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STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

BACKGROUND: Given the highly stressful environment surrounding the SARS-CoV-2 pandemic, healthcare workers (HCW) and public safety personnel (PSP) are at an elevated risk for adverse psychological outcomes, including posttraumatic stress disorder (PTSD) and alcohol/substance use problems. As such, the study aimed to identify associations between PTSD severity, related dissociation and emotion dysregulation symptoms, and alcohol/substance use problems among HCWs and PSP. METHODS: A subset of data (N = 498; HCWs = 299; PSP = 199) was extracted from a larger study examining psychological variables among Canadian HCWs and PSP during the pandemic. Structural equation modelling assessed associations between PTSD symptoms and alcohol/substance use-related problems with dissociation and emotion dysregulation as mediators. RESULTS: Among HCWs, dissociation fully mediated the relation between PTSD and alcohol-related problems (indirect effect β = .133, p = .03) and emotion dysregulation partially mediated the relation between PTSD and substance-related problems (indirect effect β = .151, p = .046). In PSP, emotion dysregulation fully mediated the relation between PTSD and alcohol-related problems (indirect effects β = .184, p = .005). For substance-related problems among PSP, neither emotion dysregulation nor dissociation (ps >.05) had any effects. CONCLUSION: To our knowledge, this is the first study examining associations between PTSD severity and alcohol/substance use-related problems via mediating impacts of emotion dysregulation and dissociation among HCWs and PSP during the SARS-CoV-2 pandemic. These findings highlight dissociation and emotion dysregulation as important therapeutic targets for structured interventions aimed at reducing the burden of PTSD and/or SUD among Canadian HCWs or PSP suffering from the adverse mental health impacts of the SARS-CoV-2 pandemic.

Background: Staffing shortages across the healthcare sector pose a threat to the continuity of the Canadian healthcare system in the post-COVID-19 pandemic era. We sought to understand factors associated with turnover intention as well as Canadian healthcare providers' (HCPs) perspectives and experiences with turnover intention as related to both organizational and professional turnover. Method: A convergent questionnaire mixed-methods design was employed. Descriptive statistics and ordinal logistic regressions were used to analyze quantitative data and ascertain factors associated with turnover intention. Thematic analysis was used to analyze qualitative open-field textbox data and understand HCPs' perspectives and experiences with turnover intention. Results: Quantitative analyses revealed that 78.6% of HCPs surveyed (N = 398) reported at least a 25% turnover likelihood regarding their organization, with 67.5% reporting at least a 25% turnover likelihood regarding their profession. Whereas regression models revealed the significant impact of years worked, burnout, and organizational support on turnover likelihood for organizations, age, sex, burnout, and organizational support contributed to the likelihood of leaving a profession. Patterns of meaning drawn from participants' qualitative responses were organized according to the following four themes: (1) Content to stay, (2) Drowning and no one cares, (3) Moral stressors, and (4) Wrestling with the costs and benefits. Conclusions: Many HCPs described weighing the costs and benefits of leaving their organization or profession during the COVID-19 pandemic. Although challenging working conditions, moral stressors, and burnout may play a significant role in HCPs' experiences of turnover intention, there is ample room to intervene with organizational support. [ABSTRACT FROM AUTHOR]

Background: A moral injury occurs when a deeply held moral code has been violated, and it can lead to the development of symptoms of posttraumatic stress disorder (PTSD). However, the neural correlates that differentiate moral injury and PTSD remain largely unknown. Intrinsic connectivity networks such as the default mode network (DMN) appear to be altered in people with PTSD who have experienced moral injury. However, brainstem, midbrain and cerebellar systems are rarely integrated into the intrinsic connectivity networks; this is a critical oversight, because these systems display marked differences in people with PTSD and are thought to underlie strong moral emotions such as shame, guilt and betrayal. Methods: We conducted an independent component analysis on data generated during script-driven memory recall of moral injury in participants with military- or law enforcement-related PTSD (n = 28), participants with civilian-related PTSD (n = 28) and healthy controls exposed to a potentially morally injurious event (n = 18). We conducted group-wise comparisons of functional network connectivity differences across a DMN-correlated independent component, with a particular focus on brainstem, midbrain and cerebellar systems. Results: We found stronger functional network connectivity in the midbrain periaqueductal grey ([t.sub.71] = 4.95, [p.sub.FDR] = 0.028, k = 39) and cerebellar lobule IX ([t.sub.71] = 4.44, [p.sub.FDR] = 0.046, k = 49) in participants with civilian-related PTSD as compared to healthy controls. We also found a trend toward stronger functional network connectivity in the midbrain periaqueductal grey ([t.sub.71] = 4.22, [p.sub.FDR] = 0.076, k = 60) in participants with military--or law enforcement-related PTSD as compared to healthy controls. Limitations: The significant clusters were large, but resolution is generally lower for subcortical structures. Conclusion: In PTSD, the DMN appears to be biased toward lower-level, midbrain systems, which may drive toxic shame and related moral emotions that are common in PTSD, highlighting the depth at which moral injuries are represented neurobiologically., Introduction In unusually high-stress situations, a person may perpetuate, fail to prevent, or witness an event that contradicts their deeply held moral beliefs and expectations. (1) When someone does something [...]

OBJECTIVES: Although dysfunctional emotion regulatory capacities are increasingly recognized as contributing to posttraumatic stress disorder (PTSD), little work has sought to identify biological markers of this vulnerability. Heart rate variability (HRV) is a promising biomarker that, together with neuroimaging, may assist in gaining a deeper understanding of emotion dysregulation in PTSD. The objective of the present study was, therefore, to characterize autonomic response patterns, and their related neuronal patterns in individuals with PTSD at rest. METHODS: PTSD patients (N = 57) and healthy controls (N = 41) underwent resting-state fMRI. Connectivity patterns of key regions within the central autonomic network (CAN)-including the ventromedial prefrontal cortex (vmPFC), amygdala, and periaqueductal gray (PAG)-were examined using a seed-based approach. Observed connectivity patterns were then correlated to resting HRV. RESULTS: In contrast to controls, individuals with PTSD exhibited lower HRV. In addition, whereas controls engaged a localized connectivity pattern of CAN-related brain regions, in PTSD, key CAN regions were associated with widespread connectivity patterns in regions related to emotional reactivity (vmPFC and amygdala to insular cortex and lentiform nucleus; PAG to insula) and motor readiness (vmPFC and amygdala to precentral gyrus; PAG to precentral gyrus and cerebellum). Critically, whereas CAN connectivity in controls was strongly related to higher HRV (insula, mPFC, superior frontal cortex, thalamus), HRV covariation was absent in PTSD subjects. CONCLUSIONS: This study provides the first evidence for a specific psychophysiological-neuronal profile in PTSD individuals characterized by lower resting HRV and a lack of HRV covariation with CAN-related brain connectivity. Hum Brain Mapp 38:27-40, 2017. © 2016 Wiley Periodicals, Inc.

Mindfulness-based treatments for posttraumatic stress disorder (PTSD) have emerged as promising adjunctive or alternative intervention approaches. A scoping review of the literature on PTSD treatment studies, including approaches such as mindfulness-based stress reduction, mindfulness-based cognitive therapy and metta mindfulness, reveals low attrition with medium to large effect sizes. We review the convergence between neurobiological models of PTSD and neuroimaging findings in the mindfulness literature, where mindfulness interventions may target emotional under- and overmodulation, both of which are critical features of PTSD symptomatology. Recent emerging work indicates that mindfulness-based treatments may also be effective in restoring connectivity between large-scale brain networks among individuals with PTSD, including connectivity between the default mode network and the central executive and salience networks. Future directions, including further identification of the neurobiological mechanisms of mindfulness interventions in patients with PTSD and direct comparison of these interventions to first-line treatments for PTSD are discussed., Introduction About 60%-75% of individuals in North America experience a traumatic event at some point in their lifetime. (1,2) The 12-month prevalence of posttraumatic stress disorder (PTSD) is estimated to [...]