Evaluation of a population-wide, systematic screening initiative for tuberculosis on Daru island, Western Province, Papua New Guinea.

BACKGROUND: A population-wide, systematic screening initiative for tuberculosis (TB) was implemented on Daru island in the Western Province of Papua New Guinea, where TB is known to be highly prevalent. The initiative used a mobile van equipped with a digital X-ray device, computer-aided detection (CAD) software to identify TB-related abnormalities on chest radiographs, and GeneXpert machines for follow-on diagnostic testing. We describe the results of the TB screening initiative, evaluate its population-level impact and examine risk factors associated with TB detection. METHODS: Through a retrospective review of screening data, we assessed the effectiveness of the screening by examining the enrolment coverage and the proportion of people with TB among screened subjects. A cascade analysis was performed to illustrate the flow of participants in the screening algorithm. We conducted univariate and multivariate analyses to identify factors associated with TB. Furthermore, we estimated the number of additional cases detected by the project by examining the trend of routine TB case notifications during the intervention period, compared to the historical baseline cases and trend-adjusted expected cases. RESULTS: Of the island's 18,854 residents, 8,085 (42.9%) were enrolled and 7,970 (98.6%) had chest X-ray interpreted by the CAD4TB software. A total of 1,116 (14.0%) participants were considered to have abnormal CXR. A total of 69 Xpert-positive cases were diagnosed, resulting in a detection rate of 853 per 100 000 population screened. 19.4% of people with TB had resistance to rifampicin. People who were in older age groups (aOR 6.6, 95%CI: 1.5-29.1 for the 45-59 age group), were severely underweight (aOR 2.5, 95%CI:1.0-6.1) or underweight (aOR 2.1, 95%CI: 1.1-3.8), lived in households < 5 people (aOR 3.4, 95%CI:1.8-6.6) and had a past history of TB (aOR 2.1, 95%CI: 1.2-3.6) were more likely to have TB. The number of bacteriologically confirmed TB notified during the intervention period was 79.3% and 90.8% higher than baseline notifications and forecasted notifications, respectively. CONCLUSION: The screening project demonstrated its effectiveness with the high Xpert-positive TB prevalence among the participants and by successfully yielding additional cases of bacteriologically confirmed TB including rifampicin-resistant TB. The results and lessons learnt from the project should inform future TB screening initiatives in Papua New Guinea.

Squaramides enhance NLRP3 inflammasome activation by lowering intracellular potassium.

The NLRP3 inflammasome is a component of the inflammatory response to infection and injury, orchestrating the maturation and release of the pro-inflammatory cytokines interleukin-1ß (IL-1ß), IL-18, and triggering pyroptotic cell death. Appropriate levels of NLRP3 activation are needed to avoid excessive tissue damage while ensuring host protection. Here we report a role for symmetrical diarylsquaramides as selective K+ efflux-dependent NLRP3 inflammasome enhancers. Treatment of macrophages with squaramides potentiated IL-1ß secretion and ASC speck formation in response to K+ efflux-dependent NLRP3 inflammasome activators without affecting priming, endosome cargo trafficking, or activation of other inflammasomes. The squaramides lowered intracellular K+ concentration which enabled cells to respond to a below-threshold dose of the inflammasome activator nigericin. Taken together these data further highlight the role of ion flux in inflammasome activation and squaramides as an interesting platform for therapeutic development in conditions where enhanced NLRP3 activity could be beneficial.

Alcohol Prevention in Urgent and Emergency Care (APUEC): Development and Evaluation of Workforce Digital Training on Screening, Brief Intervention, and Referral for Treatment.

Excessive alcohol consumption carries a significant health, social and economic burden. Screening, brief intervention and referral to treatment (SBIRT) is one approach to identifying patients with excessive alcohol consumption and providing interventions to help them reduce their drinking. However, healthcare workers in urgent and emergency care settings do not routinely integrate SBIRT into clinical practice and raise a lack of training as a barrier to SBIRT delivery. Therefore, "Alcohol Prevention in Urgent and Emergency Care" (APUEC) training was developed, delivered, and evaluated. APUEC is a brief, stand-alone, multimedia, interactive digital training package for healthcare workers. The aim of APUEC is to increase positive attitudes, knowledge, confidence and skills related to SBIRT through the provision of (a) education on the impact of alcohol and the role of urgent and emergency care in alcohol prevention, and (b) practical guidance on patient assessment, delivery of brief advice and making referral decisions. Development involved collaborative-participatory design approaches and a rigorous six-step ASPIRE methodology (involving n = 28 contributors). APUEC was delivered to healthcare workers who completed an online survey (n = 18) and then participated in individual qualitative interviews (n = 15). Analysis of data was aligned with Levels 1-3 of the Kirkpatrick Model of Training Evaluation. Survey data showed that all participants (100%) found the training useful and would recommend it to others. Insights from the qualitative data showed that APUEC digital training increases healthcare workers' perceived knowledge, confidence and skills related to alcohol prevention in urgent and emergency care settings. Participants viewed APUEC to be engaging and relevant to urgent and emergency care workers. This digital training was perceived to be useful for workforce skills development and supporting the implementation of SBIRT in clinical practice. While the impact of APUEC on clinician behaviour and patient outcomes is yet to be tested, APUEC digital training could easily be embedded within education and continuing professional development programmes for healthcare workers and healthcare trainees of any discipline. Ultimately, this may facilitate the integration of SBIRT into routine care and contribute to population health improvement.

Attitudes and current practice in alcohol screening, brief intervention, and referral for treatment among staff working in urgent and emergency settings: An open, cross-sectional international survey.

BACKGROUND: The aim of the study was to ascertain the views and experiences of those working in urgent and emergency care (UEC) settings towards screening, brief intervention, and referral to treatment (SBIRT) for alcohol, to inform future practice. OBJECTIVES: To explore i) views towards health promotion, ii) views towards and practice of SBIRT, iii) facilitators and barriers to delivering SBIRT, iv) training needs to support future SBIRT practice, and v) comparisons in views and attitudes between demographic characteristics, geographical regions, setting and occupational groups. METHODS: This was an open cross-sectional international survey, using an online self-administered questionnaire with closed and open-ended responses. Participants were ≥18 years of age, from any occupational group, working in urgent and emergency care (UEC) settings in any country or region. RESULTS: There were 362 respondents (aged 21-65 years, 87.8% shift workers) from 7 occupational groups including physicians (48.6%), nurses (22.4%) and advanced clinical practitioners (18.5%). Most believed that health promotion is part of their role, and that SBIRT for alcohol prevention is needed and appropriate in UEC settings. SBIRT was seen to be acceptable to patients. 66% currently provide brief alcohol advice, but fewer screen for alcohol problems or make alcohol-related referrals. The most common barriers were high workload and lack of funding for prevention, lack of knowledge and training on SBIRT, lack of access to high-quality resources, lack of timely referral pathways, and concerns about patient resistance to advice. Some views and attitudes varied according to demographic characteristics, occupation, setting or region. CONCLUSIONS: UEC workers are willing to engage in SBIRT for alcohol prevention but there are challenges to implementation in UEC environments and concerns about workload impacts on already-burdened staff, particularly in the context of global workforce shortages. UEC workers advocate for clear guidelines and policies, increased staff capacity and/or dedicated health promotion teams onsite, SBIRT education/training/resources, appropriate physical spaces for SBIRT conversations and improved alcohol referral pathways to better funded services. Implementation of SBIRT could contribute to improving population health and reducing service demand, but it requires significant and sustained commitment of time and resources for prevention across healthcare organisations.

Effectiveness and implementation of interventions for health promotion in urgent and emergency care settings: an umbrella review.

BACKGROUND: Urgent and emergency care (UEC) settings provide an opportunity to prevent ill-health and promote healthy lifestyles with potential to screen and deliver interventions to under-served, at-risk populations. The aim of this study was to synthesise and summarise the evidence on the effectiveness and implementation of interventions for health promotion in UEC settings. METHODS: PubMed and Embase (OVID) databases were used to search for studies published in English between January 2010 and January 2023. Systematic reviews and meta-analyses of studies that examined the effectiveness or implementation of face-to-face health promotion interventions for lifestyle behaviours delivered in UEC settings were eligible. Extracted data were synthesised and qualitatively summarised by lifestyle behaviour. Reviews were quality assessed using AMSTAR 2. RESULTS: Eighteen reviews met the inclusion criteria; all included studies were conducted in emergency departments or trauma units. We identified 15 reviews on alcohol interventions (13 on effectiveness; 2 on implementation) and 3 on smoking interventions (effectiveness). There were no reviews of intervention studies targeting physical activity or diet and nutrition. There was heterogeneity across studies for study design, target populations, intervention design and content, comparator/control groups and outcomes assessed. The effectiveness of alcohol and smoking interventions in UEC settings varied but some reviews provided evidence of a significant decrease in alcohol consumption, alcohol-related outcomes and smoking in intervention groups, particularly in the short-term and in specific population groups. Research has focused on 'brief' interventions as part of screening, brief intervention and referral to treatment (SBIRT) approaches. Interventions are delivered by a wide range of staff with substantial variation in design. Alcohol brief interventions appear to be acceptable to UEC patients but clinicians face barriers in delivering them. CONCLUSIONS: UEC settings have been under-researched and appear to be under-utilised for delivering health promotion activities, except for alcohol prevention. Review level evidence suggests alcohol and smoking interventions are warranted in some population groups. However, further research is needed to determine the optimal intervention design, content and delivery mode for lifestyle behaviours which are suitable for implementation in UEC settings and promote long-term intervention effectiveness. Changes in clinical practice may be needed, including increased training, integration into service delivery and supportive policy, to facilitate the implementation of SBIRT for lifestyle behaviours. Interventions may need to be delivered in the wider UEC system such as urgent care centres, minor injury units and walk-in centres, in addition to emergency departments and trauma units, to support and increase health promotion activities in UEC settings.

The global assessment of OCD.

Obsessive Compulsive Disorder (OCD) is a common mental disorder that often causes great sufferance, with substantial impairment in social functioning and quality of life and affects family and significant relationships. Notwithstanding its severity, OCD is often not adequately diagnosed, or it is diagnosed with delay, leading often to a long latency between onset of the OCD symptoms and the start of adequate treatments. Several factors contribute to the complexity of OCD's clinical picture: early age of onset, chronic course, heterogeneity of symptoms, high rate of comorbidity with other psychiatric disorders, slow or partial response to therapy. Therefore, it is of primary importance for clinicians involved in diagnosing OCD, to assess all aspects of the disorder. This narrative review focuses on the global assessment of OCD, highlighting crucial areas to explore, pointing out the clinical features which are relevant for the treatment of the disorder, and giving an overview of the psychometric tools that can be useful during the screening procedure.

Enablers and barriers to non-dispensing pharmacist integration into the primary health care teams of Aboriginal community-controlled health services.

BACKGROUND: The primary health care management of chronic disease affecting Aboriginal and Torres Strait Islander peoples requires healthcare quality and equity demands to be met, and systems that foster better team-based care. Non-dispensing pharmacists (NDPs) integrated within primary healthcare settings can enhance the quality of patient care, although factors that enable or challenge integration within these settings need to be better understood. OBJECTIVES: To investigate enabling factors and barriers influencing integration of NDPs within Aboriginal community-controlled health services delivering primary health care. This was achieved through qualitative evaluation of the Integrating Pharmacists within Aboriginal Community Controlled Health Services (IPAC) Trial exploring the perceptions of NDPs, community pharmacists, healthcare staff, managers, and Aboriginal and Torres Strait Islander patients of these services. METHODS: NDPs were employed across twenty urban, rural, and remote services in three Australian states and provided pre-defined medication-related roles to adult Aboriginal and Torres Strait Islander patients. Perceptions were elicited from online surveys, interviews, and focus groups. Transcripts were thematically analyzed using the constant comparison method to identify, compare, and refine emerging themes. RESULTS: One hundred and four participants informed the findings, including 24 NDPs, 13 general practitioners, 12 service managers, 10 community pharmacists, 17 health service staff, and 17 patients. Enablers of integration included: personal (previous experience with Aboriginal and Torres Strait Islander peoples, cultural awareness, skills, individual attributes); health service-related (induction programs, Aboriginal Health Worker support, team-building initiatives); and community-related factors (engaged community elders, leaders, cultural mentors, community pharmacy champions). Barriers to NDP integration included a lack of systems supports for patients and staff to adapt to NDP roles, health service factors, travel requirements, a lack of community linkages, and time and budget constraints. CONCLUSIONS: NDP integration within primary health care services has potential to enhance medication-related services to Aboriginal and Torres Strait Islander peoples if enabling factors are supported and health systems and adequate resources facilitate the integration of pharmacists within these settings.

Comparison of standard automotive industry injury predictors and actual injury sustained during significant whiplash events.

PURPOSE: We present a unique opportunity to compare standard neck injury criteria (used by the automotive industry to predict injury) with real-life injuries. The injuries sustained during, and the overall kinematics of, a television demonstration of whiplash mechanics were used to inform and validate a vertebral level model of neck mechanics to examine the relevance of current injury criteria used by the automotive industry. METHODS: Frontal and rear impact pulses, obtained from videos of sled motion, were used to drive a MADYMO human model to generate detailed segmental level biomechanics. The maximum amplitude of the frontal and rear crash pulses was 166 ms-2 and 196 ms-2, respectively, both with a duration of 0.137 s. The MADYMO model was used to predict standard automotive neck injury criteria as well as detailed mechanics of each cervical segment. RESULTS: Whilst the subject suffered significant upper neck injuries, these were not predicted by conventional upper neck injury criteria (Nij and Nkm). However, the model did predict anterior accelerations of C1 and C2 of 40 g, which is 5 times higher than the threshold of the acceleration for alar ligament injury. Similarly, excessive anterior shear displacement (15 mm) of the skull relative to C2 was predicted. Predictions of NIC, an injury criterion relevant to the lower neck, as well as maximum flexion angles for the lower cervical segments (C3-T1) exceeded injury thresholds. CONCLUSION: The criteria used by the automotive industry as standard surrogates for upper neck injury (Nij and Nkm) did not predict the significant cranio-cervical junction injury observed clinically.

NINJ1 mediates plasma membrane rupture during lytic cell death.

Plasma membrane rupture (PMR) is the final cataclysmic event in lytic cell death. PMR releases intracellular molecules known as damage-associated molecular patterns (DAMPs) that propagate the inflammatory response1-3. The underlying mechanism of PMR, however, is unknown. Here we show that the cell-surface NINJ1 protein4-8, which contains two transmembrane regions, has an essential role in the induction of PMR. A forward-genetic screen of randomly mutagenized mice linked NINJ1 to PMR. Ninj1-/- macrophages exhibited impaired PMR in response to diverse inducers of pyroptotic, necrotic and apoptotic cell death, and were unable to release numerous intracellular proteins including HMGB1 (a known DAMP) and LDH (a standard measure of PMR). Ninj1-/- macrophages died, but with a distinctive and persistent ballooned morphology, attributable to defective disintegration of bubble-like herniations. Ninj1-/- mice were more susceptible than wild-type mice to infection with Citrobacter rodentium, which suggests a role for PMR in anti-bacterial host defence. Mechanistically, NINJ1 used an evolutionarily conserved extracellular domain for oligomerization and subsequent PMR. The discovery of NINJ1 as a mediator of PMR overturns the long-held idea that cell death-related PMR is a passive event.

LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation.

The NLRP3 inflammasome is a multi-molecular protein complex that converts inactive cytokine precursors into active forms of IL-1ß and IL-18. The NLRP3 inflammasome is frequently associated with the damaging inflammation of non-communicable disease states and is considered an attractive therapeutic target. However, there is much regarding the mechanism of NLRP3 activation that remains unknown. Chloride efflux is suggested as an important step in NLRP3 activation, but which chloride channels are involved is still unknown. We used chemical, biochemical, and genetic approaches to establish the importance of chloride channels in the regulation of NLRP3 in murine macrophages. Specifically, we identify LRRC8A, an essential component of volume-regulated anion channels (VRAC), as a vital regulator of hypotonicity-induced, but not DAMP-induced, NLRP3 inflammasome activation. Although LRRC8A was dispensable for canonical DAMP-dependent NLRP3 activation, this was still sensitive to chloride channel inhibitors, suggesting there are additional and specific chloride sensing and regulating mechanisms controlling NLRP3.

Inflammation is a critical part of a healthy immune system, which protects us against harmful pathogens (such as bacteria or viruses) and works to restore damaged tissues. In the immune cells of our body, the inflammatory process can be activated through a group of inflammatory proteins that together are known as the NLRP3 inflammasome complex. While inflammation is a powerful mechanism that protects the human body, persistent or uncontrolled inflammation can cause serious, long-term damage. The inappropriate activation of the NLRP3 inflammasome has been implicated in several diseases, including Alzheimer's disease, heart disease, and diabetes. The NLRP3 inflammasome can be activated by different stimuli, including changes in cell volume and exposure to either molecules produced by damaged cells or toxins from bacteria. However, the precise mechanism through which the NLRP3 becomes activated in response to these stimuli was not clear. The exit of chloride ions from immune cells is known to activate the NLRP3 inflammasome. Chloride ions exit the cell through proteins called anion channels, including volume-regulated anion channels (VRACs), which respond to changes in cell volume. Green et al. have found that, in immune cells from mice grown in the lab called macrophages, VRACs are the only chloride channels involved in activating the NLRP3 inflammasome when the cell's volume changes. However, when the macrophages are exposed to molecules produced by damaged cells or toxins from bacteria, Green et al. discovered that other previously unidentified chloride channels are involved in activating the NLRP3 inflammasome. These results suggest that it might be possible to develop drugs to prevent the activation of the NLRP3 inflammasome that selectively target specific sets of chloride channels depending on which stimuli are causing the inflammation. Such a selective approach would minimise the side effects associated with drugs that generically suppress all NLRP3 activity by directly binding to NLRP3 itself. Ultimately, this may help guide the development of new, targeted anti-inflammatory drugs that can help treat the symptoms of a variety of diseases in humans.

Selective inhibition of the K+ efflux sensitive NLRP3 pathway by Cl- channel modulation.

The NLRP3 inflammasome regulates production of the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18, and contributes to inflammation exacerbating disease. Fenamate non-steroidal anti-inflammatory drugs (NSAIDs) were recently described as NLRP3 inflammasome inhibitors via chloride channel inhibition. Fenamate NSAIDs inhibit cyclooxygenase (COX) enzymes, limiting their potential as therapeutics for NLRP3-associated diseases due to established side effects. The aim here was to develop properties of the fenamates that inhibit NLRP3, and at the same time to reduce COX inhibition. We synthesised a library of analogues, with feedback from in silico COX docking potential, and IL-1ß release inhibitory activity. Through iterative screening and rational chemical design, we established a collection of chloride channel inhibiting active lead molecules with potent activity at the canonical NLRP3 inflammasome and no activity at COX enzymes, but only in response to stimuli that activated NLRP3 by a K+ efflux-dependent mechanism. This study identifies a model for the isolation and removal of unwanted off-target effects, with the enhancement of desired activity, and establishes a new chemical motif for the further development of NLRP3 inflammasome inhibitors.

IRF2 transcriptionally induces GSDMD expression for pyroptosis.

Gasdermin-D (GSDMD) is cleaved by caspase-1, caspase-4, and caspase-11 in response to canonical and noncanonical inflammasome activation. Upon cleavage, GSDMD oligomerizes and forms plasma membrane pores, resulting in interleukin-1ß (IL-1ß) secretion, pyroptotic cell death, and inflammatory pathologies, including periodic fever syndromes and septic shock-a plague on modern medicine. Here, we showed that IRF2, a member of the interferon regulatory factor (IRF) family of transcription factors, was essential for the transcriptional activation of GSDMD. A forward genetic screen with N-ethyl-N-nitrosourea (ENU)-mutagenized mice linked IRF2 to inflammasome signaling. GSDMD expression was substantially attenuated in IRF2-deficient macrophages, endothelial cells, and multiple tissues, which corresponded with reduced IL-1ß secretion and inhibited pyroptosis. Mechanistically, IRF2 bound to a previously uncharacterized but unique site within the GSDMD promoter to directly drive GSDMD transcription for the execution of pyroptosis. Disruption of this single IRF2-binding site abolished signaling by both the canonical and noncanonical inflammasomes. Together, our data illuminate a key transcriptional mechanism for expression of the gene encoding GSDMD, a critical mediator of inflammatory pathologies.

Alveolar Macrophage Apoptosis-associated Bacterial Killing Helps Prevent Murine Pneumonia.

Rationale: Antimicrobial resistance challenges therapy of pneumonia. Enhancing macrophage microbicidal responses would combat this problem but is limited by our understanding of how alveolar macrophages (AMs) kill bacteria. Objectives: To define the role and mechanism of AM apoptosis-associated bacterial killing in the lung. Methods: We generated a unique CD68.hMcl-1 transgenic mouse with macrophage-specific overexpression of the human antiapoptotic Mcl-1 protein, a factor upregulated in AMs from patients at increased risk of community-acquired pneumonia, to address the requirement for apoptosis-associated killing. Measurements and Main Results: Wild-type and transgenic macrophages demonstrated comparable ingestion and initial phagolysosomal killing of bacteria. Continued ingestion (for ≥12 h) overwhelmed initial killing, and a second, late-phase microbicidal response killed viable bacteria in wild-type macrophages, but this response was blunted in CD68.hMcl-1 transgenic macrophages. The late phase of bacterial killing required both caspase-induced generation of mitochondrial reactive oxygen species and nitric oxide, the peak generation of which coincided with the late phase of killing. The CD68.hMcl-1 transgene prevented mitochondrial reactive oxygen species but not nitric oxide generation. Apoptosis-associated killing enhanced pulmonary clearance of Streptococcus pneumoniae and Haemophilus influenzae in wild-type mice but not CD68.hMcl-1 transgenic mice. Bacterial clearance was enhanced in vivo in CD68.hMcl-1 transgenic mice by reconstitution of apoptosis with BH3 mimetics or clodronate-encapsulated liposomes. Apoptosis-associated killing was not activated during Staphylococcus aureus lung infection. Conclusions: Mcl-1 upregulation prevents macrophage apoptosis-associated killing and establishes that apoptosis-associated killing is required to allow AMs to clear ingested bacteria. Engagement of macrophage apoptosis should be investigated as a novel, host-based antimicrobial strategy.

Violent incidents in a secure service for individuals with learning disabilities: Incident types, circumstances and staff responses.

BACKGROUND: The issue of violence in secure services has long been recognized both in the UK and worldwide. However, there is currently scarce literature available about violence within learning disability (LD) secure settings. METHODS: Secondary data analysis was conducted on violent incidents, using information routinely collected by the staff over a 1-year period. RESULTS: Physical assaults were the most frequent type of incident, and the distribution in terms of days or months was homogenous and incidents were concentrated in the corridors, lounges and dining rooms of secure facilities. Antipsychotic medication was not regularly prescribed. Generalized linear modelling analyses revealed significant predictors that increased the chances of seclusion and physical restraint, such as being female or directing the violence towards staff. CONCLUSIONS: These findings can inform staff training on violence prevention and suggest that increased ward-based supervision and enhanced use of psychological formulations may help in reducing violence within this service context.

A qualitative meta-synthesis of emergency department staff experiences of violence and aggression.

INTRODUCTION: Patient and visitor violence or aggression against healthcare workers in the Emergency Department (ED) is a significant issue worldwide. This review synthesises existing qualitative studies exploring the first-hand experiences of staff working in the ED to provide insight into preventing this issue. METHOD: A meta-ethnographic approach was used to review papers. RESULTS: Four concepts were identified: 'The inevitability of violence and aggression'; 'Staff judgments about why they face violence and aggression'; 'Managing in isolation'; and 'Wounded heroes'. DISCUSSION: Staff resigned themselves to the inevitability of violence and aggression, doing this due to a perceived lack of support from the organisation. Staff made judgements about the reasons for violent incidents which impacted on how they coped and subsequently tolerated the aggressor. Staff often felt isolated when managing violence and aggression. Key recommendations included: Staff training in understanding violence and aggression and clinical supervision. CONCLUSION: Violence and aggression in the ED can often be an overwhelming yet inevitable experience for staff. A strong organisational commitment to reducing violence and aggression is imperative.

Management of severe dehydration.

The presented case is one of severe dehydration and acute kidney injury with significant resultant complications that required considerable fluid and electrolyte replacement. Approaches to fluid resuscitation in the context of hypernatraemia and the hyperosmolar state were considered and then judiciously combined to manage a complex case with a successful outcome. Conflicting guidance in this domain is discussed with recommendations for a future management strategy that is tailored to individual patients.

Symmetrical and asymmetrical outcomes of leader anger expression: A qualitative study of army personnel.

Recent studies have highlighted the utility of anger at work, suggesting that anger can have positive outcomes. Using the Dual Threshold Model, we assess the positive and negative consequences of anger expressions at work and focus on the conditions under which expressions of anger crossing the impropriety threshold are perceived as productive or counterproductive by observers or targets of that anger. To explore this phenomenon, we conducted a phenomenological study (n = 20) to probe the lived experiences of followers (as observers and targets) associated with anger expressions by military leaders. The nature of task (e.g. the display rules prescribed for combat situations) emerged as one condition under which the crossing of the impropriety threshold leads to positive outcomes of anger expressions. Our data reveal tensions between emotional display rules and emotional display norms in the military, thereby fostering paradoxical attitudes toward anger expression and its consequences among followers. Within this paradoxical space, anger expressions have both positive (asymmetrical) and negative (symmetrical) consequences. We place our findings in the context of the Dual Threshold Model, discuss the practical implications of our research and offer avenues for future studies.

Non-pharmacological interventions to reduce ICU-related psychological distress: a systematic review.

INTRODUCTION: Patients frequently suffer stress in intensive care units (ICUs) and many develop serious psychological morbidity after discharge. Little is known about the nature and efficacy of interventions to reduce ICU-related distress. There is growing evidence that administering sedative drugs can be harmful. Therefore we carried out a systematic review of non-pharmacological interventions to reduce ICU-related distress. EVIDENCE ACQUISITION: A systematic search was conducted using Medline, Embase, Psychinfo, Cinahl and the Web of Science. Included studies evaluated the effect of non-pharmacological interventions to reduce ICU stress. Study populations were adults in mixed or general ICUs. Outcomes were stress or psychological distress in or after the ICU, using self-report or physiological measures. No meta-analysis was possible due to heterogeneity, therefore studies were arranged according to intervention type, and outcomes examined together with risk of bias criteria. EVIDENCE SYNTHESIS: Twenty-three studies were eligible, including 15 randomized controlled trials. Non-pharmacological interventions included music therapy (11 studies), mind-body practices (5) and psychological interventions (7). 12 studies showed a beneficial effect. However only three of the 12 had a low risk of bias, and many studies in the review were under-powered to detect an effect. Only 5 studies measured a medium/long term psychological outcome such as PTSD or depression at 2-12 months. CONCLUSIONS: Evidence indicates that non-pharmacological approaches to reducing ICU distress, in particular psychological interventions, may be beneficial. The evidence base would be strengthened by the implementation of fully-powered studies using robust designs, that measure longer-term outcomes.

Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling.

Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing pyroptotic cell death, interleukin-1ß processing, and lethal septic shock. How caspase-11 executes these downstream signalling events is largely unknown. Here we show that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1ß maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice links Gsdmd to the intracellular lipopolysaccharide response. Macrophages from Gsdmd(-/-) mice generated by gene targeting also exhibit defective pyroptosis and interleukin-1ß secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, Gsdmd(-/-) mice are protected from a lethal dose of lipopolysaccharide. Mechanistically, caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify gasdermin D as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacteria.