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The foundational basis for the pneumonia etiology results from the PERCH (Pneumonia Etiology Research for Child Health) project have been published in a 23-paper supplement in Clinical Infectious Diseases. The publication details the context, methods, and preparatory results that will inform the final pneumonia etiology estimates, expected to be available in late 2017.
Adolescent hope and optimism: A scoping review of measures and their psychometric properties.
There is much research examining adolescent hope and optimism, but there is limited information on the available measures, particularly the most frequently used measures and their psychometric properties. We conducted a scoping review to: (1) identify measures of hope and optimism for use among adolescents; (2) determine the most frequently used measures of adolescent hope and optimism; (3) document the psychometric properties of the identified measures. We searched five bibliographic databases and Open Grey for relevant articles published from database inception to 03 May 2023. The search included the key terms 'adolescents', 'optimism', 'hope' and 'measures'. We targeted adolescents aged 10-19 years without country or gender restrictions. We identified 86 measures of optimism and 64 measures of hope for use among adolescents from 803 eligible studies. Most of the included studies (n = 341, 42.5%) originated from North America. We identified 22 most frequently used measures used across 603 (75.1%) of the included studies, with 509 (84.4%) of them providing their psychometric properties. The reported validity of the tools included face, content, construct, criterion, convergent, discriminant, predictive validity and measurement invariance. There are several measures of adolescent hope and optimism. The most frequently used measures of these constructs demonstrated sound psychometric properties, especially reliability. However, most of the evidence originates from high-income countries. There is a need for development, cross-cultural adaptation and validation of these tools to other settings.ContributionHope and optimism are character strengths that have been consistently linked to positive health outcomes in adolescents. Based on increasing research on adolescent hope and optimism, there have been measures developed to assess these constructs but there is no study summarising the available measures, particularly regarding the most frequently used measures and their reliability and validity across contexts. This study aimed at filling this gap. Information on this will be useful to various stakeholders to make evidence-informed choice on selection of the most relevant instrument for use in adolescents in their contexts.
Acceptability and feasibility of glucose-6-phosphate dehydrogenase (G6PD) testing using SD Biosensor by village malaria workers in Cambodia: a qualitative study.
INTRODUCTION: Plasmodium vivax is the predominant cause of malaria in the Greater Mekong Subregion. To ensure safe treatment with primaquine, point-of-care glucose-6-phosphate dehydrogenase (G6PD) testing was rolled out in Cambodia at the health facility level, although most malaria patients are diagnosed in the community. The current study aims to explore the acceptability and feasibility of implementing community-level G6PD testing in Cambodia. METHODS: Semistructured interviews and focus group discussions (FGD) were conducted. Across eight study sites in three provinces, 142 respondents, including policymakers, programme officers, healthcare providers and patients, participated in 67 interviews and 19 FGDs in 2022 and 2023. Data were analysed thematically using an adapted framework derived from Bowen et al's feasibility framework and Sekhon et al's acceptability framework. RESULTS: All stakeholders attributed value to the intervention. Acknowledging an intervention's different values can help discern policy implications for an intervention's successful implementation. Building and maintaining confidence in the device, end users, infrastructure and health systems were found to be key elements of acceptability. In general, health centre workers and village malaria workers (VMWs) had confidence that VMWs could conduct the test and administer treatment given appropriate initial training, monthly refresher training and the test's repeated use. More is required to build policymakers' confidence, while some implementation challenges, including the test's regulatory approval, stability above 30°C and cost, need to be overcome. CONCLUSION: Implementation of G6PD testing at the community level in Cambodia is an acceptable and potentially feasible option but requires addressing implementation challenges and building and maintaining confidence among stakeholders.
Handheld spatially offset raman spectroscopy for rapid non-invasive detection of ethylene glycol and diethylene glycol in medicinal syrups
We investigate the potential of Spatially Offset Raman Spectroscopy (SORS) as a rapid, non-invasive screening tool deployable in the field to detect diethylene glycol (DEG) and ethylene glycol (EG) in medicinal syrups within closed containers. Measurements were performed on neat propylene glycol (PG) and glycerol, key components of many medicinal syrups, as well as marketed medicinal syrup formulations spiked with DEG and EG at various concentration levels to assess the technique’s limit of detection in real-life samples. SORS was able to detect these down to ~0.5% concentration level in neat PG for both DEG and EG compounds and ~1% concentration level for DEG and EG in neat glycerol. The DEG and EG detection thresholds for the marketed formulations measured through original bottles was ~1%, for Benylin (active ingredient: Glycerol) and Piriteze (active ingredient: Cetirizine Hydrochloride). For Calpol (active ingredient: Paracetamol) the detection limit was higher, ~2% for EG and ~5% for DEG. Although not reaching the International Pharmacopeial 0.1% detection threshold currently required for purity checks for human consumption, the method can still be used to detect products where DEG or EG has been wrongly used instead of PG or glycerol or if present in large quantities. The technique could also be used for raw material identification testing to ensure no mislabelling has occurred in pre-production stages and as a screening device in distribution chains to detect major deviations from permitted content in non-diffusely scattering, clear formulations, to help prevent serious adverse outcomes, such as acute renal failure and deaths.
Unveiling sub-populations in critical care settings: a real-world data approach in COVID-19.
BackgroundDisease presentation and progression can vary greatly in heterogeneous diseases, such as COVID-19, with variability in patient outcomes, even within the hospital setting. This variability underscores the need for tailored treatment approaches based on distinct clinical subgroups.ObjectivesThis study aimed to identify COVID-19 patient subgroups with unique clinical characteristics using real-world data (RWD) from electronic health records (EHRs) to inform individualized treatment plans.Materials and methodsA Factor Analysis of Mixed Data (FAMD)-based agglomerative hierarchical clustering approach was employed to analyze the real-world data, enabling the identification of distinct patient subgroups. Statistical tests evaluated cluster differences, and machine learning models classified the identified subgroups.ResultsThree clusters of COVID-19 in patients with unique clinical characteristics were identified. The analysis revealed significant differences in hospital stay durations and survival rates among the clusters, with more severe clinical features correlating with worse prognoses and machine learning classifiers achieving high accuracy in subgroup identification.ConclusionBy leveraging RWD and advanced clustering techniques, the study provides insights into the heterogeneity of COVID-19 presentations. The findings support the development of classification models that can inform more individualized and effective treatment plans, improving patient outcomes in the future.
Transforming health in Nepal: a historical and contemporary review on disease burden, health system challenges, and innovations.
IntroductionNepal witnessed a tumultuous journey over past two centuries, marked by significant political, social, and cultural shifts. From fighting British colonial encroachments in 1800s, the dynastic Rana regime (1846-1951), and democracy movements in the late 1950s, 1990s and 2000s, Nepal became a federal republic in 2008. The main objective of this review is to lay out an interpretative summary on Nepal's epidemiological transition (includes general trends and disease specific topics) followed by discussion on health system development over key periods: historical period (-1950s), modern period (1950-1990), post-democracy (1991-2016), and post-federalization (2016-).MethodsWe conducted a scoping review of available literature using the Arksey and O'Malley framework to synthesize the key insights. Searches were performed in PubMed (via NLM), Embase and Google Scholar using a combination of search terms related to Nepal's health system, epidemiological transition, disease burden and emerging health issues. A total of 1204 records were identified, of which 123 documents - including peer-reviewed articles, government reports and grey literature - met the inclusion criteria.ResultsMajor advances in maternal and child health, nutritional health and reduction of infectious diseases have been observed in recent decades. The maternal mortality ratio (MMR) declined by 55% (1996-2016), and neonatal mortality halved (40 to 20 per 1000 live births) due to improved antenatal care, skilled birth attendance and family planning. Stunting rates fell from 66% (1996) to 25% (2022), yet rising non-communicable diseases (NCDs) pose new challenges. Communicable diseases, once dominant, have declined owing to expanded immunization and tuberculosis control. However, NCDs now account for over two thirds of deaths, driven by urbanization, ageing and lifestyle shifts. Health system gaps persist, with workforce shortages, rural-urban disparities and out-of-pocket health costs limiting access. Addressing rising health inequities, digital health innovations and service expansion is critical to achieving universal health coverage and sustaining Nepal's health gains.ConclusionsNepal's health care landscape has continuously evolved over the past centuries, coinciding with key demographic and political changes. Advances through innovation are necessary for the country's overstretched health system to reduce the cost of health services whilst increasing quality and access.
Factors affecting integration of an early warning system for antimalarial drug resistance within a routine surveillance system in a pre-elimination setting in Sub-Saharan Africa.
To address the current threat of antimalarial resistance, countries need innovative solutions for timely and informed decision-making. Integrating molecular surveillance for drug-resistant malaria into routine malaria surveillance in pre-elimination contexts offers a potential early warning mechanism for further investigation and response. However, there is limited evidence on what influences the performance of such a system in resource-limited settings. From March 2018 to February 2020, a sequential mixed-methods study was conducted in primary healthcare facilities in a South African pre-elimination setting to explore factors influencing the flow, quality and linkage of malaria case notification and molecular resistance marker data. Using a process-oriented framework, we undertook monthly and quarterly data linkage and consistency analyses at different levels of the health system, as well as a survey, focus group discussions and interviews to identify potential barriers to, and enhancers of, the roll-out and uptake of this integrated information system. Over two years, 4,787 confirmed malaria cases were notified from 42 primary healthcare facilities in the Nkomazi sub-district, Mpumalanga, South Africa. Of the notified cases, 78.5% (n = 3,758) were investigated, and 55.1% (n = 2,636) were successfully linked to their Plasmodium falciparum molecular resistance marker profiles. Five tangible processes-malaria case detection and notification, sample collection, case investigation, analysis and reporting-were identified within the process-oriented logic model. Workload, training, ease of use, supervision, leadership, and resources were recognized as cross-cutting influencers affecting the program's performance. Approaching malaria elimination, linking molecular markers of antimalarial resistance to routine malaria surveillance is feasible. However, cross-cutting barriers inherent in the healthcare system can influence its success in a resource-limited setting.
Antiepileptic properties of quinine: a systematic review
Background: Quinine has anti-epileptic properties in animals. However, in humans this has not been systematically investigated. Purpose: To examine the available research evidence on the effects of quinine on seizures in adults or children. Methods: We searched online databases for published and unpublished studies in any language from January 1966 to March 2011. We considered randomized controlled trials (RCTs) evaluating the use of quinine in comparison to other drugs in humans with malaria or other conditions, and that reported the prevalence of seizures. Random effects meta-analysis was used to pool effect estimates in order to determine the effect of quinine on the prevalence of seizures. Results: We identified six randomized controlled trials on severe malaria. Quinine was compared to the artemisinin derivatives in all trials. A total of 8,244 patients were included. In the meta-analysis, there was no significant effect of quinine on the prevalence of seizures when compared to the artemisinin derivatives (Odds ratio (OR) =0.90, 95% Confidence Interval (95%CI) =0.63-1.30). There was significant heterogeneity (I2=66%, Chi-square=17.44, p=0.008). Subgroup analysis showed that quinine significantly reduced seizures when compared to artemether (OR = 0.66, 95%CI = 0.49-0.88) but when compared to artesunate, prevalence of seizures increased significantly (OR = 1.24, 95%CI = 1.05-1.47). Conclusion: There is no sufficient evidence to conclude that quinine has any antiepileptic properties in humans.
Roles of medical, nursing and clinical specialists in selected African health systems: a document review of numbers, norms, training and scope of practices
Background Specialist health professionals are essential for meeting the evolving health needs of Sub-Saharan Africa (SSA), especially as the burden of complex and chronic conditions rises. They contribute not only to patient care but also to teaching, research, and policy development. However, there is a significant shortfall and uneven distribution of specialists across the region, creating major challenges for health systems. This paper examines the roles, numbers, training pathways, and scope of practice of medical, nursing, and clinical specialists in four SSA countries, with the aim of informing more effective workforce planning. Methods Between September 2023 and July 2024, we conducted a document review of policies and guidelines related to specialist health professionals in Kenya, Uganda, Nigeria, and South Africa. Sources included ministries of health, regulatory bodies, academic institutions, and professional associations. We focused on the composition of the specialist workforce, training pathways, and defined roles across different health cadres. Results There is marked variation in specialist workforce composition between countries. South Africa and Kenya reported the highest numbers of medical specialists, while nursing and clinical officer specialists were more common in Kenya and Uganda. Training pathways ranged from university-based master’s programmes to national or regional fellowship systems. However, many curricula lacked essential non-clinical competencies - such as leadership, management, and communication skills - limiting specialists’ effectiveness in broader health system roles. Conclusion Strengthening the specialist workforce in SSA requires better alignment between training and health system needs. This includes integrating non-clinical competencies into curricula, enhancing data systems for workforce planning, and addressing gaps in distribution and capacity. Policy reforms and strong leadership are critical to building a sustainable, well-equipped specialist workforce to meet the region’s growing healthcare challenges.
Using routinely collected data to inform infection-prevention policy decisions
Measures to reduce transmission are a vital response to infectious disease epidemics. Collectively such measures are effective in reducing the burden of infectious disease but effectiveness of individual interventions is less certain. Methodologies for causal inference from observational data are well developed, but many methods have requirements that are not met by epidemic data. They may require an individual's outcome to be independent of anyone else's treatment, but the very purpose of infection-prevention measures is to break chains of transmission, benefiting both treated and untreated individuals. I combine causal inference methods, mechanistic models, and observational data to estimate effects of interventions that were used to reduce the spread of severe acute respiratory syndrome coronavirus 2 in the United Kingdom. I combine difference-in-differences methodology with a renewal-equation model. If its assumptions are met, this can detect effects of interventions on transmissibility, but if assumptions are violated, erroneous results can arise with no indication that an error is occurring. I apply the method to mass testing and mandatory use of face masks. Difference-in-differences results suggest that interventions increased incidence of detected infections. I investigate optimal timing of vaccination against respiratory viral infections with models incorporating immune boosting from re-exposure to the virus. Boosting can lead to synchrony in susceptibility and cause periodic outbreaks even without seasonal variation in infectiousness. In scenarios with more immune boosting, vaccinating sooner tends to lead to fewer infections, while in scenarios with less boosting, later vaccination is beneficial. Analyses in this thesis highlight potential problems with causal analyses that disregard mechanisms of disease transmission, and with models that oversimplify immunity. These analyses suggest that greater understanding of changing immunity over time is necessary to determine optimal approaches to reducing transmission of these respiratory viral infections.
Pneumococcal density and respiratory co-detection in severe pediatric pneumonia in Laos.
There is growing evidence on the importance of bacterial/viral interaction in the course of pneumonia. In Laos, no study has investigated respiratory pathogen co-detection. We conducted a study at Mahosot Hospital in Vientiane to determine whether bacterial/viral co-detection and pneumococcal density are associated with severe pneumonia. Between December 2013 and December 2016, 934 under 5 years old hospitalized children with ARI were enrolled. Swabs from the upper respiratory tract were collected and analyzed by real-time PCR. The most common co-detected microorganisms were Streptococcus pneumoniae/Haemophilus influenzae (24%), Respiratory Syncytial Virus (RSV)/S. pneumoniae (12%) and RSV/H. influenzae (16%). Pneumococcal density was 4.52 times higher in influenza virus positive participants. RSV/S. pneumoniae and RSV/H. influenzae co-detections were positively associated with severe pneumonia in univariate analysis (OR 1.86, 95%CI:1.22-2.81, p = 0.003 and OR 2.09, 95%CI:1.46-3.00), but not confirmed in adjusted analysis (aOR 0.72, 95%CI:0.38-1.6, p = 0.309 and aOR 1.37, 95%CI:0.73-2.58). In RSV positive patients, there was no association between pneumococcal density and severe pneumonia. Our findings confirmed an association between pneumococcal density and influenza but not RSV severe pneumonia in young children. Results highlight the complexity of the interaction of viral/bacterial pathogens, which might not have a simple synergistic action in the evolution of pneumonia.
Global Immune Biomarkers and Donor Serostatus Can Predict Cytomegalovirus Infection Within Seropositive Lung Transplant Recipients.
BACKGROUND: Predicting which lung transplant recipients (LTR) will develop cytomegalovirus (CMV) infection remains challenging. The aim of this retrospective cohort study was to further explore the predictive utility of global immune biomarkers within recipient seropositive (R+) LTRs, focusing on the mitogen component of the QuantiFERON (QF)-CMV assay and the absolute lymphocyte count (ALC). METHODS: R+ LTR with QF-CMV testing performed at 5 mo posttransplant were included. ALC and mitogen were evaluated as predictors of CMV infection (>150 IU/mL) in plasma and/or bronchoalveolar lavage fluid using Cox regression, controlling for antiviral prophylaxis. Optimal cutoffs were calculated with receiver-operating characteristic curves. RESULTS: CMV infection occurred in 111 of 204 patients (54%) and was associated with donor seropositivity (80/111 [72%] versus 42/93 [45%], P
Impact of Late HIV Diagnosis on Costs of Care in a Public Health Care Setting.
Despite increased HIV testing and access to treatment in Australia, presentations with advanced disease occur, placing a significant burden on the health system. We sought to describe costs associated with HIV care in the first year post diagnosis in a specialized, tertiary-level HIV service and identify factors predicting increased health care costs. People newly diagnosed with HIV from 2016 to 2020 were included in the study. Data were gathered regarding their demographics (age, gender, birthplace, and first language), HIV parameters (viral load [VL] and CD4 cell count), antiretroviral therapy start date, opportunistic illness history, and health care costs (inpatient, outpatient, and emergency) from 12 months of diagnosis. Multivariable modeling was used to identify factors associated with increased costs. We identified 147 people; median age 38 years, 90% male, median CD4 count at diagnosis 338 cells/µL with median initial cost of care AUD $22,929 (interquartile range $11,902-$39,175). Costs associated with advanced HIV diagnosis (CD4 < 200 cells/µL; n = 52) were more than double an early HIV diagnosis (CD4 ≧ 350 cells/µL; n = 69) (median $46,406 vs. $20,274; p < .001). In univariate analysis, older age, higher VL, low CD4 count, and VL >200 copies/mL after 6 months were associated with increased costs. In multivariate analysis, older age (p = .001) and CD4 count <200 cells/µL (p = .001) were the only factors predicting increased cost in the first year after HIV diagnosis. Prioritizing HIV testing strategies to allow earlier diagnosis of HIV would significantly reduce the financial burden of HIV care.
Injecting drug use is a risk factor for methicillin resistance in patients with Staphylococcus aureus bloodstream infections.
We investigated whether injecting drug use was a risk factor for methicillin resistance among inpatients with Staphylococcus aureus bloodstream infections (SABSIs) at an Australian health service. In 273 inpatients, 46 (16.9%) of SABSIs were methicillin-resistant S. aureus (MRSA). MRSA was more frequent in those who had injected drugs in the past 6 months (20.6%) compared with other inpatients (15.7%). Injecting drug use was associated with a 4.82-fold (95% confidence interval = 1.54-16.29) increased odds of MRSA after accounting for confounders.
Study protocol for ADAPT-TDM: A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring.
IntroductionCritically ill patients are at risk of suboptimal beta-lactam antibiotic (beta-lactam) exposure due to the impact of altered physiology on pharmacokinetics. Suboptimal concentrations can lead to treatment failure or toxicity. Therapeutic drug monitoring (TDM) involves adjusting doses based on measured plasma concentrations and individualising dosing to improve the likelihood of improving exposure. Despite its potential benefits, its adoption has been slow, and data on implementation, dose adaptation and safety are sparse. The aim of this trial is to assess the feasibility and fidelity of implementing beta-lactam TDM-guided dosing in the intensive care unit setting.Methods and analysisA beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring (ADAPT-TDM) is a single-centre, unblinded, feasibility randomised controlled trial aiming to enroll up to 60 critically ill adult participants (≥18 years). TDM and dose adjustment will be performed daily in the intervention group; the standard of care group will undergo plasma sampling, but no dose adjustment. The main outcomes include: (1) feasibility of recruitment, defined as the number of participants who are recruited from a pool of eligible participants, and (2) fidelity of TDM, defined as the degree to which TDM as a test is delivered as intended, from accurate sample collection, sample processing to result availability. Secondary outcomes include target attainment, uptake of TDM-guided dosing and incidence of neurotoxicity, hepatotoxicity and nephrotoxicity.Ethics and disseminationThis study has been approved by the Alfred Hospital human research ethics committee, Office of Ethics and Research Governance (reference: Project No. 565/22; date of approval: 22/11/2022). Prospective consent will be obtained and the study will be conducted in accordance with the Declaration of Helsinki. The finalised manuscript, including aggregate data, will be submitted for publication in a peer reviewed journal. ADAPT-TDM will determine whether beta-lactam TDM-guided dose adaptation is reproducible and feasible and provide important information required to implement this intervention in a phase III trial.Trial registration numberAustralian New Zealand Clinical Trials Registry, ACTRN12623000032651.
Pilot study to evaluate the need and implementation of a multifaceted nurse-led antimicrobial stewardship intervention in residential aged care.
ObjectivesTo evaluate the need and feasibility of a nurse-led antimicrobial stewardship (AMS) programme in two Australian residential aged care homes (RACHs) to inform a stepped-wedged, cluster randomized controlled trial (SW-cRCT).MethodsA mixed-methods pilot study of a nurse-led AMS programme was performed in two RACHs in Victoria, Australia (July-December 2019). The AMS programme comprised education, infection assessment and management guidelines, and documentation to support appropriate antimicrobial use in urinary, lower respiratory and skin/soft tissue infections. The programme was implemented over three phases: (i) pre-implementation education and integration (1 month); (ii) implementation of the intervention (3 months); and (iii) post-intervention evaluation (1 month). Baseline RACH and resident data and weekly infection and antimicrobial usage were collected and analysed descriptively to evaluate the need for AMS strategies. Feedback on intervention resources and implementation barriers were identified from semi-structured interviews, an online staff questionnaire and researcher field notes.ResultsSix key barriers to implementation of the intervention were identified and used to refine the intervention: aged care staffing and capacity; access to education; resistance to practice change; role of staff in AMS; leadership and ownership of the intervention at the RACH and organization level; and family expectations. A total of 61 antimicrobials were prescribed for 40 residents over the 3 month intervention. Overall, 48% of antibiotics did not meet minimum criteria for appropriate initiation (respiratory: 73%; urinary: 54%; skin/soft tissue: 0%).ConclusionsSeveral barriers and opportunities to improve implementation of AMS in RACHs were identified. Findings were used to inform a revised intervention to be evaluated in a larger SW-cRCT.
Tocilizumab, sarilumab and anakinra in critically ill patients with COVID-19: a randomised, controlled, open-label, adaptive platform trial.
IntroductionTocilizumab improves outcomes in critically ill patients with COVID-19. Whether other immune-modulator strategies are equally effective or better is unknown.MethodsWe investigated treatment with tocilizumab, sarilumab, anakinra and no immune modulator in these patients. In this ongoing, adaptive platform trial in 133 sites in 9 countries, we randomly assigned patients with allocation ratios dependent on the number of interventions available at each site. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21 in survivors. The trial used a Bayesian statistical model with predefined triggers for superiority, inferiority, efficacy, equivalence or futility.ResultsOf 2274 critically ill participants enrolled between 25 March 2020 and 10 April 2021, 972 were assigned to tocilizumab, 485 to sarilumab, 378 to anakinra and 418 to control. Median organ support-free days were 7 (IQR -1, 16), 9 (IQR -1, 17), 0 (IQR -1, 15) and 0 (IQR -1, 15) for tocilizumab, sarilumab, anakinra and control, respectively. Median adjusted ORs were 1.46 (95% credible intervals (CrI) 1.13, 1.87), 1.50 (95% CrI 1.13, 2.00) and 0.99 (95% CrI 0.74, 1.35) for tocilizumab, sarilumab and anakinra relative to control, yielding 99.8%, 99.8% and 46.6% posterior probabilities of superiority, respectively, compared with control. All treatments appeared safe.ConclusionsIn critically ill patients with COVID-19, tocilizumab and sarilumab have equivalent effectiveness at reducing duration of organ support and death. Anakinra is not effective in this population.Trial registration numberNCT02735707.