Extracellular Vesicle ASC: A Novel Mediator for Lung-Brain Axis in Preterm Brain Injury.

Bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI) are among the most common morbidities affecting preterm infants. Although BPD is a predictor of poor NDI, it is currently uncertain how BPD contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are involved in inter-organ communication in diverse pathological processes. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly and activation of inflammatory response. We assessed expression profiles of alveolar macrophage (AM) markers, CD11b, CD11c, and CD206, and ASC in EVs isolated from the plasma of preterm infants at risk for BPD at 1 week of age. We found that infants on higher fraction inspired oxygen (FiO2) therapy (HO2, ≥30%) had increased levels of AM-derived EV-ASC compared with infants on lower FiO2 (LO2, <30%). To assess the function of these EVs, we performed adoptive transfer experiments by injecting them into the circulation of newborn mice. We discovered that mice that received EVs from infants on HO2 had increased lung inflammation, decreased alveolarization, and disrupted vascular development, the hallmarks of BPD. Importantly, these EVs crossed the blood-brain barrier and the EVs from infants on HO2 caused inflammation, reduced cell survival, and increased cell death with features of pyroptosis and necroptosis in the hippocampus. These results highlight a novel role for AM-derived EV-ASC in mediating the lung-to-brain crosstalk that is critical in the pathogenesis of BPD and brain injury and identify potential novel targets for preventing and treating BPD and brain injury in preterm infants.

Experience and Reporting of Postnatal Depression Across Cultures: A Comparison Using Anchoring Vignettes of Mothers in the United Kingdom and India.

Postnatal mental health is often assessed using self-assessment questionnaires in epidemiologic research. Differences in response style, influenced by language, culture, and experience, may mean that the same response may not have the same meaning in different settings. These differences need to be identified and accounted for in cross-cultural comparisons. Here we describe the development and application of anchoring vignettes to investigate the cross-cultural functioning of the Edinburgh Postnatal Depression Scale (EPDS) in urban community samples in India (n = 549) and the United Kingdom (n = 828), alongside a UK calibration sample (n = 226). Participants completed the EPDS and anchoring vignettes when their children were 12-24 months old. In an unadjusted item-response theory model, UK mothers reported higher depressive symptoms than Indian mothers (d = 0.48, 95% confidence interval: 0.358, 0.599). Following adjustment for differences in response style, these positions were reversed (d = -0.25, 95% confidence interval: -0.391, -0.103). Response styles vary between India and the United Kingdom, indicating a need to take these differences into account when making cross-cultural comparisons. Anchoring vignettes offer a valid and feasible method for global data harmonization.

IC100, a humanized therapeutic monoclonal anti-ASC antibody alleviates oxygen-induced retinopathy in mice.

BACKGROUND: Retinopathy of prematurity (ROP), which often presents with bronchopulmonary dysplasia (BPD), is among the most common morbidities affecting extremely premature infants and is a leading cause of severe vision impairment in children worldwide. Activations of the inflammasome cascade and microglia have been implicated in playing a role in the development of both ROP and BPD. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly. Utilizing mouse models of both oxygen-induced retinopathy (OIR) and BPD, this study was designed to test the hypothesis that hyperoxia induces ASC speck formation, which leads to microglial activation and retinopathy, and that inhibition of ASC speck formation by a humanized monoclonal antibody, IC100, directed against ASC, will ameliorate microglial activation and abnormal retinal vascular formation. METHODS: We first tested ASC speck formation in the retina of ASC-citrine reporter mice expressing ASC fusion protein with a C-terminal citrine (fluorescent GFP isoform) using a BPD model that causes both lung and eye injury by exposing newborn mice to room air (RA) or 85% O2 from postnatal day (P) 1 to P14. The retinas were dissected on P14 and retinal flat mounts were used to detect vascular endothelium with AF-594-conjugated isolectin B4 (IB4) and citrine-tagged ASC specks. To assess the effects of IC100 on an OIR model, newborn ASC citrine reporter mice and wildtype mice (C57BL/6 J) were exposed to RA from P1 to P6, then 75% O2 from P7 to P11, and then to RA from P12 to P18. At P12 mice were randomized to the following groups: RA with placebo PBS (RA-PBS), O2 with PBS (O2-PBS), O2 + IC100 intravitreal injection (O2-IC100-IVT), and O2 + IC100 intraperitoneal injection (O2-IC100-IP). Retinal vascularization was evaluated by flat mount staining with IB4. Microglial activation was detected by immunofluorescence staining for allograft inflammatory factor 1 (AIF-1) and CD206. Retinal structure was analyzed on H&E-stained sections, and function was analyzed by pattern electroretinography (PERG). RNA-sequencing (RNA-seq) of the retinas was performed to determine the transcriptional effects of IC100 treatment in OIR. RESULTS: ASC specks were significantly increased in the retinas by hyperoxia exposure and colocalized with the abnormal vasculature in both BPD and OIR models, and this was associated with increased microglial activation. Treatment with IC100-IVT or IC100-IP significantly reduced vaso-obliteration and intravitreal neovascularization. IC100-IVT treatment also reduced retinal microglial activation, restored retinal structure, and improved retinal function. RNA-seq showed that IC100 treatment corrected the induction of genes associated with angiogenesis, leukocyte migration, and VEGF signaling caused by O2. IC100 also corrected the suppression of genes associated with cell junction assembly, neuron projection, and neuron recognition caused by O2. CONCLUSION: These data demonstrate the crucial role of ASC in the pathogenesis of OIR and the efficacy of a humanized therapeutic anti-ASC antibody in treating OIR mice. Thus, this anti-ASC antibody may potentially be considered in diseases associated with oxygen stresses and retinopathy, such as ROP.

The use of parent-completed questionnaires to investigate developmental outcomes in large populations of children exposed to antiseizure medications in pregnancy.

OBJECTIVE: This study was undertaken to assess the utility of the Ages and Stages Questionnaire-3rd Edition (ASQ-3) and the Vineland Adaptive Behavior Scales-2nd Edition (VABS-II) as neurodevelopmental screening tools for infants exposed to antiseizure medications in utero, and to examine their suitability for use in large-population signal generation initiatives. METHODS: Participants were women with epilepsy who were recruited from 21 hospitals in England and Northern Ireland during pregnancy between 2014 and 2016. Offspring were assessed at 24 months old using the Bayley Scales of Infant Development-3rd Edition (BSID-III), the VABS-II, and the ASQ-3 (n = 223). The sensitivity and specificity of the ASQ-3 and VABS-II to identify developmental delay at 24 months were examined, using the BSID-III to define cases. RESULTS: The ASQ-3 identified 65 children (29.1%) as at risk of developmental delay at 24 months using standard referral criteria. Using a categorical approach and standard referral criteria to identify delay in the ASQ-3 and BSID-III at 24 months, the ASQ-3 showed excellent sensitivity (90.9%) and moderate specificity (74.1%). Utilizing different cut-points resulted in improved properties and may be preferred in certain contexts. The VABS-II exhibited the strongest psychometric properties when borderline impairment (>1 SD below the mean) was compared to BSID-III referral data (sensitivity = 100.0%, specificity = 96.6%). SIGNIFICANCE: Both the ASQ-3 and VABS-II have good psychometric properties in a sample of children exposed to antiseizure medications when the purpose is the identification of at-risk groups. These findings identify the ASQ-3 as a measure that could be used effectively as part of a tiered surveillance system for teratogenic exposure by identifying a subset of individuals for more detailed investigations. Although the VABS-II has excellent psychometric properties, it is more labor-intensive for both the research team and participants and is available in fewer languages than the ASQ-3.

Towards precision well-being in medical education.

Medical trainee well-being is often met with generalized solutions that overlook substantial individual variations in mental health predisposition and stress reactivity. Precision medicine leverages individual environmental, genetic, and lifestyle factors to tailor preventive and therapeutic interventions. In addition, an exclusive focus on clinical mental illness tends to disregard the importance of supporting the positive aspects of medical trainee well-being. We introduce a novel precision well-being framework for medical education that is built on a comprehensive and individualized view of mental health, combining measures from mental health and positive psychology in a unified, data-driven framework. Unsupervised machine learning techniques commonly used in precision medicine were applied to uncover patterns within multidimensional mental health data of medical students. Using data from 3,632 US medical students, clusters were formulated based on recognized metrics for depression, anxiety, and flourishing. The analysis identified three distinct clusters. Membership in the 'Healthy Flourishers' well-being phenotype was associated with no signs of anxiety or depression while simultaneously reporting high levels of flourishing. Students in the 'Getting By' cluster reported mild anxiety and depression and diminished flourishing. Membership in the 'At-Risk' cluster was associated with high anxiety and depression, languishing, and increased suicidality. Nearly half (49%) of the medical students surveyed were classified as 'Healthy Flourishers', whereas 36% were grouped into the 'Getting-By' cluster and 15% were identified as 'At-Risk'. Findings show that a substantial portion of medical students report diminished well-being during their studies, with a significant number struggling with mental health challenges. This novel precision well-being framework represents an integrated empirical model that classifies individual medical students into distinct and meaningful well-being phenotypes based on their holistic mental health. This approach has direct applicability to student support and can be used to evaluate the effectiveness of personalized intervention strategies stratified by cluster membership.

GSDMD gene knockout alleviates hyperoxia-induced hippocampal brain injury in neonatal mice.

BACKGROUND: Neonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have shown that hyperoxia stimulates the brain's inflammasome pathway, leading to the activation of gasdermin D (GSDMD), a key executor of pyroptotic inflammatory cell death. Moreover, we found pharmacological inhibition of caspase-1, which blocks GSDMD activation, attenuates hyperoxia-induced brain injury in neonatal mice. We hypothesized that GSDMD plays a pathogenic role in hyperoxia-induced neonatal brain injury and that GSDMD gene knockout (KO) will alleviate hyperoxia-induced brain injury. METHODS: Newborn GSDMD knockout mice and their wildtype (WT) littermates were randomized within 24 h after birth to be exposed to room air or hyperoxia (85% O2) from postnatal days 1 to 14. Hippocampal brain inflammatory injury was assessed in brain sections by immunohistology for allograft inflammatory factor 1 (AIF1) and CD68, markers of microglial activation. Cell proliferation was evaluated by Ki-67 staining, and cell death was determined by TUNEL assay. RNA sequencing of the hippocampus was performed to identify the transcriptional effects of hyperoxia and GSDMD-KO, and qRT-PCR was performed to confirm some of the significantly regulated genes. RESULTS: Hyperoxia-exposed WT mice had increased microglia consistent with activation, which was associated with decreased cell proliferation and increased cell death in the hippocampal area. Conversely, hyperoxia-exposed GSDMD-KO mice exhibited considerable resistance to hyperoxia as O2 exposure did not increase AIF1 + , CD68 + , or TUNEL + cell numbers or decrease cell proliferation. Hyperoxia exposure differentially regulated 258 genes in WT and only 16 in GSDMD-KO mice compared to room air-exposed WT and GSDMD-KO, respectively. Gene set enrichment analysis showed that in the WT brain, hyperoxia differentially regulated genes associated with neuronal and vascular development and differentiation, axonogenesis, glial cell differentiation, hypoxia-induced factor 1 pathway, and neuronal growth factor pathways. These changes were prevented by GSDMD-KO. CONCLUSIONS: GSDMD-KO alleviates hyperoxia-induced inflammatory injury, cell survival and death, and alterations of transcriptional gene expression of pathways involved in neuronal growth, development, and differentiation in the hippocampus of neonatal mice. This suggests that GSDMD plays a pathogenic role in preterm brain injury, and targeting GSDMD may be beneficial in preventing and treating brain injury and poor neurodevelopmental outcomes in preterm infants.

Multidisciplinary treatment of opioid use disorder in primary care using the collaborative care model.

Background: Treatment of opioid use disorder (OUD) is highly effective, but access is limited and care is often fragmented. Treatment in primary care can improve access to treatment and address psychiatric and physical co-morbidities in a holistic, efficient, and non-stigmatizing way. The Collaborative Care Model (CCM) of behavioral health integration into primary care has been widely disseminated and shown to improve outcomes and lower costs when studied for depression, but its use in treating substance use disorders has not been well documented. Methods: We used a mixed-methods approach to examine the impact of implementing multidisciplinary treatment of OUD in our health system's five primary care clinics using the framework of the CCM, with care shared between the primary care clinician (PCP), behavioral health clinician, and medical assistant. The implementation included staff education, creation of electronic health record tools, and implementation support, and was evaluated using data from the electronic health record, the medical staff office, and a clinician survey. Results: Over the last 2 years of implementation, the number of waivered providers increased from 11 to 35, providers prescribing for 5 or more patients increased from 2 to 18, and patients initiated on buprenorphine increased from 4/month to 18/month. 180-day treatment retention was 53%, and 81% of patients had consistently negative urine drug testing. Psychiatric and medical comorbidities were common, 70 and 44%, respectively. Although PCPs who prescribed buprenorphine found working in this model enjoyable and effective, the majority of non-waivered PCPs remained reluctant to participate. Conclusions: In our experience, treatment of OUD in primary care utilizing the CCM effectively addresses OUD and commonly comorbid anxiety and depression, and leads to an expansion of treatment. Successful implementation of OUD treatment requires addressing negative attitudes and perceptions.

Circulating extracellular vesicles activate the pyroptosis pathway in the brain following ventilation-induced lung injury.

BACKGROUND: Mechanical ventilation of preterm newborns causes lung injury and is associated with poor neurodevelopmental outcomes. However, the mechanistic links between ventilation-induced lung injury (VILI) and brain injury is not well defined. Since circulating extracellular vesicles (EVs) are known to link distant organs by transferring their cargos, we hypothesized that EVs mediate inflammatory brain injury associated with VILI. METHODS: Neonatal rats were mechanically ventilated with low (10 mL/kg) or high (25 mL/kg) tidal volume for 1 h on post-natal day 7 followed by recovery for 2 weeks. Exosomes were isolated from the plasma of these rats and adoptively transferred into normal newborn rats. We assessed the effect of mechanical ventilation or exosome transfer on brain inflammation and activation of the pyroptosis pathway by western blot and histology. RESULTS: Injurious mechanical ventilation induced similar markers of inflammation and pyroptosis, such as increased IL-1ß and activated caspase-1/gasdermin D (GSDMD) in both lung and brain, in addition to inducing microglial activation and cell death in the brain. Isolated EVs were enriched for the exosomal markers CD9 and CD81, suggesting enrichment for exosomes. EVs isolated from neonatal rats with VILI had increased caspase-1 but not GSDMD. Adoptive transfer of these EVs led to neuroinflammation with microglial activation and activation of caspase-1 and GSDMD in the brain similar to that observed in neonatal rats that were mechanically ventilated. CONCLUSIONS: These findings suggest that circulating EVs can contribute to the brain injury and poor neurodevelopmental outcomes in preterm infants with VILI through activation of GSDMD.

Emotion Recognition Performance in Children with Callous Unemotional Traits is Modulated by Co-occurring Autistic Traits.

OBJECTIVE: Atypical emotion recognition (ER) is characteristic of children with high callous unemotional (CU) traits. The current study aims to 1) replicate studies showing ER difficulties for static faces in relation to high CU-traits; 2) test whether ER difficulties remain when more naturalistic dynamic stimuli are used; 3) test whether ER performance for dynamic stimuli is moderated by eye-gaze direction and 4) assess the impact of co-occurring autistic traits on the association between CU and ER. METHODS: Participants were 292 (152 male) 7-year-olds from the Wirral Child Health and Development Study (WCHADS). Children completed a static and dynamic ER eye-tracking task, and accuracy, reaction time and attention to the eyes were recorded. RESULTS: Higher parent-reported CU-traits were significantly associated with reduced ER for static expressions, with lower accuracy for angry and happy faces. No association was found for dynamic expressions. However, parent-reported autistic traits were associated with ER difficulties for both static and dynamic expressions, and after controlling for autistic traits, the association between CU-traits and ER for static expressions became non-significant. CU-traits and looking to the eyes were not associated in either paradigm. CONCLUSION: The finding that CU-traits and ER are associated for static but not naturalistic dynamic expressions may be because motion cues in the dynamic stimuli draw attention to emotion-relevant features such as eyes and mouth. Further, results suggest that ER difficulties in CU-traits may be due, in part, to co-occurring autistic traits. Future developmental studies are required to tease apart pathways toward the apparently overlapping cognitive phenotype.

Primary Care Psychiatry eConsults at a Rural Academic Medical Center: Descriptive Analysis.

BACKGROUND: Primary care providers serve a crucial role in addressing the mental health needs of many patients. However, there are times when input from a psychiatric specialist may be helpful in supporting the mental health care provided in primary care. Psychiatry eConsults can serve as a valuable tool in providing specialist advice for primary care physicians when direct referral to specialty care is not readily available. OBJECTIVE: The goal of this study is to evaluate the content and implementation of psychiatric eConsults by primary care providers in a rural academic medical center. METHODS: This is a retrospective review of 343 eConsults placed between May 2016 and February 2019 by primary care providers at a single academic medical center. The content of eConsult requests, including patient diagnosis, consult question type, specialist recommendations, patient demographics, the distance of patient and primary care providers from the consulting provider, rate of implementation of the recommendation, and response time, were analyzed. RESULTS: The most common diagnoses associated with eConsults were depression (162/450, 36%) and anxiety (118/450, 26%). The most commonly asked eConsult question was regarding medication management, including medication choice, side effects, interactions, and medication taper (288/343, 84%). More than one recommendation was included in 76% (259/343) of eConsults, and at least one recommendation was implemented by the primary care provider in 94% (282/300) of eConsults. The average time to respond to an eConsult was 26 hours. CONCLUSIONS: This study demonstrates that psychiatry eConsults can be conducted in a timely manner and that primary care providers implement the recommendations at a high rate.

Caspase-1 Inhibition Attenuates Hyperoxia-induced Lung and Brain Injury in Neonatal Mice.

Hyperoxia plays a key role in the development of bronchopulmonary dysplasia (BPD), a chronic lung disease of preterm infants. Infants with BPD often have brain injury that leads to long-term neurodevelopmental impairment, but the underlying mechanisms that control BPD-induced neurodevelopmental impairment remain unclear. Our previous studies have shown that hyperoxia-induced BPD in rodents is associated with lung inflammasome activation. Here, we tested the hypothesis that hyperoxia-induced lung and brain injury is mediated by inflammasome activation, and that inhibition of caspase-1, a key component of the inflammasome, attenuates hyperoxia-induced lung and brain injury in neonatal mice. C57/BL6 mouse pups were randomized to receive daily intraperitoneal injections of Ac-YVAD-CMK, an irreversible caspase-1 inhibitor, or placebo during exposure to room air or hyperoxia (85% O2) for 10 days. We found that hyperoxia activated the NLRP1 inflammasome, increased production of mature IL-1ß, and upregulated expression of p30 gasdermin-D (GSDMD), the active form of GSDMD that is responsible for the programmed cell death mechanism of pyroptosis in both lung and brain tissue. Importantly, we show that inhibition of caspase-1 decreased IL-1ß activation and p30 GSDMD expression, and improved alveolar and vascular development in hyperoxia-exposed lungs. Moreover, caspase-1 inhibition also promoted cell proliferation in the subgranular zone and subventricular zone of hyperoxia-exposed brains, resulting in lessened atrophy of these zones. Thus, the inflammasome plays a critical role in hyperoxia-induced neonatal lung and brain injury, and targeting this pathway may be beneficial for the prevention of lung and brain injury in preterm infants.

Recombinant CCN1 prevents hyperoxia-induced lung injury in neonatal rats.

BackgroundCystein-rich protein 61 (Cyr61/CCN1) is a member of the CCN family of matricellular proteins that has an important role in tissue development and remodeling. However, the role of CCN1 in the pathogenesis of bronchopulmonary dysplasia (BPD) is unknown. Accordingly, we have investigated the effects of CCN1 on a hyperoxia-induced lung injury model in neonatal rats.MethodsIn experiment 1, newborn rats were randomized to room air (RA) or 85% oxygen (O2) for 7 or 14 days, and we assessed the expression of CCN1. In experiment 2, rat pups were exposed to RA or O2 and received placebo or recombinant CCN1 by daily intraperitoneal injection for 10 days. The effects of CCN1 on hyperoxia-induced lung inflammation, alveolar and vascular development, vascular remodeling, and right ventricular hypertrophy (RVH) were observed.ResultsIn experiment 1, hyperoxia downregulated CCN1 expression. In experiment 2, treatment with recombinant CCN1 significantly decreased macrophage and neutrophil infiltration, reduced inflammasome activation, increased alveolar and vascular development, and reduced vascular remodeling and RVH in the hyperoxic animals.ConclusionThese results demonstrate that hyperoxia-induced lung injury is associated with downregulated basal CCN1 expression, and treatment with CCN1 can largely reverse hyperoxic injury.

Inhibition of ß-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of premature infants. Connective tissue growth factor (CTGF) plays an important role in tissue development and remodeling. We have previously shown that targeted overexpression of CTGF in alveolar type II epithelial cells results in BPD-like pathology and activates ß-catenin in neonatal mice. METHODS: Utilizing this transgenic mouse model and ICG001, a specific pharmacological inhibitor of ß-catenin, we tested the hypothesis that ß-catenin signaling mediates the effects of CTGF in the neonatal lung. Newborn CTGF mice and control littermates received ICG001 (10 mg/kg/dose) or placebo (dimethyl sulfoxide, equal volume) by daily i.p. injection from postnatal day 5 to 15. Alveolarization, vascular development, and pulmonary hypertension (PH) were analyzed. RESULTS: Administration of ICG001 significantly downregulated expression of cyclin D1, collagen 1a1, and fibronectin, which are the known target genes of ß-catenin signaling in CTGF lungs. Inhibition of ß-catenin signaling improved alveolar and vascular development and decreased pulmonary vascular remodeling. More importantly, the improved vascular development and vascular remodeling led to a decrease in PH. CONCLUSION: ß-Catenin signaling mediates the autocrine and paracrine effects of CTGF in the neonatal lung. Inhibition of CTGF-ß-catenin signaling may provide a novel therapy for BPD.

Connective tissue growth factor acts within both endothelial cells and beta cells to promote proliferation of developing beta cells.

Type 1 and type 2 diabetes result from an absolute or relative reduction in functional ß-cell mass. One approach to replacing lost ß-cell mass is transplantation of cadaveric islets; however, this approach is limited by lack of adequate donor tissue. Therefore, there is much interest in identifying factors that enhance ß-cell differentiation and proliferation in vivo or in vitro. Connective tissue growth factor (CTGF) is a secreted molecule expressed in endothelial cells, pancreatic ducts, and embryonic ß cells that we previously showed is required for ß-cell proliferation, differentiation, and islet morphogenesis during development. The current study investigated the tissue interactions by which CTGF promotes normal pancreatic islet development. We found that loss of CTGF from either endothelial cells or ß cells results in decreased embryonic ß-cell proliferation, making CTGF unique as an identified ß cell-derived factor that regulates embryonic ß-cell proliferation. Endothelial CTGF inactivation was associated with decreased islet vascularity, highlighting the proposed role of endothelial cells in ß-cell proliferation. Furthermore, CTGF overexpression in ß cells during embryogenesis using an inducible transgenic system increased islet mass at birth by promoting proliferation of immature ß cells, in the absence of changes in islet vascularity. Together, these findings demonstrate that CTGF acts in an autocrine manner during pancreas development and suggest that CTGF has the potential to enhance expansion of immature ß cells in directed differentiation or regeneration protocols.

The Impact of Adjustment on Workplace Attitudes and Behaviors Among Health Care Workers During the COVID-19 Pandemic.

OBJECTIVE: We examined the impact of health care workers' (HCWs) adjustment to the COVID-19 pandemic on their work-related attitudes and behaviors. METHODS: HCWs ( n = 1468) participated in an observational longitudinal study in which they completed surveys of anxiety and occupational health between 2020 and 2021. RESULTS: Most HCWs reported anxiety that was consistently below the diagnostic threshold (68%) or fell below the threshold within a year (16%). Others reported consistently high (14%) or increasing (2%) anxiety, especially women, younger HCWs, those with a weakened immune system, and allied health professionals. Consistently high or increasing anxiety was associated with poorer job satisfaction, work engagement, perceived supervisor support, burnout, and turnover intentions. CONCLUSIONS: Resources to support HCWs may be focused on those who report consistently high or increasing anxiety to minimize the effects of crises and disasters on the workforce.

Collaborative Care Model Education Opportunities for Psychiatry Trainees: A Narrative Review.

Importance: The Collaborative Care Model (CoCM) is an evidence-based methodology meant to improve access to mental health care, especially in primary care settings. While evidence about the efficacy of CoCM is abundant, literature regarding how CoCM is taught to psychiatry trainees appears to be more limited. As psychiatrists play a key role within the CoCM framework, psychiatry trainee exposure to CoCM skills and concepts is imperative for growth of these services. As psychiatry trainees may one day practice CoCM, we aimed to examine available literature about educational opportunities in CoCM for psychiatry trainees.Observations: While literature was indeed sparse, we identified that CoCM is taught to psychiatry trainees in the form of clinical rotations, didactics, and leadership experiences. Future opportunities are abundant to increase educational opportunities in CoCM for psychiatry trainees.Conclusions and Relevance: Potential future studies should make use of innovative technologies (such as telehealth), should be process-oriented, and should focus more on team dynamics and opportunities for further collaboration with primary care practices within the CoCM framework.

GSDMD deficiency ameliorates hyperoxia-induced BPD and ROP in neonatal mice.

Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are among the most common morbidities affecting extremely premature infants who receive oxygen therapy. Many clinical studies indicate that BPD is associated with advanced ROP. However, the mechanistic link between hyperoxia, BPD, and ROP remains to be explored. Gasdermin D (GSDMD) is a key executor of inflammasome-induced pyroptosis and inflammation. Inhibition of GSDMD has been shown to attenuate hyperoxia-induced BPD and brain injury in neonatal mice. The objective of this study was to further define the mechanistic roles of GSDMD in the pathogenesis of hyperoxia-induced BPD and ROP in mouse models. Here we show that global GSDMD knockout (GSDMD-KO) protects against hyperoxia-induced BPD by reducing macrophage infiltration, improving alveolarization and vascular development, and decreasing cell death. In addition, GSDMD deficiency prevented hyperoxia-induced ROP by reducing vasoobliteration and neovascularization, improving thinning of multiple retinal tissue layers, and decreasing microglial activation. RNA sequencing analyses of lungs and retinas showed that similar genes, including those from inflammatory, cell death, tissue remodeling, and tissue and vascular developmental signaling pathways, were induced by hyperoxia and impacted by GSDMD-KO in both models. These data highlight the importance of GSDMD in the pathogenesis of BPD and ROP and suggest that targeting GSDMD may be beneficial in preventing and treating BPD and ROP in premature infants.

GSDMD gene knockout alleviates hyperoxia-induced hippocampal brain injury in neonatal mice.

Background: Neonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have shown that hyperoxia stimulates the brain's inflammasome pathway, leading to the activation of gasdermin D (GSDMD), a key executor of pyroptotic inflammatory cell death. Moreover, we found inhibition of GSDMD activation attenuates hyperoxia-induced brain injury in neonatal mice. We hypothesized that GSDMD plays a pathogenic role in hyperoxia-induced neonatal brain injury and that GSDMD gene knockout (KO) will alleviate hyperoxia-induced brain injury. Methods: Newborn GSDMD knockout mice and their wildtype (WT) littermates were randomized within 24 h after birth to be exposed to room air or hyperoxia (85% O2) from postnatal day 1 to 14. Hippocampal brain inflammatory injury was assessed in brain sections by immunohistology for allograft inflammatory factor 1 (AIF1), a marker of microglial activation. Cell proliferation was evaluated by Ki-67 staining, and cell death was determined by TUNEL assay. RNA sequencing of the hippocampus was performed to identify the transcriptional effects of hyperoxia and GSDMD-KO, and qRT-PCR was performed to confirm some of the significantly regulated genes. Results: Hyperoxia-exposed WT mice had increased microglia consistent with activation, which was associated with decreased cell proliferation and increased cell death in the hippocampal area. Conversely, hyperoxia-exposed GSDMD-KO mice exhibited considerable resistance to hyperoxia as O2 exposure failed to increase either AIF1+ or TUNEL+ cell numbers, nor decrease cell proliferation. Hyperoxia exposure differentially regulated 258 genes in WT and only 16 in GSDMD-KO mice compared to room air- exposed WT and GSDMD-KO, respectively. Gene set enrichment analysis showed that in the WT brain, hyperoxia differentially regulated genes associated with neuronal and vascular development and differentiation, axonogenesis, glial cell differentiation, and core development pathways hypoxia-induced factor 1, and neuronal growth factor pathways. These changes were prevented by GSDMD-KO. Conclusion: GSDMD-KO alleviates hyperoxia-induced inflammatory injury, cell survival and death, and alterations of transcriptional gene expression of pathways involved in neuronal growth, development, and differentiation in the hippocampus of neonatal mice. This suggests that GSDMD plays a pathogenic role in preterm brain injury, and targeting GSDMD may be beneficial in preventing and treating brain injury and poor neurodevelopmental outcomes in preterm infants.

Effect of exogenous testosterone in the context of energy deficit on risky choice: Behavioural and neural evidence from males.

Previous research has shown greater risk aversion when people make choices about lives than cash. We tested the hypothesis that compared to placebo, exogenous testosterone administration would lead to riskier choices about cash than lives, given testosterone's association with financial risk-taking and reward sensitivity. A double-blind, placebo-controlled, randomized trial was conducted to test this hypothesis (Clinical Trials Registry: NCT02734238, www.clinicaltrials.gov). We collected functional magnetic resonance imaging (fMRI) data from 50 non-obese males before and shortly after 28 days of severe exercise-and-diet-induced energy deficit, during which testosterone (200 mg testosterone enanthate per week in sesame oil) or placebo (sesame seed oil only) was administered. Because we expected circulating testosterone levels to be reduced due to severe energy deficit, testosterone administration served a restorative function to mitigate the impact of energy deficit on testosterone levels. The fMRI task involved making choices under uncertainty for lives and cash. We also manipulated whether the outcomes were presented as gains or losses. Consistent with prospect theory, we observed the reflection effect such that participants were more risk averse when outcomes were presented as gains than losses. Brain activation in the thalamus covaried with individual differences in exhibiting the reflection effect. Testosterone did not impact choice, but it increased sensitivity to negative feedback following risky choices. These results suggest that exogenous testosterone administration in the context of energy deficit can impact some aspects of risky choice, and that individual differences in the reflection effect engage a brain structure involved in processing emotion, reward and risk.

Core Data Elements for Pregnancy Pharmacovigilance Studies Using Primary Source Data Collection Methods: Recommendations from the IMI ConcePTION Project.

INTRODUCTION AND OBJECTIVE: The risks and benefits of medication use in pregnancy are typically established through post-marketing observational studies. As there is currently no standardised or systematic approach to the post-marketing assessment of medication safety in pregnancy, data generated through pregnancy pharmacovigilance (PregPV) research can be heterogenous and difficult to interpret. The aim of this article is to describe the development of a reference framework of core data elements (CDEs) for collection in primary source PregPV studies that can be used to standardise data collection procedures and, thereby, improve data harmonisation and evidence synthesis capabilities. METHODS: This CDE reference framework was developed within the Innovative Medicines Initiative (IMI) ConcePTION project by experts in pharmacovigilance, pharmacoepidemiology, medical statistics, risk-benefit communication, clinical teratology, reproductive toxicology, genetics, obstetrics, paediatrics, and child psychology. The framework was produced through a scoping review of data collection systems used by established PregPV datasets, followed by extensive discussion and debate around the value, definition, and derivation of each data item identified from these systems. RESULTS: The finalised listing of CDEs comprises 98 individual data elements, arranged into 14 tables of related fields. These data elements are openly available on the European Network of Teratology Information Services (ENTIS) website ( http://www.entis-org.eu/cde ). DISCUSSION: With this set of recommendations, we aim to standardise PregPV primary source data collection processes to improve the speed at which high-quality evidence-based statements can be provided about the safety of medication use in pregnancy.