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CTMGH have been nominated for the Market Research Society President's Medal, awarded annually to an organisation that conduct extraordinary research but who might not be recognised through the usual channels. Our Centre is noted for its ingenious use of freely available online satellite images to gath data on the use of antibiotics in unmapped and inaccessible villages in rural Thailand and Laos. Researchers use the images to identify representative clusters of potential participants.
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Vaccine-induced responses to R21/Matrix-M - an analysis of samples from a phase 1b age de-escalation, dose-escalation trial.
IntroductionThe pre-erythrocytic malaria vaccine R21 vaccine adjuvanted with Matrix-M reported good efficacy (75%) in an ongoing phase 3 trial and was recommended World Health Organization for use in children 5-36 months. Vaccine-induced antibodies against NANP are associated with protection, however, various factors such as age, pre-existing immunity, and vaccine dose have been shown to influence vaccine responses.MethodsSamples from adults (n =18), children (n = 17), and infants (n = 51) vaccinated with R21/Matrix-M in a phase I trial were assayed for vaccine-specific antibody responses. We measured antibodies (quantity) by MSD and ELISA; and function (quality) by complement (C1q) fixation assay, inhibition of sporozoite invasion (ISI) assay, and avidity assay. Pre-existing malaria antibody exposure was assessed using an anti-3D7 Plasmodium falciparum crude parasite lysate ELISA.ResultsVaccine-induced CSP antibodies (against full-length R21, NANP, and C terminus), exhibited complement fixation and inhibition of sporozoites. These were significantly lower in adults compared to children and infants. Additionally, children had a higher rate of decay of vaccine-induced antibodies compared to adults 2 years post-vaccination. Furthermore, a higher Matrix-M adjuvant dose resulted in significantly higher C1q fixation, and ISI than the low adjuvant dose in infants. Importantly, functional measures ISI and C1q-fixation were positively associated with the vaccine-induced antibodies overall, but avidity was not. Interestingly, in adults, previous malaria exposure was negatively associated with ISI but positively correlated with avidity and C1q fixation. At baseline, all the study participants were seropositive for anti-HBsAg IgG above the WHO-required protective threshold of 10 mIU/mL, and titers significantly increased post-vaccination.DiscussionR21/Matrix-M was immunogenic across all age groups, with age and vaccine dose significantly affecting antibody magnitude and function. These findings emphasize the importance of evaluating the right adjuvant and vaccine dose for clinical development progression. This could thus inform the development of next-generation malaria vaccines. However, additional crucial factors need further exploration.
Safety and tolerability of metformin in overweight and obese patients with dengue: An open-label clinical trial (MeDO)
Background Despite dengue being a major public health problem, there are no antiviral or adjunctive treatments for the disease. Novel therapeutics are needed, particularly for patients at high risk of severe disease, including those living with obesity. Metformin reduces dengue viral replication in vitro through AMPK activation and may also have beneficial immunomodulatory effects. Methods We conducted an open label trial at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, enrolling 120 patients with dengue and obesity (60 treatment arm, 60 control arm receiving standard of care only). Within the treatment arm, the first 10 patients were prescribed low dose metformin, and the remaining 50 patients received weight-based dosing of 1-1.5g/day. The primary outcome was the number of adverse events (AEs), and secondary outcomes were clinical and laboratory parameters, including fever clearance time, platelet nadir, percentage of haematocrit change from baseline, maximum creatinine and highest AST/ALT, and the kinetics of plasma viraemia and NS1 antigenaemia. Results The majority of patients in both groups had dengue with warning signs. Six patients in the metformin group and 5 controls developed dengue shock syndrome, and no patients died. There were more AEs recorded in the metformin treated group than in the control group (mean±SD: 15 ± 4 vs. 11 ± 6), particularly the high-dose metformin group (15 ± 5). Twenty-five patients (42%) had to stop the study drug due to AEs, including severe diarrhea (n = 12), dengue shock (n = 5), increased lactate of >3mmol/L (n = 4), hypoglycemia (n = 3), and persistent vomiting (n = 1). There were no clear differences in secondary outcomes between the two groups. Conclusions Metformin was poorly tolerated in patients with dengue, mainly due to gastrointestinal side effects. Metformin did not beneficially affect clinical evolution or virological parameters compared to supportive care alone. Our data does not support progression to larger phase 3 trials of metformin in patients with dengue. Trial registration ClinicalTrials.gov: NCT04377451 (May 6th, 2020).
Use of the International Classification of Diseases to Perinatal Mortality (ICD-PM) with verbal autopsy to determine the causes of stillbirths and neonatal deaths in rural Cambodia: a population-based, prospective, cohort study
Background: Perinatal mortality remains a significant global health challenge, particularly in low- and middle-income countries (LMICs). Accurate cause-of-death data are essential to inform effective interventions but are often scarce. This study aimed to identify causes of stillbirths and neonatal deaths in rural Cambodia using verbal autopsy (VA) and the WHO International Classification of Diseases to Perinatal Mortality (ICD-PM). Methods: A four-year prospective study (2018–2022) in Preah Vihear province, Cambodia, established a community health worker-based pregnancy surveillance system. Verbal autopsy was conducted on stillbirths and neonatal deaths, with dual physician analysis to interpret VA data. To classify causes of death, ICD-PM was applied with adaptations made for stillbirths with unknown timing of death. Findings: A total of 522 deaths (229 stillbirths, 293 neonatal deaths) were recorded, and 79.1% (413) had a VA. Applying ICD-PM, primary causes of death were identified for 36.6% of stillbirths and 95.0% of neonatal deaths. The leading cause of death was hypoxia for intrapartum stillbirths (78.3%), low birth weight and prematurity for early neonatal deaths (40.9%), and infection for late neonatal deaths (51.4%). Complications during labour and delivery were the leading maternal contributing condition for intrapartum stillbirths (63.3%) and early neonatal deaths (42.4%). Unknown timing of death was assigned to 12.0% of stillbirths. Interpretation: Application of ICD-PM with VA-derived data provides valuable insights into causes of stillbirths and neonatal deaths. However, adaptations are necessary to address ICD-PM's limitations, particularly to classify unknown timing of death. Our findings can contribute to global efforts to improve the reporting of perinatal mortality data. Funding: This study is nested in the Saving Babies' Lives study, which was supported by funding from Angkor Hospital for Children, Civil Society in Development, Fu Tak Iam Foundation, Manan Trust, T&J Meyer Family Foundation, Vitol Foundation, IF Foundation, and Wellcome Trust [220211]. This research was funded in part by the Wellcome Trust [220211/Z/20/Z].
Investigating the relationship between <i>Pfkelch13</i> mutations and response to artemisinin-based treatment for uncomplicated falciparum malaria: a protocol for a systematic review and individual patient data meta-analysis.
IntroductionArtemisinin-based combination therapies (ACTs) remain the WHO-recommended treatment for uncomplicated Plasmodium falciparum malaria. However, the emergence and spread of artemisinin resistance (ART-R) threatens ACT efficacy. ART-R is phenotypically expressed as delayed parasite clearance, which can facilitate ACT partner drug resistance. ART-R has been causally linked to specific mutations in the Pfkelch13 gene.Methods and analysisThe systematic review and associated meta-analysis aim to determine the correlation between Pfkelch13 (alleles present in the Kelch13 gene region of the P. falciparum parasite) genotypes and clinical and parasitological response to ACTs from a globally representative data set pooling individual patient data (IPD) from eligible published and unpublished studies. The eligibility criteria include Pfkelch13 genotyping results at baseline complemented by individually linked parasitological and clinical assessments following artemisinin-based treatment. The data will be curated, standardised and analysed using this proposed statistical analysis plan (SAP), adhering to PRISMA-IPD (PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Our SAP will apply hierarchical modelling to assess the effect of the P. falciparum parasite Pfkelch13 mutations on parasite clearance half-life and therapeutic efficacy across different regions. This will include study sites as random effects in the model and potential predictors such as age, sex, baseline parasite load and other potential effect modifiers as fixed effects. This analysis will enhance the understanding of the influence of Pfkelch13 mutations on malaria treatment outcomes.Ethics and disseminationData were obtained with informed consent and ethical approvals from the relevant countries and were pseudonymised before curation in the Infectious Diseases Data Observatory (IDDO)/WorldWide Antimalarial Resistance Network (WWARN) repository. Data ownership remains with contributors. This IPD meta-analysis met the Oxford Tropical Research Ethics Committee criteria for waiving ethical review, as it is a secondary analysis of existing pseudonymised data. The resulting peer-reviewed publication and conference proceedings will help strengthen and enhance the efficiency of ART-R surveillance and response and support policy decisions.Prospero registration numberCRD42019133366.
Foetal growth in pregnant women with HIV
Objective: Pregnant women with HIV (PWHIV) are at increased risk of delivering babies that are small for gestational age (SGA). We aimed to determine the foetal growth trajectories of PWHIV, compared to HIV-negative women. Design: Prospective pregnancy cohort study in Soweto, South Africa, in 2013-2016. Methods: Serial ultrasound measurements (every 5 ± 1 weeks) of foetal head circumference (HC), biparietal diameter (BPD), abdominal circumference (AC), and femur length (FL) were obtained from less than 14 weeks’ gestation to term. Multivariable linear mixed effects models were used to estimate differences in mean foetal growth measures (HC, BPD, AC, FL and estimated foetal weight (EFW)) and mean foetal growth velocity increments (for HC, BPD, AC and FL) according to maternal HIV status. Z-scores and centiles were calculated according to the INTERGROWTH-21st standards for foetal growth. Multivariable mixed effects logistic regression was used to examine the association of maternal HIV infection with in-utero SGA (EFW<10th centile) and very SGA (VSGA, EFW<3rd centile). Results: Ultrasound measurements of 228 PWHIV and 384 HIV-negative pregnant women, with a median of five antenatal ultrasound scans per women, were analysed. There were no significant differences in mean foetal growth measures of HC (-0.37mm, 95% CI -1.46, 0.72), BPD (0.07mm, -0.45, 0.30), AC (0.15mm, -1.47, 1.17), FL (0.04mm, -0.27, 0.34) and EFW (1g, 0.98, 1.02), and growth velocity increments for HC (-0.07mm/week, -0.24, 0.10), BPD (-0.01mm/week, -0.06, 0.04), AC (0.19mm/week, -0.06, 0.44) and FL (0.00mm/week, - 0.04, 0.04) between foetuses of PWHIV and HIV-negative women. The prevalence of SGA ranged between 14.2-26.4% for PWHIV and 18.5-24.1% for HIV-negative pregnant women during different gestation windows. There was no significant association between maternal HIV infection and in-utero SGA (aOR 0.90, 0.54-1.52) or VSGA (aOR 1.16, 0.55-1.54). A sensitivity analysis restricted to PWHIV who received efavirenz-based antiretroviral therapy (ART) yielded results consistent with the overall analysis. Conclusions: Maternal HIV infection treated with ART does not appear to be associated with altered foetal growth, foetal growth velocity, or in-utero SGA, compared to HIV-negative women. Our findings support current international clinical guidelines recommending ART for PWHIV to improve maternal health and reduce vertical HIV transmission.
Age differences in immunity to human seasonal coronaviruses and the immunogenicity of ChAdOx1 nCoV-19 (AZD1222).
BackgroundChAdOx1 nCoV-19 (AZD1222) vaccine was widely deployed to protect against severe COVID-19 in adults, but the relationship between pre-existing immunity to human seasonal coronaviruses (HCoVs) and vaccine-induced SARS-CoV-2 (SCoV2) response across age groups remains unclear.MethodsWe analysed SCoV2 and HCoVs antibody profiles in UK volunteers (aged 6-≥70), assessing antibody levels, avidity, and FcγR binding after receiving one or two doses of ChAdOx1 nCoV-19. Adult cohorts from trials in Brazil and Kenya were also included to evaluate geographical impacts on baseline HCoVs and SCoV2 induced response.FindingsIn the UK cohort, younger individuals had higher SCoV2 IgG, avidity, FcγR binding and cross-reactivity, particularly towards OC43 and HKU1. The greatest differences were seen after the first dose of ChAdOx1 nCoV-19, but these effects diminished after the second dose. Although baseline HCoVs IgG varied geographically, similar trends were observed across adult cohorts with younger adults showing higher SCoV2 IgG compared to older adults (UK and Brazil).InterpretationThese findings contribute to a better understanding of the immunogenicity of ChAdOx1-based vaccines in various age groups. Determining whether this applies across other vaccines using same platform is essential for evaluating the viability of one-dose regimens in outbreak responses.FundingThe clinical trials COV002, COV003, COV004, and COV006 were made possible by funding from Astra Zeneca, the NIHR and the University of Oxford, UK Department of Health and Social Care, through the UK National Institute for Health and Care Research, the Wellcome Trust (220991), and Innovate UK (project 971614).
Factors Influencing Health Workers' Acceptance of Guideline-Based Clinical Decision Support Systems for Preventive Services in Thailand: Questionnaire-Based Study.
BACKGROUND: A 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. OBJECTIVE: This study aimed to evaluate the determinants influencing the intention to use a new CDSS in preventive care within clinical practice. METHODS: A 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. RESULTS: In 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. CONCLUSIONS: There 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.
Communication Between Anaesthesia Providers for Clinical and Professional Purposes: A Scoping Review
Background: Anaesthesia providers in all contexts need to be able to communicate with colleagues to meet a variety of clinical and professional needs, including physical help, advice and support as well as learning, supervision and mentorship. Such communication can be regarded as a ‘social resource’ which underpins anaesthesia providers’ practice, but which has not itself been extensively studied. The objective of this scoping review is to provide an overview of the literature related to communication among anaesthesia providers to meet clinical and professional goals, focusing on the modalities, contexts and purposes or outcomes of such communication, as well as which providers are involved.Methods: We conducted a scoping review using the JBI methodology to examine the current literature available, searching the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials, Medline, Embase, CINAHL and Google Scholar. Papers were eligible for inclusion where they primarily addressed the subject of communication between trained anaesthesia providers for any clinical or professional purpose (excluding purely social interactions). Data were charted for the location and cadre of providers represented, means of communication and the situation, purposes and outcomes of communication.Results: 3872 records were identified for screening, and 225 papers were ultimately included. Communication was reported both as a variable influencing a wide range of clinical and nonclinical outcomes and as an outcome in itself which might be modified by other factors. It was also considered in a smaller group of studies as a resource with varying availability to anaesthesia providers. Physician providers were well represented in included documents, but nurse anaesthetists, clinical officers and other nonphysician, nonnurse anaesthetists were far less commonly included. The majority of identified studies on communication between anaesthesia providers originated from and related to high‐income countries.Conclusion: Communication between anaesthesia providers affects all aspects of their practice and has implications for both patient outcomes and workforce capacity. More research is necessary to understand how the availability of communication as a resource affects patient care and health worker well‐being, particularly in low‐ and middle‐income contexts and among nonphysician anaesthesia providers.
Core collections: Essential titles for health libraries.
Core collections have been produced by CILIP's Health Libraries Group, then called the Library Association's Medical Section, since 1952. Maintained by a Working Group of health librarians based in the UK NHS, higher education and specialist libraries, the collections provide an up-to-date curated list of reliable titles essential to health libraries. The core collections currently include nursing, midwifery, medicine and dentistry. The newest core collection is being developed in collaboration with the African Hospital Libraries to provide a list of key resources relevant to sub-Saharan Africa. Expressions of interest to help develop this latest collection are invited.
The global scope and components of family-centred care for preterm infants: An umbrella review.
Preterm birth is the leading cause of under-five mortality. Family-centred care (FCC) interventions may improve outcomes related to prematurity and may be used to address this issue to achieve the Sustainable Development Goals. We aimed to consolidate the scope of evidence and components of FCC interventions for preterm infants globally and see its relevance for low-resource settings. We conducted an umbrella review informed by the Joanna Briggs Institute (JBI) guidelines. Systematic literature reviews evaluating FCC in the preterm or high-risk infant population and their families were identified from six databases. Keywords included "family-centred care", "premature infants", "neonatal intensive care unit", and their relevant synonyms. Quality appraisal was conducted using the JBI Critical Appraisal Checklist for Systematic Reviews and Research Syntheses and data extraction performed to an agreed table. Thematic analysis was carried out to categorise the components of FCC interventions. Forty-four reviews were included in the umbrella review. Outcomes were observed on the parents in 40 studies, the infant in 19, the health care provider in 13, and the health system in 7. Most studies focused on inpatient settings (79.6%) and were conducted primarily in high-income countries (92.3%). The components identified were general FCC, health system design, parent support, partnership in care, and information and communication. Overall, FCC interventions have a positive impact on parental, infant, and health system outcomes, with consistent reporting of FCC impact on parental well-being and satisfaction, infant length of stay, feeding and growth, and hospital readmission rates. FCC interventions have the potential to improve preterm infant health system outcomes. To maximise impact, FCC interventions need to be further explored in low-resource and post-discharge settings, where the burden of premature infant morbidity and mortality is highest. Evidence in both these settings is scarce. Future research efforts should aim to close these evidence gaps.