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At this year’s ASTMH Annual Meeting the Centre for Tropical Medicine and Global Health will introduce research from our Major Overseas Programmes in Thailand, Vietnam, and Kenya, and groups based in Oxford: ERGO, IDDO, ISARIC, OHSCAR, TGHN, WWARN, and the MSc in International Health and Tropical Medicine.
An adaptive multiarm randomised trial of biomedical and psychosocial interventions to improve convalescence following severe acute malnutrition in sub-Saharan Africa: Co-SAM trial protocol.
INTRODUCTION: Children discharged from hospital following management of complicated severe acute malnutrition (SAM) have a high risk of mortality, readmission and failed nutritional recovery. Current management approaches fail to sufficiently promote convalescence after inpatient nutritional rehabilitation. Novel interventions during the post-discharge period could enhance convalescence to help children survive and thrive. METHODS AND ANALYSIS: The Co-SAM trial is an adaptive, multicountry, phase III, individually randomised clinical trial, based on the principles that (i) interacting biological and social factors drive multimorbidity in children with SAM, and (ii) both medical and psychosocial interventions may therefore ameliorate underlying causal pathways to reduce morbidity and mortality and improve recovery. Children aged 6-59 months with complicated SAM, who have stabilised and started the transition to ready-to-use therapeutic food (RUTF), will be enrolled and randomised to one of five trial arms (standard-of-care alone; antimicrobials; reformulated RUTF; psychosocial support; or a combination of all strategies). Standard-of-care, which is provided in all trial arms, includes RUTF until nutritional recovery (defined as weight-for-height Z-score >-2, mid-upper arm circumference >12.5 cm and oedema-free since the last study visit), and other management recommended in WHO guidelines. The 12-week antimicrobial package provides daily co-formulated rifampicin and isoniazid (with pyridoxine) and 3 days of azithromycin monthly. The reformulated RUTF, which incorporates medium-chain triglycerides and hydrolysed protein to increase nutrient bioavailability and reduce metabolic stress, is provided at the same dose and duration as standard RUTF. The 12-week psychosocial package includes caregiver problem-solving therapy, educational modules, peer support groups and child play. The combined arm includes all interventions. Children start their intervention package prior to hospital discharge, with follow-up data collection in study clinics at 2, 4, 6, 8, 12 and 24 weeks. The primary composite outcome is death, hospitalisation or failed nutritional recovery within 24 weeks post-randomisation. An interim analysis will allow unpromising arms to be dropped, while the final analysis will be conducted when 1266 children have completed the study. Embedded process evaluation and laboratory substudies will explore the mechanisms of action of the interventions. ETHICS AND DISSEMINATION: The trial has been approved by ethics committees in Zimbabwe, Zambia, Kenya and UK. Dissemination will be via community advisory boards in each country; Ministries of Health; and dialogue with policymakers including UNICEF. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT05994742; Pan African Clinical Trials Registry: PACTR202311478928378.
Molnupiravir or nirmatrelvir-ritonavir plus usual care versus usual care alone in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
BackgroundMolnupiravir and nirmatrelvir-ritonavir are oral antivirals that have shown efficacy in preventing disease progression in outpatients with COVID-19. We aimed to evaluate these treatments for patients hospitalised with COVID-19 pneumonia, for whom data on these antivirals are scarce.MethodsThe RECOVERY trial is a randomised, controlled, open-label, adaptive platform trial testing treatments for COVID-19. In this study we report the molnupiravir and nirmatrelvir-ritonavir comparisons from the RECOVERY trial. In each comparison, participants aged 18 years and older were randomly allocated (1:1) to the relevant antiviral (5 days of molnupiravir 800 mg twice daily or 300 mg nirmatrelvir and 100 mg ritonavir twice daily) in addition to usual care, or to usual care alone. The molnupiravir comparison was conducted at 75 hospitals in the UK, two in Nepal, and two in Indonesia; the nirmatrelvir-ritonavir comparison was conducted at 32 hospitals in the UK. Participants could take part in both comparisons. The primary outcome was 28-day mortality, and secondary outcomes were time to discharge alive from hospital and progression to invasive ventilation or death. Analysis was by intention to treat. Both comparisons were stopped because of low recruitment. This study is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.FindingsFrom Jan 24, 2022, to May 24, 2023, 923 participants were recruited to the molnupiravir comparison (445 allocated to molnupiravir and 478 to usual care), and from March 31, 2022, to May 24, 2023, 137 participants were recruited to the nirmatrelvir-ritonavir comparison (68 allocated to nirmatrelvir-ritonavir and 69 to usual care). More than three-quarters of participants were vaccinated and had antispike antibodies at randomisation, and more than two-thirds were receiving other SARS-CoV-2 antivirals. In the molnupiravir comparison, 74 (17%) participants allocated to molnupiravir and 79 (17%) allocated to usual care died within 28 days (hazard ratio [HR] 0·93 [95% CI 0·68-1·28], p=0·66). In the nirmatrelvir-ritonavir comparison, 13 (19%) participants allocated to nirmatrelvir-ritonavir and 13 (19%) allocated to usual care died within 28 days (HR 1·02 [0·47-2·23], p=0·96). In neither comparison was there evidence of any difference in the duration of hospitalisation or the proportion of participants progressing to invasive ventilation or death.InterpretationAdding molnupiravir or nirmatrelvir-ritonavir to usual care was not associated with improvements in clinical outcomes. However, low recruitment meant a clinically meaningful benefit of treatment could not be ruled out, particularly for nirmatrelvir-ritonavir.FundingUK Research and Innovation (UK Medical Research Council), the National Institute for Health and Care Research, and the Wellcome Trust.
Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans.
A leading HIV vaccine strategy requires a priming immunogen to induce broadly neutralizing antibody (bnAb) precursors, followed by a series of heterologous boosters to elicit somatic hypermutation (SHM) and produce bnAbs. In two randomized, open-label phase 1 human clinical trials, IAVI-G002 in the United States and IAVI-G003 in Rwanda and South Africa, we evaluated the safety and immunogenicity of mRNA-encoded nanoparticles as priming immunogens (both trials) and first-boosting immunogens (IAVI-G002). The vaccines were generally safe and well tolerated, except 18% of IAVI-G002 participants experienced skin reactions. Priming induced bnAb precursors with substantial frequencies and SHM, and heterologous boosting elicited increased SHM, affinity, and neutralization activity toward bnAb development. The results establish clinical proof of concept that heterologous boosting can advance bnAb-precursor maturation and demonstrate bnAb priming in Africa where the HIV burden is highest.
Detection of mpox and other orthopoxviruses using a lateral flow device as a point-of-care diagnostic.
In 2022, the World Health Organization declared the worldwide outbreak of mpox to be a public health emergency of international concern. The causative monkeypox virus (MPXV) belonged to clade IIb and is transmitted through sexual contact with a low case fatality rate (0.1%), which, together with under-detection, all contributed to a rapid global spread particularly within the MSM (men who have sex with men) community. As MPXV clade II remains circulating worldwide, a new outbreak of the more fatal clade I disease has been declared in Central and East Africa, and remains uncontrolled in part due to the lack of point-of-care (POC) diagnostics for rapid decisions on treatment and self-isolation. To address the lack of POC solutions for mpox, we have designed and evaluated an orthopoxvirus-specific lateral flow device (LFD) that could be used for the diagnosis of mpox. Using an LFD comprising four monoclonal antibodies against the A27 protein, we demonstrate sensitivity to 3 × 105 pfu/mL. This sensitivity is expected to be sufficient for the detection of MPXV from lesion sites and may also be sufficient for other sample types such as saliva and urine. We found that the presence of guanidinium thiocyanate, a common ingredient in inactivating viral transport media, masked the LFD antigen, resulting in false negatives. POC diagnosis of mpox may be possible using an LFD to reduce delays arising from sample shipment to centralized laboratory testing facilities. In order to achieve this, our work demonstrates that an LFD-optimized buffer is required, as the sample collection buffer may have a detrimental impact on sensitivity for clinical material.IMPORTANCEMpox cases have dramatically increased both in traditionally monkeypox virus endemic countries and also worldwide. This increase comes at a time when immunity derived from smallpox vaccination is no longer available. Diagnosis of mpox is complicated due to both disease presentation and the availability of local diagnostic laboratories. The availability of a point-of-care diagnostic tool such as an lateral flow device (LFD) would play an important role to both diagnose and prevent onward transmission. This manuscript provides developers and assessors with key data for defining true sensitivity and specificity of a successful LFD in addition to buffer conditions for sample collection.
Genetic surveillance of Plasmodium falciparum populations following treatment policy revisions in the Greater Mekong Subregion.
Genetic surveillance of Plasmodium falciparum (Pf) can track antimalarial-resistant strains, to inform decision-making by National Malaria Control Programmes (NMCPs). The GenRe-Mekong project prospectively collected 5982 samples in the Greater Mekong Subregion (GMS) between 2017 and 2022, genotyping drug resistance markers, and barcodes that recapitulate genetic variation. Genotypes were analyzed with the grcMalaria R package, first described in this paper, to translate genetic epidemiology data into actionable visual information. Since 2020, Pf incidences decreased rapidly, accompanied by a decline of dihydroartemisinin-piperaquine (DHA-PPQ) resistant lineages, previously dominant in the eastern GMS. The frequency of plasmepsin2/3 amplifications, conferring piperaquine resistance, dropped from 62% in 2017-2019 to 2% in 2022, coinciding with a switch in frontline therapy in Cambodia, Thailand, and Vietnam. While regional artemisinin resistance levels remained high, no evidence of emerging mefloquine resistance was found. Routine genetic surveillance proved valuable in monitoring rapid parasite population changes in response to public health interventions, providing actionable information for NMCPs.
Genomics reveals zoonotic and sustained human Mpox spread in West Africa.
Five years before the 2022 multi-country mpox outbreak, Nigeria and Cameroon reported their first cases in over three decades.1,2 While Nigeria's outbreak is recognized as an ongoing human epidemic, the drivers of Cameroon's resurgence remain unclear.3,4 The rate of zoonoses remains uncertain in both countries, and gaps in genomic data obscure the timing, zoonotic and geographic origin of mpox virus (MPXV) emergence in humans. To address these uncertainties, we generated 118 MPXV genomes from Nigeria and Cameroon from 2018-2023. Our findings show that, in contrast to Nigeria, cases in Cameroon are the result of repeated zoonoses, with two distinct zoonotic lineages circulating across the Nigeria-Cameroon border. Our findings suggest that shared animal populations in the cross-border forest ecosystems drive virus emergence and spread. Accordingly, we identify the closest zoonotic outgroup to the Nigerian human epidemic lineage (hMPXV-1) in a southern Nigerian border state. We estimate that the shared ancestor of the zoonotic outgroup and hMPXV-1 circulated in animals in southern Nigeria in late 2013. We estimate that hMPXV-1 emerged in humans in August 2014 in the southern Rivers State and circulated undetected for three years. Rivers State acted as the main source of viral spread across the human epidemic. Our study sheds light on MPXV's recent establishment in the human population and highlights the risk of persistent zoonotic emergence of MPXV in the complex border regions of Cameroon and Nigeria.
Fatal Mycobacterium avium meningitis in an HIV-negative Vietnamese man: a case report
Background: Nontuberculous mycobacteria are environmental mycobacteria that rarely cause human disease, especially in the central nervous system. Central nervous system infection by Mycobacterium avium complex, the most common pathogen among nontuberculous mycobacteria species, is rare and seldom reported, even in those with advanced human immunodeficiency virus infection. We describe a case of Mycobacterium avium complex meningitis with cerebral hemorrhage in an human immunodeficiency virus uninfected man in Vietnam. Case presentation: A 56-year-old Vietnamese man with hypertension was hospitalized with a 5-day history of headache, dizziness, low-grade fever, and unresponsive to 5 days of oral antibiotics. A brain magnetic resonance imaging, performed on day 12, showed hydrocephalus and lacunar infarct. The patient did not improve with 8 days of empirical treatment with ceftriaxone, vancomycin, dexamethasone, and meropenem, and was transferred to a referral hospital for tropical diseases. At the second hospital admission, a cerebrospinal fluid analysis showed a white cell count of 22,518 cells/μL with 81% neutrophils, protein 1.72 g/L, and glucose 0.85 mmol/L. Acid-fast bacilli smear of the cerebrospinal fluid was positive. Molecular testing of the cerebrospinal fluid was negative on GeneXpert Ultra testing, while the line probe assay was positive for Mycobacterium avium. Blood cultures at two sites, cerebrospinal fluid cultures for bacteria and fungi, and human immunodeficiency virus Ag/Ab test were negative. The patient was continuously administered meropenem with the addition of azithromycin, rifampin, and ethambutol. Then, 1 day after nontuberculous mycobacteria treatment, he developed right-sided hemiplegia, and brain computed tomography showed a hemorrhage in the parietal area, adjacent to the left lateral ventricle, and left lateral intraventricular hemorrhage shifts the midline to the right. He was transferred to the third referral general hospital and died 22 days after the onset of symptoms. Conclusion: Nontuberculous mycobacteria-central nervous system infection might mimic unresponsive pyogenic bacterial meningitis. A rapid and accurate diagnosis is essential for initiating appropriate therapy for this deadly disease.
Digital Health Policy and Programs for Hospital Care in Vietnam: Scoping Review
Background There are a host of emergent technologies with the potential to improve hospital care in low- and middle-income countries such as Vietnam. Wearable monitors and artificial intelligence–based decision support systems could be integrated with hospital-based digital health systems such as electronic health records (EHRs) to provide higher level care at a relatively low cost. However, the appropriate and sustainable application of these innovations in low- and middle-income countries requires an understanding of the local government’s requirements and regulations such as technology specifications, cybersecurity, data-sharing protocols, and interoperability. Objective This scoping review aims to explore the current state of digital health research and the policies that govern the adoption of digital health systems in Vietnamese hospitals. Methods We conducted a scoping review using a modification of the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) guidelines. PubMed and Web of Science were searched for academic publications, and Thư Viện Pháp Luật, a proprietary database of Vietnamese government documents, and the Vietnam Electronic Health Administration website were searched for government documents. Google Scholar and Google Search were used for snowballing searches. The sources were assessed against predefined eligibility criteria through title, abstract, and full-text screening. Relevant information from the included sources was charted and summarized. The review process was primarily undertaken by one researcher and reviewed by another researcher during each step. Results In total, 11 academic publications and 20 government documents were included in this review. Among the academic studies, 5 reported engineering solutions for information systems in hospitals, 2 assessed readiness for EHR implementation, 1 tested physicians’ performance before and after using clinical decision support software, 1 reported a national laboratory information management system, and 2 reviewed the health system’s capability to implement eHealth and artificial intelligence. Of the 20 government documents, 19 were promulgated from 2013 to 2020. These regulations and guidance cover a wide range of digital health domains, including hospital information management systems, general and interoperability standards, cybersecurity in health organizations, conditions for the provision of health information technology (HIT), electronic health insurance claims, laboratory information systems, HIT maturity, digital health strategies, electronic medical records, EHRs, and eHealth architectural frameworks. Conclusions Research about hospital-based digital health systems in Vietnam is very limited, particularly implementation studies. Government regulations and guidance for HIT in health care organizations have been released with increasing frequency since 2013, targeting a variety of information systems such as electronic medical records, EHRs, and laboratory information systems. In general, these policies were focused on the basic specifications and standards that digital health systems need to meet. More research is needed in the future to guide the implementation of digital health care systems in the Vietnam hospital setting.
Kinetics of Neutralizing Antibodies against Omicron Variant in Vietnamese Healthcare Workers after Primary Immunization with ChAdOx1-S and Booster Immunization with BNT162b2
ABSTRACT. We studied the development and persistence of neutralizing antibodies against SARS-CoV-2 ancestral strain, and Delta and Omicron (BA.1 and BA.2) variants in Vietnamese healthcare workers (HCWs) up to 15 weeks after booster vaccination. We included 47 HCWs, including group 1 (G1, N = 21) and group 2 (G2; N = 26) without and with breakthrough Delta variant infection before booster immunization, respectively). The study participants had completed primary immunization with ChAdOx1-S and booster vaccination with BNT162b2. Neutralizing antibodies were measured using a surrogate virus neutralization assay. Of the 21 study participants in G1, neutralizing antibodies against ancestral strain, Delta variant, BA.1, and BA.2 were (almost) abolished at month 8 after the second dose, but all had detectable neutralizing antibodies to the study viruses at week 2 post booster dose. Of the 26 study participants in G2, neutralizing antibody levels to BA.1 and BA.2 were significantly higher than those to the corresponding viruses measured at week 2 post breakthrough infection and before the booster dose. At week 15 post booster vaccination, neutralizing antibodies to BA.1 and BA.2 dropped significantly, with more profound changes observed in those without breakthrough Delta variant infection. Booster vaccination enhanced neutralizing activities against ancestral strain and Delta variant compared with those induced by primary vaccination. These responses were maintained at high levels for at least 15 weeks. Our findings emphasize the importance of the first booster dose in producing cross-neutralizing antibodies against Omicron variant. A second booster to maintain long-term vaccine effectiveness against the currently circulating variants merits further research.
Dengue
With an estimated global incidence of 390 million infections per year, dengue is the most widely distributed arthropod-borne virus (arbovirus) to infect humans. Billions of people live at risk of infection, and recent changes in global climate and human living patterns have allowed dengue incidence to increase at a faster rate than that of any other communicable disease except SARS-CoV-2. Rapidly urbanizing societies, increasing movement of people, and geographical expansion of the key mosquito vectors, Aedes aegypti and Aedes albopictus, mean that dengue incidence is projected to continue rising for much of the remainder of this century. With the majority of clinically apparent infections giving rise to mild disease, overall mortality is less than 0.1%, but the associated social and economic burden is high, with low- and middle-income countries being disproportionately affected. In its severest form, dengue can be rapidly life-threatening, when development of capillary leakage leads to hypovolaemic shock and organ dysfunction. Children, pregnant women, older people, and individuals with comorbidities are at risk of severe disease, as are those with pre-existing sub-neutralizing levels of dengue IgG as a result of prior infection with alternative viral serotypes. Despite significant recent investment in dengue research, effective antivirals and adjunctive therapies remain elusive, so clinical management relies on meticulous clinical monitoring and judicious fluid replacement. Various strategies for dengue prevention are under development, including infection of mosquitoes with the dengue-limiting bacteria Wolbachia, and identification of several potential vaccine candidates. Disappointingly, however, suitability of the first licensed dengue vaccine, Dengvaxia, has been shown to be limited to baseline seropositive individuals only. This chapter describes dengue’s epidemiology, transmission characteristics, and pathogenesis, as well as the typical clinical presentation and optimal management of cases. It concludes by discussing current and future strategies for vector control and disease prevention.
At-admission prediction of mortality and pulmonary embolism in an international cohort of hospitalised patients with COVID-19 using statistical and machine learning methods.
By September 2022, more than 600 million cases of SARS-CoV-2 infection have been reported globally, resulting in over 6.5 million deaths. COVID-19 mortality risk estimators are often, however, developed with small unrepresentative samples and with methodological limitations. It is highly important to develop predictive tools for pulmonary embolism (PE) in COVID-19 patients as one of the most severe preventable complications of COVID-19. Early recognition can help provide life-saving targeted anti-coagulation therapy right at admission. Using a dataset of more than 800,000 COVID-19 patients from an international cohort, we propose a cost-sensitive gradient-boosted machine learning model that predicts occurrence of PE and death at admission. Logistic regression, Cox proportional hazards models, and Shapley values were used to identify key predictors for PE and death. Our prediction model had a test AUROC of 75.9% and 74.2%, and sensitivities of 67.5% and 72.7% for PE and all-cause mortality respectively on a highly diverse and held-out test set. The PE prediction model was also evaluated on patients in UK and Spain separately with test results of 74.5% AUROC, 63.5% sensitivity and 78.9% AUROC, 95.7% sensitivity. Age, sex, region of admission, comorbidities (chronic cardiac and pulmonary disease, dementia, diabetes, hypertension, cancer, obesity, smoking), and symptoms (any, confusion, chest pain, fatigue, headache, fever, muscle or joint pain, shortness of breath) were the most important clinical predictors at admission. Age, overall presence of symptoms, shortness of breath, and hypertension were found to be key predictors for PE using our extreme gradient boosted model. This analysis based on the, until now, largest global dataset for this set of problems can inform hospital prioritisation policy and guide long term clinical research and decision-making for COVID-19 patients globally. Our machine learning model developed from an international cohort can serve to better regulate hospital risk prioritisation of at-risk patients.