A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS.

The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαβ+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET- expression pattern. These unconventional T cells are present in healthy individuals, are generated before birth, are enriched in lymphoid tissue, and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative, noncytotoxic T cells with an IL-10 cytokine bias. Mechanistically, regulation of this physiological population is mediated by FAS and CTLA4 signaling, and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease

The influence of contextual factors on healthcare quality improvement initiatives:a realist review

Background Recognising the influence of context and the context-sensitive nature of quality improvement (QI) interventions is crucial to implementing effective improvements and successfully replicating them in new settings, yet context is still poorly understood. To address this challenge, it is necessary to capture generalisable knowledge, first to understand which aspects of context are most important to QI and why, and secondly, to explore how these factors can be managed to support healthcare improvement, in terms of implementing successful improvement initiatives, achieving sustainability and scaling interventions. The research question was how and why does context influence quality improvement initiatives in healthcare? Methods A realist review explored the contextual conditions that influence healthcare improvement. Realist methodology integrates theoretical understanding and stakeholder input with empirical research findings. The review aimed to identify and understand the role of context during the improvement cycle, i.e. planning, implementation, sustainability and transferability; and distil new knowledge to inform the design and development of context-sensitive QI initiatives. We developed a preliminary theory of the influence of context to arrive at a conceptual and theoretical framework. Results Thirty-five studies were included in the review, demonstrating the interaction of key contextual factors across healthcare system levels during the improvement cycle. An evidence-based explanatory theoretical model is proposed to illustrate the interaction between contextual factors, system levels (macro, meso, micro) and the stages of the improvement journey. Findings indicate that the consideration of these contextual factors would enhance the design and delivery of improvement initiatives, across a range of improvement settings. Conclusions This is the first realist review of context in QI and contributes to a deeper understanding of how context influences quality improvement initiatives. The distillation of key contextual factors offers the potential to inform the design and development of context-sensitive interventions to enhance improvement initiatives and address the challenge of spread and sustainability. Future research should explore the application of our conceptual model to enhance improvement-planning processes

Investigating organizational quality improvement systems, patient empowerment, organizational culture, professional involvement and the quality of care in European hospitals: the 'Deepening our Understanding of Quality Improvement in Europe (DUQuE)' project

BACKGROUND: Hospitals in European countries apply a wide range of quality improvement strategies. Knowledge of the effectiveness of these strategies, implemented as part of an overall hospital quality improvement system, is limited. METHODS/DESIGN: We propose to study the relationships among organisational quality improvement systems, patient empowerment, organisational culture, professionals' involvement with the quality of hospital care, including clinical effectiveness, patient safety and patient involvement. We will employ a cross-sectional, multi-level study design in which patient-level measurements are nested in hospital departments, which are in turn nested in hospitals in different EU countries. Mixed methods will be used for data collection, measurement and analysis. Hospital/care pathway level constructs that will be assessed include external pressure, hospital governance, quality improvement system, patient empowerment in quality improvement, organisational culture and professional involvement. These constructs will be assessed using questionnaires. Patient-level constructs include clinical effectiveness, patient safety and patient involvement, and will be assessed using audit of patient records, routine data and patient surveys. For the assessment of hospital and pathway level constructs we will collect data from randomly selected hospitals in eight countries. For a sample of hospitals in each country we will carry out additional data collection at patient-level related to four conditions (stroke, acute myocardial infarction, hip fracture and delivery). In addition, structural components of quality improvement systems will be assessed using visits by experienced external assessors. Data analysis will include descriptive statistics and graphical representations and methods for data reduction, classification techniques and psychometric analysis, before moving to bi-variate and multivariate analysis. The latter will be conducted at hospital and multilevel. In addition, we will apply sophisticated methodological elements such as the use of causal diagrams, outcome modelling, double robust estimation and detailed sensitivity analysis or multiple bias analyses to assess the impact of the various sources of bias. DISCUSSION: Products of the project will include a catalogue of instruments and tools that can be used to build departmental or hospital quality and safety programme and an appraisal scheme to assess the maturity of the quality improvement system for use by hospitals and by purchasers to contract hospitals

The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1

PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients. METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients. RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61 %). Out of 39 familial cases from 11 families, 26 patients (67 %) from 9 families and out of 18 sporadic cases, 9 patients (50 %) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients. CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing

The integrated GOR-COVID-19 health monitor: research-informed policy-making through dialogue.

ABSTRACT: Introduction Like in many other countries, the COVID-19 pandemic and the government restrictions introduced to contain the spread of the virus had major consequences for the health and wellbeing of the population in the Netherlands. To monitor the short and long-term public health impact, a nationally coordinated research program was initiated with the intention to guide decision-making by local and national public health authorities. This contribution presents the process to establish a continuous dialogue with end-users of information to add focus to the monitor, make sense of the findings and formulate policy recommendation and practical guidance, both at the national and regional level. Methods To facilitate the translation and dissemination of research results among policy makers, practitioners and scientists, an ongoing series of dialogue sessions is organized during the monitoring program. Apart from the objective of evidence-informed public health decision-making, the dialectic process seeks to ensure multi-sectoral learning and co-creation and contribute to a broad sense of ownership among stakeholders. National and regional health participants serve as hub coordinators. New stakeholders are invited and will be actively approached wherever considered relevant. Results At the EUPHA conference experiences with organizing the dialogue in app. the first two years of the program will be presented together with preliminary results and a reflection on factors that helped or hindered the implementation and uptake of findings. Discussion Monitoring data collected using robust methods and analyzed in such a way that vulnerability factors are carefully considered, is invaluable for decision-making. However, in order to effectively serve as guidance to public health policy, whether in the context of the COVID-19 pandemic or in non-crisis situations, a constructive, ongoing exchange between end-users of the information needs to be facilitated

The integrated GOR-COVID-19 health monitor: quarterly reporting ("long-cycle monitoring'')

ABSTRACT: Introduction Because of foreseeable COVID-19- related mental and physical health risks for the general population, a longitudinal health monitor was launched in the Netherlands. The monitoring program includes multiple methods. The current contribution places an emphasis on the so-called “long-cycle” monitoring activities at the national and regional level. The aim is to produce (bi-)annual reports on developments in health status of the general population and several potentially vulnerable subgroups (e.g. psychological and somatic comorbidities, lower socio-economic status). Methods Primary care registrations and questionnaire data were used. Both depend on existing methods of data collection, cover a broad spectrum of health aspects and offer the possibility of pre-COVID-19-comparison. Primary care data were obtained from electronic health records of general practices in the Nivel Primary Care Database. Large-scale survey research with questionnaires was conducted in all the 25 health regions of the Netherlands among 2nd and 4th graders in high schools, adults, elderly and young adults (16-25 years old). Where possible, data were combined with data on socio-economic status and additional health aspects from Statistics Netherlands (CBS). Results The first results from both data sources show that the COVID-19 pandemic undeniably had an effect on the mental health of youth. Compared to 2019, there was a general decrease in overall health and happiness in 2020 and a perceivable increase in social problems as well as health symptoms such as lack of smell and taste. Furthermore, a smaller groups of people experienced more psychological symptoms, serious problems like suicidal thoughts and PTSD symptomatology. Discussion Adverse effects of the pandemic on youth are already visible in the first year after the outbreak. It is crucial to closely monitor the course of this health impact in the years to come, based on the combination of large, representative databases.