Hair cortisol as a risk marker for increased depressive symptoms among older adults during the COVID-19 pandemic.

Determining pre-existing biological risk markers of incident depression and other mental health sequelae after exposure to a new stressor would help identify vulnerable individuals and mechanistic pathways. This study investigated primarily whether hair cortisol predicted elevated depressive symptoms in middle-aged and older adults during the COVID-19 pandemic, 6 years later. A secondary aim was to deduce whether any association differed by sex. METHODS: We studied 1025 adults aged 50 and older (75% female) as part of The Irish Longitudinal Study on Ageing. Hair cortisol samples were collected at 2014 (Wave 3) and depressive symptoms were assessed using the 8-item Center for Epidemiological Studies Depression Scale in 2014 (Wave 3), 2016 (Wave 4), 2018 (Wave 5) and again in 2020 as part of TILDA's COVID-19 Study. Hierarchical mixed effects logistic regression models were applied to investigate the association between cortisol levels and clinically significant depressive symptoms before and during the COVID-19 pandemic. RESULTS: In a full covariate adjusted model there was a significant interaction between cortisol and wave on depressive symptoms (χ2 = 8.5, p = .03). Cortisol was positively and significantly associated with elevated depressive symptoms during the COVID-19 Study (OR =1.3, 95% CI 1.11, 1.56, p = .003), and was associated with an increased likelihood of reporting clinically significant depressive symptoms during first year of the COVID-19 pandemic, when compared with before, OR = 1.4, 95% CI 1.05, 1.9, p = .015. There was no evidence of effect modification by sex. CONCLUSIONS: Higher hair cortisol, assessed 6 years previously, predicted clinically significant depressive symptoms among middle-aged and older adults during (but not before) the pandemic. Findings suggest a biological phenotype which denotes increased susceptibility to the negative impact of environmental stress on psychological health.

Follow Your Nose: A Key Clue to Understanding and Treating COVID-19.

This paper suggests that ATP release induced by the SARS-CoV-2 virus plays a key role in the genesis of the major symptoms and complications of COVID-19. Infection of specific cells which contain the Angiotensin-Converting Enzyme 2 (ACE2) receptor results in a loss of protection of the Mineralocorticoid Receptor (MR). Local activation by cortisol stimulates the release of ATP initially into the basolateral compartment and then by lysosomal exocytosis from the cell surface. This then acts on adjacent cells. In the nose ATP acts as a nociceptive stimulus which results in anosmia. It is suggested that a similar paracrine mechanism is responsible for the loss of taste. In the lung ATP release from type 2 alveolar cells produces the non-productive cough by acting on purinergic receptors on adjacent neuroepithelial cells and activating, via the vagus, the cough reflex. Infection of endothelial cells results in the exocytosis of WeibelPalade bodies. These contain the Von Willebrand Factor responsible for micro-clotting and angiopoietin-2 which increases vascular permeability and plays a key role in the Acute Respiratory Distress Syndrome. To test this hypothesis this paper reports proof of concept studies in which MR blockade using spironolactone and low dose dexamethasone (SpiDex) was given to PCR-confirmed COVID-19 patients. In 80 patients with moderate to severe respiratory failure 40 were given SpiDex and 40 conventional treatment with high dose dexamethasone (HiDex). There was 1 death in the HiDex group and none in the SpiDex. As judged by clinical, biochemical and radiological parameters there were clear statistically significant benefits of SpiDex in comparison to HiDex. A further 20 outpatients with COVID-19 were given SpiDex. There was no control group and the aim was to demonstrate safety. No adverse effects were noted and no patient became hyperkalaemic. 90% were asymptomatic at 10 days. The very positive results suggest that blockade of the MR can produce major benefit in COVID19 patients. Further larger controlled studies of inpatients and outpatients are required not only for SARS-CoV-2 infection per se but also to determine if this treatment affects the incidence of Long COVID.

The 3D-Transition Study: Objectives, Methods, and Implementation of an Innovative Planned Missing-Data Design.

The prevalence of mental health problems represents a significant burden on school and community health resources as early as preschool. Reducing this burden requires a better understanding of the developmental mechanisms linking children's early vulnerabilities with mental health after the transition to formal schooling. The 3D-Transition Study (2017-2021) follows 939 participants from a pregnancy cohort in the province of Québec, Canada, as they transition to kindergarten and first grade to examine these mechanisms. Biannual assessments include completed questionnaires from 2 parents as well as teachers, parent-child observations, anthropometric measurements, and age-sensitive cognitive assessments. Saliva is also collected on 11 days over a 16-month period in a subsample of 384 participants to examine possible changes in child salivary cortisol levels across the school transition and their role in difficulties observed during the transition. A combination of planned missing-data designs is being implemented to reduce participant burden, where incomplete data are collected without introducing bias after the use of multiple imputation. The 3D-Transition Study will contribute to an evidence-based developmental framework of child mental health from pregnancy to school age. In turn, this framework can help inform prevention programs delivered in health-care settings during pregnancy and in child-care centers, preschools, and schools.

Management and Medical Therapy of Mild Hypercortisolism.

Mild hypercortisolism (mHC) is defined as an excessive cortisol secretion, without the classical manifestations of clinically overt Cushing's syndrome. This condition increases the risk of bone fragility, neuropsychological alterations, hypertension, diabetes, cardiovascular events and mortality. At variance with Cushing's syndrome, mHC is not rare, with it estimated to be present in up to 2% of individuals older than 60 years, with higher prevalence (up to 10%) in individuals with uncontrolled hypertension and/or diabetes or with unexplainable bone fragility. Measuring cortisol after a 1 mg overnight dexamethasone suppression test is the first-line test for searching for mHC, and the degree of cortisol suppression is associated with the presence of cortisol-related consequences and mortality. Among the additional tests used for diagnosing mHC in doubtful cases, the basal morning plasma adrenocorticotroph hormone, 24-h urinary free cortisol and/or late-night salivary cortisol could be measured, particularly in patients with possible cortisol-related complications, such as hypertension and diabetes. Surgery is considered as a possible therapeutic option in patients with munilateral adrenal incidentalomas and mHC since it improves diabetes and hypertension and reduces the fracture risk. In patients with mHC and bilateral adrenal adenomas, in whom surgery would lead to persistent hypocortisolism, and in patients refusing surgery or in whom surgery is not feasible, medical therapy is needed. Currently, promising though scarce data have been provided on the possible use of pituitary-directed agents, such as the multi-ligand somatostatin analog pasireotide or the dopamine agonist cabergoline for the-nowadays-rare patients with pituitary mHC. In the more frequently adrenal mHC, encouraging data are available for metyrapone, a steroidogenesis inhibitor acting mainly against the adrenal 11-ßhydroxylase, while data on osilodrostat and levoketoconazole, other new steroidogenesis inhibitors, are still needed in patients with mHC. Finally, on the basis of promising data with mifepristone, a non-selective glucocorticoid receptor antagonist, in patients with mild cortisol hypersecretion, a randomized placebo-controlled study is ongoing for assessing the efficacy and safety of relacorilant, a selective glucocorticoid receptor antagonist, for patients with mild adrenal hypercortisolism and diabetes mellitus/impaired glucose tolerance and/or uncontrolled systolic hypertension.

Impact of loneliness on diurnal cortisol in youth.

Loneliness is associated with multiple forms of psychopathology in youth. However, we do not yet know how loneliness gets "under the skin" in ways that may impact the long-term health and development of early adolescents. In particular, loneliness may influence youths' patterns of diurnal cortisol, an index of hypothalamic-pituitary-adrenal (HPA) axis functioning and a central predictor of health across the lifespan. The current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, or COVID-19) pandemic represents a salient period in which to study the consequences of loneliness, as recent work has provided evidence that the physical-distancing measures put in place to contain the virus have resulted in greater loneliness, particularly among youth. Thus, the current study aimed to examine the prospective association between loneliness during the COVID-19 pandemic and diurnal cortisol in early adolescents. We found that greater loneliness was associated with higher levels of cortisol at waking and a blunted cortisol awakening response (CAR). These results held even when controlling for covariates that can influence diurnal trajectories of cortisol. Critically, this pattern of HPA-axis functioning increases risk for adverse mental and physical health outcomes across adolescence and into adulthood. This study is the first to examine the prospective association between loneliness and diurnal cortisol in early adolescence, and the first to identify mechanisms that contribute to biological markers of distress during the COVID-19 pandemic. Findings underscore the importance of developing and distributing strategies to mitigate feelings of loneliness among youth.

Competitive anxiety or Coronavirus anxiety? The psychophysiological responses of professional football players after returning to competition during the COVID-19 pandemic.

OBJECTIVE: This study aimed to examine the relationship between competitive anxiety, fear/anxiety of COVID-19, and autonomic and endocrine stress responses in professional football players after returning to competition during the COVID-19 pandemic. METHODS: Ninety male professional football players (age: 26.33 ± 2.48 yr) volunteered to participate in this study, which included an official competition. Psychophysiological responses, including the Fear of COVID-19 Scale, the Coronavirus Anxiety Scale, and the Competitive State Anxiety Inventory-2 Revised, were collected 30 min before the competition. In addition, salivary alpha-amylase (sAA) and salivary cortisol (sCort) were collected at 8 a.m. and 15 min before the competition. RESULTS: The main findings, based on the Pearson correlation, showed significant positive correlations between COVID-19 anxiety and somatic competitive anxiety (p = 0.01), cognitive competitive anxiety (p = 0.01), and competition response of sCort and sAA (p = 0.01). Moreover, fear of COVID-19 was positively correlated with COVID-19 anxiety (p = 0.01). On the contrary, the awakening response of sCort and sAA was not found to be correlated with psychological parameters (all p > 0.05). The analysis also indicated that there was no significant correlation between self-confidence with other psychological and physiological variables (all p > 0.05). The regression analysis showed that cognitive anxiety was a relevant predictor for the competition response of sCort and sAA (p < 0.05). Moreover, COVID-19 anxiety was the only predictor of somatic and cognitive anxiety (p < 0.05). CONCLUSIONS: The present study provides the first preliminary evidence that COVID-19 anxiety and competitive anxiety might pose a negative impact on the athletic performance of professional football players during COVID-19 pandemic competitions. Thus, research is needed to build a strategy to reduce the psychophysiological stress related to COVID-19 and competition response.

Stress and hair cortisol concentrations in nurses during the first wave of the COVID-19 pandemic.

During the COVID-19 pandemic, frontline healthcare workers have been exposed to very stressful conditions. Measuring hair cortisol concentrations (HCCs), which reflect the integrated long-term cortisol levels, may elucidate the impact of COVID-19 related stress on healthcare professionals. In the current study, we investigated experienced stress in 693 healthcare workers, with hair samples for cortisol analysis collected from a subset of 67 female nurses. The HCCs in two 3 cm hair segments corresponding to periods before and during the peak of the first wave of COVID-19 were compared. To evaluate the effect of working in the first line, the sample was divided into two groups based on the COVID-19 risk estimated by the nurses. Covariates in the model included perceived stress (PSS), perceived social support (MSPSS), and quality of sleep (PSQI) measured via an online questionnaire. The data showed that more than 75% of healthcare workers agreed that COVID-19 led to increased stress at their workplace. The hair cortisol analysis showed higher HCCs in the hair segments corresponding to the time of the pandemic compared to hair corresponding to an earlier period (partial η290%CI = 0.123-0.397); in the same model, higher HCCs were also found in nurses from high-risk environments compared to low-risk ones (partial η290%CI = 0.002-0.176). None of the subjective questionnaire measures were significant predictors of HCCs. In conclusion, these data showed that HCCs reflect the increased stress among nurses during the COVID-19 pandemic as well as the difference in nurses between high- and low-risk environments.

Evaluation of stress, burnout and hair cortisol levels in health workers at a University Hospital during COVID-19 pandemic.

In the critical context of COVID-19 pandemic, healthcare workers are on the front line, participating directly in the care, diagnosis, and treatment of patients with COVID-19. This exposes them to a higher risk of developing chronic stress, psychological distress, and any other mental health symptoms. OBJECTIVE: to evaluate stress and burnout in a health workers population and, in addition, to measure hair cortisol concentration as a current biomarker of stress. MATERIALS AND METHODS: 234 health workers from Hospital de Clínicas "José de San Martín", Buenos Aires University, were included in this study. In this population hair samples were obtained from the posterior vertex as close to the scalp as possible and the individuals completed the following surveys: perceived stress, social support, burnout scale, life event scale, and sociodemographic data. Hair cortisol was measured by an automated chemiluminescent method. The studied population was divided into three groups considering those individuals below the healthy reference sample range (< 40 pg/mg hair), within the healthy reference range (40-128 pg/mg hair) and above the reference range (> 128 pg/mg hair). This study used a transversal and observational design. RESULTS: Our results show that 40% of the studied population presented hair cortisol values outside of the healthy reference range. In the whole studied population, a direct correlation was found between hair cortisol concentration and perceived stress as well as between hair cortisol concentration and the emotional exhaustion component of burnout (r = 0.142, p = 0.030; r = 0.143, p = 0.029, respectively). 12% of the studied population showed Burnout (52% doctors and residents, 19% nurses, 19% administrative personnel). Higher values in hair cortisol levels were found in the group with burnout versus individuals without burnout (p = 0.034). Finally, a mediation analysis was performed, finding that depersonalization is a mediating variable in the relationship between self-perceived stress and hair cortisol level (F = 4.86, p = 0.0086; indirect effect IC: 0.0987-1.8840). CONCLUSION: This is the first study in which a stress biomarker such as hair cortisol is evaluated in this population and in this context. Healthcare workers are subjected to increased levels of stress and burnout. High depersonalization, emotional exhaustion, and decreased personal sense of accomplishment characterize this population. It is the responsibility of the health authorities to implement strategies to manage this psychological emergency.

New Horizons: Does Mineralocorticoid Receptor Activation by Cortisol Cause ATP Release and COVID-19 Complications?

This paper attempts to explain how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes the complications that make coronavirus disease 2019 (COVID-19) a serious disease in specific patient subgroups. It suggests that cortisol-associated activation of the mineralocorticoid receptor (MR) in epithelial and endothelial cells infected with the virus stimulates the release of adenosine 5'-triphosphate (ATP), which then acts back on purinergic receptors. In the lung this could produce the nonproductive cough via purinergic P2X3 receptors on vagal afferent nerves. In endothelial cells it could stimulate exocytosis of Weibel-Palade bodies (WPBs) that contain angiopoietin-2, which is important in the pathogenesis of acute respiratory distress syndrome (ARDS) by increasing capillary permeability and von Willebrand factor (VWF), which mediates platelet adhesion to the endothelium and hence clotting. Angiopoietin-2 and VWF levels both are markedly elevated in COVID-19-associated ARDS. This paper offers an explanation for the sex differences in SARS-CoV-2 complications and also for why these are strongly associated with age, race, diabetes, and body mass index. It also explains why individuals with blood group A have a higher risk of severe infection than those with blood group O. Dexamethasone has been shown to be of benefit in coronavirus ARDS patients and has been thought to act as an anti-inflammatory drug. This paper suggests that a major part of its effect may be due to suppression of cortisol secretion. There is an urgent need to trial the combination of dexamethasone and an MR antagonist such as spironolactone to more effectively block the MR and hence the exocytosis of WPBs.