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Oxford Centre for Tropical Medicine and Global Health
Full-length MSP1 is a major target of protective immunity after controlled human malaria infection.
The merozoite surface protein 1 (MSP1) is the most abundant protein on the surface of the invasive merozoite stages of Plasmodium falciparum and has long been considered a key target of protective immunity. We used samples from a single controlled human malaria challenge study to test whether the full-length version of MSP1 (MSP1FL) induced antibodies that mediated Fc-IgG functional activity in five independent assays. We found that anti-MSP1FL antibodies induced complement fixation via C1q, monocyte-mediated phagocytosis, neutrophil respiratory burst, and natural killer cell degranulation as well as IFNγ production. Activity in each of these assays was strongly associated with protection. The breadth of MSP1-specific Fc-mediated effector functions was more strongly associated with protection than the individual measures and closely mirrored what we have previously reported using the same assays against merozoites. Our findings suggest that MSP1FL is an important target of functional antibodies that contribute to a protective immune response against malaria.
The hidden emotional labour behind ensuring the social value of research: Experiences of frontline health policy and systems researchers based in Kenya during COVID-19.
Health policy and systems research (HPSR) is a multi-disciplinary, largely applied field of research aimed at understanding and strengthening the performance of health systems, often with an emphasis on power, policy and equity. The value of embedded and participatory HPSR specifically in facilitating the collection of rich data that is relevant to addressing real-world challenges is increasingly recognised. However, the potential contributions and challenges of HPSR in the context of shocks and crises are not well documented, with a particular gap in the literature being the experiences and coping strategies of the HPSR researchers who are embedded in health systems in resource constrained settings. In this paper, we draw on two sets of group discussions held among a group of approximately 15 HPSR researchers based in Nairobi, Kenya, who were conducting a range of embedded HPSR studies throughout the COVID-19 pandemic. The researchers, including many of the authors, were employed by the KEMRI-Wellcome Trust Research Programme (KWTRP), which is a long-standing multi-disciplinary partnership between the Kenya Medical Research Institute and the Wellcome Trust with a central goal of contributing to national and international health policy and practice. We share our findings in relation to three inter-related themes: 1) Ensuring the continued social value of our HPSR work in the face of changing priorities; 2) Responding to shifting ethical procedures and processes at institutional and national levels; and 3) Protecting our own and front-line colleagues' well-being, including clinical colleagues. Our experiences highlight that in navigating research work and responsibilities to colleagues, patients and participants through the pandemic, many embedded HPSR staff faced difficult emotional and ethical challenges, including heightened forms of moral distress, which may have been better prevented and supported. We draw on our findings and the wider literature to discuss considerations for funders and research leads with an eye to strengthening support for embedded HPSR staff, not only in crises such as the on-going COVID-19 pandemic, but also more generally.
Budget monitoring, accountability practices and their influence on the efficiency of county health systems in Kenya.
Public Finance Management (PFM) practices influence the attainment of health system goals. PFM processes are implemented within the budget cycle which entails the formulation, execution, and monitoring of government budgets. Budget monitoring and accountability actors, structures, and processes are important in improving the efficiency of health systems. This study examined how the budget monitoring and accountability processes influence the efficiency of county health systems in KenyaWe conducted a qualitative case study of four counties in Kenya selected based on their relative technical efficiency. We collected data using in-depth interviews with health and finance stakeholders (n = 70), and document reviews. We analyzed data using a thematic approach, informed by our study conceptual framework. We found that weak budget monitoring and accountability mechanisms compromised county health system efficiency by a) weakening the effective implementation of the budget formulation and execution steps of the budget cycle, b) enabling the misappropriation of public resources, and c) limiting evidence-informed decision-making by weakening feedback that would be provided by effective monitoring and accountability. Devolution meant that accountability actors were closer to implementation actors which promoted timely problem solving and the relevance of solutions. Internal audit practices were supportive and provided useful feedback to health system managers that facilitated improvements in budget formulation and execution. The efficiency of county health systems can be improved by strengthening the budget monitoring and accountability processes. This can be achieved by increasing the population's budget literacy, supporting participatory budgeting, synchronizing performance and financial accountability, implementing the existent budget monitoring and accountability mechanisms, rewarding efficiency, and sanctioning inefficiency.
Examining health sector stakeholder perceptions on the efficiency of county health systems in Kenya.
Efficiency gains is a potential strategy to expand Kenya's fiscal space for health. We explored health sector stakeholders' understanding of efficiency and their perceptions of the factors that influence the efficiency of county health systems in Kenya. We conducted a qualitative cross-sectional study and collected data using three focus group discussions during a stakeholder engagement workshop. Workshop participants included health sector stakeholders from the national ministry of health and 10 (out 47) county health departments, and non-state actors in Kenya. A total of 25 health sector stakeholders participated. We analysed data using a thematic approach. Health sector stakeholders indicated the need for the outputs and outcomes of a health system to be aligned to community health needs. They felt that both hardware aspects of the system (such as the financial resources, infrastructure, human resources for health) and software aspects of the system (such as health sector policies, public finance management systems, actor relationships) should be considered as inputs in the analysis of county health system efficiency. They also felt that while traditional indicators of health system performance such as intervention coverage or outcomes for infectious diseases, and reproductive, maternal, neonatal and child health are still relevant, emerging epidemiological trends such as an increase in the burden of non-communicable diseases should also be considered. The stakeholders identified public finance management, human resources for health, political interests, corruption, management capacity, and poor coordination as factors that influence the efficiency of county health systems. An in-depth examination of the factors that influence the efficiency of county health systems could illuminate potential policy levers for generating efficiency gains. Mixed methods approaches could facilitate the study of both hardware and software factors that are considered inputs, outputs or factors that influence health system efficiency. County health system efficiency in Kenya could be enhanced by improving the timeliness of financial flows to counties and health facilities, giving health facilities financial autonomy, improving the number, skill mix, and motivation of healthcare staff, managing political interests, enhancing anticorruption strategies, strengthening management capacity and coordination in the health sector.
Diabetes and risk of hospitalisation due to infection in northeastern Thailand: Retrospective cohort study using population-based healthcare service data.
BackgroundPopulation-based studies describing the association between diabetes and increased risk of infection have largely been based in high-income countries. There is limited information describing the burden of infectious disease attributable to diabetes in low and middle-income countries. This study aimed to describe the burden and risk of infectious disease hospitalisation in people with diabetes compared to those without diabetes in northeastern Thailand.MethodsIn a retrospective cohort study using electronic health record data for 2012-2018 for 3.8 million people aged ≥20 years in northeastern Thailand, hospitalisation rates for any infectious diseases (ICD-10 codes A00-B99) were estimated and negative binomial regression used to estimate rate ratios (RR) for the association between diabetes and infectious disease hospitalisation adjusted for age, sex and area of residence.ResultsIn this study, 164,177 people had a diagnosis of diabetes mellitus at any point over the study period. Infectious disease hospitalisation rates per 1000 person-years (95%CI) were 71.8 (70.9, 72.8), 27.7 (27.1, 28.3) and 7.5 (7.5, 7.5) for people with prevalent diabetes, incident diabetes and those without diabetes respectively. Diabetes was associated with a 4.6-fold higher risk of infectious disease hospitalisation (RR (95% CI) 4.59 (4.52, 4.66)). RRs for infectious disease hospitalisation were 3.38 (3.29, 3.47) for people with diabetes managed by lifestyle alone and 5.29 (5.20, 5.39) for people receiving prescriptions for diabetes drugs.ConclusionsIn this Thai population, diabetes was associated with substantially increased risk of hospitalisation due to infectious diseases and people with diabetes who were on pharmacological treatment had a higher risk than those receiving lifestyle modification advice alone.
Breadth of Fc-mediated effector function correlates with clinical immunity following human malaria challenge.
Malaria is a life-threatening disease of global health importance, particularly in sub-Saharan Africa. The growth inhibition assay (GIA) is routinely used to evaluate, prioritize, and quantify the efficacy of malaria blood-stage vaccine candidates but does not reliably predict either naturally acquired or vaccine-induced protection. Controlled human malaria challenge studies in semi-immune volunteers provide an unparalleled opportunity to robustly identify mechanistic correlates of protection. We leveraged this platform to undertake a head-to-head comparison of seven functional antibody assays that are relevant to immunity against the erythrocytic merozoite stage of Plasmodium falciparum. Fc-mediated effector functions were strongly associated with protection from clinical symptoms of malaria and exponential parasite multiplication, while the gold standard GIA was not. The breadth of Fc-mediated effector function discriminated clinical immunity following the challenge. These findings present a shift in the understanding of the mechanisms that underpin immunity to malaria and have important implications for vaccine development.
Transforming Rapid Diagnostic Tests for Precision Public Health: Open Guidelines for Manufacturers and Users.
Precision public health (PPH) can maximize impact by targeting surveillance and interventions by temporal, spatial, and epidemiological characteristics. Although rapid diagnostic tests (RDTs) have enabled ubiquitous point-of-care testing in low-resource settings, their impact has been less than anticipated, owing in part to lack of features to streamline data capture and analysis. We aimed to transform the RDT into a tool for PPH by defining information and data axioms and an information utilization index (IUI); identifying design features to maximize the IUI; and producing open guidelines (OGs) for modular RDT features that enable links with digital health tools to create an RDT-OG system. We reviewed published papers and conducted a survey with experts or users of RDTs in the sectors of technology, manufacturing, and deployment to define features and axioms for information utilization. We developed an IUI, ranging from 0% to 100%, and calculated this index for 33 World Health Organization-prequalified RDTs. RDT-OG specifications were developed to maximize the IUI; the feasibility and specifications were assessed through developing malaria and COVID-19 RDTs based on OGs for use in Kenya and Indonesia. The survey respondents (n=33) included 16 researchers, 7 technologists, 3 manufacturers, 2 doctors or nurses, and 5 other users. They were most concerned about the proper use of RDTs (30/33, 91%), their interpretation (28/33, 85%), and reliability (26/33, 79%), and were confident that smartphone-based RDT readers could address some reliability concerns (28/33, 85%), and that readers were more important for complex or multiplex RDTs (33/33, 100%). The IUI of prequalified RDTs ranged from 13% to 75% (median 33%). In contrast, the IUI for an RDT-OG prototype was 91%. The RDT open guideline system that was developed was shown to be feasible by (1) creating a reference RDT-OG prototype; (2) implementing its features and capabilities on a smartphone RDT reader, cloud information system, and Fast Healthcare Interoperability Resources; and (3) analyzing the potential public health impact of RDT-OG integration with laboratory, surveillance, and vital statistics systems. Policy makers and manufacturers can define, adopt, and synergize with RDT-OGs and digital health initiatives. The RDT-OG approach could enable real-time diagnostic and epidemiological monitoring with adaptive interventions to facilitate control or elimination of current and emerging diseases through PPH.
Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.
BACKGROUND: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism. METHODS: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography mass-spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins. RESULTS: CSF tryptophan was associated with 60-day mortality from tuberculous meningitis (HR=1.16, 95%CI=1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and HIV-positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95%CI=1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis. CONCLUSION: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of mortality. These findings may reveal new targets for host-directed therapy. FUNDING: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).
Talaromycosis
Talaromycosis is an invasive fungal infection affecting primarily immunosuppressed individuals. Talaromycosis is caused by the thermally dimorphic fungus Talaromyces marneffei that is endemic in Southeast Asia, southern China, and northeastern India. Its intersection with the HIV epidemic in Southeast Asia has transformed talaromycosis from a rare human disease to a leading cause of death in people with advanced HIV disease. At least 288,000 cases and 87,900 deaths have been reported in the literature in 33 countries to date, and an estimate of 17,300 cases and 4900 deaths occur annually. Ninety percent of global cases occur in HIV-infected individuals, and 0.5% occur in infants and children. Incidence is increasing in non-HIV-infected individuals with secondary immunodeficiency due to increasing use of immunosuppressive therapies. Talaromycosis is increasingly reported in travelers to and immigrants from the endemic region. The clinical features are diverse, ranging from primary pulmonary to localized to disseminated infections involving multiple organ systems. Current diagnosis is based on culture isolation of T. marneffei demonstrating the temperature-dependent morphological switch between the mold and yeast forms. Culture isolation takes up to 28 days, leading to delays in treatment and high mortality. Promising molecular amplification and antigen detection methods offer improved sensitivities and speed and are undergoing clinical validation for clinical use. Induction therapy with amphotericin B reduces mortality, and is associated with faster fungal clearance from blood and reduced incidence of relapse and other complications compared to itraconazole. Amphotericin B is recommended as first line induction therapy regardless of disease severity. The mortality with treatment is high, and treatment options remain limited. Strategies for early diagnosis using non-culture diagnostics, use of effective but less toxic antifungal regimens, and more cost-effective disease prevention are critical to reduce morbidity and mortality.
The ability of a 3-gene host signature in blood to distinguish tuberculous meningitis from other brain infections.
BackgroundTuberculous meningitis (TBM) is difficult to diagnose. We investigated whether a 3-gene host response signature in blood can distinguish TBM from other brain infections.MethodsThe expression of 3 genes (Dual specificity phosphatase 3- DUSP3, Guanylate-binding protein- GBP5, Krupple-like factor 2- KLF2) was analysed by RNA sequencing of archived whole blood from four cohorts of Vietnamese adults: 281 with TBM; 279 with pulmonary tuberculosis; 50 with other brain infections; and 30 healthy controls. 'TB scores' (combined 3-gene expression) were calculated following published methodology and discriminatory performance compared using area under a receiver operator characteristic curve (AUC).ResultsGBP5 was upregulated in TBM compared to other brain infections (p ConclusionThe 3-gene host signature in whole blood has the ability to discriminate TBM from other brain infections, including in HIV-positive individuals. Validation in large prospective diagnostic study is now required.
Acceptance and User Experiences of a Wearable Device for the Management of Hospitalized Patients in COVID-19–Designated Wards in Ho Chi Minh City, Vietnam: Action Learning Project
Background Wearable devices have been used extensively both inside and outside of the hospital setting. During the COVID-19 pandemic, in some contexts, there was an increased need to remotely monitor pulse and saturated oxygen for patients due to the lack of staff and bedside monitors. Objective A prototype of a remote monitoring system using wearable pulse oximeter devices was implemented at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, from August to December 2021. The aim of this work was to support the ongoing implementation of the remote monitoring system. Methods We used an action learning approach with rapid pragmatic methods, including informal discussions and observations as well as a feedback survey form designed based on the technology acceptance model to assess the use and acceptability of the system. Based on these results, we facilitated a meeting using user-centered design principles to explore user needs and ideas about its development in more detail. Results In total, 21 users filled in the feedback form. The mean technology acceptance model scores ranged from 3.5 (for perceived ease of use) to 4.4 (for attitude) with behavioral intention (3.8) and perceived usefulness (4.2) scoring in between. Those working as nurses scored higher on perceived usefulness, attitude, and behavioral intention than did physicians. Based on informal discussions, we realized there was a mismatch between how we (ie, the research team) and the ward teams perceived the use and wider purpose of the technology. Conclusions Designing and implementing the devices to be more nurse-centric from their introduction could have helped to increase their efficiency and use during the complex pandemic period.
Rifampicin resistant Mycobacterium tuberculosis in Vietnam, 2020-2022.
ObjectiveWe conducted a descriptive analysis of multi-drug resistant tuberculosis (MDR-TB) in Vietnam's two largest cities, Hanoi and Ho Chi Minh city.MethodsAll patients with rifampicin resistant tuberculosis were recruited from Hanoi and surrounding provinces between 2020 and 2022. Additional patients were recruited from Ho Chi Minh city over the same time period. Demographic data were recorded from all patients, and samples collected, cultured, whole genome sequenced and analysed for drug resistance mutations. Genomic susceptibility predictions were made on the basis of the World Health Organization's catalogue of mutations in Mycobacterium tuberculosis associated with drug resistance, version 2. Comparisons were made against phenotypic drug susceptibility test results where these were available. Multivariable logistic regression was used to assess risk factors for previous episodes of tuberculosis.Results233/265 sequenced isolates were of sufficient quality for analysis, 146 (63 %) from Ho Chi Minh City and 87 (37 %) from Hanoi. 198 (85 %) were lineage 2, 20 (9 %) were lineage 4, and 15 (6 %) were lineage 1. 17/211 (8 %) for whom HIV status was known were infected, and 109/214 (51 %) patients had had a previous episode of tuberculosis. The main risk factor for a previous episode was HIV infection (odds ratio 5.1 (95 % confidence interval 1.3-20.0); p = 0.021). Sensitivity for predicting first-line drug resistance from whole genome sequencing data was over 90 %, with the exception of pyrazinamide (85 %). For moxifloxacin and amikacin it was 50 % or less. Among rifampicin-resistant isolates, prevalence of resistance to each non-first-line drug was ConclusionsDrug resistance among most MDR-TB strains in Vietnam's two largest cities is confined largely to first-line drugs. Living with HIV is the main risk factor among patients with MDR-TB for having had a previous episode of tuberculosis.
Use of antimicrobials during the COVID-19 pandemic: A qualitative study among stakeholders in Nepal.
The COVID-19 pandemic was a major public health threat and the pressure to find curative therapies was tremendous. Particularly in the early critical phase of the pandemic, a lot of empirical treatments, including antimicrobials, were recommended. Drawing on interviews with patients, clinicians and drug dispensers, this article explores the use of antimicrobials for the management of COVID-19 in Nepal. A total of 30 stakeholders (10 clinicians, 10 dispensers and 10 COVID-19 patients) were identified purposively and were approached for an interview. Clinicians and dispensers in three tertiary hospitals in Kathmandu assisted in the recruitment of COVID-19 patients who were undergoing follow-up at an out-patient department. Interviews were audio recorded, translated and transcribed into English, and were analyzed thematically. The respondents report that over-the-counter (OTC) use of antibiotics was widespread during the COVID-19 pandemic in Nepal. This was mostly rooted in patients' attempts to mitigate the potential severity of respiratory illnesses, and the fear of the stigmatization and social isolation linked to being identified as a COVID-19 patient. Patients who visited drug shops and physicians reportedly requested specific medicines including antibiotics. Clinicians reported uncertainty when treating COVID-19 cases that added pressure to prescribe antimicrobials. Respondents from all stakeholder groups recognized the dangers of excessive use of antimicrobials, with some referring to the development of resistance. The COVID-19 pandemic added pressure to prescribe, dispense and overuse antimicrobials, accentuating the pre-existing OTC use of antimicrobials. Infectious disease outbreaks and epidemics warrant special caution regarding the use of antimicrobials and specific policy response.
Molecular markers of artemisinin resistance during falciparum malaria elimination in Eastern Myanmar.
BackgroundArtemisinin resistance in Plasmodium falciparum threatens global malaria elimination efforts. To contain and then eliminate artemisinin resistance in Eastern Myanmar a network of community-based malaria posts was instituted and targeted mass drug administration (MDA) with dihydroartemisinin-piperaquine (three rounds at monthly intervals) was conducted. The prevalence of artemisinin resistance during the elimination campaign (2013-2019) was characterized.MethodsThroughout the six-year campaign Plasmodium falciparum positive blood samples from symptomatic patients and from cross-sectional surveys were genotyped for mutations in kelch-13-a molecular marker of artemisinin resistance.ResultThe program resulted in near elimination of falciparum malaria. Of 5162 P. falciparum positive blood samples genotyped, 3281 (63.6%) had K13 mutations. The prevalence of K13 mutations was 73.9% in 2013 and 64.4% in 2019. Overall, there was a small but significant decline in the proportion of K13 mutants (p ConclusionThe malaria elimination program in Kayin state, eastern Myanmar, led to a substantial reduction in falciparum malaria. Despite the intense use of artemisinin-based combination therapies, both in treatment and MDA, this did not select for artemisinin resistance.