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Medullary thymic epithelial cells (mTECs) are essential for the establishment of T cell central tolerance. The transcription factor Aire plays a key role in this process, but other factors remain understudied. We found that a small population of mTECs expressed the coinhibitory receptor cytotoxic T lymphocyte-associated protein 4 (CTLA-4). These CTLA-4⁺ cells were detectable in perinates, peaked around young adulthood and expanded sixfold in the absence of Aire. Single-cell transcriptomics revealed CTLA-4⁺ mTECs to express a distinct gene signature encoding molecules associated with antigen presentation and interferon-gamma signaling. Mice conditionally lacking CTLA-4 in thymic epithelial cells had no major immunological deficiencies but displayed a mildly increased inflammatory tone and a partial defect in the generation of Foxp3⁺CD4⁺ regulatory T cells. Consequently, these mice developed modest levels of autoantibodies and lymphocytic infiltration of peripheral tissues. Thus, CTLA-4 expression in mTECs complements Aire to establish T cell central tolerance.

The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3⁺ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlatingwith poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19–linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.

Evidence-based interventions are often unavailable in everyday clinical settings. This may partly reflect practitioners’ assumptions that research evidence does not reflect “real-world” conditions. To examine this further, we systematically assessed the clinical effectiveness of parent management training (PMT) for the treatment of child disruptive behavior across different real-world practice contexts. We identified 28 relevant randomized controlled trials from a systematic search of electronic bibliographic databases and conducted a meta-analysis of child outcomes across trials. Planned subgroup analyses involved comparisons between studies grouped according to individual real-world practice criteria and total real-world practice criteria scores, reflecting the extent to which PMT was delivered by non-specialist therapists, to a clinic-referred population, in a routine setting, and as part of a routine service. Meta-analysis revealed a significant overall advantage for PMT compared with waitlist control conditions. Subgroup analyses did not demonstrate significant differences in effect size estimates according to the total number of real-world practice criteria met by studies. Moreover, no consistent relationships were found between specific practice criteria and effect size estimates. In conclusion, PMT appears to be an effective treatment for children with disruptive behavior problems. There was no clear evidence that conducting PMT in real-world practice contexts is a deterrent to achieving effective child behavior outcomes, although relative advantage to “usual care” was not directly examined and the power of the analysis was limited as a result of significant heterogeneity. More research is needed to investigate whether this finding is generalizable to other psychological interventions. Suggestions are also made for developing more differentiated criteria to assist with evaluating the specific applicability of research evidence to different care providers.

School absences have risen following the COVID-19 pandemic and persistent absenteeism remains high in primary and secondary schools in England compared with pre-pandemic levels. This coincides with an upward trend in emotionally based school avoidance (EBSA). EBSA adversely affects children’s educational attainment, health, social functioning and life prospects and warrants early intervention before a pattern of absenteeism becomes entrenched. In this article, we consider how the COVID-19 pandemic and its sequelae have created a ‘perfect storm’ of conditions, amplifying known school, family and child-based risk factors for EBSA while simultaneously reducing access to support services. We then outline priorities for developing new EBSA interventions and argue for a multi-component approach, which works across education, health and social care, and voluntary sectors to address the complex interplay between risk factors. Given the difficulties that families often face in obtaining timely support for EBSA, it is also essential that new interventions are accessible, resource-efficient and scalable. To this end, we specifically discuss the potential for contextually-sensitive, parent-focused interventions that can be delivered online with minimal synchronous support from a trained coach or facilitator.

Aire controls immunological tolerance by driving promiscuous expression of a large swath of the genome in medullary thymic epithelial cells (mTECs). Its molecular mechanism remains enigmatic. High-resolution chromosome-conformation capture (Hi-C) experiments on ex vivo mTECs revealed Aire to have a widespread impact on higher-order chromatin structure, disfavoring architectural loops while favoring transcriptional loops. In the presence of Aire, cohesin complexes concentrated on superenhancers together with mediator complexes, while the CCCTC-binding factor (CTCF) was relatively depleted from structural domain boundaries. In particular, Aire associated with the cohesin loader, NIPBL, strengthening this factor’s affiliation with cohesin’s enzymatic subunits. mTEC transcripts upregulated in the presence of Aire corresponded closely to those down-regulated in the absence of one of the cohesin subunits, SA-2. A mechanistic model incorporating these findings explains many of the unusual features of Aire’s impact on mTEC transcription, providing molecular insight into tolerance induction.

Following acute injury, stromal cells promote tissue regeneration by a diversity of mechanisms. Time-resolved single-cell RNA sequencing of muscle mesenchymal stromal cells (MmSCs) responding to acute injury identified an ‘early-responder’ subtype that spiked on day 1 and expressed a notable array of transcripts encoding immunomodulators. IL-1β, TNF-α and oncostatin M each strongly and rapidly induced MmSCs transcribing this immunomodulatory program. Macrophages amplified the program but were not strictly required for its induction. Transfer of the inflammatory MmSC subtype, tagged with a unique surface marker, into healthy hindlimb muscle induced inflammation primarily driven by neutrophils and macrophages. Among the abundant inflammatory transcripts produced by this subtype, Cxcl5 was stroma-specific and highly upregulated with injury. Depletion of this chemokine early after injury revealed a substantial impact on recruitment of neutrophils, a prolongation of inflammation to later times and an effect on tissue regeneration. Mesenchymal stromal cell subtypes expressing a comparable inflammatory program were found in a mouse model of muscular dystrophy and in several other tissues and pathologies in both mice and humans. These ‘early-responder’ mesenchymal stromal cells, already in place, permit rapid and coordinated mobilization and amplification of critical cell collaborators in response to injury. Mathis and colleagues identify a subset of muscle mesenchymal stromal cells that coordinates tissue immune responses and drives regenerative mechanisms following muscle injury.

Background Codesign of mental health interventions entails the active involvement of end users and other stakeholders in various stages of the developmental process. This has emerged as a promising approach for developing evidence‐based mental health interventions aligned with minoritised populations' needs and preferences. However, key questions remain about the methods and outcomes of codesign studies focused on young people from racially minoritised groups. The current review aimed to explore the codesign approaches and phases used in developing mental health interventions with young people from racially minoritised populations, analyse the codesign outcomes for participants and examine the contextual enablers and barriers impacting the codesign process. Methods A systematic search was conducted across MEDLINE, EMBASE, PsycINFO, Global Health, Web of Science and Scopus. Citations and references of included studies were also checked. Study quality and reporting of codesign were assessed using the Mixed Method Appraisal Tools and the Guidance for Reporting Involvement of Patients and the Public‐2 checklist. Data were synthesised using narrative synthesis, content analysis and meta‐synthesis. Results Eighteen eligible studies reported various codesign and participatory approaches, including community‐based participatory research, co‐production, human‐centred design, youth and family codesign model, community engagement research, community development model, participatory evaluation model, participatory research design approach and community participatory research partnership. The most common codesign stages followed were exploring problems and solutions, ideating and creating, and refining. In terms of outcomes, the reported benefits of codesign for young people included personal development and well‐being, enhanced knowledge and career skills, and better mental health outcomes. Codesigning with youth and other stakeholders (e.g., family members, other caregivers, community members and practitioners) also improved the research projects by identifying specific problems, increasing participant recruitment and enhancing data collection. Additionally, other stakeholders gained a platform to share their expertise, understand youth mental health and build capacity through codesign. Regarding enablers and barriers, reducing power differentials, fostering community engagement and collaboration with other stakeholders facilitated the codesign process, whereas barriers included lack of resources, power imbalances, lack of rapport building and selection bias. Conclusions This review outlines the potential benefits of codesign for developing mental health interventions for racially minoritised youth. These benefits include continuous stakeholder engagement to understand community needs better, reducing power differentials and building trust through culturally tailored activities and communication strategies. Patient and Public Contribution Patients and the public did not contribute directly to this review though the reviewed literature was specifically concerned with participatory research activities.

Young women who are not in education, employment, or training (NEET) experience poorer health and social outcomes compared to non-NEET young women and to NEET young men, especially in deprived areas with intersecting inequalities. The evidence on effective public health approaches is scarce. Interventions that target hope, which NEET young women notably lack, offer a promising theory-driven and intuitive means to prevent mental health problems and improve social outcomes. Hope can be defined as a goal-focused mindset comprising self-agency (motivation and self-belief) and pathways (identifying routes to achieving goals). Hope is implicated in a variety of evidence-based psychosocial interventions for young people, but is not directly targeted by existing prevention programmes for NEET populations. The current study used a phased qualitative research design and participatory methods to model a hope-focused intervention for NEET young women. Phase 1 investigated population needs and intervention parameters through semi-structured interviews with 28 key informants living or working in disadvantaged coastal communities in South-East England. The sample comprised eight NEET young women, four family members, and 16 practitioners from relevant support organisations. Phase 2 refined intervention parameters and outcomes through co-design sessions with four NEET young women, followed by a theory of change workshop with 10 practitioners. The resulting intervention model is articulated as a mentor-supported, in-person psychosocial intervention that builds hope by enhancing positive sense of self and time spent in meaningful activities, before explicitly teaching the skills needed to identify, set, and pursue personally meaningful goals.

Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provokes a potentially fatal pneumonia with multiorgan failure, and high systemic inflammation. To gain mechanistic insight and ferret out the root of this immune dysregulation, we modeled, by in vitro coculture, the interactions between infected epithelial cells and immunocytes. A strong response was induced in monocytes and B cells, with a SARS-CoV-2–specific inflammatory gene cluster distinct from that seen in influenza A or Ebola virus-infected cocultures, and which reproduced deviations reported in blood or lung myeloid cells from COVID-19 patients. A substantial fraction of the effect could be reproduced after individual transfection of several SARS-CoV-2 proteins (Spike and some nonstructural proteins), mediated by soluble factors, but not via transcriptional induction. This response was greatly muted in monocytes from healthy children, perhaps a clue to the age dependency of COVID-19. These results suggest that the inflammatory malfunction in COVID-19 is rooted in the earliest perturbations that SARS-CoV-2 induces in epithelia.

Weather radar research has produced numerous radar-based rainfall estimators based on climate, rainfall intensity, a variety of ground-truthing instruments and sensors (e.g., rain gauges, disdrometers), and techniques. Although each research direction gives improvement, their collective application in an operational sense still yields uncertainty in rainfall estimation at times. This study aims to explore the concept of implementing Machine Learning (ML) models in optimizing the radar-based rainfall estimations at the bin level from a group of estimator. The Canadian King City C-Band radar was used with a GEONOR T-200B rain gauge (a total of 263 sample points) to establish a group of polarimetric-based rainfall estimators (R(Z), R(Z, ZDR), R(KDP)). The estimators were used to train three ML models, namely Decision Tree, Random Forest, and Gradient Boost, to choose the optimal rainfall estimators based on radar variables (Z, ZDR, KDP). Data from the Canadian Exeter C-Band radar and a Texas Electronics TE525 tipping bucket gauge at a different location were used to verify the ML models and compare their results to the most commonly used Z-R relations. The verification process shows promising results for the ML models, specifically the Gradient Boost model. These encouraging results need to be further explored with more sample points to further refine the ML models.