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Largest genome-wide study of parasite provides clearest picture yet of genetic changes driving artemisinin resistance artemisinin-genetics-resistance. Hinxton, Cambridge, UK, 19 January 2015 – The largest genome-wide association study to date of the malaria parasite Plasmodium falciparum unveils a complex genetic architecture that enables the parasite to develop resistance to our most effective antimalarial drug, artemisinin.
A comparison of national seasonal influenza treatment guidelines across the Asia Pacific region.
Seasonal influenza leads to 2-3 million infections and up to 650,000 global deaths annually, with particularly high mortality in Asia and relatively low annual vaccination rates for prevention. Relatively lower attention is paid to antiviral treatment as a facet of influenza response strategy both in research and national policy. This study compares national influenza treatment guidelines across countries in the Asia Pacific region, and assesses the antiviral recommendations, comprehensiveness, availability, and quality, compared with World Health Organisation (WHO) guidelines. Ministry of Health websites were searched, and key stakeholders were contacted to obtain national influenza treatment guidelines. Official guidelines detailing pharmacologic treatment for seasonal influenza were included. Key data for comparison were extracted and quality appraisal was conducted using the AGREE II instrument. Out of 49 countries and areas in the World Health Organisation Western Pacific and South-East Asia regions, under half (14/49; 28.6%) had established national influenza treatment guidelines. Nine (9/49; 18.4%) reported no seasonal flu guidelines at all, and information could not be obtained for 25 (51.0%). All guidelines recommend oseltamivir in line with WHO recommendations, although rationale and evidence reviews were often missing. There was variation in recommendations for other antivirals, indications for treatment, definitions of severity and recency of publication. The AGREE II tool quality assessments revealed the highest average scores were observed in the 'presentation' domain and lowest scores in 'editorial independence' and 'rigour of development' domains, demonstrating limited evidence-based guideline development. The variability in recommendations and definitions highlight the need for a stronger evidence base with direct comparisons of antiviral treatment for hard and soft endpoints, and improvements in systematic guideline development. Established treatment guidelines are a key component of national influenza response strategy and in the post-covid pandemic era, renewed attention to seasonal influenza management is surely warranted.
Hide and seek with falsified medicines: Current challenges and physico-chemical and biological approaches for tracing the origin of trafficked products.
The criminal trafficking of falsified medical products is a worldwide, yet still largely overlooked, public health problem. A falsified medicine fraudulently misrepresents its identity, composition and/or source, often being ineffective or toxic for patients. Although techniques have been developed to detect falsified medicines, it remains a challenge to trace where- and by whom- the products are manufactured. We aim to discuss plausible biological and physico-chemical analytical techniques that could reveal information about the origin of medical falsifications. We first provide a brief overview on the prevalence, criminal activities, health impacts and (bio)chemical features of falsified medical products. We then explore diverse laboratory approaches, that are used in food fraud, illicit drug and wildlife trafficking investigations, and discuss how they could be combined and redirected towards tracing falsified medicine origin and hence empowering enforcement to counter this pernicious but neglected global health problem.
Understanding the primary healthcare context in rural South and Southeast Asia: a village profiling study
Abstract Background Understanding contextual factors is critical to the success of health service planning and implementation. However, few contextual data are available at the village level in rural South and Southeast Asia. This study addressed the gap by profiling representative villages across seven sites in Thailand (n=3), Cambodia, Laos, Myanmar and Bangladesh. Methods Key informant surveys supplemented by other information sources were used to collect data from 687 villages on four key indicators (literacy rate, and percentages of attended deliveries, fully immunised children and latrine coverage), as well as access to various services. Data were analysed descriptively. Results Sites varied considerably. Five were highly diverse ethno-culturally and linguistically, and all relied on primary health centres and village health/malaria workers as the main providers of primary healthcare. These were generally bypassed by severely ill patients for urban first-level referral hospitals and private sector facilities. While >75% of villages were near primary schools, educational attainment was generally low. Over 70% of villages at each site had mobile phone coverage and availability of electricity was high (≥65% at all sites bar Myanmar). Conclusion These results illustrate the similarities and differences of villages in this region that must be considered in public health research and policymaking.
Lung ultrasound for the diagnosis and monitoring of pneumonia in a tuberculosis-endemic setting: a prospective study.
Lung ultrasound (LUS) has proven high diagnostic accuracy for community-acquired pneumonia (CAP) in developed countries. However, its diagnostic performance in resource-limited settings with high pulmonary tuberculosis (TB) incidence is less established. Additionally, the role of LUS in monitoring CAP progression remains underexplored.ObjectivesTo validate the diagnostic performance, monitoring and prognostic utility of LUS for CAP in a high pulmonary TB incidence setting.DesignProspective single-centre cohort study.SettingPulmonary department of a tertiary hospital in Vietnam.ParticipantsA total of 158 patients suspected of having CAP were enrolled, with 136 (mean age 62 years, 72.8% male) included in the final analysis.InterventionsPatients underwent LUS and chest X-ray (CXR) within 24 hours of admission, with a follow-up LUS on days 5-8.Primary and secondary outcome measuresThe primary outcome was the diagnostic accuracy of LUS and CXR compared with discharge diagnosis. Secondary outcomes included the accuracy compared with CT scan results, changes in LUS parameters-consolidation size, number and Lung Ultrasound Score (LUSS)-and their association with in-hospital mortality.ResultsLUS demonstrated higher sensitivity than CXR (96.0% (95% CI 90.0% to 99.0%) vs 82.8% (95% CI 73.9% to 89.7%)). LUS specificity was 64.9% (95% CI 47.5% to 80.0%), compared with 54.1% (95% CI 36.9% to 70.5%) for CXR. The moderate specificity for LUS was due to sonographic-similar conditions, notably TB in 5.1% of patients. Consolidation size and numbers showed marginal resolution, while LUSS showed more pronounced decreases over time. The baseline LUSS showed limited discriminative ability for predicting mortality (area under the curve, AUC 0.65, 95% CI 0.55 to 0.75), while follow-up LUSS and changes in LUSS (ΔLUSS) demonstrated higher levels of discrimination (AUC 0.81 (95% CI 0.71 to 0.89) and 0.89 (95% CI 0.80 to 0.95), respectively). For each one-point increase in ΔLUSS, the odds of in-hospital mortality went up by 70% (p=0.002). An improved LUSS effectively ruled out mortality (negative predictive value 97.4%).ConclusionAlthough LUS is highly sensitive for diagnosing CAP, its specificity in TB-endemic regions warrants further caution. Serial LUS assessments, particularly monitoring LUSS changes, are valuable for tracking disease progression and prognostication, with increasing LUSS indicating potential clinical deterioration.
Suitability of low and middle-income country data-derived prognostics models for benchmarking mortality in a multinational Asia critical care registry network: a multicentre study
Background: This study evaluates the predictive performance of prognostic models derived from low- and middle-income country (LMIC) data using a multinational Asian critical care dataset. The research also seeks to identify opportunities for improving these models' accuracy and utility in clinical research and for international benchmarking of critical care outcomes Methods This retrospective multicenter study evaluated the performance of four prognostic models: e-Tropical Intensive Care Score (e-TropICS), Tropical Intensive Care Score (TropICS), Simplified Mortality Score for the Intensive Care Unit (SMS-ICU), and Rwanda Mortality Probability Model (R-MPM) using a dataset of 64,327 ICU admissions from 109 ICUs across six Asian countries. The models' discriminative abilities were assessed using ROC curves, and calibration was evaluated with Hosmer-Lemeshow C-statistics and calibration curves. Recalibration was performed to improve model accuracy, and the impact of the COVID-19 pandemic on model performance was also analysed. Results The e-TropICS and R-MPM models showed relatively good discriminative power, with AUCs of 0.71 and 0.69, respectively. However, all models exhibited significant calibration issues, particularly at higher predicted probabilities, even after recalibration. The study also revealed variability in model performance across different countries, with India's data demonstrating the highest discriminative power. Conclusions The study highlights the challenges of applying existing prognostic models in diverse ICU settings, particularly in LMICs. While the e-TropICS and R-MPM models performed relatively well, significant calibration issues indicate a need for further refinement. Future efforts should focus on developing adaptable models that can effectively accommodate the diverse and dynamic nature of ICU populations worldwide, ensuring their utility in global healthcare benchmarking and decision-making.
An All-in-One Nanoheater and Optical Thermometer Fabricated from Fractal Nanoparticle Assemblies.
We designed and optimized a dual-functional photothermal agent that performs as a nanoheater and real-time optical thermometer by leveraging gold nanoparticle (AuNP) self-assembly and anti-Stokes thermometry. We engineered colloidally stable fractal AuNP clusters with well-defined nanogaps to absorb strongly in the near-infrared and enhance anti-Stokes vibrational modes via surface-enhanced Raman scattering (SERS) for electromagnetic (EM) hotspot-localized thermometry during plasmonic heating. Photothermal characterization and simulations of a range of AuNP building block sizes demonstrated that 40 nm AuNPs are optimum for combined plasmonic heating and SERS due to the high probability of in resonance chains within assemblies. We explored the relationship between the far-field of our AuNP clusters and the near-field enhancement of anti-Stokes modes in the context of SERS thermometry, setting out design considerations for applying SERS thermometry. Finally, using a single near-infrared (NIR) laser source, we demonstrated plasmonic heating of a colloidal system with simultaneous accurate temperature measurement from EM hotspots via the thermal information encoded in the anti-Stokes mode of surface-bound Raman reporter molecules. Ultimately, our approach could enable real-time noninvasive temperature feedback from plasmonic nanoparticles within tumor tissue environments to guide safe and effective temperature increases during cancer photothermal therapy.
Epidemiology of Burkholderia pseudomallei, Streptococcus suis, Salmonella spp., Shigella spp. and Vibrio spp. infections in 111 hospitals in Thailand, 2022
The information on notifiable diseases in low- and middle-income countries is often incomplete, limiting our understanding of their epidemiology. Our study addresses this knowledge gap by analyzing microbiology laboratory and hospital admission data from 111 of 127 public referral hospitals in Thailand, excluding Bangkok, from January to December 2022. We evaluated factors associated with the incidence of notifiable bacterial diseases (NBDs) caused by 11 pathogens; including Brucella spp., Burkholderia pseudomallei, Corynebacterium diphtheriae, Neisseria gonorrhoeae, Neisseria meningitidis, non-typhoidal Salmonella spp. (NTS), Salmonella enterica serovar Paratyphi, Salmonella enterica serovar Typhi, Shigella spp., Streptococcus suis, and Vibrio spp.. We used multivariable Poisson random-effects regression models. Additionally, we compared their yearly incidence rates in 2022 with those from 2012-2015 in hospitals where paired data were available. In 2022, the NBD associated with the highest total number of deaths was B. pseudomallei (4,407 patients; 1,219 deaths) infection, followed by NTS (4,501 patients; 461 deaths), S. suis (867 patients, 134 deaths) and Vibrio spp. (809 patients, 122 deaths) infection. The incidence rates of B. pseudomallei, S. suis and Vibrio spp. infections were highest in the northeast, upper central and west, respectively. The incidence rate of NTS infection was generally high across all geographical regions. The yearly incidence rates of B. pseudomallei and S. suis infections in 2022 were higher than those between 2012-2015, while those of fecal-oral transmitted NBDs including NTS infection, typhoid, shigellosis and vibriosis were lower. Overall, B. pseudomallei and S. suis infections are emerging and associated with a very high number of deaths in Thailand. Although the incidence of NTS infection and vibriosis are decreasing, they are still associated with a high number of cases and deaths. Specific public health interventions are warranted.
Why the growth of arboviral diseases necessitates a new generation of global risk maps and future projections.
Global risk maps are an important tool for assessing the global threat of mosquito and tick-transmitted arboviral diseases. Public health officials increasingly rely on risk maps to understand the drivers of transmission, forecast spread, identify gaps in surveillance, estimate disease burden, and target and evaluate the impact of interventions. Here, we describe how current approaches to mapping arboviral diseases have become unnecessarily siloed, ignoring the strengths and weaknesses of different data types and methods. This places limits on data and model output comparability, uncertainty estimation and generalisation that limit the answers they can provide to some of the most pressing questions in arbovirus control. We argue for a new generation of risk mapping models that jointly infer risk from multiple data types. We outline how this can be achieved conceptually and show how this new framework creates opportunities to better integrate epidemiological understanding and uncertainty quantification. We advocate for more co-development of risk maps among modellers and end-users to better enable risk maps to inform public health decisions. Prospective validation of risk maps for specific applications can inform further targeted data collection and subsequent model refinement in an iterative manner. If the expanding use of arbovirus risk maps for control is to continue, methods must develop and adapt to changing questions, interventions and data availability.
How do study participants want to be informed about study results: Findings from a malaria trial in Cambodia, Ethiopia, Pakistan and Indonesia
Background. Researchers acknowledge the need to share study results with the patients and their communities, but this is not done consistently due to a plethora of barriers, including a paucity of data to guide best practice approaches in different populations. Methods. This study was nested within a large multi-centre randomized controlled trial of antimalaria treatment. Data on dissemination preferences were collected at the third month follow-up visit using a short questionnaire. Data were analysed using descriptive statistics and subsequently fed into an iterative process with key stakeholders, to develop suitable strategies for result dissemination. Results. A total of 960 patients were enrolled in the trial, of whom 84.0% participated in the nested survey. A total of 601 (74.6%) participants indicated interest in receiving trial results. There was significant heterogeneity by study country, with 33.3% (58/174) of patients indicating being interested in Cambodia, 100% (334/334) in Ethiopia, 97.7% (209/214) in Pakistan, but none (0/85) in Indonesia. The preferred method of dissemination varied by site, with community meetings favoured in Ethiopia (79.0%, 264/334) and individualised communication such as a letter (27.6%, 16/58) or phone calls (37.9%, 22/58) in Cambodia. Dissemination strategies were designed with key stakeholders and based on patient preferences but required adaptation to accommodate local logistical challenges. Conclusion. The varying preferences observed across different sites underscore that a onesize- fits-all approach is inadequate. Strategies can be tailored to patient preference but require adaptation to accommodate logistical challenges.
Parasitaemia and fever in uncomplicated Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis.
BackgroundParasite density thresholds used for diagnosing symptomatic malaria are defined by the relationship between parasitaemia and fever. This relationship can inform the design and development of novel diagnostic tests but appropriate parasitaemia thresholds for Plasmodium vivax malaria remain poorly defined.Methodology/principal findingsWe undertook an individual patient data meta-analysis of P. vivax clinical trials mapped to the WorldWide Antimalarial Resistance Network (WWARN) repository and used parasitaemia centiles of febrile patients at enrolment to derive proportions of patients who would have been diagnosed at different parasite densities. Febrile and afebrile patients with recurrent infections were selected to estimate pyrogenic densities using receiver operating characteristic curve analysis. In total 13,263 patients from 50 studies were included in the analysis. In 27 studies (8,378 febrile patients) in which a parasitaemia threshold was not applied as an inclusion criterion, the median parasitaemia at enrolment was 3,280/µL (interquartile range, 968 - 8,320); 90% of patients had a parasitaemia above 278/µL (10th centile), and 95% above 120/µL (5th centile). The 10th centile was higher in children <5 years old (368/µL) compared to adults ≥15 years (240/µL). In high relapse periodicity regions (Southeast Asia and Oceania) febrile patients presented with lower parasitaemias (10th centile 185/µL vs. 504/µL) and a wider range of parasitaemias compared to those from low relapse periodicity regions (interquartile range 760/µL - 8,774/µL vs. 1,204/µL - 8,000/µL). In total 2,270 patients from 41 studies had at least one episode of recurrent P. vivax parasitaemia, of whom 43% (849/1,983) were febrile at their first recurrence. The P. vivax pyrogenic density at first recurrence was 1,063/µL, defining fever with 74% sensitivity and 65% specificity. The pyrogenic density was lower in young children compared to adults ≥15 years (935/µL vs. 1,179/µL).Conclusions/significanceThe derived parasitaemia centiles will inform the use of current and design of novel point-of-care tests to diagnose patients with symptomatic vivax malaria. Variation by age and location should be considered when selecting diagnostic thresholds and interpreting results.Trial registrationThis trial was registered with PROSPERO: CRD42021254905. The date of the first registration was 17th May 2021.
Performance of quantitative point-of-care tests to measure G6PD activity: An individual participant data meta-analysis.
BackgroundGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the main risk factor for severe haemolysis following treatment with 8-aminoquinolines (8AQ). The World Health Organization recommends G6PD testing prior to 8AQ-based hypnozoitocidal treatment.MethodsWe undertook an individual level meta-analysis of the performance of commercially available quantitative point-of-care diagnostics (PoCs) compared with reference spectrophotometry. A systematic literature search (PROSPERO: CRD42022330733) identified 595 articles of which 16 (2.7%) fulfilled pre-defined inclusion criteria and were included in the analysis, plus an additional 4 datasets. In total there were 12,678 paired measurements analyzed, 10,446 (82.4%) by STANDARD G6PD Test (SD Biosensor, RoK, [SDB]), 2,042 (16.1%) by CareStart G6PD Biosensor (AccessBio, USA, [CSA]), 150 (1.2%) by CareStart Biosensor (WellsBio, RoK [CSW]), and 40 (0.3%) by FINDER (Baebies, USA, [FBA]).FindingsThe pooled sensitivities of the SDB when measuring G6PD activity <30% of normal were 0.82 (95% confidence interval [CI]: 0.72-0.89) for capillary and 0.93 (95% CI: 0.75-0.99) for venous blood samples. The corresponding values for measuring <70% G6PD activity were 0.93 (95% CI: 0.67-0.99) and 0.89 (95% CI: 0.73-0.96), respectively. The pooled specificity of the SDB was high (>96%) for all blood samples and G6PD activity thresholds. Irrespective of the blood samples and thresholds applied, sensitivity of the CSA did not exceed 62%, although specificity remained high at both 30% and 70% thresholds (>88%). Only one study each for CSW and FBA was included. Sensitivities of the CSW were 0.04 (95% CI: 0.01-0.14) and 0.81 (95% CI: 0.71-0.89) at the 30% and 70% thresholds, respectively (venous blood samples). Sensitivities of the FBA were 1.00 (95% CI: 0.29-1.00) and 0.75 (95% CI: 0.19-0.99) at the 30% and 70% thresholds (venous blood samples). Specificities of the CSW and FBA were consistently high (>90%) at both thresholds. Accuracy of the SDB was higher in females at the 30% cut-off (OR: 3.49, p=0.002) and lower in malaria patients at the 70% cut-off (OR: 0.59, p = 0.005).ConclusionsThe SDB performed better than other PoCs. More evidence was available for the performance of the SDB compared to other PoCs, giving higher confidence in its utility in diagnosing G6PD deficiency.
Leptospirosis, melioidosis, and rickettsioses in the vicious circle of neglect
The global priorities in the field of infectious diseases are constantly changing. While emerging viral infections have regularly dominated public health attention, which has only intensified after the COVID-19 pandemic, numerous bacterial diseases have previously caused, and continue to cause, significant morbidity and mortality—deserving equal attention. Three potentially life-threatening endemic bacterial diseases (leptospirosis, melioidosis, and rickettsioses) are a huge public health concern especially in low- and middle-income countries. Despite their continued threat, these diseases do not receive proportionate attention from global health organizations and are not even included on the WHO list of neglected tropical diseases (NTDs). This, in turn, has led to a vicious circle of neglect with continued, yet conceivably preventable, hospitalizations and deaths each year especially in the vulnerable population. This is a call from a group of multi-institutional experts on the urgent need to directly address the circle of neglect and raise support in terms of funding, research, surveillance, diagnostics, and therapeutics to alleviate the burden of these 3 diseases.
Incidence of Scrub Typhus in Rural South India.
BackgroundHospital studies suggest that scrub typhus is a leading cause of severe undifferentiated fever in regions across Asia where the disease is endemic, but the population-based incidence of infection and illness has been little studied.MethodsWe conducted a population-based cohort study to assess epidemiologic and clinical characteristics of scrub typhus in 37 villages in Tamil Nadu, India, where the disease is highly endemic. Study participants were visited every 6 to 8 weeks over a period of 2 years; a venous blood sample was obtained from those who had had fever since the last visit. A subcohort of participants underwent blood sampling to estimate the incidence of serologically confirmed Orientia tsutsugamushi infection.ResultsWe systematically assessed 32,279 participants from 7619 households for acute febrile illness. During 54,588 person-years of follow-up, we observed 6175 episodes of fever. A blood sample was obtained in 4474 episodes (72.5%), of which 328 (7.3%) met the clinical case definition of scrub typhus (detection of IgM against O. tsutsugamushi on enzyme-linked immunosorbent assay [ELISA] or detection of O. tsutsugamushi on polymerase-chain-reaction assay). The incidence of clinical infection was 6.0 cases per 1000 person-years (95% confidence interval [CI], 4.8 to 7.5). A total of 71 clinical cases (21.6%) resulted in hospitalization (incidence, 1.3 events per 1000 person-years; 95% CI, 1.0 to 1.7). A total of 29 clinical cases (8.8%) were severe, as indicated by the presence of organ dysfunction or adverse pregnancy outcomes (incidence, 0.5 cases per 1000 person-years; 95% CI, 0.4 to 0.8). Among 2128 participants in the subcohort who provided samples at the beginning and end of a study year, the incidence of seroconversion independent of any symptoms was 81.2 events per 1000 person-years (95% CI, 70.8 to 91.6). The incidence of clinical infection was higher in older age groups than in younger age groups and higher among female participants than among male participants. By contrast, the age-adjusted rate of severe infection was similar among male and female participants. Among 5602 participants assessed at the start of the first year of the study, the seroprevalence of IgG as assessed with ELISA was 42.8% (95% CI, 35.8 to 50.2). IgG seropositivity at the beginning of years 1 or 2 did not protect against clinical illness during the subsequent year but was associated with less severe disease than IgG seronegativity.ConclusionsWe describe the burden of scrub typhus, including the incidence of asymptomatic infection, in a region of Asia where the disease is endemic. (Funded by the U.K. Medical Research Council; ClinicalTrials.gov number, NCT04506944.).