HOIL1 Regulates Group 3 Innate Lymphoid Cells in the Colon and Protects against Systemic Dissemination, Colonic Ulceration, and Lethality from Citrobacter rodentium Infection.

Heme-oxidized IRP2 ubiquitin ligase-1 (HOIL1)-deficient patients experience chronic intestinal inflammation and diarrhea as well as increased susceptibility to bacterial infections. HOIL1 is a component of the linear ubiquitin chain assembly complex that regulates immune signaling pathways, including NF-κB-activating pathways. We have shown previously that HOIL1 is essential for survival following Citrobacter rodentium gastrointestinal infection of mice, but the mechanism of protection by HOIL1 was not examined. C. rodentium is an important murine model for human attaching and effacing pathogens, enteropathogenic and enterohemorrhagic Escherichia coli that cause diarrhea and foodborne illnesses and lead to severe disease in children and immunocompromised individuals. In this study, we found that C. rodentium infection resulted in severe colitis and dissemination of C. rodentium to systemic organs in HOIL1-deficient mice. HOIL1 was important in the innate immune response to limit early replication and dissemination of C. rodentium. Using bone marrow chimeras and cell type-specific knockout mice, we found that HOIL1 functioned in radiation-resistant cells and partly in radiation-sensitive cells and in myeloid cells to limit disease, but it was dispensable in intestinal epithelial cells. HOIL1 deficiency significantly impaired the expansion of group 3 innate lymphoid cells and their production of IL-22 during C. rodentium infection. Understanding the role HOIL1 plays in type 3 inflammation and in limiting the pathogenesis of attaching and effacing lesion-forming bacteria will provide further insight into the innate immune response to gastrointestinal pathogens and inflammatory disorders.

Extreme Stress Events in a Forensic Hospital Setting: Prevalence, Impact, and Protective Factors in Staff.

The current research explored the prevalence of stressful events in a forensic hospital setting, and their impact on staff. A systematic review of the literature on responses following exposure to extreme stress comprised 46 articles. This was followed by a Delphi study of professionals based in a forensic hospital (n = 43) to explore views on the factors that affect responses to extreme stress. This comprised three rounds to build consensus. Finally, a study of forensic hospital staff was conducted (n = 153, 47% male) to capture current trauma symptoms. The systematic review indicated three superordinate themes: outcomes adversely impacting staff and patients; personal characteristics moderating the impact of events; and organisational and interpersonal support moderating the impact of events. The Delphi supported these themes and noted the importance of factors external to the workplace and internal factors, such as self-blame. The final study demonstrated how a fifth of the workforce showed at least some trauma symptomology. Those who experienced less burnout reported lower trauma symptoms, while staff who experienced higher levels of secondary trauma at work reported higher levels of trauma symptoms. A higher level of resilience was related to lower levels of trauma symptomology. Findings are discussed in relation to the importance of recognising trauma in staff and implementing strategies to reduce and/or buffer the impact of stress on wellbeing. In doing so, the research presents a new model for consideration and development, the Impact and Amelioration of extreme stress events Model (IA-Model).

HOIL1 Is Essential for the Induction of Type I and III Interferons by MDA5 and Regulates Persistent Murine Norovirus Infection.

The linear ubiquitin chain assembly complex (LUBAC), composed of heme-oxidized IRP2 ubiquitin ligase 1 (HOIL1), HOIL1-interacting protein (HOIP), and SHANK-associated RH domain-interacting protein (SHARPIN), is a crucial regulator of multiple immune signaling pathways. In humans, HOIL1 or HOIP deficiency is associated with an immune disorder involving autoinflammation, immunodeficiency, and inflammatory bowel disease (IBD)-like symptoms. During viral infection, LUBAC is reported to inhibit the induction of interferon (IFN) by the cytosolic RNA sensor retinoic acid-inducible gene I (RIG-I). Surprisingly, we found that HOIL1 is essential for the induction of both type I and type III IFNs, as well as the phosphorylation of IFN regulatory factor 3 (IRF3), during murine norovirus (MNoV) infection in cultured dendritic cells. The RIG-I-like receptor, melanoma differentiation-associated protein 5 (MDA5), is also required for IFN induction and IRF3 phosphorylation during MNoV infection. Furthermore, HOIL1 and MDA5 were required for IFN induction after Theiler's murine encephalomyelitis virus infection and poly(I·C) transfection, but not Sendai virus or vesicular stomatitis virus infection, indicating that HOIL1 and LUBAC are required selectively for MDA5 signaling. Moreover, Hoil1-/- mice exhibited defective control of acute and persistent murine norovirus infection and defective regulation of MNoV persistence by the microbiome as also observed previously for mice deficient in interferon lambda (IFN-λ) receptor, signal transducer and activator of transcription factor 1 (STAT1), and IRF3. These data indicate that LUBAC plays a critical role in IFN induction to control RNA viruses sensed by MDA5.IMPORTANCE Human noroviruses are a leading cause of gastroenteritis throughout the world but are challenging to study in vivo and in vitro Murine norovirus (MNoV) provides a tractable genetic and small-animal model to study norovirus biology and immune responses. Interferons are critical mediators of antiviral immunity, but excessive expression can dysregulate the immune system. IFN-λ plays an important role at mucosal surfaces, including the gastrointestinal tract, and both IFN-λ and commensal enteric bacteria are important modulators of persistent MNoV infection. LUBAC, of which HOIL1 is a component, is reported to inhibit type I IFN induction after RIG-I stimulation. We show, in contrast, that HOIL1 is critical for type I and III IFN induction during infection with MNoV, a virus that preferentially activates MDA5. Moreover, HOIL1 regulates MNoV infection in vivo These data reveal distinct functions for LUBAC in these closely related signaling pathways and in modulation of IFN expression.

Transforming community services through the use of a multidimensional model of clinical leadership.

AIMS AND OBJECTIVES: To evaluate the application of a Multidimensional Model of Clinical Leadership on the community healthcare leader and on transforming community services. BACKGROUND: Healthcare policy advocates clinical leadership as the vehicle to transform community and healthcare services. Few studies have identified the key components of an effective clinical leadership development model. DESIGN: The first two stages of Kirkpatrick's (Personnel Administrator 28, 1983, 62) Four/Five Levels of Evaluation were used to evaluate the application of the multidimensional model of clinical leadership. METHODS: Eighty community healthcare leaders were exposed to this multidimensional clinical leadership development model through attendance of a community clinical leadership development programme. Twenty five leaders participated in focus group interviews. Data from the interviews were analysed utilising thematic content analysis. RESULTS: Three key themes emerged that influenced the development of best practice principles for clinical leadership development: 1. Personal leadership development 2. Organisational leadership 3. The importance of multiprofessional action learning/reflective groups CONCLUSIONS: Emergent best practice principles for clinical leadership development include adopting a multidimensional development approach. This approach encompasses: preparing the individual leader in the role and seeking organisational leadership development that promotes the vision and corporate values of the organisation and delivers on service improvement and innovation. Moreover, application of the Multidimensional Model of Clinical Leadership could offer the best platform for embedding the Six C's of Nursing (Compassion in Practice - Our Culture of Compassionate Care, Department of Health, Crown Copyright, 2012) within the culture of the healthcare organisation: care, compassion, courage, commitment, communication, and competency. This is achieved in part through the application of emotional intelligence to understand self and to develop the personal integrity of the healthcare leader and through supporting a culture of lifelong leadership learning. RELEVANCE TO CLINICAL PRACTICE: Embedding the best practice principles of clinical leadership development within a multidimensional model of clinical leadership provides a promising approach to: equipping the healthcare leader with those transferable leadership skills required to help them embark on a journey of lifelong leadership learning; and producing the healthcare leader who is caring, compassionate and can confidently and effectively transform community services.

HOIL1 regulates group 2 innate lymphoid cell numbers and type 2 inflammation in the small intestine.

Patients with mutations in HOIL1 experience a complex immune disorder including intestinal inflammation. To investigate the role of HOIL1 in regulating intestinal inflammation, we employed a mouse model of partial HOIL1 deficiency. The ileum of HOIL1-deficient mice displayed features of type 2 inflammation including tuft cell and goblet cell hyperplasia, and elevated expression of Il13, Il5 and Il25 mRNA. Inflammation persisted in the absence of T and B cells, and bone marrow chimeric mice revealed a requirement for HOIL1 expression in radiation-resistant cells to regulate inflammation. Although disruption of IL-4 receptor alpha (IL4Rα) signaling on intestinal epithelial cells ameliorated tuft and goblet cell hyperplasia, expression of Il5 and Il13 mRNA remained elevated. KLRG1hi CD90lo group 2 innate lymphoid cells were increased independent of IL4Rα signaling, tuft cell hyperplasia and IL-25 induction. Antibiotic treatment dampened intestinal inflammation indicating commensal microbes as a contributing factor. We have identified a key role for HOIL1, a component of the Linear Ubiquitin Chain Assembly Complex, in regulating type 2 inflammation in the small intestine. Understanding the mechanism by which HOIL1 regulates type 2 inflammation will advance our understanding of intestinal homeostasis and inflammatory disorders and may lead to the identification of new targets for treatment.

Initial Validation of the Suicide Competency Assessment Form among Behavioral Health Staff in the National Health Services Trust.

The Suicide Competency Assessment Form (SCAF) provides a framework for suicide prevention skills training. This study assessed SCAF psychometric properties in a sample of behavioral health staff. A cross-sectional survey of National Health Services (NHS) staff from varying disciplines (N = 170) was conducted. The SCAF yielded a 1-factor structure with high internal consistency. Nursing assistants reported lower SCAF scores compared to other professionals. SCAF scores demonstrated positive associations with prior suicide prevention training, job enthusiasm, and several suicide/self-injury prevention outcome expectations (i.e., optimism working with self-harming patients and perceived ability to help self-harming patients). SCAF scores further demonstrated incremental validity in the form of multivariate model associations with suicide/self-injury prevention outcome expectations. Improved job satisfaction mediated the pathway from SCAF scores to perceived ability to help self-harming patients. The SCAF can be utilized in suicide prevention training and clinical supervision.

Coping, mental health, and subjective well-being among mental health staff working in secure forensic psychiatric settings: Results from a workplace health assessment.

Given raised rates of patient suicide and violence in secure psychiatric facilities, staff in such settings are arguably at increased risk for burnout and reduced mental health. The present article responds to the recent U.K. National Institute for Health and Care Excellence (NICE) call to assess workforce well-being. This article held the following aims: (1) to quantify existing levels of mental health (i.e., depression, anxiety, distress, and posttraumatic stress) and subjective well-being (i.e., job satisfaction, life satisfaction, and four domains of burnout) and (2) to evaluate Coping Self-Efficacy (CSE) and Need for Affect (NFA) as factors associated with staff mental health and subjective well-being. We conducted a voluntary cross-sectional health needs assessment of forensic mental health staff (N = 170) between 2017 and 2018 from one National Health Service (NHS) Trust. Descriptive findings suggest staff possessed nonclinical average ranges of mental health symptoms. Subjective well-being findings showed burnout was relatively low, whereas job and life satisfaction were modest. Regression models demonstrated that (a) thought/emotion stopping beliefs were negatively associated with psychological exhaustion; (b) social support beliefs were positively associated with life satisfaction and job enthusiasm; (c) NFA Avoidance was linked with poor mental health and burnout, and; (d) NFA Approach was positively associated with two health subjective well-being indicators. Overall, assessment results suggest NHS forensic mental health staff reported relatively good health. Cognitive- and emotion-focused coping beliefs demonstrate promise as content for prevention programming. Using Emotional Labor Theory, we offer psychological services-based recommendations for future prevention programming and research. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Glycopyrrolate in comparison to hyoscine hydrobromide and placebo in the treatment of hypersalivation induced by clozapine (GOTHIC1): a feasibility study.

BACKGROUND: Clozapine-induced hypersalivation (CIH) is a common side effect of clozapine treatment and is disliked by clozapine patients, potentially threatening adherence to clozapine treatment. We proposed a trial of alternative medications, hyoscine and glycopyrrolate, for the treatment of CIH and the primary objective of the feasibility study was to assess the recruitment and retention of community clozapine patients as well as assess the metrics of the primary hypersalivation measure. METHODS: This 11-month trial took place in two NHS trusts in northwest UK. Participants were community-dwelling clozapine patients aged 18-65 years who were suffering from CIH, and were recruited from community mental health clinics. They were randomised using a telephone randomisation service to receive either hyoscine (1 week at 0.6 mg daily, 3 weeks at 0.9 mg daily), glycopyrrolate (1 week at 2 mg daily, 3 weeks at 3 mg daily) or placebo. Participants and investigators were blinded to which study arm the participants had been randomised to. We collected data on salivation levels and side effects on a weekly basis and also assessed cognition at the beginning and end of the trial. We also interviewed a sample of participants after the trial to gather information on their experience of having taken part. RESULTS: One hundred and thirty-eight potential participants agreed to being contacted by researchers about participation in the trial and of these, 29 participants were randomised. Of these, four participants exited the trial before taking any trial medication, and two participants left the study owing to concerns of side effects. Data from four participants was missing, and complete data was available for 19 participants who completed the trial. The mean recruitment rate overall was 1.3 participants per site per month, and the overall retention rate was 76%. Interview data suggested that participants' experiences of trial participation were overwhelmingly positive. CONCLUSIONS: The feasibility study demonstrated that a trial of alternative medications in the treatment of CIH is feasible; patients were willing to be randomised to the trial and retention rate was high. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02613494, registered 24 November 2015.

The prevalence of constant supportive observations in high, medium and low secure services.

Aims and method We explored the prevalence and use of constant supportive observations (CSO) in high, medium and low secure in-patient services in a single National Health Service (NHS) mental health trust. From clinical records, we extracted data on the length of time of CSO, the reason for the initiation of CSO and associated adverse incidents for all individuals who were placed on CSO between July 2013 and June 2014. RESULTS: A small number of individuals accounted for a disproportionately large proportion of CSO hours in each setting. Adverse incident rates were higher on CSO than when not on CSO. There was considerable variation between different settings in terms of CSO use and the reasons for commencing CSO. Clinical implications The study describes the prevalence and nature of CSO in secure forensic mental health services and the associated organisational costs. The marked variation in CSO use between settings suggests that mental health services continue to face challenges in balancing risk management with minimising restrictive interventions. Declaration of interest A.B. and J.L.I. are both directly employed by the NHS trust in which the study was conducted.