Epigenetic changes are considered the main mechanisms behind the interplay of environment and genetic susceptibility in major depressive disorder (MDD). However, studies focusing on epigenetic dysregulation of the HPA axis stress response in MDD are lacking. Our objective was to simultaneously asses DNA methylation of the glucocorticoid receptor gene (NR3C1) and serotonin transporter gene (SLC6A4) and HPA axis response to stress in MDD. We recruited 80 depressed inpatients and 58 gender and age matched healthy controls. All participants underwent the Trier Social Stress Test (TSST) and salivary cortisol was repeatedly measured to assess HPA axis reactivity. DNA methylation of the NR3C1 (exon 1 F) and SLC6A4 CpG islands was quantified from whole blood DNA. In the MDD group, clinical assessment was repeated at 8-week follow-up to test the predictive potential of DNA methylation for symptom improvement. Depressed patients had blunted cortisol reactivity to TSST compared to healthy controls (p = 0.01). In addition, they presented with increased average SLC6A4 (p = 0.003) and NR3C1 methylation (p = 0.03), as well as methylation of two individual NR3C1 CpG loci overlapping with the NGFI-A-binding sites (CpG12 and CpG20). Methylation of one of these two loci (CpG20) predicted lower symptom improvement at the follow-up (p = 0.007). Both, average NR3C1 and SLC6A4 methylation were associated with lower cortisol reactivity in the MDD group and explained about 16% of variability in cortisol response to TSST. We provide evidence of the role of NR3C1 and SLC6A4 DNA methylation in HPA axis dysregulation in MDD, which needs to be further explored.

The World Health Organization (WHO) and the International Labour Organization (ILO) are developing Joint Estimates of the work-related burden of disease and injury (WHO/ILO Joint Estimates), with contributions from a large network of experts. Evidence from mechanistic data suggests that exposure to long working hours may increase alcohol consumption and cause alcohol use disorder. In this paper, we present a systematic review and meta-analysis of parameters for estimating the number of deaths and disability-adjusted life years from alcohol consumption and alcohol use disorder that are attributable to exposure to long working hours, for the development of the WHO/ILO Joint Estimates. We aimed to systematically review and meta-analyse estimates of the effect of exposure to long working hours (three categories: 41-48, 49-54 and ≥55 h/week), compared with exposure to standard working hours (35-40 h/week), on alcohol consumption, risky drinking (three outcomes: prevalence, incidence and mortality) and alcohol use disorder (three outcomes: prevalence, incidence and mortality). We developed and published a protocol, applying the Navigation Guide as an organizing systematic review framework where feasible. We searched electronic bibliographic databases for potentially relevant records from published and unpublished studies, including the WHO International Clinical Trials Register, Ovid MEDLINE, PubMed, Embase, and CISDOC on 30 June 2018. Searches on PubMed were updated on 18 April 2020. We also searched electronic grey literature databases, Internet search engines and organizational websites; hand-searched reference list of previous systematic reviews and included study records; and consulted additional experts. We included working-age (≥15 years) workers in the formal and informal economy in any WHO and/or ILO Member State but excluded children (<15 years) and unpaid domestic workers. We considered for inclusion randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies with an estimate of the effect of exposure to long working hours (41-48, 49-54 and ≥55 h/week), compared with exposure to standard working hours (35-40 h/week), on alcohol consumption (in g/week), risky drinking, and alcohol use disorder (prevalence, incidence or mortality). At least two review authors independently screened titles and abstracts against the eligibility criteria at a first stage and full texts of potentially eligible records at a second stage, followed by extraction of data from publications related to qualifying studies. Two or more review authors assessed the risk of bias, quality of evidence and strength of evidence, using Navigation Guide and GRADE tools and approaches adapted to this project. Fourteen cohort studies met the inclusion criteria, comprising a total of 104,599 participants (52,107 females) in six countries of three WHO regions (Americas, South-East Asia, and Europe). The exposure and outcome were assessed with self-reported measures in most studies. Across included studies, risk of bias was generally probably high, with risk judged high or probably high for detection bias and missing data for alcohol consumption and risky drinking. Compared to working 35-40 h/week, exposure to working 41-48 h/week increased alcohol consumption by 10.4 g/week (95% confidence interval (CI) 5.59-15.20; seven studies; 25,904 participants, I2 71%, low quality evidence). Exposure to working 49-54 h/week increased alcohol consumption by 17.69 g/week (95% confidence interval (CI) 9.16-26.22; seven studies, 19,158 participants, I2 82%, low quality evidence). Exposure to working ≥55 h/week increased alcohol consumption by 16.29 g/week (95% confidence interval (CI) 7.93-24.65; seven studies; 19,692 participants; I2 82%, low quality evidence). We are uncertain about the effect of exposure to working 41-48 h/week, compared with working 35-40 h/week on developing risky drinking (relative risk 1.08; 95% CI 0.86-1.36; 12 studies; I2 52%, low certainty evidence). Working 49-54 h/week did not increase the risk of developing risky drinking (relative risk 1.12; 95% CI 0.90-1.39; 12 studies; 3832 participants; I2 24%, moderate certainty evidence), nor working ≥55 h/week (relative risk 1.11; 95% CI 0.95-1.30; 12 studies; 4525 participants; I2 0%, moderate certainty evidence). Subgroup analyses indicated that age may influence the association between long working hours and both alcohol consumption and risky drinking. We did not identify studies for which we had access to results on alcohol use disorder. Overall, for alcohol consumption in g/week and for risky drinking, we judged this body of evidence to be of low certainty. Exposure to long working hours may have increased alcohol consumption, but we are uncertain about the effect on risky drinking. We found no eligible studies on the effect on alcohol use disorder. Producing estimates for the burden of alcohol use disorder attributable to exposure to long working hours appears to not be evidence-based at this time. PROTOCOL IDENTIFIER: https://doi.org/10.1016/j.envint.2018.07.025. CRD42018084077.

The novel coronavirus disease (COVID-19) has become a global pandemic. Drastic measures are being taken to flatten the peak and slow down its progression to reduce fatalities caused by the collapse of healthcare systems and overstretched hospital capacity [1]. Intensive care physicians, emergency doctors, general practitioners, nurses and even cleaning staff are making a huge effort to support patients. As we have learned from China, Italy and previous outbreaks (e.g. SARS and MERS), medical professionals and first responders have a very high risk of infection. During the SARS outbreak, for example, one in five cases globally were healthcare workers [2]. Recent data from the COVID-19 crisis in Italy are equally alarming, indicating that 20% of Italian healthcare workers were infected [3].

There is a growing interest concerning the relevance of salivary cortisone levels in stress-related research. However, studies investigating morning patterns and day-to-day variability of cortisone versus cortisol levels are lacking. Cortisol and cortisone analysis by liquid chromatography-tandem mass spectroscopy (LC-MS/MS) has been widely used for routine laboratory measurements in the last years. The aim of this study was to develop an ultra-performance LC-MS/MS method for the simultaneous quantification of salivary cortisol and cortisone levels for assessing the temporal variability of these hormones. Saliva samples were collected from 18 healthy volunteers at 0, 15, and 30 min after awakening on each day for 1 week and analysed with the newly developed method. We used a novel atmospheric pressure ionization source, which resulted in high sensitivity and specificity for both cortisol and cortisone as well as higher peak values and signal-to-noise ratio as compared with the electrospray ionization source. Cortisone showed similar morning patterns as cortisol: a 25% and 49% increase in levels at 15 and 30 min after awakening, respectively. Most cortisone indices showed somewhat lower day-to-day variability and were less affected by state-related covariates. We recommend further exploration of the potential of salivary cortisone as a biomarker in stress-related research.