technique commonly used for uniformity content analysis of manufactured pharmaceutical products to quantify the active pharmaceutical ingredients and excipients in the final formulation. Such samples are subjected to a variety of physical-chemical stressors during the manufacture such as compaction force or thickness variations. These effects can impact the effective optical paths Raman photons traverse inside the sample and hence impose different attenuation to emerging Raman photons through near infrared absorption resulting in distortions of Raman spectral profiles. These distortions can propagate to quantitative models and manifest themselves as systematic errors in predictions. In this work, we studied the impact of thickness, porosity and compaction force variations on the predictive capability of a quantitative model and propose a basic spectral standardization technique to correct for it. We observed an improvement in the statistical metrics used to evaluate the performance of the model built on the whole calibration set (RMSE from 2.5 % to 2.0 %) and near complete elimination of the present bias between the most extreme values of compaction (from 8.40 to ∼0 %) accompanied by the corresponding reduction in residuals (RMSE from 8.63 % to 2.06 %).
Acceptability and feasibility of glucose-6-phosphate dehydrogenase (G6PD) testing using SD Biosensor by village malaria workers in Cambodia: a qualitative study
IntroductionPlasmodium vivaxis the predominant cause of malaria in the Greater Mekong Subregion. To ensure safe treatment with primaquine, point-of-care glucose-6-phosphate dehydrogenase (G6PD) testing was rolled out in Cambodia at the health facility level, although most malaria patients are diagnosed in the community. The current study aims to explore the acceptability and feasibility of implementing community-level G6PD testing in Cambodia.MethodsSemistructured interviews and focus group discussions (FGD) were conducted. Across eight study sites in three provinces, 142 respondents, including policymakers, programme officers, healthcare providers and patients, participated in 67 interviews and 19 FGDs in 2022 and 2023. Data were analysed thematically using an adapted framework derived from Bowenet al’s feasibility framework and Sekhonet al’s acceptability framework.ResultsAll stakeholders attributed value to the intervention. Acknowledging an intervention’s different values can help discern policy implications for an intervention’s successful implementation. Building and maintaining confidence in the device, end users, infrastructure and health systems were found to be key elements of acceptability. In general, health centre workers and village malaria workers (VMWs) had confidence that VMWs could conduct the test and administer treatment given appropriate initial training, monthly refresher training and the test’s repeated use. More is required to build policymakers’ confidence, while some implementation challenges, including the test’s regulatory approval, stability above 30°C and cost, need to be overcome.ConclusionImplementation of G6PD testing at the community level in Cambodia is an acceptable and potentially feasible option but requires addressing implementation challenges and building and maintaining confidence among stakeholders.
Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial
Background Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use. Methods and findings Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507. Interpretation In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs. Trial registration ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947.
The intracellular bacterium Orientia tsutsugamushi uses the autotransporter ScaC to activate BICD adaptors for dynein-based motility.
The intracellular bacterium Orientia tsutsugamushi relies on the microtubule cytoskeleton and the motor protein dynein to traffic to the perinuclear region within infected cells. However, it remains unclear how the bacterium is coupled to the dynein machinery and how transport is regulated. Here, we discover that O. tsutsugamushi uses its autotransporter protein ScaC to recruit the dynein adaptors BICD1 and BICD2 for movement to the perinucleus. We show that ScaC is sufficient to engage dynein-based motility in the absence of other bacterial proteins and that BICD1 and BICD2 are required for efficient movement of O. tsutsugamushi during infection. Using TIRF single-molecule assays, we demonstrate that ScaC induces BICD2 to adopt an open conformation which activates the assembly of dynein-dynactin complexes. Our results reveal a role for BICD adaptors during bacterial infection and provide mechanistic insights into the life cycle of an important human pathogen.
Comparative virulence analysis of seven diverse strains of Orientia tsutsugamushi reveals a multifaceted and complex interplay of virulence factors responsible for disease.
Orientia tsutsugamushi is an obligate intracellular bacterium found in Leptotrombidium mites that causes the human disease scrub typhus. A distinguishing feature of O. tsutsugamushi is its extensive strain diversity, yet differences in virulence between strains are not well defined nor well understood. We sought to determine the bacterial drivers of pathogenicity by comparing seven strains using murine infections combined with epidemiological human data to rank each strain in terms of relative virulence. Murine cytokine expression data revealed that the two most virulent strains, Ikeda and Kato, induced higher levels of IL-6, IL-10, IFN-γ and MCP-1 than other strains, consistent with increased levels of these cytokines in patients with severe scrub typhus. We sought to identify the mechanistic basis of the observed differential virulence between strains by comparing their genomes, in vitro growth properties and cytokine/chemokine induction in host cells. We found that there was no single gene or gene group that correlated with virulence, and no clear pattern of in vitro growth rate that predicted disease. However, microscopy-based analysis of the intracellular infection cycle revealed that the only fully avirulent strain in our study, TA686, differed from all the virulent strains in its subcellular localisation and expression of its surface protein ScaC. This leads us to a model whereby drivers of pathogenicity in Orientia tsutsugamushi are distributed throughout the genome, likely in the large and varying arsenal of effector proteins encoded by different strains, and that these interact in complex ways to induce differing immune responses and thus differing disease outcomes in mammalian hosts.
Optimizing dog population control strategies in Thailand using mathematical and economic modeling.
A mathematical model was constructed to investigate dog population dynamics and explore the impact of population management and rabies prevention. We aimed to evaluate cost-effective sterilization and vaccination strategies for dog population control and rabies prevention in Thailand. The developed compartmental model was calibrated with dog population data from Lopburi province (between 2019 and 2022) and simulated five sterilization scenarios. These measures included a combined 80% coverage of the rabies vaccine and 20% coverage of a sterilization program among non-specific dog types. Our findings indicated that sterilization programs targeting female indoor, outdoor, and stray dogs may prove to be the most effective in reducing the total dog population above 50% over a five-year period, surpassing the efficacy of the current intervention. Furthermore, the cost-effectiveness analysis showed that the two female dog sterilization strategies were cost-saving compared to the current practice, as the total costs of sterilization and vaccination decreased over time due to the reduction in the dog population. In conclusion, targeting female dog sterilization could reduce the population and was cost-saving compared to current strategies. Further data to inform dog population demographic and available resources including manpower, rabies vaccine, sterilization toolkits, and related materials will be required to fully explore intervention accessibility and feasibility within the context of rabies prevention and control in Thailand.
Factors Influencing Health Workers' Acceptance of Guideline-Based Clinical Decision Support Systems for Preventive Services in Thailand: Questionnaire-Based Study.
BackgroundA guideline-based clinical decision support system (CDSS) is a knowledge-based system designed to collect crucial data from electronic medical records to generate decision-making based on system data requirements and inputs from standard guidelines. Despite the potential to enhance health care delivery, the adoption rate of CDSSs in clinical practice remains suboptimal.ObjectiveThis study aimed to evaluate the determinants influencing the intention to use a new CDSS in preventive care within clinical practice.MethodsA single-center, questionnaire-based, cross-sectional study was conducted among physicians and medical students responsible for providing comprehensive preventive services at the Continuity of Care Clinic, Siriraj Hospital, Thailand.ResultsIn total, 89 participants were enrolled. Relationships between factors impacting the adoption of CDSSs were analyzed using correlation and regression analysis. We found that physicians' intentions to adopt the CDSS for preventive care were high, with 79% (70/89) of participants expressing their intention to use the system. According to the study's conceptual framework, modified from the original unified theory of acceptance and use of technology model, physicians' positive attitudes toward CDSS use in preventive services and a high level of effort expectancy emerged as crucial factors influencing the intention to use the new CDSS. The odds ratios for these factors were 5.44 (95% CI 1.62-18.34, P=.006) and 7.60 (95% CI 1.55-31.37, P=.01), respectively. Similar results were observed for medical students and for physicians who had graduated. The most prevalent barriers to CDSS implementation were related to physicians' attitudes, followed by issues such as the accuracy and burden of data input, time constraints for clinicians, and the risk of workflow disruption.ConclusionsThere was a high intention to adopt the CDSS in preventive care. Positive physician attitudes toward CDSS use in preventive services and effort expectancy were found to be critical factors influencing the intention to use the new CDSS.
Optimization of heat inactivation protocols for Orientia and Rickettsia species.
Heat treatment, or thermal disinfection, is one of the simplest and most widely used methods for microbial inactivation. Proper heat inactivation protocols are essential to ensure the safe transportation and handling of infectious materials, particularly for organisms in risk group 3, such as Rickettsia and Orientia. In this study, we examined the inactivation of four bacterial species-Orientia tsutsugamushi, Rickettsia typhi, Rickettsia conorii, and Rickettsia honei-at temperatures of 56 °C, 80 °C, and 90 °C for durations of 5, 15, 30, and 60 min. Observations were made at 0, 1, 3, 7, 10, and 14 days post-infection (dpi) to assess bacterial infectivity by monitoring bacterial DNA copies in newly infected cells. Our results indicate that 56 °C for 5 min was the minimum temperature and time required to inactivate O. tsutsugamushi, R. typhi, R. conorii, and R. honei. O. tsutsugamushi exhibited a higher reduction factor at 56 °C compared to R. typhi, R. conorii, and R. honei. Additionally, a strong inverse correlation between incubation time and log10 reduction factor was observed for O. tsutsugamushi and R. typhi, underscoring the importance of both time and temperature in effective heat treatment. However, no such correlation was observed for R. conorii and R. honei. These findings highlight the variable responses of bacteria to heat, emphasizing the need for pathogen-specific approaches in inactivation protocols. Optimizing heat treatment strategies based on these insights is critical for enhancing biosafety and ensuring effective pathogen eradication.
The epidemiology and burden of ten mental disorders in countries of the Association of Southeast Asian Nations (ASEAN), 1990-2021: findings from the Global Burden of Disease Study 2021.
BackgroundThe Association of Southeast Asian Nations (ASEAN), a geopolitical and economic network of ten member states, recognises mental disorders as a health priority; however, sparse epidemiological data hinder the development of effective strategies to reduce their prevalence and burden. We aimed to examine the prevalence, morbidity, and disease burden associated with ten mental disorders from 1990 to 2021 in the ASEAN.MethodsAs part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD 2021), we analysed estimates for depressive disorders, anxiety disorders, bipolar disorders, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder (ADHD), eating disorders, idiopathic developmental intellectual disability, and other mental disorders in ten ASEAN member states (Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, the Philippines, Singapore, Thailand, and Viet Nam). Case definitions were based on Diagnostic and Statistical Manual of Mental Disorders or ICD criteria. Prevalence estimates by age, sex, year, and location were derived using DisMod-MR 2.1, a Bayesian meta-regression modelling tool. Disease burden was quantified by estimating years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs). Estimates are presented with 95% uncertainty intervals (UIs).FindingsIn 2021, 80·4 million (95% UI 73·8-87·2) cases of mental disorders were reported across ASEAN countries, representing a 70·0% (63·5-77·2) increase since 1990. The age-standardised prevalence of mental disorders was 11·9% (10·9-12·9) in 2021, ranging from 10·1% (9·1-11·3) in Viet Nam to 13·2% (11·6-15·3) in Malaysia, with anxiety and depressive disorders being the most common. The age-standardised prevalence of mental disorders increased by 6·5% (3·7-9·8) between 1990 and 2021. Mental disorders accounted for 11·2 million (8·5-14·3) DALYs in 2021, representing an 87·4% (81·1-94·0) increase since 1990. The 10-14 years age group had the highest disease burden attributable to mental disorders, which accounted for 16·3% (12·7-20·5) of total DALYs in this age group. The largest relative increases in the number of cases of mental disorders between 1990 and 2021 were seen in older adults (182·8% [174·9-192·1] among those aged ≥70 years), despite small relative changes in prevalence in these age groups.InterpretationThe increase in mental disorder prevalence and burden found in this study might partly reflect recent improvements in detection. However, mental disorders now rank among the top ten causes of disease burden in all ASEAN countries except Myanmar, underscoring the urgent need for a comprehensive intersectoral approach to address prevention and treatment gaps across entire populations.FundingGates Foundation.