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The Randomised Evaluation of COVID-19 Therapy (RECOVERY) has demonstrated that an anti-inflammatory treatment, tocilizumab, reduces the risk of death when given to hospitalised patients with severe COVID-19.
Consultation report - considerations for a regulatory pathway for bivalent Salmonella Typhi/Paratyphi A vaccines for use in endemic countries.
Enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi A and, to a lesser extent, S. Paratyphi B and C, remains a significant cause of mortality and morbidity in resource-constrained settings. Typhoid conjugate vaccines (TCVs) protect against S. Typhi but no vaccine to date protects against paratyphoid fever. There are several bivalent S. Typhi/Paratyphi A products in development; however, the low incidence of paratyphoid fever in many settings limits the feasibility of phase 3 efficacy studies. Two bivalent vaccines adding the S. Paratyphi A-specific O:2 lipopolysaccharide conjugated to a protein carrier to TCV constructs have successfully completed phase 1 studies and will progress rapidly in their development. The WHO's Product Development for Vaccines Advisory Committee (PDVAC) endorsed a regulatory pathway for a bivalent S. Typhi/Paratyphi A vaccine that contemplates demonstrating protective efficacy against S. Paratyphi A infection in a controlled human infection model (CHIM). Since the use of CHIM data in lieu of phase 3 efficacy studies and to identify markers of immune protection is not yet widely accepted by regulatory bodies, the WHO organized a consultation with vaccine developers, manufacturers, and regulators. The purpose of the meeting was to discuss the feasibility and considerations for the licensure of a bivalent S. Typhi/Paratyphi A vaccine. The aim of the consultation was to gain alignment among key stakeholders and facilitate the pathway to licensure in endemic countries.
Metabolic mapping of the human solute carrier superfamily.
Solute carrier (SLC) transporters govern most of the chemical exchange across cellular membranes and are integral to metabolic regulation, which in turn is linked to cellular function and identity. Despite their key role, individual functions of the SLC superfamily members were not evaluated systematically. We determined the metabolic and transcriptional profiles upon SLC overexpression in knock-out or wild-type isogenic cell backgrounds for 378 SLCs and 441 SLCs, respectively. Targeted metabolomics provided a fingerprint of 189 intracellular metabolites, while transcriptomics offered insights into cellular programs modulated by SLC expression. Beyond the metabolic profiles of 102 SLCs directly related to their known substrates, we identified putative substrates or metabolic pathway connections for 71 SLCs without previously annotated bona fide substrates, including SLC45A4 as a new polyamine transporter. By comparing the molecular profiles, we identified functionally related SLC groups, including some with distinct impacts on osmolyte balancing and glycosylation. The assessment of functionally related human genes presented here may serve as a blueprint for other systematic studies and supports future investigations into the functional roles of SLCs.
Malaria morbidity, mortality and associated costs in Indonesia: analysis of the National Health Insurance claim dataset.
INTRODUCTION: Data on morbidity, mortality and cost for malaria-related hospitalisation are important for prioritising resources for malaria control strategies, but these data are often limited. The aim of this study was to understand the current malaria service delivery in Indonesia, including referral rates to hospitals, mortality outcomes and malaria-related costs at hospitals, using data from National Health Insurance claims. METHODS: Data were gathered from the recent Indonesian National Health Insurance dataset for claims made between 2015 and 2020. Cases were selected for any diagnosis with the international classification of diseases-10th revision codes for malaria-related diseases. Patients' sociodemographic status, repeated presentations to healthcare facilities, referral patterns and costs of treatment for the hospital settings were assessed by malaria species. Costs were reported in 2020 US$. RESULTS: Data were available for 12 970 episodes of malaria, which occurred in 8833 patients. Plasmodium falciparum accounted for 6019 (46.4%) episodes, and P. vivax for 4307 (33.2%) episodes. The incidence rates were 0.38 (95% CI 0.29 to 0.47) per person-years for P. falciparum and 0.33 (95% CI 0.19 to 0.52) for P. vivax. 46% of malaria cases initially presented at the hospital. Among these patients, the mean cost was US$16.2 (SD 4.4) for an outpatient consultation and US$228.7 (SD 122.6) for inpatient care. In total, 4.8% (623) of patients re-presented to the hospital within 30 days of a malaria episode, of whom 1.7% (219) required admission for inpatient care, which was estimated to cost US$230.0 (SD 105.5). The risk of mortality for inpatients with P. falciparum malaria was 2.1% (36/1718) compared with 1.2% (16/1359) for patients with P. vivax malaria; p=0.069. CONCLUSIONS: The National Health Insurance claim data provide detailed costing estimates. Integrating data from the existing malaria information system with the data from the National Health Insurance claims can provide important insights into the healthcare costs associated with the management of malaria that could help optimise national antimalarial policy.
Safety and efficacy of single-dose primaquine to interrupt Plasmodium falciparum malaria transmission in children compared with adults: a systematic review and individual patient data meta-analysis.
BackgroundAdding a single dose of primaquine to artemisinin-based combination therapy (ACT) for the treatment of falciparum malaria can reduce the transmission of Plasmodium falciparum and could limit the spread of artemisinin partial resistance, including in Africa, where the disease burden is greatest. We aimed to compare the safety and efficacy of single-dose primaquine plus ACT between young children (aged <5 years) and older children (aged 5 years to <15 years) and adults (aged ≥15 years), and between low and moderate-to-high transmission areas.MethodsFor this systematic review and individual patient data meta-analysis, we searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, WHO Global Index Medicus, OpenGrey.eu, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform, from database inception to April 3, 2024, with no language restrictions. We included prospective studies on efficacy against falciparum malaria that enrolled at least one child younger than 15 years and involved a study group given a single dose of primaquine (≤0·75 mg/kg) plus ACT. Studies involving mass drug administration, healthy volunteers, or patients with severe malaria or mixed (with non-falciparum) infections were excluded. For inclusion in the efficacy analysis, data on transmission potential (as determined by gametocytaemia, infectivity, or both) at enrolment and follow-up (day 3, day 7, or day 14) were required; the safety analysis required data on haemoglobin concentrations or haematocrit values at enrolment and at one or more follow-up visits by day 7, any data on adverse events, or both. After independent screening of the search results by two reviewers, the investigators of eligible studies were invited to contribute individual patient data. We quantified day 7 gametocyte carriage, probability of infecting a mosquito, decreases (>25%) in haemoglobin concentration associated with anaemia, and adverse events until day 28 using regression analyses, with random study-site intercepts to account for clustered data. These analyses were registered with PROSPERO, CRD42021279363 (safety) and CRD42021279369 (efficacy).FindingsOf 5697 records identified by the search, 30 studies were eligible for analysis. Of these, individual patient data were shared for 23 studies, including 6056 patients from 16 countries: 1171 (19·3%) young children (aged <5 years), 2827 (46·7%) older children (aged 5 years to <15 years), and 2058 (34·0%) adults (aged ≥15 years). Adding a single low dose of primaquine (0·2-0·25 mg/kg) to ACTs reduced day 7 gametocyte positivity (adjusted odds ratio [aOR] 0·34, 95% CI 0·22-0·52; p<0·001) and infectivity to mosquitoes over time (aOR per day 0·02, 0·01-0·07, p<0·001). No difference was found in the effect of single low-dose primaquine both on gametocyte positivity in young children compared with older children (1·08, 0·52-2·23; p=0·84) and adults (0·50, 0·20-1·25; p=0·14) and between low-transmission and moderate-to-high transmission settings (1·07, 0·46-2·52; p=0·86), and on infectivity to mosquitoes in young children compared with older children (1·36, 0·07-27·71; p=0·84) and adults (0·31, 0·01-8·84; p=0·50) and between low-transmission and moderate-to-high transmission settings (0·18, 0·01-2·95; p=0·23). Gametocyte clearance was also similar for different ACTs (dihydroartemisinin-piperaquine vs artemether-lumefantrine) when combined with a primaquine target dose of 0·25 mg/kg (1·56, 0·65-3·79; p=0·32 at day 7). However, patients given a primaquine dose of less than 0·2 mg/kg with dihydroartemisinin-piperaquine were more likely to have gametocytaemia than those treated with artemether-lumefantrine (5·68, 1·38-23·48; p=0·016 at day 7). There was no increase in anaemia-associated declines in haemoglobin concentration (>25%) at a primaquine dose of 0·25 mg/kg, regardless of age group, transmission setting, and glucose-6-phosphate dehydrogenase status. The risks of adverse events of grade 2 or higher and of serious adverse events were similar between primaquine and no-primaquine groups, including in young children.InterpretationRegardless of malaria transmission intensity and age group, a single dose of 0·25 mg/kg primaquine is safe and efficacious for reducing P falciparum transmission. These findings underscore the need for primaquine formulations suitable for young children, and also provide supportive evidence to expand the use of single low-dose primaquine in regions with a moderate-to-high transmission rate that are threatened by artemisinin partial resistance.FundingThe EU and the Bill & Melinda Gates Foundation.
Defining the noma research agenda.
• A 1-day symposium brought together over 100 individuals with lived experience of noma, expertise in neglected tropical diseases, and public health, including researchers, health advocates, and clinicians. The involvement of noma survivors was invaluable and added an important perspective in defining the research agenda. • The most pressing research needs identified were: ○ Clear case definition of noma ○ Early case detection and robust surveillance ○ Psychosocial and economic impact of noma ○ Decision support for diagnosing acute necrotizing gingivitis and associated antibiotic regimen(s) with treatment duration ○ Deeper understanding of risk factors and social determinants ○ Identification of effective information, education, and communication strategies ○ Effectiveness of surgical services ○ Testing decentralized follow-up for patients • An important conclusion was that noma research and control activities must be integrated across sectors and disciplines, such as neglected tropical diseases, oral health, nutrition, and child health programs including immunization.
Retrospective analysis of the sensitivity of reporting of thoracic computed tomography for pleural malignancy: an Australian multi-centre study
Background: Contrast-enhanced computed tomography (CE-CT) is crucial in the early detection of malignant pleural effusion (MPE) and has significant impacts on diagnosis, staging and guiding procedural intervention. In real world practice, the sensitivity of CE-CT for MPE is significantly lower than initially described in the literature. We aim to assess the sensitivity of CE-CT reporting in assessment of suspected MPE in a real-world setting. Methods: A multi-centre retrospective review of pleural procedures in the years 2019–2020 at two tertiary centres (John Hunter Hospital, Calvary Mater Hospital) in Newcastle, Australia was performed. Patients with new MPE and a CT performed before histocytological confirmation of malignancy were included. CT reports were reviewed based on the use of pre-determined terminology indicating MPE. Results: A total of 101 patients were included for analysis. Sixty-eight studies were arterial phase, 25 were CT pulmonary angiograms and 2 were delayed venous phase. Seventy-one patients had reports indicating a malignant cause, yielding a sensitivity of 70% [95% confidence interval (CI): 61–78%]. The sensitivity was similar regardless of the contrast phase used. When using only the presence of Leung criteria the overall sensitivity dropped to 42% (95% CI: 32–51%) with a greater decrease seen especially with CT pulmonary angiogram (sensitivity 16%, 95% CI: 6–35%). Conclusions: This is, to our knowledge, the first evaluation of CE-CT use and its sensitivity in MPE assessment outside of Western Europe. This study highlights the limitations of CT in diagnosing MPE and supports early histocytological sampling. Further studies to evaluate the role of CE-CT in the pleural diagnostic pathway are needed.
Understanding the primary healthcare context in rural South and Southeast Asia: a village profiling study
Abstract Background Understanding contextual factors is critical to the success of health service planning and implementation. However, few contextual data are available at the village level in rural South and Southeast Asia. This study addressed the gap by profiling representative villages across seven sites in Thailand (n=3), Cambodia, Laos, Myanmar and Bangladesh. Methods Key informant surveys supplemented by other information sources were used to collect data from 687 villages on four key indicators (literacy rate, and percentages of attended deliveries, fully immunised children and latrine coverage), as well as access to various services. Data were analysed descriptively. Results Sites varied considerably. Five were highly diverse ethno-culturally and linguistically, and all relied on primary health centres and village health/malaria workers as the main providers of primary healthcare. These were generally bypassed by severely ill patients for urban first-level referral hospitals and private sector facilities. While >75% of villages were near primary schools, educational attainment was generally low. Over 70% of villages at each site had mobile phone coverage and availability of electricity was high (≥65% at all sites bar Myanmar). Conclusion These results illustrate the similarities and differences of villages in this region that must be considered in public health research and policymaking.
Diagnostic Challenges in Detecting Rubella Viral RNA in Cases of Congenital Rubella Syndrome Using RT-PCR in the Era of Elimination.
BACKGROUND: Confirming the detection of rubella virus (RUBV) genotypes is crucial for tracking the transmission and evolution of the virus, which is essential for eliminating rubella. Reverse transcription-polymerase chain reaction (RT-PCR) plays a crucial role in identifying the viral genotype, but it comes with various challenges from sample collection to data interpretation. The present study aimed to explore the complexities of confirming the detection of RUBV in patients with congenital rubella infection using RT-PCR, discussing potential pitfalls and optimization strategies. METHODS: From July 2019 to December 2021, we isolated the RUBV from throat swabs, lens materials, and urine samples obtained from patients with serologically confirmed and clinically compatible congenital rubella syndrome (CRS). The case definition and final classification of CRS were adapted from the World Health Organization-recommended CRS surveillance standard. We utilized the RT-PCR assay to detect the presence of RUBV ribonucleic acid (RNA). RESULTS: During the study period, 126 patients with suspected CRS underwent complete clinical and serological examinations. Of these, 30 patients were included, and 22 were laboratory-confirmed. Using RT-PCR, RUBV was detected in only 42.1% of the laboratory-confirmed group. Overall, the lens material showed the highest positivity for detecting RUBV RNA. No correlation was found between the cycle threshold values and patient age at viral RNA testing. CONCLUSIONS: The present study underscores the critical need for a multifaceted approach for accurately diagnosing CRS, particularly in the context of rubella elimination efforts. RT-PCR testing can be particularly useful for diagnosing CRS in patients over 12 months of age. By addressing the challenges and building upon the insights gained from our research, healthcare systems can enhance CRS diagnosis, guide timely interventions and ultimately contribute to the global rubella.
Influence of context on engagement with COVID-19 testing: a scoping review of barriers and facilitators to testing for healthcare workers, care homes and schools in the UK
ObjectiveThe UK government’s response to the COVID-19 pandemic included a ‘test, trace and isolate’ strategy. Testing services for healthcare workers, care homes and schools accounted for the greatest spend and volume of tests. We reviewed relevant literature to identify common and unique barriers and facilitators to engaging with each of these testing services.DesignScoping review.Search strategyPubMed, Scopus and the WHO COVID-19 Research Database were searched for evidence published between 1 January 2020 and 7 November 2022. This was supplemented by evidence identified via free-text searches on Google Scholar and provided by the UK Health Security Agency (UKHSA).Data extraction and synthesisData were extracted by a team of reviewers and synthesised thematically under the broad headings of perceptions, experiences, barriers and facilitators to engaging with the COVID-19 testing programme.ResultsThis study included 40 sources, including 17 from projects that informed UKHSA’s decisions during the pandemic. Eight themes emerged and were used to categorise barriers and facilitators to engaging with the testing services for healthcare workers, care homes and schools: (1) perceived value, (2) trust in the tests and public bodies, (3) importance of infrastructure, (4) impact of media and social networks, (5) physical burden of the test, (6) perceived capability to undertake testing, (7) importance of relevant information and 8) consequences of testing.ConclusionsUniversal barriers and facilitators to engagement with the testing programme related to the core elements of each testing service, such as uncomfortable specimen collection and the influence of media and peers; these could be mitigated or leveraged to increase engagement across settings. However, the individuals involved, perceptions of value and available resources differed across services, leading to unique experiences between settings. Thus, consideration of context is crucial when designing and implementing a testing programme in response to a pandemic.
Operational evaluation of the deployment of Malaria/CRP Duo and Dengue Duo rapid diagnostic tests for the management of febrile illness by village malaria workers in rural Cambodia
Abstract Introduction The decline in malaria cases in Cambodia has led to a relative increase in non-malarial febrile illness. In rural Cambodia, village malaria workers (VMWs) provide early diagnosis and treatment for malaria, but their role and relevance are diminishing as malaria cases decline. Expanding VMW roles would ensure continued utilisation of their services until malaria elimination is achieved and strengthen community health services. Methods A mixed methods operational research study was implemented to evaluate the use of two combination-RDTs (combo-RDTs) as an expansion of the VMW role, enabling VMWs in Cambodia to test for diseases other than malaria for the first time. VMWs in 78 villages in Battambang and Pailin Provinces were trained and provided with either a Malaria/CRP Duo or Dengue Duo RDT to assess febrile patients. Data were collected on VMW consultations, and combo-RDT usage and results. Focus group discussions (FGDs) and competency assessments of combo-RDT usage were conducted with VMWs. The main objectives were to determine whether VMWs could perform these combo-RDTs correctly and follow management algorithms, and whether deployment had an impact on VMW consultation rates. Perspectives concerning role expansion and the feasibility of conducting additional tests were also explored. Results Between June 2022, and May 2023, a total of 2,425 febrile patients were assessed with either a Malaria/CRP Duo or Dengue Duo RDT. Active dengue infection (NS1- and/or IgM-positive) was identified in 1.2% (11/915) of patients. Positive CRP results (> 20 mg/L) were found for 3.2% (48/1,510) of patients. Following deployment, there was an immediate mean increase of 4.4 VMW consultations per month, from 9.0 to 13.4 (p < 0.01). Competency assessments revealed that some VMWs had difficulty performing the Dengue Duo RDT, particularly in collecting the correct blood volume. This limitation may have led to false-negative dengue NS1 results. VMWs and community members were keen to broaden the skills and responsibilities of VMWs. Conclusions Deploying combo-RDTs to VMWs led to a higher utilization of their services. Difficulties performing some aspects of the Dengue Duo RDT, low positivity rates, and a lack of actionable outcomes within the existing context of VMW services suggest that alternative interventions may be better suited for VMW role expansion at this time. Overall, VMWs and community members were receptive to the expansion of the VMW role for a wider range of diseases other than malaria.
The impact of mass screening and treatment interventions on malaria incidence and prevalence: a retrospective analysis of a malaria elimination programme in eastern Myanmar, and systematic review and meta-analysis
Abstract Background Targeted interventions are often needed to accelerate malaria elimination efforts. Mass screening and treatment (MSAT) involves testing all eligible and consenting individuals in an area for malaria and treating all positive individuals simultaneously. However, there are concerns regarding the impact of MSAT. This study evaluates the impact of MSAT on malaria incidence in Karen State, Myanmar, using routine surveillance data, and investigates the impact of MSAT in other settings through a systematic review and meta-analysis. Methods To investigate the impact of MSAT in Karen State, we retrospectively analysed routine malaria surveillance data collected in 10 villages where MSAT was done in 2018. Pre- and post-MSAT malaria incidences were compared, and a negative binomial mixed-effects model was used to estimate the relative change in monthly incidence for each additional year since MSAT. To investigate the impact of MSAT in other settings, we searched Scopus, Ovid MEDLINE, and Web of Science (end date 11th July 2022) for studies assessing the impact of MSAT interventions on the incidence or prevalence of malaria infections. Studies were summarized, and a random-effects meta-analysis was performed on studies grouped according to study design and the comparator used to assess the impact of MSAT. Results In the 10 villages in Karen State, there was an overall reduction in P. falciparum incidence following MSAT (Incidence Rate Ratio 0.37; 95% CI: 0.19, 0.73). However, this is likely due to the ongoing impact of early diagnosis and treatment services offered in these communities, as shown by an overall reduction in incidence in the surrounding area. Results from nine studies identified in the systematic review demonstrate the variable impact of MSAT, which is likely influenced by a variety of factors, including intervention coverage and uptake, baseline malaria endemicity, and methods used for MSAT delivery. Conclusions This retrospective analysis and systemic review highlights the complexities behind the success of targeted interventions for malaria elimination. While these interventions are important drivers for achieving elimination goals, particularly in high-burden settings, it is important that various factors be considered when determining their suitability and how to optimize implementation.
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.
A phase 1/2a clinical trial to assess safety and immunogenicity of an adenoviral-vectored capsular group B meningococcal vaccine
Capsular group B meningococcus (MenB) remains an important cause of disease globally, and additional vaccines against MenB would aid in reducing the incidence of infection. Previous work has demonstrated that a MenB adenoviral-vectored vaccine, ChAdOx1 MenB.1, elicited high serum bactericidal responses in preclinical models after a single dose, supporting further clinical development of this vaccine. Here, we report the results of a trial designed to assess the safety and immunogenicity of ChAdOx1 MenB.1 in healthy adults aged 18 to 50. In this phase 1/2a, single-center trial, participants received one or two doses of ChAdOx1 MenB.1 at days 0 and 180. One dose of ChAdOx1 MenB.1 was also given at day 180 to some individuals primed with one dose of 4CMenB at day 0. Participants recorded their symptoms in an electronic diary after vaccination, and safety blood readouts were monitored. Serum bactericidal antibody (SBA) assays were performed against a panel of MenB target strains. ChAdOx1 MenB.1 was well tolerated with no safety concerns and elicited protective SBA titers against a MenB strain expressing a homologous factor H–binding protein (fHbp) variant in 100% of participants after two doses. However, cross-reactivity analysis indicated a low SBA response to strains expressing heterologous fHbp, suggesting that a multivalent vaccine may be needed. In sum, ChAdOx1 MenB.1 is immunogenic in humans, and addition of another fHbp variant or of another antigen in this platform could provide an approach to extend protection against endemic MenB disease.