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Value of using artificial intelligence derived clusters by health and social care need in primary care: A qualitative interview study with patients living with multiple long-term conditions, carers and health care professionals.
BackgroundPeople living with MLTCs attending primary care often have unmet social care needs (SCNs), which can be challenging to identify and address. Artificial intelligence (AI) derived clusters could help to identify patients at risk of SCNs. Evidence is needed on views about the use of AI-derived clusters, to inform acceptable and meaningful implementation within interventions.MethodQualitative semi-structured interviews (online and telephone), including a description of AI-derived clusters and a tailored vignette, with 24 people living with MLTCs and 20 people involved in the care of MLTCs (carers and health care professionals). Interviews were analysed using Reflexive and Codebook Thematic Analysis.ResultsPrimary care was viewed as an appropriate place to have conversations about SCNs. However, participants felt health care professionals lack capacity to have these conversations and to identify support. AI was perceived as a tool that could potentially increase capacity but only when supplemented with effective, clinical conversations. Interventions harnessing AI should be brief, be easy to use and remain relevant over time, to ensure no additional burden on clinical capacity. Interventions must allow flexibility to be used by multidisciplinary teams within primary care, frame messages positively and facilitate conversations that remain patient centered.ConclusionOur findings suggest that implementing AI-derived clusters to identify and support SCNs in primary care is perceived as valuable and can be used as a tool to inform and prioritse effective clinical conversations. But concerns must be addressed, including how AI-derived clusters can be used in a way that considers personal context.
Subclinical Postpartum Renal Structure After Hypertensive Pregnancy Disorders.
BACKGROUND: Hypertensive pregnancies are associated with increased risks of renal failure in pregnancy and later life. However, traditional markers of renal function normalize postpartum, making identification of those at future disease risk difficult. We studied whether the type and severity of hypertensive pregnancy associated with postpartum renal structure. METHODS: One hundred twenty-five women from interventional trials (61 preeclamptic, 33 gestational hypertension, and 31 normotensive pregnancy), aged ≥18 years, were imaged using magnetic resonance imaging 6 to 12 months postpartum. Anthropometric, demographic, blood pressure, and blood sample data were collected during pregnancy and postpartum. Kidney volume indexed to body surface area and corticomedullary differentiation were compared between groups using a 1-way ANCOVA, whereas associations with other outcomes were assessed using correlation tests. RESULTS: Postpartum total kidney volume indexed to body surface area was smaller in women who had preeclampsia compared with those who had gestational hypertension or a normotensive pregnancy (P=0.049). Total kidney volume postpartum correlated with estimated glomerular filtration rate at delivery (P<0.001). However, smaller volumes were not explained by reduced corticomedullary differentiation, which only differed in women with gestational hypertension compared with preeclamptic (P=0.02) and normotensive women (P=0.007). There were no associations between renal measures and blood pressure during or after pregnancy. CONCLUSIONS: At 6 to 12 months postpartum, preeclamptic women have smaller kidney volumes than women with gestational hypertension or normotensive pregnancies. These smaller volumes relate to lower renal function at delivery but not corticomedullary differentiation, which only differed in women with gestational hypertension. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT04273854 and NCT05434195.
Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells
Abstract Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogate how physiologically low iron availability affects CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation does not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalls proliferation (without influencing cell viability), alters histone methylation status, gene expression, and disrupts mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle is limited and partially reverses to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Despite aberrant TCA cycling, aspartate is increased in stalled iron deficient CD8+ T cells but is not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescues expansion and some functions of severely iron-deficient CD8+ T cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.
Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in children aged 6-17 years: Final results of a phase 2, single-blind, randomised controlled trial (COV006).
Paediatric COVID-19 vaccination programmes were initiated in response to the coronavirus pandemic declared by the World Health Organisation (WHO) in 2020. Ten COVID-19 vaccines received WHO Emergency Use Listing, however, only five were approved for use in children. ChAdOx1 nCoV-19 (AZD1222) was approved in adults in a two-dose regimen. We previously reported interim findings of a phase 2 study of ChAdOx1 nCoV-19 in children with immunogenicity, comparable with adults. Final results after 12 month follow-up are reported. Single-blind, randomised controlled trial across four UK centres, recruiting 261 children and adolescents (aged 6-17 years). Participants received either two doses of ChAdOx1 nCoV-19 or Bexsero vaccine (controls). The primary outcome was safety (adverse events for 28 days following vaccination and serious adverse events throughout), and secondary outcome was immunogenicity (measured by SARS-CoV-2 anti-spike enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent spot (ELISpot)). Five serious adverse events and four adverse events of special interest were reported. None were related to study vaccinations, and there were no deaths. Geometric mean titres (GMTs) from an anti-spike (Wuhan) ELISA in participants aged 6-11 years were 1 EU/ml (95% CI 1-2) at baseline versus 796 EU (95% CI 161-3948, n =4) at D364. In participants aged 12-17 years, GMTs were 1 EU/ml (95% CI 1-2, n=3) at baseline versus 1432 EU/ml (95% CI 2337-6083; n=6) at D364 (2 dose regimen at 112-day interval), compared to 3 EU/ml (95% CI 0-62) at baseline versus 392 EU/ml (95% CI 24, 6493; n=3) at D364 (2 dose regimen at a 28-day interval). A two-dose regimen of ChAdOx1 nCoV-19 was immunogenic and safe in the trial population. No vaccine-related serious adverse events were reported. Immune responses persisted to 12 months in participants who did not experience breakthrough infection, This trial was registered with ISRCTN, trial number 15638344. The study was funded by the Department of Health and Social Care, through the National Institute for Health Research, and AstraZeneca.
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.
Evaluation of 1<sup>st</sup> WHO anti-malaria reference reagent for competition ELISA harmonisation and development of ADAMSEL analytical platform.
This study focuses on harmonising the competition ELISA (cELISA) assay for Plasmodium falciparum (P. falciparum), using the 1st WHO reference reagent for anti-malaria (P. falciparum) human reference serum (10/198). Antibody-mediated immune responses against the Apical Membrane Antigen 1 (AMA1) play a significant role in protection against malaria. However, the sequence diversity of AMA1 and cross-reactivity among variants pose challenges in assessing antibody responses. To address this, the cELISA assay was selected to examine cross-reactive antibody responses against different variants. The harmonisation process for cELISA was performed in three laboratories. The 10/198 served as an internal standard for the calculation of IgG concentrations in the cELISA using ADAMSEL software. Additionally, a novel semi-automated analytical tool was developed in the R-statistics environment. This tool is freely available for download and streamlines generating results while minimising human error. This study demonstrated the effectiveness of the 1st WHO reference reagent as a standard for cELISA. Additionally, the ADAMSEL software and R-platform tool provide a user-friendly and accessible tool for the analysis of cELISA data. Its automation capabilities improve efficiency and ensure global accessibility at no cost, benefitting laboratories with limited resources.
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.
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.
The contribution of minimally invasive tissue sampling compared to antemortem-derived cause of death determination among inpatient child deaths: the minimally invasive tissue sampling in Malawi study.
BackgroundImproved causes of death (CoD) understanding in low- and middle-income countries is needed to reduce child mortality. Compared to full autopsy, minimally invasive tissue sampling (MITS), using transcutaneous needle sampling, is a feasible, socially acceptable, and validated method. We aimed to quantify the additional contribution of MITS to CoD attribution based on clinical records and inpatient research data with intensive patient characterisation.MethodsWe enrolled children aged seven days to 59 months who died while on admission for acute illness and/or severe malnutrition to Queen Elizabeth Central Hospital in Blantyre, Malawi. Standard MITS procedures included histologic, immunohistochemical, and microbiologic testing. Phase 1 CoD determination was based on medical records alone, Phase 2 also included research data, and Phase 3 included all data, including from MITS.ResultsWe enrolled 29 children. Based on clinical notes alone (Phase 1), we identified 60 causal and 39 contributing conditions. Of the 45 (45%) infectious conditions, pathogens were identified in 15 (33%). Only one patient's (3%) CoD was unchanged compared to including all data (Phase 3). Further, we identified 69 new (n = 43) or adjusted (n = 26) diagnoses among 28 cases (97%); the majority were undernutrition-related (n = 22, 32%) or infectious (n = 41, 59%) conditions. Overall, the majority of final Phase 3 conditions were also undernutrition-related (n = 46, 32%) or infectious (n = 61, 43%) and a pathogen was identified in 54 (89%) of the infectious conditions. Klebsiella pneumoniae was the most prevalent aetiology in both pneumonia and sepsis.ConclusionsThe addition of MITS to clinical and inpatient research data led to almost all (97%) of cases receiving new and/or refined diagnoses, including microbe identification in infectious conditions. Pathogens not specifically addressed by current clinical guidelines, such as Klebisiella pneumoniae, were commonly identified. Our findings support the utility of MITS to understand CoD even after thorough clinical characterisation of children during hospitalisation.
Supporting pregnant and mothering adolescents in their schooling: Insights for policy and practice
Adolescent parenthood is a significant issue in Sub-Saharan Africa, which can have adverse effects on mothers, their children and families. South Africa faces challenges in ensuring inclusive education for adolescent girls and young women due to high dropout rates resulting in and contributing to adolescent pregnancy. While a sound policy framework for pregnant and mothering adolescents exists, implementation challenges persist, emphasising the need for effective interventions to support pregnant and mothering adolescents return to and complete their schooling. This commentary brings together quantitative data from surveys with 1046 adolescent mothers in South Africa's Eastern Cape province, coupled with participatory design incubators with young people (N = 13) in the same setting to provide implementation recommendations for policy and practice, with specific reference to the Department of Basic Education's Policy on the Prevention and Management of Learner Pregnancy in Schools. Analysing across the two data sources involved using a socio-ecological lens that acknowledges the multi-level factors and longer-term trajectories that influence adolescent mothers’ schooling trajectories. Three inter-related implementation recommendations to support pregnant and mothering adolescents schooling emerge through data triangulation and analyses: (1) supportive school environment, (2) promoting peer-based support, and (3) establishing strong partnerships and referral mechanisms beyond the school setting. These recommendations are grounded in evidence, align with South Africa's existing policy framework, and speak to the expressed needs of adolescents and young people, aiming to address the complex challenges faced by pregnant and mothering adolescents. Evidence-informed interventions to support pregnant and mothering adolescents schooling can ultimately contribute to health, education, and gender equality goals. Stakeholder engagement, especially co-design engagements with pregnant and mothering adolescents, and research, monitoring and evaluation to test intervention feasibility and acceptability are essential for refining and scaling-up interventions to improve the well-being of adolescent mothers and their children.
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.