Critical Illness-Related Corticosteroid Insufficiency (CIRCI) Among Patients with COVID-19 at a Tertiary Hospital: Clinical Characteristics and Outcomes.

Objectives: Among critically ill patients, there is usually impairment of the hypothalamic-pituitary-adrenal axis, leading to a condition known as critical illness-related corticosteroid insufficiency (CIRCI). This investigation aims to determine the incidence of and characterize CIRCI among patients with COVID-19 as well as to analyze the outcomes of these critically ill patients. Methodology: This is a single-center, retrospective cohort study that investigated the occurrence of CIRCI among critically ill patients infected with COVID-19. Results: In this cohort, there were 145 COVID-19-positive patients with refractory shock, which reflects that 22.94% of the COVID-19 admissions have probable CIRCI.Patients who were given corticosteroids were found to have statistically significant longer median days on a ventilator (p=0.001). However, those on the corticosteroid arm were at higher risk of morbidity and mortality and a greater proportion had organ dysfunction. Multivariable logistic regression analysis revealed that SOFA score was a significant predictor of mortality in CIRCI (p=0.013). Conclusion: CIRCI has a unique presentation among patients with COVID-19 because of the presence of a high level of inflammation in this life-threatening infection. It is possibly a harbinger of a markedly increased risk of mortality in these patients.

Intertwined associations between oxytocin, immune system and major depressive disorder.

Major depressive disorder (MDD) is a prominent psychiatric disorder with a high prevalence rate. The recent COVID-19 pandemic has exacerbated the already high prevalence of MDD. Unfortunately, a significant proportion of patients are unresponsive to conventional treatments, necessitating the exploration of novel therapeutic strategies. Oxytocin, an endogenous neuropeptide, has emerged as a promising candidate with anxiolytic and antidepressant properties. Oxytocin has been shown to alleviate emotional disorders by modulating the hypothalamic-pituitary-adrenal (HPA) axis and the central immune system. The dysfunction of the immune system has been strongly linked to the onset and progression of depression. The central immune system is believed to be a key target of oxytocin in ameliorating emotional disorders. In this review, we examine the evidence regarding the interactions between oxytocin, the immune system, and depressive disorder. Moreover, we summarize and speculate on the potential roles of the intertwined association between oxytocin and the central immune system in treating emotional disorders.

Characterising approaches to steroid therapy in paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2.

AIM: We describe approaches to steroid therapy use in paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and examine the association between steroid therapy and key clinical markers of severity. METHODS: We conducted a retrospective review of children (<18 years) admitted to a tertiary paediatric hospital in the UK with PIMS-TS. We collected data on if and why steroid therapy was used; the duration, type and dosing of steroids prescribed; and approaches to hypothalamo-pituitary-adrenal (HPA) axis monitoring, if performed. We examined associations between steroid exposure/total steroid dose (mg/m2 /day) and paediatric intensive care unit admission, mechanical ventilation and inotropic support. RESULTS: Steroid therapy was commenced in most children (84.9%, n = 104) with a median total daily steroid dose (hydrocortisone equivalent) of 271.0 mg/m2 /day (interquartile range 232.5-355.5) and treatment length of 26.0 days (interquartile range 19.0-32.0). Dosing regimens predominantly involved a short course of high-dose methylprednisolone followed by tapering oral prednisolone. Basal and/or dynamic testing of the HPA axis was conducted in a minority (11.8%, n = 15) and was normal. Duration of steroid therapy correlated positively with durations of paediatric intensive care unit admission (r = 0.407, P < 0.001) and mechanical ventilation (r = 0.797, P < 0.001). A greater proportion of children receiving steroid therapy also received inotropic support compared to those that did not receive steroid therapy (71.4% vs. 45.5%, P = 0.025). CONCLUSION: Prolonged, high-dose steroid therapy is often used in the management of severe PIMS-TS with the potential for HPA axis suppression and should be withdrawn carefully.

Adolescent non-suicidal self-injury during the COVID-19 pandemic: A prospective longitudinal study of biological predictors of maladaptive emotion regulation.

BACKGROUND: Non-suicidal self-injury (NSSI) in adolescence is thought to stem from interactions between vulnerability in developing biological systems and experience of stressors. The current study assesses whether multiple levels of the stress system's response to threat could prospectively predict NSSI engagement during the COVID-19 pandemic, a shared, time-locked stressor. METHODS: Participants were 64 female adolescents (ages 12-16) from community and clinical settings who were oversampled for NSSI histories. Prior to the onset of the COVID-19 pandemic, adolescents completed a protocol that measured hypothalamic-pituitary-adrenal axis response to a social stressor (via salivary cortisol), amygdala volume, amygdala emotion-evoked activation, and frontolimbic resting-state functional connectivity. During early months of the pandemic (Summer 2020), measures of NSSI behavior (Inventory of Statements About Self-Injury), emotion regulation difficulties (Difficulties in Emotion Regulation Scale), perceived stress (Perceived Stress Scale), and pandemic-related stressors (Epidemic Pandemic Impacts Inventory) were collected. Multinomial logistic regression was used to assess if pre-pandemic biomarkers predicted mid-pandemic NSSI engagement: persistence of NSSI (Persist; N = 21), cessation of NSSI (Desist; N = 26), and no history of NSSI (Never; N = 17). Linear regressions explored if pre-pandemic biomarkers predicted mid-pandemic difficulties in emotion regulation and perceived stress. RESULTS: Higher pre-pandemic overall cortisol response to stress and amygdala emotion-evoked activation characterized adolescents who persisted in NSSI, compared to those who desisted. These findings remained significant when controlling for pandemic related stressors. Lower prepandemic cortisol reactivity predicted more difficulties in emotion regulation during the pandemic. This finding did not remain significant after controlling for pandemic related stressors. CONCLUSIONS: Findings suggest that patterns in key biological threat response systems may confer vulnerability for risk outcomes including NSSI engagement in adolescent females in the context of a shared, novel, naturally-occurring stressor. The results point to the importance of multi-level, longitudinal approaches for understanding the interface between developing neurobiological systems and experiential stress in at-risk adolescents. Identified patterns give insight into potential risk assessment strategies based on an understanding of the multi-level threat response.

Stress and the hypothalamic-pituitary-adrenal axis: How can the COVID-19 pandemic inform our understanding and treatment of acute insomnia?

Stress and sleep are very closely linked, and stressful life events can trigger acute insomnia. The ongoing COVID-19 pandemic is highly likely to represent one such stressful life event. Indeed, a wide range of cross-sectional studies demonstrate that the pandemic is associated with poor sleep and sleep disturbances. Given the high economic and health burden of insomnia disorder, strategies that can prevent and treat acute insomnia, and also prevent the transition from acute insomnia to insomnia disorder, are necessary. This narrative review outlines why the COVID-19 pandemic is a stressful life event, and why activation of the hypothalamic-pituitary-adrenal axis, as a biological marker of psychological stress, is likely to result in acute insomnia. Further, this review outlines how sleep disturbances might arise as a result of the COVID-19 pandemic, and why simultaneous hypothalamic-pituitary-adrenal axis measurement can inform the pathogenesis of acute insomnia. In particular, we focus on the cortisol awakening response as a marker of hypothalamic-pituitary-adrenal axis function, as cortisol is the end-product of the hypothalamic-pituitary-adrenal axis. From a research perspective, future opportunities include identifying individuals, or particular occupational or societal groups (e.g. frontline health staff), who are at high risk of developing acute insomnia, and intervening. From an acute insomnia treatment perspective, priorities include testing large-scale online behavioural interventions; examining if reducing the impact of stress is effective and, finally, assessing whether "sleep vaccination" can maintain good sleep health by preventing the occurrence of acute insomnia, by preventing the transition from acute insomnia to insomnia disorder.

Stress reactivity in salivary cortisol and electrocardiogram in adolescents: Investigating sleep disturbances and insomnia.

This study examined the role of sleep disturbances and insomnia in the context of stress reactivity in adolescence. One-hundred and thirty-five 11-18 year olds (Mage  = 14.2 years, SD = 1.9, 52% female) completed the Trier Social Stress Test for Children. Salivary cortisol and subjective stress ratings were collected at six time points, and heart rate as well as heart rate variability were measured pre-, during and post-stress induction. Additionally, sleep disturbances and insomnia diagnosis were assessed by a self-report questionnaire and a sleep interview. Robust mixed models investigated if adolescents with compared with adolescents without (a) sleep disturbances and (b) insomnia differ regarding cortisol, heart rate, heart rate variability and psychological stress reactivity considering gender effects. The results indicated that boys with high sleep disturbances showed higher cortisol activity compared with boys with low sleep disturbances, B = 0.88, p < 0.05. Moreover, in boys with insomnia, heart rate and alpha 1 significantly differ less than in boys without insomnia. These findings support the notion of sex differences regarding the association between poor sleep and increased activity of the hypothalamic-pituitary-adrenal axis, and a less adaptable autonomic nervous system in boys in response to an experimental social stress task.

Increases in stress hormone levels in a UK population during the COVID-19 pandemic: A prospective cohort study.

BACKGROUND: Research suggests that psychological factors may influence vulnerability to SARS-CoV-2 infection, although the mechanisms are unclear. PURPOSE: We examined whether the hypothalamic-pituitary-adrenal axis may be a possible mechanism, by measuring the relationship between indices of psychological distress and cortisone in hair (hairE) in a UK cohort during the COVID-19 pandemic. METHODS: Participants (N = 827) provided two 3 cm hair samples over a 6-month period between April-September 2020. Samples reflected hairE in the 3 months prior to the collection date. RESULTS: HairE in the first samples (T1: commenced April 2020) did not differ significantly from pre-pandemic population norms. However, hairE in the second samples (T2: commenced July 2020) were significantly higher than T1 and pre-pandemic population norms, with a 23% increase between T1 and T2. Linear regressions, controlling for age and gender, demonstrated that at both timepoints, hairE levels were greatest in people with a history of mental health difficulties. In addition, stress reported at T1 predicted greater hairE at T2 and a greater change in hairE between T1 and T2. CONCLUSIONS: These findings demonstrate that during the COVID-19 pandemic hairE was substantially elevated across a large community cohort, with greatest levels in those with a history of mental health difficulties and greatest changes in those reporting greatest levels of stress early in the pandemic. Further research is required with verified SARS-CoV-2 outcomes to determine whether the HPA axis is among the mechanisms by which a history of mental health difficulties and stress influence SARS-CoV-2 outcomes.

The neurobiology of childhood trauma, from early physical pain onwards: as relevant as ever in today's fractured world.

Background: The situation in the world today, encompassing multiple armed conflicts, notably in Ukraine, the Coronavirus pandemic and the effects of climate change, increases the likelihood of childhood exposure to physical injury and pain. Other effects of these worldwide hardships include poverty, malnutrition and starvation, also bringing with them other forms of trauma, including emotional harm, neglect and deliberate maltreatment. Objective: To review the neurobiology of the systems in the developing brain that are most affected by physical and emotional trauma and neglect. Method: The review begins with those that mature first, such as the somatosensory system, progressing to structures that have a more protracted development, including those involved in cognition and emotional regulation. Explored next are developing stress response systems, especially the hypothalamic-pituitary-adrenal axis and its central regulator, corticotropin-releasing hormone. Also examined are reward and anti-reward systems and genetic versus environmental influences. The behavioural consequences of interpersonal childhood trauma, focusing on self-harm and suicide, are also surveyed briefly. Finally, pointers to effective treatment are proffered. Results: The low-threshold nature of circuitry in the developing brain and lack of inhibitory connections therein result in heightened excitability, making the consequences of both physical and emotional trauma more intense. Sensitive and critical periods in the development of structures such as the amygdala render the nervous system more vulnerable to insults occurring at those points, increasing the likelihood of psychiatric disorders, culminating in self-harm and even suicide. Conclusion: In view of the greater excitability of the developing nervous system, and its vulnerability to physical and psychological injuries, the review ends with an exhortation to consider the long-term consequences of childhood trauma, often underestimated or missed altogether when faced with adults suffering mental health problems.

Antecedentes: La situación en el mundo actual, que abarca múltiples conflictos armados, mayormente en Ucrania, la pandemia del Coronavirus y los efectos del cambio climático, aumenta la probabilidad de exposición infantil a lesiones físicas y dolor. Otros efectos de estas dificultades mundiales incluyen pobreza, desnutrición y hambruna, también traen consigo otras formas de trauma, incluyendo daño emocional, negligencia y maltrato deliberado.Objetivo: Revisar la neurobiología de los sistemas en el cerebro en desarrollo que se ven más afectados por el trauma físico y emocional y la negligencia.Método: La revisión comienza con aquellos que maduran primero, como el sistema somatosensorial, progresando hacia estructuras que tienen un desarrollo más prolongado, incluidas las involucradas en la cognición y regulación emocional. A continuación se exploraron los sistemas de respuesta al estrés en desarrollo, especialmente el eje hipotálamo-hipófisis-adrenal y su regulador central, la hormona liberadora de corticotrofina. También se examinaron los sistemas de recompensa y anti-recompensa e influencias genéticas versus ambientales. Tambien se investigaron brevemente, las consecuencias conductuales del trauma infantil interpersonal, centrándose en las autolesiones y suicidio. Finalmente, se ofrecieron indicaciones para un tratamiento eficaz.Resultados: La naturaleza de bajo umbral de los circuitos en el cerebro en desarrollo y la falta de conexiones inhibitorias en ellos dan como resultado una mayor excitabilidad, lo que hace que las consecuencias del trauma físico y emocional sean más intensas. Los periodos críticos y sensibles en el desarrollo de estructuras como la amígdala hacen que el sistema nervioso sea más vulnerable a las agresiones que ocurren en esos puntos, lo que aumenta la probabilidad de trastornos psiquiátricos, culminando en autolesiones e incluso suicidio.Conclusión: En vista de la mayor excitabilidad del sistema nervioso en desarrollo y su vulnerabilidad a las lesiones físicas y psicológicas, la revisión termina con una exhortación a considerar las consecuencias a largo plazo del trauma infantil, con frecuencia subestimado o ignorado totalmente cuando nos enfrentamos con adultos que sufren de problemas de salud mental.

New Insights on Effects of Glucocorticoids in Patients With SARS-CoV-2 Infection.

OBJECTIVE: Since January 2020, the highly contagious novel coronavirus SARS-CoV-2 has caused a global pandemic. Severe COVID-19 leads to a massive release of proinflammatory mediators, leading to diffuse damage to the lung parenchyma, and the development of acute respiratory distress syndrome. Treatment with the highly potent glucocorticoid (GC) dexamethasone was found to be effective in reducing mortality in severely affected patients. METHODS: To review the effects of glucocorticoids in the context of COVID-19 we performed a literature search in the PubMed database using the terms COVID-19 and glucocorticoid treatment. We identified 1429 article publications related to COVID-19 and glucocorticoid published from 1.1.2020 to the present including 238 review articles and 36 Randomized Controlled Trials. From these studies, we retrieved 13 Randomized Controlled Trials and 86 review articles that were relevant to our review topics. We focused on the recent literature dealing with glucocorticoid metabolism in critically ill patients and investigating the effects of glucocorticoid therapy on the immune system in COVID-19 patients with severe lung injury. RESULTS: In our review, we have discussed the regulation of the hypothalamic-pituitary-adrenal axis in patients with critical illness, selection of a specific GC for critical illness-related GC insufficiency, and recent studies that investigated hypothalamic-pituitary-adrenal dysfunction in patients with COVID-19. We have also addressed the specific activation of the immune system with chronic endogenous glucocorticoid excess, as seen in patients with Cushing syndrome, and, finally, we have discussed immune activation due to coronavirus infection and the possible mechanisms leading to improved outcomes in patients with COVID-19 treated with GCs. CONCLUSION: For clinical endocrinologists prescribing GCs for their patients, a precise understanding of both the molecular- and cellular-level mechanisms of endogenous and exogenous GCs is imperative, including timing of administration, dosage, duration of treatment, and specific formulations of GCs.

Protracted stress-induced hypocortisolemia may account for the clinical and immune manifestations of Long COVID.

About one out of eight people to convalesce from COVID-19 suffer from the so called Long COVID, a syndrome of non-specific symptoms with unclear pathogenesis. In a recent study published in Cell Long COVID participants reporting respiratory symptoms had low cortisol levels. In an as yet unpublished analysis from Yale University low plasma cortisol levels discriminated Long COVID from asymptomatic convalescent or healthy non-infected controls. Although various immune perturbations were present in Long COVID, low levels of cortisol were prominent and strikingly, depression and anxiety were increased. It has become clear that Long COVID features may be similar to those described in myalgic encephalomyelitis/chronic fatigue syndrome, post-SARS sickness syndrome, and various chronic stress syndromes which have been linked to hypocortisolemia. Notably, lack of response of the hypothalamic-pituitary-adrenal axis to hypocortisolemia shows a suppressed axis in Long COVID. We suggest that the inability of hypothalamic-pituitary-adrenal axis to recover after the acute illness, perhaps due to protracted stress in predisposed individuals, may represent the pathogenetic basis of the Long COVID-associated clinical and immunological manifestations.

Possible Stress-Neuroendocrine System-Psychological Symptoms Relationship in Pregnant Women during the COVID-19 Pandemic.

The COVID-19 pandemic induced long-term damages that weigh on the national health systems of various countries in terms of support and care. This review aimed to highlight the mental health impact of the COVID-19 pandemic in pregnant women. We first report data on the immune system physiopathology and the main viral infections in pregnancy, including COVID-19. Then, the attention is focused on the main factors that affect the mental health of pregnant women during the COVID-19 pandemic, such as (1) the fear of being infected and transmitting the infection to the fetus, (2) the cancellation of checkups and pre-child courses, and (3) confinement and the inability to have close friends or a partner at the time of delivery or in the first days after delivery, as well as family tensions. Because of all this, pregnant women find themselves in a stressful condition independent of the pregnancy, and thus experience anxiety, depression, insomnia, hostility, delirium, and an alteration of the mother-baby relationship. Several studies have shown an involvement of the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-thyroid axis in response to the pandemic. We propose a possible involvement of the neuroendocrine system as a mediator of the psychological symptoms of pregnant women induced by COVID-19-related stress.

The Role of Psychobiotics to Ensure Mental Health during the COVID-19 Pandemic-A Current State of Knowledge.

Psychobiotics are defined as probiotics, mainly of the genus Lactobacillus and Bifidobacterium, that confer mental health benefits to the host when consumed in a particular quantity through the interaction with commensal gut microbiota. The gut microbiota, which means a diverse and dynamic population of microorganisms harboring the gastrointestinal tract, communicates with the brain and vice versa through the brain-gut axis. The mechanisms of action of psychobiotics may be divided into four groups: synthesis of neurotransmitters and neurochemicals, regulation of the HPA axis, influence on the immune system, and synthesis of metabolites. Recent years showed that the COVID-19 pandemic affected not only physical, but also mental health. Social isolation, fear of infection, the lack of adequate vaccine, disinformation, increased number of deaths, financial loss, quarantine, and lockdown are all factors can cause psychiatric problems. The aim of this review was to discuss the potential role of psychobiotic in light of the current problems, based on in vitro and in vivo studies, meta-analyses, clinical trials evidence, and registered studies assessing probiotics' therapeutic administration in the prevention or treatment of symptoms or side effects of COVID-19.

The effects of momentary loneliness and COVID-19 stressors on hypothalamic-pituitary adrenal (HPA) axis functioning: A lockdown stage changes the association between loneliness and salivary cortisol.

The COVID-19 pandemic can be characterized as a chronic stressor affecting the hypothalamic-pituitary-adrenal (HPA) axis, indexed by glucocorticoids (e.g., cortisol). We investigated whether salivary cortisol level is increased during a lockdown and whether a lockdown condition affects the association between loneliness, specific COVID-19 related stressors and salivary cortisol level. We conducted a smartphone-based ecological momentary assessment (EMA) study with 280 participants in Germany who experienced at least mild loneliness and distress amid COVID-19 from August 2020 to March 2021. We measured their momentary loneliness and COVID-related stressors including worries, information seeking behaviors and feelings of restriction during "no-lockdown" or "lockdown" stages amid COVID-19. Their salivary cortisol was measured 4 times on the last day of a 7-day EMA study. We found a significant increase in salivary cortisol levels during lockdown compared to no-lockdown. Lockdown stage was found to moderate the relationship between momentary loneliness and salivary cortisol level, i.e., loneliness was positively related to cortisol level specifically during lockdown. Mechanisms explaining the effect of forced social isolation on the association between loneliness and salivary cortisol need to be investigated in future studies.

Prenatal hair cortisol concentrations during the COVID-19 outbreak: Associations with maternal psychological stress and infant temperament.

BACKGROUND: Maternal psychological stress during pregnancy, including stress resulting from disasters and trauma, has been linked to temperamental difficulties in offspring. Although heightened cortisol concentrations are often hypothesized as an underlying mechanism, evidence supporting this mechanism is not consistent, potentially because of methodological issues and low stress in the population. AIM: To address these issues, this preregistered study investigated the following associations between: 1) prenatal psychological stress and hair cortisol, as a biomarker for chronic stress, during the COVID-19 outbreak (i.e., as a major worldwide psychological stressor), and 2) maternal hair cortisol during the COVID-19 outbreak and later infant temperamental negative affectivity and orienting/regulation. Additionally, we explored whether associations were different for women with low versus high socioeconomic status (SES; maternal education and annual household income) and at different stages of pregnancy. METHOD: Pregnant women (N = 100) filled out online questionnaires during the first COVID-19 lockdown. Six months later, when most mothers were still pregnant or had just given birth, maternal hair samples were collected during home visits. When infants were six months old, mothers reported on their infant's temperament. RESULTS: Although hierarchical regression analyses revealed no associations between prenatal COVID-19 psychological stress and hair cortisol during the COVID-19 outbreak, SES proved to be a moderator in this association. Only pregnant women with higher levels of SES, not lower levels, showed a positive association between work-related and social support-related COVID-19 worries and hair cortisol. Finally, prenatal hair cortisol was not associated with later infant temperamental negative affectivity and orienting/regulation. CONCLUSION: Although the COVID-19 outbreak proved to be a major psychological stressor worldwide, the physiological impact of the crisis might be different for pregnant women with higher SES as compared to lower SES.

Bone, Brain, Heart study protocol: A resilient nested, tripartite prospective cohort study of the role of estrogen depletion on HIV pathology.

PURPOSE: We describe the rationale for and design of an innovative, nested, tripartite prospective observational cohort study examining whether relative estrogen insufficiency-induced inflammation amplifies HIV-induced inflammation to cause end organ damage and worsen age-related co-morbidities affecting the neuro-hypothalamic-pituitary-adrenal axis (Brain), skeletal (Bone), and cardiovascular (Heart/vessels) organ systems (BBH Study). METHODS: The BBH parent study is the Multicenter AIDS Cohort/Women's Interagency HIV Study Combined Cohort Study (MWCCS) with participants drawn from the Atlanta MWCCS site. BBH will enroll a single cohort of n = 120 women living with HIV and n = 60 HIV-negative women, equally distributed by menopausal status. The innovative multipart nested study design of BBH, which draws on data collected by the parent study, efficiently leverages resources for maximum research impact and requires extensive oversight and management in addition to careful implementation. The presence of strong infrastructure minimized BBH study disruptions due to changes in the parent study and the COVID-19 pandemic. CONCLUSION: BBH is poised to provide insight into sex and HIV associations with the neuro-hypothalamic-pituitary-adrenal axis, skeletal, and cardiovascular systems despite several major, unexpected challenges.

COVID-19 Infections in Gonads: Consequences on Fertility?

COVID-19 may influence human fertility and sexuality in several ways. Different cell types in gonads show a constitutive expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2), which provide potential entry pathways for SARS-CoV-2. In addition to the biological effects of a COVID-19 infection on the gonads, the impact of the ongoing COVID-19 pandemic on mental health issues and sexual behavior may affect reproduction. This review summarizes the current knowledge on the influence of COVID-19 on the gonads and discusses possible consequences on human fertility. In this context, the close interaction between the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis in response to COVID-19-related stress is discussed. Some women noticed changes in their menstrual cycle during the COVID-19 pandemic, which could be due to psychological stress, for example. In addition, occasional cases of reduced oocyte quality and ovarian function are described after COVID-19 infection. In men, COVID-19 may cause a short-term decrease in fertility by damaging testicular tissue and/or impairing spermatogenesis. Moreover, decreased ratio testosterone/LH and FSH/LH in COVID-19 compared to aged-matched healthy men has been reported. Available data do not suggest any effect of the available SARS-CoV-2 vaccines on fertility. The effects of long COVID on human fertility have been reported and include cases with premature ovarian failure and oligomenorrhoea in women and erectile dysfunction in men. Despite the increasing knowledge about the effects of COVID-19 infections on human gonads and fertility, the long-term consequences of the COVID-19 pandemic cannot yet be assessed in this context.

ACE2, Circumventricular Organs and the Hypothalamus, and COVID-19.

The SARS-CoV-2 virus gains entry to cells by binding to angiotensin-converting enzyme 2 (ACE2). Since circumventricular organs and parts of the hypothalamus lack a blood-brain barrier, and immunohistochemical studies demonstrate that ACE2 is highly expressed in circumventricular organs which are intimately connected to the hypothalamus, and the hypothalamus itself, these might be easy entry points for SARS-CoV-2 into the brain via the circulation. High ACE2 protein expression is found in the subfornical organ, area postrema, and the paraventricular nucleus of the hypothalamus (PVH). The subfornical organ and PVH are parts of a circuit to regulate osmolarity in the blood, through the secretion of anti-diuretic hormone into the posterior pituitary. The PVH is also the stress response centre in the brain. It controls not only pre-ganglionic sympathetic neurons, but is also a source of corticotropin-releasing hormone, that induces the secretion of adrenocorticotropic hormone from the anterior pituitary. It is proposed that the function of ACE2 in the circumventricular organs and the PVH could be diminished by binding with SARS-CoV-2, thus leading to a reduction in the ACE2/Ang (1-7)/Mas receptor (MasR) signalling axis, that modulates ACE/Ang II/AT1R signalling. This could result in increased presympathetic activity/neuroendocrine secretion from the PVH, and effects on the hypothalamic-pituitary-adrenal axis activity. Besides the bloodstream, the hypothalamus might also be affected by SARS-CoV-2 via transneuronal spread along the olfactory/limbic pathways. Exploring potential therapeutic pathways to prevent or attenuate neurological symptoms of COVID-19, including drugs which modulate ACE signalling, remains an important area of unmet medical need.

Exploring Daily Salivary Cortisol Patterns as Biomarkers of Chronic Chemotherapy-Induced Peripheral Neuropathy Pain.

OBJECTIVES: Little is known about the biologic mechanisms of chronic chemotherapy-induced peripheral neuropathy (CIPN) pain. The purpose of this secondary analysis was to explore salivary cortisol patterns among cancer survivors with chronic CIPN pain to provide preliminary data regarding the role of hypothalamic-pituitary-adrenal axis dysregulation in the pathophysiology of this condition. SAMPLE & SETTING: 13 cancer survivors with chronic CIPN pain recruited from the breast, gastrointestinal, and gynecologic cancer centers at Dana-Farber Cancer Institute in Boston, Massachusetts. METHODS & VARIABLES: Salivary cortisol was collected on awakening, 30 minutes after awakening, and before going to bed on two consecutive days. Cortisol awakening response and diurnal cortisol slope were calculated by averaging results across two days. RESULTS: Cortisol was available from 13 participants. The median cortisol awakening response was -0.03 mcg/dl, and the average diurnal cortisol slope was -0.24 mcg/dl. IMPLICATIONS FOR NURSING: Mechanism-based treatments are needed for cancer survivors with chronic CIPN pain. Nurse scientists may use study results to explore stress-related mechanisms of chronic CIPN pain.

Modulation of innate immune response to viruses including SARS-CoV-2 by progesterone.

Whether and how innate antiviral response is regulated by humoral metabolism remains enigmatic. We show that viral infection induces progesterone via the hypothalamic-pituitary-adrenal axis in mice. Progesterone induces downstream antiviral genes and promotes innate antiviral response in cells and mice, whereas knockout of the progesterone receptor PGR has opposite effects. Mechanistically, stimulation of PGR by progesterone activates the tyrosine kinase SRC, which phosphorylates the transcriptional factor IRF3 at Y107, leading to its activation and induction of antiviral genes. SARS-CoV-2-infected patients have increased progesterone levels, and which are co-related with decreased severity of COVID-19. Our findings reveal how progesterone modulates host innate antiviral response, and point to progesterone as a potential immunomodulatory reagent for infectious and inflammatory diseases.

Long COVID and long chain fatty acids (LCFAs): Psychoneuroimmunity implication of omega-3 LCFAs in delayed consequences of COVID-19.

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the lasting pandemic of coronavirus disease 2019 (COVID-19) and the post-acute phase sequelae of heterogeneous negative impacts in multiple systems known as the "long COVID." The mechanisms of neuropsychiatric complications of long COVID are multifactorial, including long-term tissue damages from direct CNS viral involvement, unresolved systemic inflammation and oxidative stress, maladaptation of the renin-angiotensin-aldosterone system and coagulation system, dysregulated immunity, the dysfunction of neurotransmitters and hypothalamus-pituitaryadrenal (HPA) axis, and the psychosocial stress imposed by societal changes in response to this pandemic. The strength of safety, well-acceptance, and accumulating scientific evidence has now afforded nutritional medicine a place in the mainstream of neuropsychiatric intervention and prophylaxis. Long chain omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) might have favorable effects on immunity, inflammation, oxidative stress and psychoneuroimmunity at different stages of SARS-CoV-2 infection. Omega-3 PUFAs, particularly EPA, have shown effects in treating mood and neurocognitive disorders by reducing pro-inflammatory cytokines, altering the HPA axis, and modulating neurotransmission via lipid rafts. In addition, omega-3 PUFAs and their metabolites, including specialized pro-resolvin mediators, accelerate the process of cleansing chronic inflammation and restoring tissue homeostasis, and therefore offer a promising strategy for Long COVID. In this article, we explore in a systematic review the putative molecular mechanisms by which omega-3 PUFAs and their metabolites counteract the negative effects of long COVID on the brain, behavior, and immunity.