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A novel dominant-negative variant of IRF8 in a mother and son: Clinical, phenotypic and biological characteristics.
BACKGROUND: The few reported patients with pathogenic IRF8 variants have manifested 2 distinct phenotypes: (1) an autosomal recessive severe immunodeficiency with significant neutrophilia and absence of or significant decrease in monocytes and dendritic cells and (2) a dominant-negative form with only a decrease in conventional type 2 dendritic cells (cDC2s) and susceptibility to mycobacterial disease. OBJECTIVES: Genetic testing of a child with persistent EBV viremia identified a novel IRF8 variant: c.1279dupT (p.∗427Leuext∗42). The variant was also found in his mother, who was subsequently diagnosed with a human papillomavirus-positive tumor. We sought to examine the pathogenicity of the identified IRF8 variant and its phenotypic and functional characteristics. METHODS: Immunophenotypic and functional flow cytometry, natural killer cell cytotoxicity, matrix-assisted laser desorption/ionization-time of flight mass spectrometry, T-cell receptor Vβ spectratyping, Sanger sequencing, RNA-sequencing, Olink proteomics, immunoblotting, molecular cloning, dual-luciferase reporter assay, immunofluorescence microscopy, and image analysis. RESULTS: The 42 amino acid C-terminal extension of the mutant IRF8 (∼4 kDa heavier than wild type) impaired IRF8 nuclear localization in a dominant-negative manner and inhibited IRF1/IRF8-mediated transcriptional activities. Both patients had a decrease in plasmacytoid dendritic cells (pDCs) and in cDC1s, a mild neutrophilia and a mild monocytosis. Their existing pDCs had impaired IFN-α production. On TLR engagement, the production of IL-1β, IL-6, IL-10, and IL-12 by their monocytes and of IL-12 by their myeloid DCs were within normal limits. Natural killer cell development and cytolytic activity were essentially normal. RNA-sequencing and proteomic approaches bolstered the phenotypic and functional findings. CONCLUSIONS: This study defines the pathogenic nature of the c.1279dupT (p.∗427Leuext∗42) IRF8 variant, determines its dominant-negative mechanism of action, and broadens the existing phenotype of human IRF8 immunodeficiency.
The Challenges of Implementing a Health Referral System in South Africa: A Qualitative Study.
INTRODUCTION: Health system strengthening efforts also entails streamlining an existing referral system in a particular context to improve quality of health care offered to people. Conceptually, the referral system in South Africa, is seemingly sound. Nevertheless, gaps exist in its implementation. The aim of this study was to explore health care professionals' perceptions of referral system implementation in the Buffalo City Metropolitan Municipality (BCMM) in the Eastern Cape Province of South Africa. METHODS: This qualitative study included 12 health care professionals as participants. Each participant was interviewed using a semi-structured interview guide; with their consent, the interviews were audio recorded and transcribed verbatim. For data analysis, a thematic content analysis was used. RESULTS: The participants identified many impediments to the effective implementation of the referral system in BCCM. The main obstacles were deteriorating infrastructure, inadequate staffing, lack of transportation, and inadequate medical supplies and medications. CONCLUSION: In mitigation, the participants proposed suggestions such as increasing the capacity of the health workforce, allocating personnel appropriately, increasing the availability of transportation, and providing essential medications to all levels of care. They also suggested involving all stakeholders in the referral process, providing education and training to health professionals on the referral system, and enhancing communication and feedback between the various levels of care. These challenges emphasised in this study highlight the need for targeted interventions to improve the referral system in this setting.
Peer review reports of randomized controlled trials in oncology can be short and superficial.
OBJECTIVES: To evaluate the quality of open peer review reports published alongside articles of randomised controlled trials (RCTs) in oncology. METHODS: We searched and sampled from completed parallel RCT articles published in 2021 in 62 BioMed Central journals operating open peer review and evaluated their first-round peer review report. We assessed and described the peer review report content, clarity, and completeness and explored whether reviewers commented on the manuscript's importance, robustness, interpretation, discussion of results, and RCT reporting. Two investigators evaluated the review reports independently, with conflict resolution involving a third author. RESULTS: We sampled 26 RCTs and evaluated their 59 first peer review reports. Median word count was 276 (range=0-1047). Only 11 reports were constructive (19%), suggesting solutions for the problems noted. Of reviewers commenting on the manuscript's methods section (n=46/59,78%), 74% (n=34/46) addressed the suitability of the methodology. Fewer commented on the adequacy of conclusions (n=15/59; 25%) or the applicability of results (n=5/59; 9%), or whether study limitations had been acknowledged by authors (n=11/59; 18%). Only four (7%) commented on open research practices, including deviations from protocols, completeness of reporting, and sharing of data and materials. CONCLUSIONS: Peer review reports of published RCTs in oncology were short, superficial, and rarely constructive. Although there is indication that reviewers commented on study methodology, little attention was paid to study conclusions, deviation from study protocols, completeness of reporting or data availability. Such review reports would be of limited value to authors for improving their trial study manuscripts, or to editors in deciding on manuscript publication.
Ex vivo model of functioning human lymph node reveals role for innate lymphocytes and stroma in response to vaccine adjuvant.
Immunological processes that underpin human immune responses to therapeutics and vaccine components, such as vaccine adjuvants, remain poorly defined due to a paucity of models that faithfully recapitulate immune activation in lymphoid tissues. We describe precision-cut human lymph node (LN) slices as a functioning, architecturally preserved, full-organ cross-sectional model system. Using single-cell transcriptomics and multiplexed imaging, we explore early inflammatory response to a potent, clinically relevant liposomal vaccine adjuvant containing a TLR4-agonist and QS-21 saponin. Both TLR4 and NLRP3 inflammasome activation are involved in the direct initiation of the inflammatory response to adjuvant by monocytes and macrophages (Mon./Mac.) with secretion of interleukin (IL)-1β, but not IL-18, dependent on TLR4 signaling. Innate lymphoid cells, including natural killer cells, are indirectly activated by Mon./Mac.-produced cytokines, signaling downstream to B cells via interferon-γ secretion. Resident LN stromal populations, primed both directly and indirectly by vaccine adjuvant, are instrumental in mediating inflammatory cell recruitment, particularly neutrophils.
STAT3 phosphorylation in the rheumatoid arthritis immunological synapse.
Targeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including the critical IL-6/STAT3 axis, thereby effectively targeting different aspects of the pathological process. However, despite their clinical efficacy, a subset of RA patients remains refractory to JAK inhibition, underscoring the need for alternative approaches. Here, we identify a novel JAK-independent mechanism of STAT3 activation, which is triggered by the formation of the immunological synapse (IS) in naive CD4+ T cells. Our data demonstrates that LCK mediates the TCR-dependent phosphorylation of STAT3 at the IS, highlighting this pathway as a previously unrecognized hallmark of early T cell activation. Furthermore, we show that the synaptic LCK/TCR-STAT3 pathway is compromised in RA. This discovery highlights a new therapeutic target for RA beyond JAK inhibitors, offering potential avenues for treating patients resistant to current therapies.
Patient and surgeon perspectives of a large-scale system for automated, real-time monitoring and feedback of shared decision-making integrated into surgical practice: a qualitative study.
OBJECTIVE: To explore patient and healthcare professional perceptions about the acceptability and impact of a large-scale system for automated, real-time monitoring and feedback of shared decision-making (SDM) that has been integrated into surgical care pathways. DESIGN: Qualitative, semistructured interviews were conducted with patients and healthcare professionals between June and November 2021. Data were analysed using deductive and inductive approaches. SETTING: Large-scale monitoring of SDM has been integrated in NHS surgical care across two large UK National Health Service Trusts. PARTICIPANTS: Adult surgical patients (N=18, 56% female), following use of an SDM real-time monitoring and feedback system, and healthcare professionals (N=14, 36% female) involved in their surgical care. Patient recruitment was conducted through hospital research nurses and professionals by direct approach from the study team to sample individuals purposively from seven surgical specialties (general, vascular, urology, orthopaedics, breast, gynaecology and urgent cardiac). RESULTS: 10 themes were identified within three areas of exploration that described factors underpinning: (1) the acceptability of large-scale automated, real-time monitoring of SDM experiences, (2) the acceptability of real-time feedback and addressing SDM deficiencies and (3) the impact of real-time monitoring and feedback. There was general support for real-time monitoring and feedback because of its perceived ability to efficiently address deficiencies in surgical patients' SDM experience at scale, and its perceived benefits to patients, surgeons and the wider organisation. Factors potentially influencing acceptability of large-scale automated, real-time monitoring and feedback were identified for both stakeholder groups, for example, influence of survey timing on patient-reported SDM scores, disease-specific risks, patients' dissatisfaction with hospital processes. Factors particularly important for patients included concerns over digital exclusion exacerbated by electronic real-time monitoring. Factors unique to professionals included the need for detailed, qualitative feedback of SDM to contextualise patient-reported SDM scores. CONCLUSIONS: This study explored factors influencing the acceptability of automated, real-time monitoring and feedback of patients' experiences of SDM integrated into surgical practice, at scale among key stakeholders. Findings will be used to guide refinement and implementation of SDM monitoring and feedback prior to formal development, evaluation and implementation of an SDM intervention in the NHS. TRIAL REGISTRATION NUMBER: ISRCTN17951423. THE ORIGINAL PROTOCOL: doi: 10.1136/bmjopen-2023-079155.
Imminent fracture risk assessments in the UK FLS setting: implications and challenges.
With the recognition that a sentinel fracture leads to a high imminent risk of fracture, we discuss the implications and challenges of using imminent fracture risk in the secondary fracture prevention setting.
Potential lifetime quality of life benefits of choroideremia gene therapy: projections from a clinically informed decision model.
BACKGROUND: The first gene therapy for an inherited retinal dystrophy recently received market approval in the United States; multiple other gene therapies are in the clinical pipeline. Thus far, gene therapy has commanded prices in the range of $500,000 to over $1,000,000 for the one-time doses and have been indicated for highly orphan diseases where there is no other viable treatment option. To be adopted by healthcare systems, gene therapy will need to show clinical benefit in line with its increased costs. Before longitudinal patient studies are available, model-based estimations will be necessary to project the full clinical benefit of gene therapy. METHODS: To investigate the lifetime benefit of gene therapy for the retinal dystrophy choroideremia, we have built a Markov model of disease progression informed by clinical data of AAV.REP1 and voretigene neparvovec (Luxturna, Spark Therapeutics). Gene therapy patient benefit was estimated by quality-adjusted life years (QALYs) in three hypothetical disease severity patient groups. The severity of disease was defined by the combined effect of remaining retinal area and visual acuity and assigned corresponding health utility values. RESULTS: Early-stage patients treated with gene therapy were estimated to gain, in average, 14.30 QALYs over standard-of-care, mid-stage patients 6.22 QALYs, and late-stage patients 1.48 QALYs over untreated patients during their lifetime owing to treatment. Cost-effectiveness was not assessed as AAV.REP1 is still in clinical trials. CONCLUSIONS: In young adults in the earlier stages of choroideremia, successful gene therapy is expected to provide a significant increase in health-related quality of life.