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In this Science Blog published on Oxford University website, Prof Paul Newton, Head of the Medicine Quality Group at the Infectious Diseases Data Observatory (IDDO) and the MORU Tropical Health Network and NDM Professor of Tropical Medicine i, explains the need for new strategies for tackling poor quality medical products.
Metformin as adjunctive therapy in overweight and obese patients with dengue: trial data
Trial dataset supporting publications.
Antimicrobial resistance among children in Southeast Asia: a systematic review
IntroductionThere is increasing evidence that antimicrobial resistance (AMR) is responsible for a large burden of morbidity and mortality in children, potentially compounded by reduced efficacy of many commonly recommended empirical antibiotic regimens to treat infections in children.MethodsWe used the PRISMA framework to systematically review studies describing AMR in children (0 to 18 years) in Southeast Asia. We analysed bacterial pathogens with a focus on the Global Antimicrobial Resistance Surveillance System (GLASS) reported in studies published between 2010 and 2023. For each pathogen, non-susceptibility to currently recommended WHO empirical antibiotics was analysed with descriptive statistics.ResultsWe evaluated AMR profiles for 21 191 bacterial isolates collated across 111 studies incorporating 484 540 children. Most published data (71 studies) arose from India. High levels of non-susceptibility were evident in gram-negative pathogens, withKlebsiellaspp. exhibiting particularly high levels of resistance to gentamicin (median: 64%; IQR 38 to 81, n=2097) and third-generation cephalosporins (median 76%; IQR 40 to 92, n=2415). Furthermore, a median of 73% (IQR 50 to 86, n=4405) ofEscherichia coliisolates were non-susceptible to third-generation cephalosporins, and 48% (IQR 32 to 64, n=3659) were non-susceptible to gentamicin. Among gram-positive pathogens, the median methicillin resistance toStaphylococcus aureuswas 43% (IQR 33 to 60, n=1139).ConclusionsThere are very high rates of AMR in pathogens isolated from children with common infectious illnesses in Southeast Asia. However, published data available are of variable quality and are heavily weighted towards South Asian countries (India, Nepal and Bangladesh), limiting the generalisability of these findings and highlighting the need for enhanced clinical surveillance networks to improve the surveillance within this populous and high-burden region.PROSPERO registration numberCRD42021259320.
Integrating community health workers to sustain malaria services in the Greater Mekong Subregion: Findings from implementer case studies
Many countries in the Asia Pacific rely on community health workers (CHWs) to care for various health needs. In the Greater Mekong Subregion (GMS), malaria CHWs have been an essential component of malaria elimination. Yet as the malaria burden declines, the role of malaria CHWs in local health systems and communities is changing. There is a need to expand malaria CHW roles to take on the provision of health services beyond malaria. This study sought to understand the process and experience of this role expansion including implementation, financing, policy, and sustainability within the Asia Pacific region. We documented malaria CHW programs that included health services in addition to malaria. We conducted 21 key-stakeholder interviews from thirteen programs in eight countries throughout the Asia Pacific region virtually in English and findings were analyzed using rapid-matrix analysis. Participants were recruited by an online landscaping survey, with an inclusion criterion of five + years’ work experience and English speaking. Governments ran five of the thirteen programs; six were international non-governmental organizations (INGOs), and two were academic. Senior staff from programs that have expanded roles of malaria CHWs or integrated CHW programs explained expansion processes, challenges, and opportunities. We found that integration can occur in multiple program domains and does not necessarily occur in all domains simultaneously. We identified entry points for role expansion: integrated policy and financing, planning, assessments, and research. Operational entry points included the selection, training, motivation, management, supervision, and monitoring of CHWs. Enabling factors included decentralized management structures, health system linkages, commodity provision and referral procedures, and community engagement. While there is not a linear or unique path towards integration, we provide considerations for the policy level, practical implementation steps, and enabling factors for countries in the GMS to consider as they move towards sustainable, integrated malaria CHWs.
Short tandem repeat polymorphism in the promoter region of cyclophilin 19B drives its transcriptional upregulation and contributes to drug resistance in the malaria parasite Plasmodium falciparum.
Resistance of the human malaria parasites, Plasmodium falciparum, to artemisinins is now fully established in Southeast Asia and is gradually emerging in Sub-Saharan Africa. Although nonsynonymous SNPs in the pfk13 Kelch-repeat propeller (KREP) domain are clearly associated with artemisinin resistance, their functional relevance requires cooperation with other genetic factors/alterations of the P. falciparum genome, collectively referred to as genetic background. Here we provide experimental evidence that P. falciparum cyclophilin 19B (PfCYP19B) may represent one putative factor in this genetic background, contributing to artemisinin resistance via its increased expression. We show that overexpression of PfCYP19B in vitro drives limited but significant resistance to not only artemisinin but also piperaquine, an important partner drug in artemisinin-based combination therapies. We showed that PfCYP19B acts as a negative regulator of the integrated stress response (ISR) pathway by modulating levels of phosphorylated eIF2α (eIF2α-P). Curiously, artemisinin and piperaquine affect eIF2α-P in an inverse direction that in both cases can be modulated by PfCYP19B towards resistance. Here we also provide evidence that the upregulation of PfCYP19B in the drug-resistant parasites appears to be maintained by a short tandem repeat (SRT) sequence polymorphism in the gene's promoter region. These results support a model that artemisinin (and other drugs) resistance mechanisms are complex genetic traits being contributed to by altered expression of multiple genes driven by genetic polymorphism at their promoter regions.
Incorporating acute HIV infection screening, same‐day diagnosis and antiretroviral treatment into routine services for key populations at sexual health clinics in Indonesia: a baseline analysis of the INTERACT prospective study
Introduction: Indonesia has an escalated HIV epidemic concentrated among key populations. To strengthen the care cascade, we implemented a care pathway for the screening of individuals for acute HIV infection (AHI), to achieve prompt diagnosis and antiretroviral treatment (ART) initiation, at three non‐governmental sexual health clinics in Jakarta and Bali. We assessed the AHI testing uptake, yield and prevalence, and the care cascade. Methods: This is a cross‐sectional baseline analysis of individuals (≥16 years) who presented for HIV testing and were consecutively enrolled (May 2023−November 2024). We used an AHI risk‐score self‐assessment and test algorithm comprising a fourth‐generation antibody/p24 antigen rapid diagnostic test (4gRDT; Abbott Determine HIV Early Detect) and, if negative/discordant, followed by HIV‐PCR (Cepheid Xpert) (either individual or pooled‐sample testing). AHI was pragmatically defined as having negative/discordant RDT results with positive HIV‐PCR (ISRCTN41396071). Results: Three thousand seven hundred and ninety‐seven (44.0%) of 8665 individuals were screened for study eligibility, and 3689 (97.2%) were enrolled. Median age was 28 years, and 78.2% were male. Men who have sex with men (MSM) accounted for 53.3%, clients of sex workers 19.2%, persons having a sex partner living with HIV 8.9% and sex workers 4.1%. We diagnosed 229 (6.3%; 229/3662) persons with RDT‐positive (chronic) HIV, and we additionally identified 13 persons with AHI—that is a diagnostic yield of 5.6% (95% CI 3.1−9.5; 13/229) overall, and 6.1% (95% CI 3.2−10.3; 12/198) among MSM. AHI prevalence was 0.38% (95% CI 0.20−0.65; 13/3429) overall, and 0.72% (95% CI 0.37−1.2; 12/1677) among MSM. The number of persons needed to test to identify one person with AHI was 264 (3429/13) overall and 140 (1677/12) among MSM. The 4gRDT's performance to detect AHI was poor (2/13). Most participants received their HIV‐PCR results on the same day (84.8%, 2907/3429) or within 24 hours (92.8%, 3182/3429). Of the 242 newly HIV‐diagnosed individuals, 236 (97.5%) started ART, of whom 158 (67.0%) on the same day and 215 (91.1%) within 1 week. Conclusions: We successfully implemented prompt AHI diagnosis and treatment, and identified a high AHI prevalence among Indonesian MSM. Prioritizing access to AHI testing can create opportunities for enhanced interventions to curb the HIV epidemic among key populations.
Creating different global health futures: mapping the health research ecosystem and taking decolonial action.
This paper promotes reflexive consideration of health research practices using a decolonisation lens. We propose both incremental and more radical action in five domains: knowledge production, funding and programmes, dissemination, uptake, and education and training. We suggest four steps towards transformation and share a reflexive tool to operationalise these steps.
T cell memory response to MPXV infection exhibits greater effector function and migratory potential compared to MVA-BN vaccination.
In 2022, a global mpox outbreak occurred, and remains a concern today. The T cell memory response to MPXV (monkeypox virus) infection has not been fully investigated. In this study, we evaluate this response in convalescent and MVA-BN (Modified Vaccinia Ankara - Bavarian Nordic) vaccinated individuals using VACV-infected cells. Strong CD8+ and CD4+ T cell responses are observed, and T cell responses are biased towards viral early expressed proteins. We identify seven immunodominant HLA-A*02:01 restricted MPXV-specific epitopes and focus our detailed phenotypic and scRNAseq analysis on the immunodominant HLA-A*02:01-G5R18-26-specific CD8+ T cell response. While tetramer+CD8+ T cells share similar differentiation and activation phenotypes, T cells from convalescent individuals show greater cytotoxicity, migratory potential to site of infection and TCR clonal expansion. Our data suggest that effective functional profiles of MPXV-specific memory T cells induced by Mpox infection may have an implication on the long-term protective responses to future infection.
Effectiveness and safety of shortened intensive treatment for children with tuberculous meningitis (SURE): a protocol for a phase 3 randomised controlled trial evaluating 6 months of antituberculosis therapy and 8 weeks of aspirin in Asian and African children with tuberculous meningitis
IntroductionChildhood tuberculous meningitis (TBM) is a devastating disease. The long-standing WHO recommendation for treatment is 2 months of intensive phase with isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E), followed by 10 months of isoniazid and rifampicin. In 2022, WHO released a conditional recommendation that 6 months of intensified antituberculosis therapy (ATT) could be used as an alternative for drug-susceptible TBM. However, this has never been evaluated in a randomised clinical trial. Trials evaluating ATT shortening regimens using high-dose rifampicin and drugs with better central nervous system penetration alongside adjuvant anti-inflammatory therapy are needed to improve outcomes.Methods and analysisTheShortened Intensive Therapy for Children with Tuberculous Meningitis (SURE) trial is a phase 3, randomised, partially blinded, factorial trial being conducted in Asia (India and Vietnam) and Africa (Uganda, Zambia and Zimbabwe). It is coordinated by the Medical Research Council Clinical Trial Unit at University College London (MRCCTU at UCL). 400 children (aged 29 days to <18 years) with clinically diagnosed TBM will be randomised, using a factorial design, to either a 24-week intensified regimen (isoniazid (20 mg/kg), rifampicin (30 mg/kg), pyrazinamide (40 mg/kg) and levofloxacin (20 mg/kg)) or the standard 48-week ATT regimen and 8 weeks of high-dose aspirin or placebo. The primary outcome for the first randomisation is all-cause mortality, and for the second randomisation is the paediatric modified Rankin Scale (mRS), both at 48 weeks. Nested substudies include pharmacokinetics, pharmacogenetics, pathophysiology, diagnostics and prognostic biomarkers, in-depth neurodevelopmental outcomes, MRI and health economics.Ethics and disseminationLocal ethics committees at all participating study sites and respective regulators approved the SURE protocol. Ethics approval was also obtained from UCL, UK (14935/001). Informed consent from parents/carers and assent from age-appropriate children are required for all participants. Results will be published in international peer-reviewed journals, and appropriate media will be used to summarise results for patients and their families and policymakers.Trial registrationISRCTN40829906(registered 13 November 2018).
Mass testing for discovery and control of COVID-19 outbreaks in adult social care: an observational study and cost-effectiveness analysis of 14 805 care homes in England
IntroductionWe retrospectively evaluated the impact of COVID-19 testing among residents and staff in social care homes in England.MethodsWe obtained 80 million reported PCR and lateral flow device (LFD) test results, from 14 805 care homes (residents and staff) in England, conducted between October 2020 and March 2022. These testing data were then linked to care home characteristics, test costs and 24 500 COVID-19-related deaths of residents. We decomposed the mechanism of outbreak mitigation into outbreak discovery and outbreak control and used Poisson regressions to investigate how reported testing intensity was associated with the size of outbreak discovered and to uncover its association with outbreak control. We used negative binomial regressions to determine the factors influencing COVID-19-related deaths subsequent to outbreaks. We performed a cost-effectiveness analysis of the impact of testing on preventing COVID-19-related deaths of residents.ResultsReported testing intensity generally reflected changes in testing policy over time, although there was considerable heterogeneity among care homes. Client type was the strongest determinant of whether COVID-19-related deaths in residents occurred subsequent to testing positive. Higher staff-to-resident ratios were associated with larger outbreak sizes but rapid outbreak control and a decreased risk of COVID-19-related deaths. Assuming our regression estimates represent causal effects, care home testing in England was cost-effective at preventing COVID-19-related deaths among residents during the pandemic and approximately 3.5 times more cost-effective prior to the vaccine rollout.ConclusionsPCR and LFD testing was likely an impactful intervention for detecting and controlling COVID-19 outbreaks in care homes in England and cost-effective for preventing COVID-19-related deaths among residents. In future pandemics, testing must be prioritised for care homes, especially if severe illness and death particularly affect older people or individuals with characteristics similar to care home residents, and an efficacious vaccine is unavailable.
The TyphiNET data visualisation dashboard: unlocking Salmonella Typhi genomics data to support public health
Abstract Background Salmonella enterica subspecies enterica serovar Typhi (abbreviated as ‘Typhi’) is the bacterial agent of typhoid fever. Effective antimicrobial therapy reduces complications and mortality; however, antimicrobial resistance (AMR) is a major problem in many endemic countries. Prevention through vaccination is possible through recently-licensed typhoid conjugate vaccines (TCVs). National immunisation programs are currently being considered or deployed in several countries where AMR prevalence is known to be high, and the Gavi vaccine alliance has provided financial support for their introduction. Pathogen whole genome sequence data are a rich source of information on Typhi variants (genotypes or lineages), AMR prevalence, and mechanisms. However, this information is currently not readily accessible to non-genomics experts, including those driving vaccine implementation or empirical therapy guidance. Results We developed TyphiNET (https://www.typhi.net), an interactive online dashboard for exploring Typhi genotype and AMR distributions derived from publicly available pathogen genome sequences. TyphiNET allows users to explore country-level summaries such as the frequency of pathogen lineages, temporal trends in resistance to clinically relevant antimicrobials, and the specific variants and mechanisms underlying emergent AMR trends. User-driven plots and session reports can be downloaded for ease of sharing. Importantly, TyphiNET is populated by high-quality genome data curated by the Global Typhoid Pathogen Genomics Consortium, analysed using the Pathogenwatch platform, and identified as coming from non-targeted sampling frames that are suitable for estimating AMR prevalence amongst Typhi infections (no personal data is included in the platform). As of February 2024, data from a total of n = 11,836 genomes from 101 countries are available in TyphiNET. We outline case studies illustrating how the dashboard can be used to explore these data and gain insights of relevance to both researchers and public health policy-makers. Conclusions The TyphiNET dashboard provides an interactive platform for accessing genome-derived data on pathogen variant frequencies to inform typhoid control and intervention strategies. The platform is extensible in terms of both data and features, and provides a model for making complex bacterial genome-derived data accessible to a wide audience.
Improving access to human milk for vulnerable infants in resource-limited settings: an empirical ethics study
Following the WHO’s guidelines for optimal feeding of vulnerable infants, human milk banks (HMBs) have been developed to improve access to human milk for vulnerable infants and to ensure that milk is safely collected and stored, quality checked, and equitably distributed. While there are over 600 HMBs globally, very few are in sub-Saharan Africa, and there is limited evidence on the ethical issues surrounding the implementation of HMBs in resource-limited settings. Research is therefore needed to inform guidelines and subsequent policy development in the region. The main objective of my research was to examine the ethical issues involved in the implementation of HMBs in sub-Saharan African health systems and to consider how these issues might inform future ethics guidance and practice. To achieve this, I designed and conducted an empirical ethics case study around the first HMB in Kenya at the Pumwani Maternity Hospital in Nairobi; with additional insights from experts in the region. In a pilot phase, Pumwani HMB offered an opportunity to prospectively study ethical issues in practice. My empirical ethics methodology combines a case study approach with a literature review and ethical analysis. I conducted a scoping review of the literature on the ethics of HMBs globally. This was followed by case study work involving 75 hours of observations and informal conversations at Pumwani newborn unit, 25 in-depth interviews with health workers, managers and mothers, and one focus group discussion with a mothers’ support group. I also interviewed 10 expert stakeholders in Kenya and internationally. These conversations focused on perceptions and experiences of implementing and/or utilising an HMB, and recommendations for scale. I utilised framework and narrative approaches for data analysis. My study and ethical analysis were shaped by my literature review and the empirical data. I did not find ethics specific literature from the sub-Saharan Africa region. Available literature was mainly from North America, where ethical issues are likely to differ due to different disease profiles, and community and health systems contexts. The available ethics literature led me to conceptualise HMB as a complex intervention implemented in complex health systems. I developed and utilised a multilevel ethics framework, bringing together considerations from clinical, care, public health, implementation science, health systems and African ethics frameworks, mapped across socioecological domains. I utilised the framework to identify stakeholders, develop tools and to inform subsequent data analysis. Indeed, from the empirical study, the context within which the HMB was introduced was complex, as were the vulnerabilities of the mothers and babies meant to be served by the HMB. These complexities presented actors with ethical dilemmas and trade-offs to negotiate in everyday practice as well as in considerations about scaling access and sustaining the HMB. For example, there were many perceived benefits of access to human milk, such as, reduction in complications and prompt weight gain for babies. The HMB also offered an opportunity to provide structured lactation support for mothers. However, such benefits were accompanied by burdens to mothers, staff and the institution, such as difficult screening processes, significant increases in staff workload, and a need for institutional reorganisation. There were persisting concerns about sustainability of the HMB and calls for additional evidence, funding, and responsiveness to the sociocultural context to ensure that the intended benefits are realised, and unintended consequences minimised.
Monitoring the Long-Term Effectiveness of Miltefosine in Indian Post-Kala-Azar Dermal Leishmaniasis.
Post-kala-azar dermal leishmaniasis (PKDL), the dermal sequel to visceral leishmaniasis (VL), is characterized by hypopigmented macules (macular) and/or papules and nodules (polymorphic). Post-kala-azar dermal leishmaniasis plays a significant role in disease transmission, emphasizing the need for monitoring chemotherapeutic effectiveness. Accordingly, this study aimed to quantify the parasite burden in PKDL patients after treatment with miltefosine by a quantitative polymerase chain reaction (qPCR). A Leishmania kinetoplastid gene-targeted qPCR was undertaken using DNA from skin biopsy specimens of patients with PKDL at three time points, i.e., at disease presentation (week 0, n = 157, group 1), upon completion of treatment (week 12, n = 39, group 2), and at any time point 6 months after completion of treatment (week ≥36, n = 54, group 3). A cycle threshold (Ct) <30 was considered the cutoff for positivity, and load was quantified as the number of parasites/µg genomic DNA (gDNA); cure was considered when samples had a Ct >30. The parasite load at disease presentation (group 1) was 10,769 (1,339-80,441)/µg gDNA (median [interquartile range]). In groups 2 and 3, qPCR results were negative in 35/39 cases (89.7%) and 48/54 cases (88.8%), respectively. In the 10/93 (10.8%) qPCR-positive cases, the parasite burdens in groups 2 and 3 were 2,420 (1,205-5,661)/µg gDNA and 22,195 (5,524-100,106)/µg gDNA, respectively. Serial monitoring was undertaken in 45 randomly selected cases that had completed treatment; all cases in groups 2 or 3 had a Ct >30, indicating cure. Overall, qPCR confirmed an 89.2% cure (as 83/93 cases showed parasite clearance), and the persistent qPCR positivity was attributed to nonadherence to treatment or unresponsiveness to miltefosine and remains to be investigated.
Global spatiotemporal analysis of suicide epidemiology and risk factor associations from 2000 to 2019 using Bayesian space time hierarchical modeling.
Suicide is a significant global public health issue, with marked disparities in rates between countries. Much of the existing research has concentrated on high-income nations, creating a gap in the understanding of global suicide epidemiology. This study aims to address this gap through a comprehensive spatiotemporal analysis of global suicide trends from 2000 to 2019. Data were collected from the Global Health Observatory, encompassing 183 countries across five regions. Bayesian spatiotemporal modeling and cluster detection techniques were employed to assess variations in suicide rates and identify high-risk clusters, alongside examining associations with various risk factors. The findings indicate diverse global and regional age-standardized suicide trends, with overall rates decreasing from an average of 12.97 deaths per 100,000 population in 2000 to 9.93 deaths per 100,000 in 2019. Significant regional variations were noted, particularly in Europe, Asia, and Africa, where high-risk clusters were identified. Additionally, age and sex-specific trends revealed consistently higher rates among males, although these rates have been declining over time. Spatial maps illustrated hotspots of elevated suicide rates, which can inform targeted intervention strategies. Risk factor analysis further revealed associations with socioeconomic and health indicators. The results underscore the necessity for tailored prevention strategies and highlight the importance of international collaboration and surveillance systems in addressing the complexities of global suicide epidemiology. This study contributes valuable insights into suicide patterns and offers implications for mental health policies worldwide.