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Antimicrobial usage among acutely ill hospitalised children aged 2‒23 months in sub-Saharan Africa and South Asia
Abstract Background Understanding patterns of antimicrobial use is critical to supporting antibiotic stewardship and limiting antimicrobial resistance (AMR). We aimed to describe antimicrobial prescribing in acutely ill hospitalised children aged 2-23 months across a range of rural and urban hospital settings in sub-Saharan Africa and South Asia. Methods The CHAIN cohort collected data daily throughout hospitalisation from children with acute illness aged 2-23 months admitted to nine hospitals from November 2016 to January 2019. We determined proportions of children receiving antimicrobials, inpatient-days receiving antimicrobials, antimicrobial classes, WHO Access, Watch, and Reserve (AWaRe) classifications, and examined factors associated with Watch antimicrobial use. Results Of 3101 admissions, 1422 (46%) received antimicrobials prior to hospitalization. 2816 (91%) children received antimicrobials during 19398/21807 (93%) inpatient child-days. 2477 (76%), 1092 (35%), and 12 (0.3%) children received Access, Watch, and Reserve antimicrobials, mostly <48 hours from admission. 341 (11%) of admissions received an antimicrobial without any indication. Prior admission, chronic illness, diagnoses of sepsis or meningitis, hypoglycemia and duration of admission were associated with receiving Watch antimicrobials, whilst WHO danger signs, severe malnutrition, HIV and receipt of prior antimicrobials were not, despite their known association with mortality and AMR. Conclusions Antimicrobial use was similar across sites with some overuse, and notably limited escalation and de-escalation, likely due to guideline adherence. Guidelines need updating for the absence of relevant antimicrobial sensitivities, to include risk-based antimicrobial prescribing considering mortality risk and prior exposure to antimicrobials and the hospital environment. Hence, clinical trials of risk-differentiated care are needed.
Dosing interval is a major factor determining the quality of T cells induced by SARS-CoV-2 mRNA and adenoviral vector vaccines
Functional T cell responses are crucial for protective immunity induced by COVID-19 vaccination, but factors influencing the quality of these responses are incompletely understood. We used an activation-induced marker (AIM) assay and single-cell transcriptomic sequencing to analyze SARS-CoV-2 spike-responsive T cells after mild SARS-CoV-2 infection or after one or two doses of mRNA–lipid nanoparticle (mRNA-LNP) or adenoviral-vectored COVID-19 vaccines. Our findings revealed broad functional and clonal heterogeneity in T cells generated by vaccination or infection, including multiple distinct effector populations. T cell function was largely conserved between COVID-19 vaccine platforms but was distinct compared with SARS-CoV-2 infection. Notably, the dosing interval greatly influenced the quality of T cells after two vaccine doses, particularly after mRNA-LNP vaccination, where a longer interval led to reduced inflammatory signaling and increased secondary proliferation. These insights enhance our understanding of SARS-CoV-2–specific T cells and inform the optimization of mRNA vaccination regimens.
MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines
Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes—mucosal-associated invariant T (MAIT) cells and Vδ2 + γδ T cells—which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)–mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell–derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ–licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.
Synovial tissue atlas in juvenile idiopathic arthritis reveals pathogenic niches associated with disease severity
Precision application of targeted therapies is urgently needed to improve long-term clinical outcomes for children affected by inflammatory arthritis, known as juvenile idiopathic arthritis (JIA). Progress has been hampered by our limited understanding of the cellular basis of inflammation in the target tissue of the disease, the synovial membrane. Here, we analyzed biopsies from the inflamed joints of treatment-naïve children with JIA, early in the course of their disease, using single-cell RNA sequencing, multiplexed immunofluorescence, and spatial transcriptomics to establish a cellular atlas of the JIA synovium. We identified distinct spatial tissue niches, composed of specific stromal and immune cell populations. In addition, we localized genes linked to arthritis severity and disease risk to effector cell populations, including tissue resident SPP1 + macrophages and fibrin-associated myeloid cells. Combined analyses of synovial fluid and peripheral blood from matched individuals revealed differences in cellular composition, signaling pathways, and transcriptional programs across these distinct anatomical compartments. Furthermore, our analysis revealed several pathogenic cell populations that are shared with adult-onset inflammatory arthritis, as well as age-associated differences in tissue vascularity, prominence of innate immunity, and enrichment of TGF-β–responsive stromal subsets that up-regulate expression of disease risk–associated genes. Overall, our findings demonstrate the need for age-specific analyses of synovial tissue pathology to guide targeted treatment strategies in JIA.
Proposed framework for triage of putative germline variants detected via tumour genomic testing in UK oncology practice.
In the UK, most patients receive publicly funded medical care through the National Health Service (NHS), which funds tumour and/or germline testing for eligible patients with cancer to inform clinical management.Testing on tumour-derived DNA may identify putative heritable variants, with implications for the proband and their wider family, but is not a reliable substitute for germline genetic testing when hereditary cancer predisposition is suspected.The likelihood that a variant identified through tumour testing is of germline origin depends on multiple clinical and technical factors. Certain genotypes significantly influence a patient's cancer risk, and intervention in those carriers may facilitate cancer prevention or early detection, while other genotypes are associated with lower cancer risk, and associated intervention in such cases have limited clinical utility.We convened a national meeting of clinical cancer genetics and scientific leads to rationalise germline follow-up testing of variants identified through tumour-based testing. After contrasting potential approaches, implementation of an NHS-contextualised 'intermediate conservative' approach was agreed and refined by the authors, with the final pathway recirculated to the UK clinical and scientific community for consensus agreement and publication.We outline relevant patient, genetic and technical considerations informing likely origin of variants, a review of current relevant guidance and NHS laboratory practices and a workflow for laboratory and clinical teams to triage tumour-detected variants requiring onward germline follow-up. This approach aims to direct limited resources towards identifying germline variants associated with the greatest potential clinical impact, with a view to supporting more efficient and equitable delivery of genomic medicine in oncology.
Estimates of HIV-1 within-host recombination rates across the whole genome.
Recombination plays a pivotal role in generating within-host diversity and enabling HIV's evolutionary success, particularly in evading the host immune response. Despite this, the variability in recombination rates across different settings and the underlying factors that drive these differences remain poorly understood. In this study, we analysed a large dataset encompassing hundreds of untreated, longitudinally sampled infections using both whole-genome long-read and short-read sequencing datasets. By quantifying recombination rates, we uncover substantial variation across subtypes, viral loads, and stages of infection. We also map recombination hot and cold spots across the genome using a sliding window approach, finding that previously reported inter-subtype regions of high or low recombination are replicated at the within-host level. Importantly, our findings reveal the significant influence of selection on recombination, showing that the presence and success of recombinant genomes is strongly interconnected with the fitness landscape. These results offer valuable insights into the contribution of recombination to evolutionary dynamics and demonstrate the enhanced resolution that long-read sequencing offers for studying viral evolution.
Comparative performance of the InBios SCoV-2 Detect TM IgG ELISA and the in-house KWTRP ELISA in detecting SARS-CoV-2 spike IgG antibodies in Kenyan populations.
The InBios SCoV-2 Detect™ IgG ELISA (InBios) and the in-house KWTRP ELISA (KWTRP) have both been used in the estimation of SARS-CoV-2 seroprevalence in Kenya. Whereas the latter has been validated extensively using local samples, the former has not. Such validation is important for informing the comparability of data across the sites and populations where seroprevalence has been reported. We compared the assays directly using pre-pandemic serum/plasma collected in 2018 from 454 blood donors and 173 malaria cross-sectional survey participants, designated gold standard negatives. As gold standard SARS-CoV-2 positive samples: we assayed serum/plasma from 159 SARS-CoV-2 PCR-positive patients and 166 vaccination-confirmed participants. The overall agreement on correctly classified samples was >0.87 for both assays. The overall specificity was 0.89 (95% CI, 0.87-0.91) for InBios and 0.99 (95% CI, 0.97-0.99) for KWTRP among the gold standard negative samples while the overall sensitivity was 0.97 (95% CI, 0.94-0.98) and 0.93 (95% CI, 0.90- 0.95) for InBios and KWTRP ELISAs respectively, among the gold standard positive samples. In all, the positive predictive value for InBios was 0.83 (95% CI, 0.79-0.87) and 0.98 (95% CI, 0.96-0.99) for KWTRP while the negative predictive value was 0.98 (95% CI, 0.97- 0.99) and 0.97 (95% CI, 0.95-0.98) for InBios and KWTRP respectively. Overall, both assays showed sufficient sensitivity and specificity to estimate SARS-CoV-2 antibodies in different populations in Kenya.
Human tonsil organoids reveal innate pathways modulating humoral and cellular responses to ChAdOx1.
The COVID-19 pandemic response demonstrated the effectiveness of adenovirus vector vaccines in inducing protective cellular and antibody responses. However, we still lack mechanistic understanding of the factors regulating immunity induced by this platform, especially innate pathways. We utilized a human tonsil organoid model to study the regulation of adaptive responses to ChAdOx1 nCoV-19. Innate activation and cytokine release occurred within 24 hours and T and B cell activation and antigen-specific antibody secretion occurred during the ensuing 14-day culture. Among the immune cell populations, plasmacytoid dendritic cells (pDCs) exhibited the highest ChAdOx1 transduction levels. pDC-derived IFN-ɑ was critical for humoral responses, but production of antigen in pDCs was dispensable. Furthermore, IL-6 enhanced humoral responses in both IFN-⍺-dependent and independent manners, indicating intricate signaling interplay. IFN-ɑ and IL-6 also regulated the function of vaccine-activated CD4+ T cells, including TFH. These data provide key insights into innate pathways regulating ChAdOx1-induced immunity and highlights the promise of this model for vaccine platform mechanistic studies.
Is health, growth and development impaired in children who are Hepatitis B-exposed but uninfected?
An estimated 254 million people are living with chronic hepatitis B virus (HBV) infection worldwide. Many infants are born to mothers with HBV but do not themselves acquire the infection. It is unclear whether this exposure to HBV in early life - without the development of active infection - may be associated with adverse outcomes. We propose the term “HBV-exposed uninfected (HBEU)”, drawing parallels with the HIV field which recognises that children who are HIV-exposed but uninfected face an increased risk of adverse health outcomes. This paper explores the potential health consequences for children HBEU. We summarise existing evidence reporting on children HBEU, and also review existing knowledge from the HIV field that could inform insights. We hypothesise that children HBEU may be at increased risk of preterm birth, and/or impaired growth and neurodevelopmental delay, but comprehensive, longitudinal studies are currently lacking to support this. We propose a conceptual framework to hypothesise how exposure to HBV could potentially lead to adverse growth and neurodevelopment through both HBV-specific and universal pathways, and review the available evidence and research gaps. Data are needed to establish whether short- and long-term sequelae exist for children HBEU, and to inform evidence-based interventions to mitigate against detrimental outcomes. Establishing a comprehensive understanding of the long-term trajectory of health and well-being among children HBEU throughout childhood into adolescence will require longitudinal observational studies with appropriate control groups to characterise outcomes, identify risk factors and explore underlying mechanistic pathways.
TCF1 and LEF1 promote B-1a cell homeostasis and regulatory function.
B-1 cells are innate-like immune cells abundant in serosal cavities with antibodies enriched in bacterial recognition, yet their existence in humans has been controversial1-3. The CD5+ B-1a subset expresses anti-inflammatory molecules including IL-10, PDL1 and CTLA4 and can be immunoregulatory4-6. Unlike conventional B cells that are continuously replenished, B-1a cells are produced early in life and maintained through self-renewal7. Here we show that the transcription factors TCF1 and LEF1 are critical regulators of B-1a cells. LEF1 expression is highest in fetal and bone marrow B-1 progenitors, whereas the levels of TCF1 are higher in splenic and peritoneal B-1 cells than in B-1 progenitors. TCF1-LEF1 double deficient mice have reduced B-1a cells and defective B-1a cell maintenance. These transcription factors promote MYC-dependent metabolic pathways and induce a stem-like population upon activation, partly via IL-10 production. In the absence of TCF1 and LEF1, B-1 cells proliferate excessively and acquire an exhausted phenotype with reduced IL-10 and PDL1 expression. Furthermore, adoptive transfer of B-1 cells lacking TCF1 and LEF1 fails to suppress brain inflammation. These transcription factors are also expressed in human chronic lymphocytic leukaemia B cells and in a B-1-like population that is abundant in pleural fluid and circulation of some patients with pleural infection. Our findings define a TCF1-LEF1-driven transcriptional program that integrates stemness and regulatory function in B-1a cells.
Temporo-spatial cellular atlas of the regenerating alveolar niche in idiopathic pulmonary fibrosis
Abstract Healthy alveolar repair relies on the ability of alveolar stem cells to differentiate into specialized epithelial cells for gas exchange. In chronic fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF), this regenerative process is abnormal but the underlying mechanisms remain unclear. Here, using human lung tissue that represents different stages of disease and a 33-plex single-cell imaging mass cytometry (IMC), we present a high-resolution, temporo-spatial cell atlas of the regenerating alveolar niche. With unbiased mathematical methods which quantify statistically enriched interactions, CD206himacrophage subtype and an alveolar basal intermediate epithelial cell emerge as the most statistically robust spatial association in the epithelial and immune cell interactome, found across all stages of disease. Spatially resolved receptor–ligand analysis further offers an in silico mechanism by which these macrophages may influence epithelial regeneration. These findings provide a foundational step toward understanding immune–epithelial dynamics in aberrant alveolar regeneration in IPF.