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ALARUM: Active One Health surveillance in LMICs to monitor and predict Antimicrobial Resistance Using Metagenomics - a cross-sectional study protocol

Por: van der Sande · M. A. B. · Valia · D. · Tigoi · C. · Stoesser · N. · Stamm · L. · Marten · A. · Riems · B. · Musyimi · R. · Sibidou · Y. · Schurch · A. C. · Tiendrebeogo · E. W. · Mwaringa · S. · Kohns Vasconcelos · M. · Ingelbeen · B. · Tinto · H. · Bielicki · J. A. · Cooper · B. S. · B
Background

In rural sub-Saharan Africa (sSA), the burden of antimicrobial resistance (AMR) remains high. As AMR continues to rise, there is a strong need for practical, implementable surveillance to monitor and mitigate risks, as well as inform timely, evidence-based clinical decision-making. Emerging evidence points to possible community-level drivers, such as transmission between human, animal and environmental reservoirs as contributing factors, yet microbiological surveillance or opportunities for wastewater-based surveillance are often limited and insufficient in these settings. Therefore, alternative sustainable and affordable approaches are needed. We intend to build on the demonstrated potential of metagenomic profiling of pooled faecal material, which accurately predicted population-level AMR prevalence in invasive Enterobacterales infections.

Methods and analysis

We aim to validate this metagenomic pooled approach on additional populations, and to evaluate whether AMR patterns could be similarly predicted from surveillance of community One Health reservoirs. We will assemble existing data from hospital-based microbiology diagnostic laboratories in rural Burkina Faso and Kenya, and determine to what extent community-level metagenomic data, and/or faecal material of patients on hospital admission, can predict AMR in clinical isolates. We will perform community-level surveys in eight clusters per country, randomly selecting 15 households per cluster. We will systematically sample suspected environmental AMR exposure sites in and around households (soil, drinking water, latrines, chicken faeces) and collect data on community-level antibiotic use, hygiene practices, contact with domestic animals and sanitary facilities. Samples and data will be collected twice: during the dry and during the rainy season.

In addition to evaluating the accuracy of predicting resistance in clinical isolates, we will quantify community-level exposure risks. We will conduct metagenomic profiling on pooled DNA extracts from human stool samples (hospital and community-level) and from household environments. Bayesian statistical models will quantify relationships between AMR gene abundance in the environment and in human stool, and invasive bacteria identified among clinical patients, accounting for geography and seasonality. A cost-utility analysis will determine under what circumstances the use of pooled metagenomic data to inform empirical antibiotic policies would represent an efficient use of resources.

Ethics and dissemination

The proposed surveillance protocol is developed in partnership with local communities and local and international researchers and has received ethical approval in Kenya and Burkina Faso. It will assess whether intermittent, pooled-sample metagenomics provides a viable, low-cost and practical approach for population-level AMR surveillance in settings that—like many in rural sSA—lack systematic microbiological diagnostics and where sewage systems for wastewater-based surveillance are absent. By providing an alternative to routine microbiological-based surveillance where this proves challenging to implement, this approach may help improve treatment outcomes, contribute to equity and public health. Findings will be disseminated through peer-reviewed publications and academic conferences and will contribute to the recently proposed WHO AMR surveillance strategy, which combines survey-based approaches with routine AMR surveillance.

Dupilumab attenuates the expression of TSLP and IL-8 induced by dsRNA and IL-4/IL-13 co-stimulation in human small airway epithelial cells

by Aditya Sri Listyoko, Ryota Okazaki, Tomoya Harada, Genki Inui, Hiroki Kohno, Miyu Nishigami, Miki Takata, Masato Morita, Akira Yamasaki

Background

The interaction between viral components and type 1 or type 2 cytokines during asthma exacerbations in the airway epithelium may contribute to worsening inflammation. However, these interactions in the small airway epithelium—particularly those involving alarmins (TSLP, IL-25, and IL-33) and IL-8—remain unclear. Dupilumab, a biologic agent used in severe asthma, blocks IL-4 receptor alpha (IL-4Rα) and may offer therapeutic benefits in virus-induced asthma exacerbations. In this study, we evaluate the effects of double-stranded RNA (dsRNA), in combination with various cytokines and dupilumab, on the Human Small Airway Epithelial Cells (HSAECs) line.

Methods

Primary HSAECs were preincubated with dsRNA to induce the gene and protein expression of alarmins and IL-8. To evaluate the effects of cytokines on dsRNA-induced alarmin and IL-8 expression, various type 1 and type 2 cytokines were co-stimulated with dsRNA. Dupilumab was used as a pretreatment prior to co-stimulation with dsRNA and IL-4 or IL-13. Gene expression of TSLP, IL-25, IL-33, and IL-8 was assessed by quantitative PCR, and protein expression was evaluated by Western Blotting.

Results

dsRNA significantly increased the expression of TSLP and IL-8. IL-4 and IL-13 further enhanced dsRNA-induced TSLP and IL-8 gene and protein expression. In contrast, TNF-α reduced dsRNA-induced TSLP expression but enhanced IL-8 gene and protein expression. Dupilumab attenuated the expression of TSLP and IL-8 induced by co-stimulation with dsRNA and IL-4 or IL-13 in HSAECs.

Conclusion

In the microenvironment of small airway epithelial cells, particularly during viral infections, the presence of IL-4 or IL-13 may enhance the expression of TSLP and IL-8. Dupilumab attenuates this expression, potentially offering additional benefits in the treatment of asthma, especially during virus-induced asthma exacerbations.

Optimising Paediatric Transition to Intensive Care for Adults (OPTICAL): study protocol for a mixed method study

Por: Huang · Q. · Kohn · C. · Abraham · S. B. · Malbon · K. · Mallick · A. · Mouncey · P. R. · Oulton · K. · Pagel · C. · Rose · L. · Seaton · S. E. · Taylor · J. · Thomas · R. · Windsor · C. · Wray · J. · Ramnarayan · P. · Crowe · S.
Introduction

An increasing number of teenagers and young adults (TYA) with chronic conditions and complex needs are transitioning from paediatric to adult services, including admission to intensive care units (ICUs). As these services are often ill-equipped to care for TYA, there is a risk of compromised care. Despite recent guidelines from the UK Paediatric Critical Care and Intensive Care Societies highlighting the importance and urgency of improving ICU transition, current recommendations are not evidence-based and established pathways for ICU transition remain limited.

Methods and analysis

This mixed-methods research study aims to generate evidence to underpin national policy on transition from paediatric to adult ICUs that will improve clinical care and patient experience. To do this, we will: (1) link and analyse UK national data (years 2017–2024) on paediatric and adult ICU admissions, hospital inpatient, outpatient and emergency care visits and survival status, to determine the clinical characteristics and healthcare resource utilisation from teenage years to early adulthood of people admitted to an ICU as a young person (admission aged 14 and 15), and how these relate to ICU admissions after age 16; (2) conduct semistructured interviews, online forums and surveys with TYA patients, carers and health professionals to understand their experience of transition in ICU services; and (3) synthesise these strands of evidence and use a structured process of stakeholder engagement to propose potential targeted improvements as appropriate.

Ethics and dissemination

This study was approved by the East of England - Cambridge South Research Ethics Committee on 1 August 2024 (research ethics committee number 24/EE/0108), and the Health Research Authority Confidentiality Advisory Group (CAG) on 7 October 2024 (CAG number 24/CAG/0068). Study results will be actively disseminated through peer-reviewed journals, conference presentations and accessible lay texts and graphic summaries for the use of charities and patients including those with learning disabilities and neurodevelopmental disorders.

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