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Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure: A Validation Cohort of the EMPEROR Program.
Get PDFBACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a distinctive pattern of direct biological effects on the heart and kidney under experimental conditions, but the meaningfulness of these signatures for patients with heart failure has not been fully defined.
OBJECTIVES: We performed the first mechanistic validation study of large-scale proteomics in a double-blind randomized trial of any treatment in patients with heart failure.
METHODS: In a discovery cohort from the EMPEROR (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction) program, we studied the effect of randomized treatment with placebo or empagliflozin on 1,283 circulating proteins in 1,134 patients with heart failure with a reduced or preserved ejection fraction. In a validation cohort, we expanded the number to 2,155 assessed proteins, which were measured in 1,120 EMPEROR participants who had not been studied previously.
RESULTS: In the validation cohort, 25 proteins were the most differentially enriched by empagliflozin (ie, ≥15% between-group difference and false discovery rate 1 domain. These biological signatures replicated those observed in our discovery cohort. When the threshold for a meaningful between-group difference was lowered to ≥10%, there were 58 additional differentially enriched proteins with actions on the heart and kidney, but the biological signatures remained the same.
CONCLUSIONS: The replication of mechanistic signatures across discovery and validation cohorts closely aligns with the experimental effects of SGLT2 inhibitors. Thus, the actions of SGLT2 inhibitors-to promote autophagy, restore mitochondrial health and production of ATP, promote iron mobilization and erythropoiesis, influence renal tubular ion reabsorption, and normalize cardiac and renal structure and function-are likely to be relevant to patients with heart failure. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved], NCT03057951; EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced], NCT03057977)
Inference of epidemic dynamics in the COVID-19 era and beyond.
Get PDFThe COVID-19 pandemic demonstrated the key role that epidemiology and modelling play in analysing infectious threats and supporting decision making in real-time. Motivated by the unprecedented volume and breadth of data generated during the pandemic, we review modern opportunities for analysis to address questions that emerge during a major modern epidemic. Following the broad chronology of insights required - from understanding initial dynamics to retrospective evaluation of interventions, we describe the theoretical foundations of each approach and the underlying intuition. Through a series of case studies, we illustrate real life applications, and discuss implications for future work
Estimation of potential social support requirement for tuberculosis patients in India.
Get PDFProviding social support to tuberculosis (TB) patients is a recommended strategy as households having TB patients find themselves in a spiral of poverty because of high cost, huge income loss and several other economic consequences associated with TB treatment. However, there are few examples of social support globally. The Indian government introduced the 'Nikshay Poshan Yojana' scheme in 2018 to provide nutritional support for all registered TB patients. A financial incentive of 500 Indian Rupee (6 United States Dollars) per month was proposed to be transferred directly to the registered beneficiaries' validated bank accounts. We examined the reach, timing, amount of benefit receipt and the extent to which the benefit alleviated catastrophic costs (used as a proxy to measure the impact on permanent economic welfare as catastrophic cost is the level of cost that is likely to result in a permanent negative economic impact on households) by interviewing 1482 adult drug-susceptible TB patients from 16 districts of four states during 2019 to 2023, using the methods recommended by the World Health Organization for estimating household costs of TB nationally. We also estimated the potential amount of social support required to achieve a zero catastrophic cost target. At the end of treatment, 31-54% of study participants received the benefit. In all, 34-60% of TB patients experienced catastrophic costs using different estimation methods and the benefit helped 2% of study participants to remain below the catastrophic cost threshold. A uniform benefit amount of Indian Rupee 10 000 (127 United States Dollars) for 6 months of treatment could reduce the incidence of catastrophic costs by 43%. To improve the economic welfare of TB patients, levels of benefit need to be substantially increased, which will have considerable budgetary impact on the TB programme. Hence, a targeted rather than universal approach may be considered. To maximize impact, at least half of the revised amount should be given immediately after treatment registration
Longitudinal lung function trajectories in response to azithromycin therapy for chronic lung disease in children with HIV infection: a secondary analysis of the BREATHE trial.
Get PDFBACKGROUND: Chronic lung disease (CLD) is common among children with HIV (CWH) including in those taking antiretroviral therapy (ART). Azithromycin has both antimicrobial and anti-inflammatory effects and has been effective in improving lung function in a variety of lung diseases. We investigated lung function trajectories among CWH with CLD on ART enrolled in a randomized controlled trial of adjuvant azithromycin. We also investigated factors that modified the effect of azithromycin on lung function.
METHODS: The study used data from a double-blinded placebo-controlled trial conducted in Malawi and Zimbabwe of 48 weeks on azithromycin (BREATHE: ClinicalTrials.gov NCT02426112) among CWH aged 6 to 19 years taking ART for at least six months who had a forced expiratory volume in one second (FEV1) z-score <-1.0. Participants had a further follow-up period of 24 weeks after intervention cessation. FEV1, forced vital capacity (FVC) and FEV1/FVC were measured at baseline, 24, 48 and 72-weeks and z-scores values calculated. Generalized estimating equations (GEE) models were used to determine the mean effect of azithromycin on lung-function z-scores at each follow-up time point.
RESULTS: Overall, 347 adolescents (51% male, median age 15 years) were randomized to azithromycin or placebo. The median duration on ART was 6.2 (interquartile range: 3.8-8.6) years and 56.2% had an HIV viral load < 1000copies/ml at baseline. At baseline, the mean FEV1 z-score was - 2.0 (0.7) with 44.7% (n = 155) having an FEV1 z-score <-2, and 10.1% had microbiological evidence of azithromycin resistance. In both trial arms, FEV1 and FVC z-scores improved by 24 weeks but appeared to decline thereafter. The adjusted overall mean difference in FEV1 z-score between the azithromycin and placebo arms was 0.004 [-0.08, 0.09] suggesting no azithromycin effect and this was similar for other lung function parameters. There was no evidence of interaction between azithromycin effect and baseline age, lung function, azithromycin resistance or HIV viral load.
CONCLUSION: There was no observed azithromycin effect on lung function z-scores at any time point suggesting no therapeutic effect on lung function.
TRIAL REGISTRATION: ClinicalTrials.gov NCT02426112. First registered on 24/04/2015
Comparison of INTERGROWTH- 21st and Fenton growth standards to assess size at birth and at discharge in preterm infants in the United Arab Emirates.
Get PDFBACKGROUND: Accurate growth assessment of preterm infants is essential in guiding medical care and suitable nutritional interventions. Currently, different growth references are used across hospitals in the United Arab Emirates (UAE). This study aims to compare the INTERGROWTH-21st standards with Fenton growth references regarding birth size classification and at the time of discharge in a sample of preterm infants in the UAE.
METHODS: A retrospective single-center evaluation of medical records of infants born < 37 weeks of gestation was conducted using data from 2018 to 2020. Anthropometric measurements (weight, length, and head circumference) were obtained at birth and at the time of discharge, and then converted to percentiles according to the two reference standards.
RESULTS: A total of 1537 infants with a median birth gestation of 35.3 weeks, and a median birthweight of 2320 g were included. The rates of SGA, AGA, and LGA at birth were 11.5%, 80.42%, and 9.08% using INTERGROWTH-21st growth charts compared to 9.5%, 83.2%, and 7.3% respectively according to Fenton charts. The findings indicated statistically significant differences between the two growth charts classifying of preterm infants based on weight, length, and head circumference (p < 0.05). For every 5 cases assessed as SGA at discharge according to Fenton charts, only 3 were classified as SGA by INTERGROWTH-21st curves.
CONCLUSIONS: Differences exist between the two growth charts with only moderate agreement. Thus, there is a need for harmonizing growth assessment standards. Misclassification of these vulnerable infants would affect their in-hospital and post-discharge nutrition and medical care plan
Challenges to research implementation during public health emergencies: anecdote of insights and lessons learned during the COVID-19 pandemic in Gujarat, India.
Get PDFHealth emergencies, including pandemics, are not new occurrences; some notable ones occurred in the past. However, the scale of the COVID-19 pandemic is unprecedented. The COVID-19 pandemic exposed the unpreparedness of national health systems in effectively managing health emergencies. During the pandemic, controlling the spread of the virus and hopes of exiting into a post-pandemic era were reliant on research to improve patient care and inform government policies. Nonetheless, research implementation during health emergencies can be challenging in low-resourced settings. This paper presents anecdotes of experiences and offers insight into ways research can be supported during health emergencies. We implemented a longitudinal study to investigate the impact of the COVID-19 pandemic, including SARS-CoV-2 infection, during pregnancy on maternal and child health outcomes. The study utilized hospital databases to recruit women who were infected and with no known SARS-CoV-2 infection during pregnancy. Mother-infant pairs in the infected and uninfected group were then followed longitudinally for 3 years. Observations, including challenges during planning, record retrieval, tracking, recruitment, and follow-up of eligible women, were reported by research staff. The challenges observed were group into three overarching themes: (a) individual factors, (b) health system challenges, and (c) research operational challenges. Some notable observations include misinformation, misconception, mistrust, underdeveloped health record systems, stigma, and hesitance. Early planning, effective communication, and community awareness can help in implementing a successful research project. Additionally, efforts to improve collaboration and co-creation between health practitioners, researchers, and the public may benefit the implementation of research projects during a health emergency
Treatment adherence and clinical outcomes amongst in people with drug-susceptible tuberculosis using medication monitor and differentiated care approach compared with standard of care in South Africa: a cluster randomized trial.
Get PDFBACKGROUND: Poor treatment adherence contributes to lower treatment completion and higher loss to follow-up among people with tuberculosis (PWTB). Medication monitors have shown some evidence of improved adherence.
METHODS: We conducted a cluster randomised trial in 18 primary health clinics in South Africa between May 2019-February 2022. Persons (aged ≥ 2 years) with drug-sensitive tuberculosis (DS-TB) were enrolled. All participants were provided with monitors which were silent in the standard of care (SoC) arm. In the intevention arm, weekly adherence reports were reviewed and participants received intensified support as appropriate (text, phone call, home visit, motivational counselling). The primary outcome was adherence, which was calculated as days box was opened (proxy for drug taken)/total expected treatment days as a binary variable (<80% versus ≥80%). Analysis took into account clustered design. The trial was registered with the Pan African Trial Registry PACTR20190268115772.
FINDINGS: We enrolled 2727 participants (38% women, median age 36 (IQR 27-45 years), of whom 2584 had available adherence data. The primary outcome (measured as ≥80% adherence) was higher in intervention versus SoC arm (81.0% versus 50.8%, adjusted risk ratio (ARR) 1.51 (1.36-1.66). Similarly, overall percentage adherence was higher in intervention versus SoC arm (88.5% versus 69.7%, adjusted risk difference 16.8% (13.3%-20.4%)).
INTERPRETATION: People with DS-TB had improved treatment adherence in the intervention arm. We believe the effect on adherence is important and warrants continued use and evaluation of these technologies.
FUNDING: The study is funded by Bill & Melinda Gates Foundation, Uinted States, the Stop TB Partnership, Switzerland, and the South African Medical Research Council, South Africa
Optimal human papillomavirus vaccination strategies in the context of vaccine supply constraints in 100 countries.
Get PDFBACKGROUND: Countries are recommended to immunise adolescent girls routinely with one or two doses of human papillomavirus (HPV) vaccines to eliminate cervical cancer as a public health problem. With most existing vaccine doses absorbed by countries (mostly high-income) with existing HPV vaccination programmes, limited supply has been left for new country introductions until 2022; many of those, low- and middle-income countries with higher mortality. Several vaccination strategies were considered by the Strategic Advisory Group of Experts on Immunization to allow more countries to introduce vaccination despite constrained supplies.
METHODS: We examined the impact of nine strategies for allocating limited vaccine doses to 100 pre-introduction countries from 2020 to 2030. Two algorithms were used to optimise the total number of cancer deaths that can be averted worldwide by a limited number of doses (knapsack and decreasing order of country-specific mortality rates), and an unoptimised algorithm (decreasing order of Human Development Index) were used.
FINDINGS: Routinely vaccinating 14-year-old girls with either one or two doses and switching to a routine 9-year-old programme when supply is no longer constrained could prevent the most cervical cancer deaths, regardless of allocation algorithm. The unoptimised allocation averts fewer deaths because it allocates first to higher-income countries, usually with lower cervical cancer mortality.
INTERPRETATION: To optimise the deaths averted through vaccination when supply is limited, it is important to prioritise high-burden countries and vaccinating older girls first. FUNDING: WHO, Bill & Melinda Gates Foundation
Patient experience of the process to diagnosis of chronic limb-threatening ischaemia: A qualitative study.
Get PDFINTRODUCTION: Delays exist at each stage of the chronic limb-threatening ischaemia (CLTI) care pathway, but there is little known about patient factors influencing delay to diagnosis of CLTI. This study explores the experiences and perceptions of patients recently diagnosed with CLTI.
METHODS: A qualitative interview study was conducted. Sixteen participants underwent semi-structured interviews. Reflexive thematic analysis was performed on the data, aiming to understand factors which can influence delay in the CLTI care pathway.
RESULTS: Five interrelated themes were developed: CLTI is a devastating condition; Reluctance to ask for help; When we are empowered we get better care; Luck plays a role in the process to diagnosis; and Vascular units can do better, comprising sub-themes of information transfer-consider communication and arterial versus non-arterial centres-proximity isn't everything.
CONCLUSIONS: The five themes generated from the interview data describe factors relevant to delay given meaning by participants who have lived experience of CLTI. Theme content should be noted by clinicians, commissioners and providers looking to improve care pathways for patients with CLTI. The importance of awareness for the public, patients and clinicians linked ideas in some themes and interventions to raise awareness should be considered
Monitoring the progress and impact of a multicountry, interdisciplinary research project on childhood stunting: the UKRI GCRF Action Against Stunting Hub MEL protocol.
Get PDFINTRODUCTION: Monitoring, Evaluation and Learning (MEL) is an integral part of research, programme and policy development and implementation. However, MEL methods used to monitor and evaluate interdisciplinary research projects are often informal and under-reported. This article describes the MEL protocol of the UKRI GCRF Action Against Stunting Hub (AASH).
METHODS AND ANALYSIS: The AASH conducts interdisciplinary research into childhood stunting in India, Indonesia and Senegal across 23 distinct work packages. Project-specific MEL framework and methods will be implemented. A logframe will be developed to monitor and evaluate the research activities across the field sites including the number of participants recruited, questionnaires, measurements and procedures completed. MEL dashboards using Tableau and Glasscubes will be used to track and report progress, milestones and outcomes of the project. Dashboard outputs will be reported as numbers and percentages, with additional graphs/charts for easy visualisation. A 'learning' framework will be developed to outline appropriate pipelines for the dissemination of the research findings. This includes a theory of change explicating the overarching ambitions of the project in influencing policy, practice and research, and strategic engagement of relevant stakeholders to evaluate knowledge, attitudes and best practices for impactful engagement and dissemination of the research findings.
ETHICS AND DISSEMINATION: Ethical approval was granted by the Ethics Committee of the London School of Hygiene & Tropical Medicine (17915/RR/17513); National Institute of Nutrition (ICMR)-Ministry of Health and Family Welfare, Government of India (CR/04/I/2021); Health Research Ethics Committee, University of Indonesia and Cipto Mangunkusumo Hospital (KET-887/UN2.F1/ETIK/PPM.00.02/2019); and the National Ethics Committee for Health Research (CNERS), Senegal (Protocole SEN19/78). Findings from this work will be published in peer-reviewed journals, presented in conferences and disseminated to policy makers and research communities