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Pregnant women as a sentinel population for genomic surveillance of malaria in the Democratic Republic of the Congo: a population-based study.
BackgroundGenomic surveillance is a valuable tool for detecting changes in the drug susceptibility of malaria parasites, enabling timely adjustments to treatment strategies. However, implementation can be costly and challenging in high-burden countries, especially when targeting cohorts of children. To address these challenges, we investigated whether in the Democratic Republic of the Congo pregnant women attending antenatal care services could act as an effective sentinel population for children in the same area.MethodsThis population-based study aimed to target pregnant women in Kinshasa (Democratic Republic of the Congo), regardless of age, trimester of pregnancy, parity, or previous antenatal care centre attendance, and children younger than 14 years living in the same area. Women were invited to participate and enrolled during their routine antenatal care visit. For children, we originally planned to conduct standard school-based surveys, but implementation was affected by the COVID-19 pandemic and subsequent vaccination campaign. Therefore, we adopted an alternative approach, setting up screening posts in existing health centres and, with the support of community health workers, encouraging families to visit the posts at their convenience. The study was done in two areas of Kinshasa, urban (Binza) and semirural (Maluku), where malaria transmission is endemic and perennial. Blood samples from malaria-positive cases were genotyped using an amplicon sequencing platform, to allow comparisons of Plasmodium falciparum genomes between the two cohorts and estimations of drug resistance mutation prevalence. The study is registered with ClinicalTrials.gov, NCT05072613.FindingsBetween Nov 11, 2021, and June 21, 2023, 2794 children and 4001 pregnant women were recruited to the study. Malaria prevalence by rapid diagnostic test was 49·0% (95% CI 47·1-50·8) in children and 19·1% (17·9-20·3) in pregnant women. Parasite populations sampled from the two cohorts showed highly similar allele frequencies at all tested loci, including drug resistance markers potentially under selection. Pregnant women did not have higher frequencies of sulfadoxine-pyrimethamine resistant haplotypes, which undermine preventive treatments, than children and we did not find any kelch13 mutations at significant frequency. Although parasite densities were lower in pregnant women, the complexity of infection was similar to that in children. We found no evidence of Plasmodium vivax infections in the study.InterpretationA cohort of pregnant women produced highly similar results for antimalarial drug resistance surveillance as a cohort of children from the same area, through implementation of simple and efficient genomic surveillance systems integrated into routine antenatal care activities, while benefiting women with diagnosis and treatment.FundingBill & Melinda Gates Foundation and Wellcome Trust.
Assessment of utilization of automated systems and laboratory information management systems in clinical microbiology laboratories in Thailand.
Clinical microbiology laboratories are essential for diagnosing and monitoring antimicrobial resistance (AMR). Here, we assessed the systems involved in generating, managing and analyzing blood culture data in these laboratories in an upper-middle-income country. From October 2023 to February 2024, we conducted a survey on the utilization of automated systems and laboratory information management systems (LIMS) for blood culture specimens in 2022 across 127 clinical microbiology laboratories (one each from 127 public referral hospitals) in Thailand. We categorized automated systems for blood culture processing into three steps: incubation, bacterial identification, and antimicrobial susceptibility testing (AST). Of the 81 laboratories that completed the questionnaires, the median hospital bed count was 450 (range, 150-1,387), and the median number of blood culture bottles processed was 17,351 (range, 2,900-80,330). All laboratories (100%) had an automated blood culture incubation system. Three-quarters of the laboratories (75%, n = 61) had at least one automated system for both bacterial identification and AST, about a quarter (22%, n = 18) had no automated systems for either step, and two laboratories (3%) outsourced both steps. The systems varied and were associated with the hospital level. Many laboratories utilized both automated systems and conventional methods for bacterial identification (n = 54) and AST (n = 61). For daily data management, 71 laboratories (88%) used commercial microbiology LIMS, three (4%) WHONET, three (4%) an in-house database software and four (5%) did not use any software. Many laboratories manually entered data of incubation (73%, n = 59), bacterial identification (27%, n = 22) and AST results (25%, n = 20) from their automated systems into their commercial microbiology LIMS. The most common barrier to data analysis was 'lack of time', followed by 'lack of staff with statistical skills' and 'difficulty in using analytical software'. In Thailand, various automated systems for blood culture and LIMS are utilized. However, barriers to data management and analysis are common. These challenges are likely present in other upper-middle-income countries. We propose that guidance and technical support for automated systems, LIMS and data analysis are needed.
Factors Associated with Mortality in Nosocomial Lower Respiratory Tract Infections: An ENIRRI Analysis.
Background: Nosocomial lower respiratory tract infections (nLRTIs) are associated with unfavorable clinical outcomes and significant healthcare costs. nLRTIs include hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and other ICU-acquired pneumonia phenotypes. While risk factors for mortality in these infections are critical to guide preventive strategies, it remains unclear whether they vary based on their requirement of invasive mechanical ventilation (IMV) at any point during the hospitalization. Objectives: This study aims to identify risk factors associated with short- and long-term mortality in patients with nLRTIs, considering differences between those requiring IMV and those who do not. Methods: This multinational prospective cohort study included ICU-admitted patients diagnosed with nLRTI from 28 hospitals across 13 countries in Europe and South America between May 2016 and August 2019. Patients were selected based on predefined inclusion and exclusion criteria, and clinical data were collected from medical records. A random forest classifier determined the most optimal clustering strategy when comparing pneumonia site acquisition [ward or intensive care unit (ICU)] versus intensive mechanical ventilation (IMV) necessity at any point during hospitalization to enhance the accuracy and generalizability of the regression models. Results: A total of 1060 patients were included. The random forest classifier identified that the most efficient clustering strategy was based on ventilation necessity. In total, 76.4% of patients [810/1060] received IMV at some point during the hospitalization. Diabetes mellitus was identified to be associated with 28-day mortality in the non-IMV group (OR [IQR]: 2.96 [1.28-6.80], p = 0.01). The 90-day mortality-associated factor was MDRP infection (1.98 [1.13-3.44], p = 0.01). For ventilated patients, chronic liver disease was associated with 28-day mortality (2.38 [1.06-5.31] p = 0.03), with no variable showing statistical and clinical significance at 90 days. Conclusions: The risk factors associated with 28-day mortality differ from those linked to 90-day mortality. Additionally, these factors vary between patients receiving invasive mechanical ventilation and those in the non-invasive ventilation group. This underscores the necessity of tailoring therapeutic objectives and preventive strategies with a personalized approach.
Tracing epistemic injustice in global antimicrobial resistance research.
This commentary explores whether there is epistemic injustice in global antimicrobial resistance (AMR) research - who sets priorities, who produces knowledge, and which types of knowledge are valued. We argue that epistemic injustice may have created blind spots in policy. Addressing this requires a commitment to diversity, equity, and inclusion.
Understanding the primary healthcare context in rural South and Southeast Asia: a village profiling study.
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. 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. 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). These results illustrate the similarities and differences of villages in this region that must be considered in public health research and policymaking.
Noninvasive Characterization of Preservation Fluids through Glass Container Using Spatially Offset Raman Spectroscopy: Potential in Heritage Science.
The conservation and characterization of preservation fluids are crucial for maintaining specimen integrity in natural history fluid collections. However, characterizing these fluids analytically poses significant challenges, especially as noninvasive methods are preferred to avoid opening jars and reduce the risk of compromising specimens. This proof-of-concept study investigates the feasibility of using a hand-held spatially offset Raman spectroscopy (SORS) instrument to determine the chemical composition of preservation fluids through their original glass containers. Results demonstrate that SORS can noninvasively verify the chemical identity of dominant excipients in these fluids measured through a historic glass jar. Additionally, multivariate analysis combined with SORS measurements successfully differentiated several types of typical preservation fluids prepared as mixtures of different alcohols in water, such as glycerol, ethanol, methanol, and formaldehyde. The proposed noninvasive approach was also able to differentiate between different concentration points of components in water within the same type of preservation fluid.
Economic Evaluation of Interventions to Reduce Antimicrobial Resistance: A Systematic Literature Review of Methods.
BACKGROUND AND OBJECTIVE: Economic evaluation of antimicrobial resistance (AMR) interventions is complicated by the multisectoral, inter-temporal and international aspects of the problem, further hindered by a lack of available data and theoretical understanding of the emergence and transmission of AMR. Despite the substantial global focus on the problem, there is a lack of comprehensive economic evaluation literature on AMR policies. The goal of this work is to review the available literature on the economic evaluation of AMR interventions focusing on methods used to quantify the effects on AMR and the associated health consequences and costs. METHODS: The studies included in the review were identified by a previous study by Painter et al. that included all full economic evaluations of AMR policies in the peer-reviewed and grey literature published between 2000 and 2020. The current review extracted additional information to (1) summarise the types and the key features of the AMR intervention economic evaluation literature available; (2) systemise the types of intervention effects on AMR quantified and describe these across the dimensions of AMR burden: time, space, wider pathogen pool and different sectors (One Health framework); and (3) categorise the methods used to derive these outcomes and how were these linked to health consequences and costs. RESULTS: Thirty-one studies were included within this review, of which 18 evaluated interventions that aimed to reduce infection rates and 11 evaluated interventions that aimed to optimise antimicrobial use. Almost all were conducted with a high-income and/or upper-middle income country perspective and focused on human health. Thirteen of 31 studies were cost-utility analyses. Fifteen of 31 and 7/31 studies estimated the AMR effects through decision tree and/or Markov models and transmission models, respectively. Transmission models and linkage of AMR outcomes to quality-adjusted life-years and costs were more common in evaluations of interventions aimed at reducing infection rates. Most of the included studies restricted the scope of evaluation to a short time horizon and a narrow geographical scope and did not consider the wider impact on other pathogens and other settings, potentially resulting in an incomplete capture of the effects of interventions. CONCLUSIONS: This review found limited available literature that mainly focused on high-income countries and infection prevention/reduction strategies. Most evaluations used a narrow study scope, which might have prevented the full capture of the costs and outcomes associated with interventions. Finally, despite the known complexities associated with quantifying AMR effects, and the corresponding methodological challenges, the implications of these choices were rarely discussed explicitly.
The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT
Background Type 1 diabetes is an autoimmune disease affecting over 400,000 children and adults in the United Kingdom for which currently the only available therapy is insulin. Objective(s) To determine the efficacy and safety of the monoclonal antibody ustekinumab targeting the interleukin 12/interleukin 23 immune pathway that generates T helper 1/T helper 17 T cells to slow down the autoimmune process and preserve beta cell production in type 1 diabetes. Design Randomised, double-blind, placebo-controlled, parallel-group phase II trial. Setting Paediatric and young adult diabetes clinics across 16 sites in the United Kingdom. Participants Newly diagnosed with type 1 diabetes and aged 12–18 years. Eligibility criteria Type 1 diabetes confirmed by islet autoantibody testing, within 100 days of first insulin injection, and with residual beta cell function (stimulated C-peptide level > 0.2 nmol/l). Interventions Ustekinumab at the highest approved doses or control (saline) subcutaneously at weeks 0, 4 and 12 and subsequently every 8 weeks to week 44 (seven doses). Main outcome measures Preservation of Mixed Meal Tolerance Test stimulated 2-hour insulin C-peptide area under the curve at week 52 as compared to control (saline) treatment by analysis of covariance adjusted for baseline parameters. Randomisation 2 : 1 Remote computerised randomisation with minimisation by age and baseline C-peptide groups. Blinding Blinding of participants, investigators, laboratory and trial staff. Numbers randomised Seventy-two participants were randomised, 60% male, 18% aged 16–18 years. Recruitment Two hundred and eight potentially eligible patients were approached, and 88 patients were screened. Four participants were lost to follow-up (6%). Four participants withdrew from the treatment but attended the primary end-point assessment. Numbers analysed Six participants were missing baseline data for the primary analysis. The final analysable sample was n = 62. Outcome Ustekinumab was associated with a 49% higher endogenous stimulated insulin production than control at week 52 after adjustments for baseline factors [geometric ratio of ustekinumab to control was 1.49 (95% confidence interval 1.08 to 2.06; p = 0.02)]. Secondary analyses showed no difference in C-peptide at week 28 suggesting that the effect was ‘late’ or ‘delayed’. Ancillary analysis showed a significant reduction in activated T helper 17.1 T cells (p < 0.001) in the treatment group which was associated with C-peptide preservation from week 28 to week 52. Harms No severe adverse events were reported and there were no differences between ustekinumab and control groups in the proportion of participants overall experiencing mild (87% vs. 88%) or moderate (32% vs. 32%) events. Limitations Sensitivity analysis showed the primary end point to be robust to exclusion of small numbers of participants with some protocol deviations and extreme values in key covariates, but not to imputation of all missing data. Conclusions Ustekinumab appears to slow down the autoimmune process providing the first clinical trial evidence that interleukin 17-secreting T cells play a pathogenic role in type 1 diabetes. Alone, it is insufficient to halt the autoimmune process. Future work Replication of this result is ongoing in a trial with a similar design in Canada. If confirmed, consideration may be given to testing other drugs targeting the interleukin 17 pathway, using ustekinumab in combination with other agents or using it earlier in the disease pathway (preclinical disease) since it is so well tolerated and simple to use. Study registration Current Controlled Trials ISRCTN14274380. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 16/36/01) and is published in full in Efficacy and Mechanism Evaluation; Vol. 12, No. 1. See the NIHR Funding and Awards website for further award information.
Insights of SEDRIC, the Surveillance and Epidemiology of Drug-Resistant Infections Consortium.
The increasing threat from infection with drug-resistant pathogens is among the most serious public health challenges of our time. Formed by Wellcome in 2018, the Surveillance and Epidemiology of Drug-Resistant Infections Consortium (SEDRIC) is an international think tank whose aim is to inform policy and change the way countries track, share, and analyse data relating to drug-resistant infections, by defining knowledge gaps and identifying barriers to the delivery of global surveillance. SEDRIC delivers its aims through discussions and analyses by world-leading scientists that result in recommendations and advocacy to Wellcome and others. As a result, SEDRIC has made key contributions in furthering global and national actions. Here, we look back at the work of the consortium between 2018-2024, highlighting notable successes. We provide specific examples where technical analyses and recommendations have helped to inform policy and funding priorities that will have real-world impact on the surveillance and epidemiology of infections with drug-resistant pathogens.
Detection of Mycoplasma pneumoniae in hospitalized children with pneumonia in Laos
Mycoplasma pneumoniae has been described worldwide as an important cause of community-acquired pneumonia. From December 2013 to December 2014, 461 children admitted to Mahosot Hospital, Vientiane, Laos, with acute respiratory infection were investigated for upper respiratory microorganisms using probe-based real-time polymerase chain reaction (PCR) (FTD33). M. pneumoniae was detected by FTD33 in the upper respiratory tract of three patients, two girls and one boy, 5.7 and 3.9 years old and 13.6 years old, respectively. They presented with clinical features compatible with M. pneumoniae infection. They improved without M. pneumoniae directed therapy. The two girls were also positive for other potential pathogens. The boy had abnormal pulmonary auscultation, and one of the girls had significant anaemia. These results suggest that enhancement of diagnostic systems for M. pneumoniae detection is needed to improve understanding of the epidemiology of M. pneumoniae infection in Laos.
Perspectives on public health interventions in the management of the COVID-19 pandemic in Thailand
Background: Any government needs to react quickly to a pandemic and make decisions on healthcare interventions locally and internationally with little information regarding the perceptions of people and the reactions they may receive during the implementation of restrictions. Methods: We report an anonymous online survey in Thailand conducted in May 2020 to assess public perceptions of three interventions in the Thai context: isolation, quarantine and social distancing. A total of 1,020 participants, of whom 52% were women, responded to the survey. Results: Loss of income was the main concern among respondents (>80% for all provinces in Thailand). Traditional media and social media were important channels for communication during the pandemic. A total of 92% of respondents reported that they changed their social behaviour even before the implementation of government policy with 94% reporting they performed social distancing, 97% reported using personal protective equipment such as masks and 95% reported using sanitizer products. Conclusions: This study showed a high level of compliance from individuals with government enforced or voluntarily controls such as quarantine, isolation and social distancing in Thailand. The findings from this study can be used to inform future government measures to control the pandemic and to shape communication strategies.
Optimizing nanopore adaptive sampling for pneumococcal serotype surveillance in complex samples using the graph-based GNASTy algorithm
Serotype surveillance ofStreptococcus pneumoniae(the pneumococcus) is critical for understanding the effectiveness of current vaccination strategies. However, existing methods for serotyping are limited in their ability to identify the co-carriage of multiple pneumococci and detect novel serotypes. To develop a scalable and portable serotyping method that overcomes these challenges, we employed Nanopore Adaptive Sampling (NAS), an on-sequencer enrichment method that selects for target DNA in real-time, for direct detection ofS. pneumoniaein complex samples. Whereas NAS targeting the wholeS. pneumoniaegenome was ineffective in the presence of nonpathogenic streptococci, the method was both specific and sensitive when targeting the capsular biosynthetic locus (CBL), the operon that determinesS. pneumoniaeserotype. NAS significantly improved coverage and yield of the CBL relative to sequencing without NAS, and accurately quantified the relative prevalence of serotypes in samples representing co-carriage. To maximize the sensitivity of NAS to detect novel serotypes, we developed and benchmarked a new pangenome-graph algorithm, named GNASTy. We show that GNASTy outperforms the current NAS implementation, which is based on linear genome alignment, when a sample contains a serotype absent from the database of targeted sequences. The methods developed in this work provide an improved approach for novel serotype discovery and routineS. pneumoniaesurveillance that is fast, accurate and feasible in low-resource settings. Although NAS facilitates whole-genome enrichment under ideal circumstances, GNASTy enables targeted enrichment to optimize serotype surveillance in complex samples.
Data repositories
Have you wondered what happens to data when a research study is completed? Supposing you are a researcher who wants to share a copy of the data you have been recently working on with me, how would you do it? Would you give me a USB drive with the data on it, send it to me through email, or perhaps upload the files to Dropbox? If I requested to see data you worked on 6 months ago, a year ago, or even 5 years ago, would you be able to find it easily and share it with me? Where might these data be stored - on an old laptop, a hard drive, or in your email archives? There are two important aspects here: how to store data and how to transfer the data to someone else. We can see the ideal system emerging slowly: we need to focus on long-term data preservation. Data preservation involves safeguarding digital data against corruption, loss, or damage. It ensures future accessibility and usability of the data despite changes in technology and in data formats. In this module, we discuss how data repositories solve problems with data storage and access.
Social, ethical and behavioural aspects of COVID-19
Introduction: Vaccines and drugs for the treatment and prevention of COVID-19 require robust evidence generated from clinical trials before they can be used. Decisions on how to apply non-pharmaceutical interventions such as quarantine, self-isolation, social distancing and travel restrictions should also be based on evidence. There are some experiential and mathematical modelling data for these interventions, but there is a lack of data on the social, ethical and behavioural aspects of these interventions in the literature. Therefore, our study aims to produce evidence to inform (non-pharmaceutical) interventions such as communications, quarantine, self-isolation, social distancing, travel restrictions and other public health measures for the COVID-19 pandemic. Methods: The study will be conducted in the United Kingdom, Italy, Malaysia and Thailand. We propose to conduct 600-1000 quantitative surveys and 25-35 qualitative interviews per country. Data collection will follow the following four themes: (1) Quarantine and self-isolation (2) social distancing and travel restrictions (3) wellbeing and mental health (4) information, misinformation and rumours. In light of limitations of travel and holding in-person meetings, we will use online/remote methods for collecting data. Study participant will be adults who have provided informed consent from different demographic, socio-economic and risk groups. Discussion: At the time of writing, United Kingdom, Italy, Malaysia and Thailand have initiated strict public health measures and varying degrees of “lockdowns” to curb the pandemic. It is anticipated that these public health measures will continue in some countries (e.g. Italy, Malaysia) or be tightened further in other countries (e.g. Thailand, UK) to control the spread of the disease in the coming weeks and months. The data generated from our study could inform these strategies in real time.