Adenylate cyclase type 9 antagonizes cAMP accumulation and regulates endothelial signalling involved in atheroprotection.

AIMS: The adenylate cyclase type 9 (ADCY9) gene appears to determine atherosclerotic outcomes in patients treated with dalcetrapib. In mice, we recently demonstrated that Adcy9 inactivation potentiates endothelial function and inhibits atherogenesis. The objective of this study was to characterize the contribution of ADCY9 to the regulation of endothelial signalling pathways involved in atherosclerosis. METHODS AND RESULTS: We show that ADCY9 is expressed in the endothelium of mouse aorta and femoral arteries. We demonstrate that ADCY9 inactivation in cultured endothelial cells paradoxically increases cAMP accumulation in response to the adenylate cyclase activators forskolin and vasoactive intestinal peptide (VIP). Reciprocally, ADCY9 overexpression decreases cAMP production. Using mouse femoral artery arteriography, we show that Adcy9 inactivation potentiates VIP-induced endothelial-dependent vasodilation. Moreover, Adcy9 inactivation reduces mouse atheroma endothelial permeability in different vascular beds. ADCY9 overexpression reduces forskolin-induced phosphorylation of Ser157-vasodilator-stimulated phosphoprotein (VASP) and worsens thrombin-induced fall of RAP1 activity, both leading to increased endothelial permeability. ADCY9 inactivation in thrombin-stimulated human coronary artery endothelial cells results in cAMP accumulation, increases p-Ser157-VASP, and inhibits endothelial permeability. MLC2 phosphorylation and actin stress fibre increases in response to thrombin were reduced by ADCY9 inactivation, suggesting actin cytoskeleton regulation. Finally, using the Miles assay, we demonstrate that Adcy9 regulates thrombin-induced endothelial permeability in vivo in normal and atherosclerotic animals. CONCLUSION: Adcy9 is expressed in endothelial cells and regulates local cAMP and endothelial functions including permeability relevant to atherogenesis.

Evolution of burnout and psychological distress in healthcare workers during the COVID-19 pandemic: a 1-year observational study.

BACKGROUND: Long-term psychological impacts of the COVID-19 pandemic on healthcare workers remain unknown. We aimed to determine the one-year progression of burnout and mental health since pandemic onset, and verify if protective factors against psychological distress at the beginning of the COVID-19 pandemic (Cyr et al. in Front Psychiatry; 2021) remained associated when assessed several months later. METHODS: We used validated questionnaires (Maslach Burnout Inventory, Hospital Anxiety and Depression and posttraumatic stress disorder [PTSD] Checklist for DSM-5 scales) to assess burnout and psychological distress in 410 healthcare workers from Quebec, Canada, at three and 12 months after pandemic onset. We then performed multivariable regression analyses to identify protective factors of burnout and mental health at 12 months. As the equivalent regression analyses at three months post-pandemic onset had already been conducted in the previous paper, we could compare the protective factors at both time points. RESULTS: Prevalence of burnout and anxiety were similar at three and 12 months (52% vs. 51%, p = 0.66; 23% vs. 23%, p = 0.91), while PTSD (23% vs. 11%, p < 0.0001) and depression (11% vs. 6%, p = 0.001) decreased significantly over time. Higher resilience was associated with a lower probability of all outcomes at both time points. Perceived organizational support remained significantly associated with a reduced risk of burnout at 12 months. Social support emerged as a protective factor against burnout at 12 months and persisted over time for studied PTSD, anxiety, and depression. CONCLUSIONS: Healthcare workers' occupational and mental health stabilized or improved between three and 12 months after the pandemic onset. The predominant protective factors against burnout remained resilience and perceived organizational support. For PTSD, anxiety and depression, resilience and social support were important factors over time.

Fourteen-Day Evolution of COVID-19 Symptoms during the Third Wave in Nonvaccinated Subjects and Effects of Hesperidin Therapy: A Randomized, Double-Blinded, Placebo-Controlled Study.

COVID-19 symptoms can cause substantial disability, yet no therapy can currently reduce their frequency or duration. We conducted a double-blind placebo-controlled trial of hesperidin 1000 mg once daily for 14 days in 216 symptomatic nonvaccinated COVID-19 subjects. Thirteen symptoms were recorded after 3, 7, 10, and 14 days. The primary endpoint was the proportion of subjects with any of four cardinal (group A) symptoms: fever, cough, shortness of breath, or anosmia. At the baseline, symptoms in decreasing frequency were as follows: cough (53.2%), weakness (44.9%), headache (42.6%), pain (35.2%), sore throat (28.7%), runny nose (26.9%), chills (22.7%), shortness of breath (22.2%), anosmia (18.5%), fever (16.2%), diarrhea (6.9%), nausea/vomiting (6.5%), and irritability/confusion (3.2%). Group A symptoms in the placebo vs. hesperidin group were 88.8% vs. 88.5% (day 1) and reduced to 58.5 vs. 49.4% at day 14 (OR 0.69, 95% CI 0.38-1.27, p = 0.23). At day 14, 15 subjects in the placebo group and 28 in the hesperidin group failed to report their symptoms. In an attrition bias analysis imputing "no symptoms" to missing values, the hesperidin group showed reduction of 14.5% of group A symptoms from 50.9% to 36.4% (OR: 0.55, 0.32-0.96, p = 0.03). Anosmia, the most frequent persisting symptom (29.3%), was lowered by 7.3% to 25.3% in the hesperidin group vs. 32.6% in the placebo group (p = 0.29). The mean number of symptoms in the placebo and hesperidin groups was 5.10 (SD 2.26) vs. 5.48 (SD 2.35) (day 1) and 1.40 (SD 1.65) vs. 1.38 (SD 1.76) (day 14) (p = 0.92). In conclusion, most nonvaccinated COVID-19 infected subjects remain symptomatic after 14 days with anosmia being the most frequently persisting symptom. Hesperidin 1 g daily may help reduce group A symptoms. Earlier treatment of longer duration and/or higher dosage should be tested.

Hair cortisol change at COVID-19 pandemic onset predicts burnout among health personnel.

BACKGROUND: The COVID-19 pandemic has put chronic pressure on worldwide healthcare systems. While the literature regarding the prevalence of psychological distress and associated risk factors among healthcare workers facing COVID-19 has exploded, biological variables have been mostly overlooked. METHODS: 467 healthcare workers from Quebec, Canada, answered an electronic survey covering various risk factors and mental health outcomes three months after the onset of the COVID-19 pandemic. Of them, 372 (80%) provided a hair sample, providing a history of cortisol secretion for the three months preceding and following the pandemic's start. We used multivariable regression models and a receiver operating characteristic curve to study hair cortisol as a predictor of burnout and psychological health, together with individual, occupational, social, and organizational factors. RESULTS: As expected, hair cortisol levels increased after the start of the pandemic, with a median relative change of 29% (IQR = 3-59%, p < 0.0001). There was a significant association between burnout status and change in cortisol, with participants in the second quarter of change having lower odds of burnout. No association was found between cortisol change and post-traumatic stress disorder, anxiety, and depression symptoms. Adding cortisol to individual-occupational-socio-organizational factors noticeably enhanced our burnout logistic regression model's predictability. CONCLUSION: Change in hair cortisol levels predicted burnout at three months in health personnel at the onset of the COVID-19 pandemic. This non-invasive biological marker of the stress response could be used in further clinical or research initiatives to screen high-risk individuals to prevent and control burnout in health personnel facing an important stressor.

Factors Associated With Burnout, Post-traumatic Stress and Anxio-Depressive Symptoms in Healthcare Workers 3 Months Into the COVID-19 Pandemic: An Observational Study.

Objective: This study examined how best to identify modifiable protective and risk factors for burnout in healthcare workers in the face of the COVID-19 pandemic. Individual, occupational, organizational and social factors were investigated. The study also assessed the impact of these factors on post-traumatic stress disorder (PTSD), anxiety, and depression. Methods: Healthcare workers in the Quebec (Canada) healthcare system were recruited between May 21 to June 5, 2020. Participants answered an electronic survey 3 months after the COVID-19 epidemic outbreak began in Canada. Using the Maslach Burnout Inventory, PTSD Checklist for DSM-5, and Hospital Anxiety and Depression Scale, we studied the prevalence of burnout, PTSD, anxiety and depression in this cohort. Multivariable logistic or linear regression models including resilience, social and organizational support, workload and access to mental health help, simulation techniques and protective personal equipment (PPE) as well as perception of PPE security were conducted for each outcome. Results: In mid-June 2020, 467 participants completed the survey. We found that half (51.8%) of the respondents experienced burnout characterized by emotional exhaustion and/or depersonalization at least once a week. In total, 158 healthcare workers (35.6%) displayed severe symptoms of at least one of the mental health disorders (24.3% PTSD, 23.3% anxiety, 10.6% depression). Resilience (OR = 0.69, 95% CI: [0.55-0.87]; p = 0.002) and perceived organizational support (OR = 0.75, 95% CI: [0.61-0.93]; p = 0.009) were significantly associated with burnout and other outcomes. Social support satisfaction, perception of PPE security, work type and environment, mental health antecedents and reassignment were associated with PTSD and/or anxiety and/or depression, but not burnout. Conclusion: Future studies should address primarily resilience and perceived organizational support to promote mental health and prevent burnout, PTSD, anxiety and depression.