Development of health care workers' mental health during the SARS-CoV-2 pandemic in Switzerland: two cross-sectional studies.

BACKGROUND: Virus outbreaks such as the current SARS-CoV-2 pandemic are challenging for health care workers (HCWs), affecting their workload and their mental health. Since both, workload and HCW's well-being are related to the quality of care, continuous monitoring of working hours and indicators of mental health in HCWs is of relevance during the current pandemic. The existing investigations, however, have been limited to a single study period. We examined changes in working hours and mental health in Swiss HCWs at the height of the pandemic (T1) and again after its flattening (T2). METHODS: We conducted two cross-sectional online studies among Swiss HCWs assessing working hours, depression, anxiety, and burnout. From each study, 812 demographics-matched participants were included into the analysis. Working hours and mental health were compared between the two samples. RESULTS: Compared to prior to the pandemic, the share of participants working less hours was the same in both samples, whereas the share of those working more hours was lower in the T2 sample. The level of depression did not differ between the samples. In the T2 sample, participants reported more anxiety, however, this difference was below the minimal clinically important difference. Levels of burnout were slightly higher in the T2 sample. CONCLUSIONS: Two weeks after the health care system started to transition back to normal operations, HCWs' working hours still differed from their regular hours in non-pandemic times. Overall anxiety and depression among HCWs did not change substantially over the course of the current SARS-CoV-2 pandemic.

Delirium in trauma patients: a 1-year prospective cohort study of 2026 patients.

BACKGROUND: Delirium in trauma surgery is common, especially post-operatively, but medical characteristics, risk factors and residence post-discharge have not comprehensively been investigated in all trauma patients. METHODS: Over 1 year, 2026 trauma patients were prospectively screened for delirium with the following tools: Delirium Observation screening scale (DOS), Intensive Care Delirium Screening Checklist (ICDSC) and a DSM (Diagnostic and Statistical Manual)-5, nursing tool (ePA-AC) construct. Risk factors-predisposing und precipitating-for delirium were assessed via multiple regression analysis. RESULTS: Of 2026 trauma patients, 440 (21.7%) developed delirium, which was associated with an increased risk of assisted living (OR 6.42, CI 3.92-10.49), transfer to nursing home (OR 4.66, CI 3.29-6.6), rehabilitation (OR 3.96, CI 3.1-5.1), or death (OR 70.72, CI 22-227.64). Intensive care management (OR 18.62, CI 14.04-24.68), requirement of ventilation (OR 32.21, CI 21.27-48.78), or its duration (OR 67.22, CI 33.8-133.71) all increased the risk for developing delirium. Relevant predisposing risk factors were dementia (OR 50.92, CI 15.12-171.45), cardiac insufficiency (OR 11.76, CI 3.6-38.36), and polypharmacy (OR 5.9, CI 4.01-8.68).Relevant precipitating risk factors were brain edema (OR 40.53, CI 4.81-341.31), pneumonia (OR 39.66, CI 8.89-176.93) and cerebral inflammation (OR 21.74, CI 2.34-202.07). CONCLUSION: Delirium in trauma patients is associated with poor outcome as well as with intensive care management and various predisposing and/or precipitating factors. Three quarters of patients who had undergone delirium were not able to live independently at home any more.

Burnout, depression and anxiety among Swiss medical students - A network analysis.

It is well established that burnout in medical students is associated with depression and anxiety at a syndromal level. Moreover, there is an ongoing debate about the extent to which burnout overlaps with depression and anxiety. The emerging network approach to psychopathology offers a new perspective on the interrelations between mental disorders focusing on symptom-level association. In this cross-sectional study, we exploratively investigated the associations among burnout, depression, and anxiety in 574 swiss medical students using a network analytic approach for the first time. Symptoms of depression and anxiety were assessed with the Patient Health Questionnaire and Generalized Anxiety Disorder respectively. Burnout was assessed with two single-item questions, one referring to emotional exhaustion and the other to depersonalization. We found a dense network in which at least one dimension of burnout was related to eleven of the sixteen included symptoms. This suggests that burnout is closely related to depression and anxiety but also has its own characteristics. Notably, suicidal ideation was not associated with either emotional exhaustion or depersonalization after adjusting for the influence of the remaining symptoms of anxiety and depression. Hence, the well-documented relationship between burnout and suicidal ideation in medical students may be entirely mediated by the experience of anxiety and depression. Hence, the well-documented relationship between burnout and suicidal ideation in medical students might be fully mediated by the experience of anxiety and depression. The collection of the sample after the first wave of infections during the SARS-CoV2 pandemic and the non-representativeness of the investigated sample limit the study's generalizability.

Health Care Workers' Mental Health During the First Weeks of the SARS-CoV-2 Pandemic in Switzerland-A Cross-Sectional Study.

Objective: The current SARS-CoV-2 pandemic poses various challenges for health care workers (HCWs). This may affect their mental health, which is crucial to maintain high quality medical care during a pandemic. Existing evidence suggests that HCWs, especially women, nurses, frontline staff, and those exposed to COVID-19 patients, are at risk for anxiety and depression. However, a comprehensive overview of risk and protective factors considering their mutual influence is lacking. Therefore, this study aimed at exploring HCWs' mental health during the SARS-CoV-2 pandemic in Switzerland, investigating the independent effect of various demographic, work- and COVID-related factors on HCWs' mental health. Methods: In an exploratory, cross-sectional, nation-wide online survey, we assessed demographics, work characteristics, COVID-19 exposure, and anxiety, depression, and burnout in 1,406 HCWs during the beginning of the SARS-CoV-2 pandemic in Switzerland. Network analysis was used to investigate the associations among the included variables. Results: Women (compared to men), nurses (compared to physicians), frontline staff (compared to non-frontline workers), and HCWs exposed to COVID-19 patients (compared to non-exposed) reported more symptoms than their peers. However, these effects were all small. Perceived support by the employer independently predicted anxiety and burnout after adjustment for other risk factors. Conclusion: Our finding that some HCWs had elevated levels of anxiety, depression, and burnout underscores the importance to systematically monitor HCWs' mental health during this ongoing pandemic. Because perceived support and mental health impairments were negatively related, we encourage the implementation of supportive measures for HCWs' well-being during this crisis.

Death in delirious palliative-care patients occurs irrespective of age: A prospective, observational cohort study of 229 delirious palliative-care patients.

OBJECTIVES: Patients with terminal illness are at high risk of developing delirium, in particular, those with multiple predisposing and precipitating risk factors. Delirium in palliative care is largely under-researched, and few studies have systematically assessed key aspects of delirium in elderly, palliative-care patients. METHODS: In this prospective, observational cohort study at a tertiary care center, 229 delirious palliative-care patients stratified by age: <65 (N = 105) and ≥65 years (N = 124), were analyzed with logistic regression models to identify associations with respect to predisposing and precipitating factors. RESULTS: In 88% of the patients, the underlying diagnosis was cancer. Mortality rate and median time to death did not differ significantly between the two age groups. No inter-group differences were detected with respect to gender, care requirements, length of hospital stay, or medical costs. In patients ≥65 years, exclusively predisposing factors were relevant for delirium, including hearing impairment [odds ratio (OR) 3.64; confidence interval (CI) 1.90-6.99; P < 0.001], hypertension (OR 3.57; CI 1.84-6.92; P < 0.001), and chronic kidney disease (OR 4.84; CI 1.19-19.72; P = 0.028). In contrast, in patients <65 years, only precipitating factors were relevant for delirium, including cerebral edema (OR 0.02; CI 0.01-0.43; P = 0.012). SIGNIFICANCE OF RESULTS: The results of this study demonstrate that death in delirious palliative-care patients occurs irrespective of age. The multifactorial nature and adverse outcomes of delirium across all age in these patients require clinical recognition. Potentially reversible factors should be detected early to prevent or mitigate delirium and its poor survival outcomes.

Delirium at the end of life.

BACKGROUND: The general in-hospital mortality and interrelationship with delirium are vastly understudied. Therefore, this study aimed to assess the rates of in-hospital mortality and terminal delirium. METHOD: In this prospective cohort study of 28,860 patients from 37 services including 718 in-hospital deaths, mortality rates and prevalence of terminal delirium were determined with simple logistic regressions and their respective odds ratios (ORs). RESULTS: Although overall in-hospital mortality was low (2.5%), substantial variance between services became apparent: Across intensive care services the rate was 10.8% with a 5.8-fold increased risk, across medical services rates were 4.4% and 2.4-fold, whereas at the opposite end, across surgical services rates were 0.7% and 87% reduction, respectively. The highest in-hospital mortality rate occurred on the palliative care services (27.3%, OR 19.45). The general prevalence of terminal delirium was 90.7% and ranged from 83.2% to 100%. Only across intensive care services (98.1%, OR 7.48), specifically medical intensive care (98.1%, OR 7.48) and regular medical services (95.8%, OR 4.12) rates of terminal delirium were increased. In contrast, across medical services (86.4%, OR 0.32) and in particular oncology (73.9%, OR 0.25), pulmonology (72%, OR 0.31) and cardiology (63.2%, OR 0.4) rates were decreased. For the remaining services, rates of terminal delirium were the same. SIGNIFICANCE OF RESULTS: Although in-hospital mortality was low, the interrelationship with delirium was vast: most patients were delirious at the end of life. The implications of terminal delirium merit further studies.

The prevalence rates and sequelae of delirium at age older than 90 years.

OBJECTIVE: Although age and pre-existent dementia are robust risk factors for developing delirium, evidence for patients older than 90 years is lacking. Therefore, this study assesses the delirium prevalence rates and sequelae in this age group. METHOD: Based on a Diagnostic and Statistical Manual (DSM)-5, Delirium Observation screening scale (DOS), and Intensive Care Delirium Screening Checklist (ICDSC) construct, in this prospective cohort study, the prevalence rates and sequelae of delirium were determined in 428 patients older than 90 years by simple logistic regressions and corresponding odds ratios (ORs). RESULTS: The overall prevalence delirium rate was 45.2%, with a wide range depending upon specialty: intermediate and intensive care services (83.1%), plastic surgery and palliative care (75%), neurology (72%), internal medicine (69%) vs. dermatology (26.5%), and angiology (14.5%). Delirium occurred irrespective of age and gender; however, pre-existent dementia was the strongest delirium predictor (OR 36.05). Delirious patients were less commonly admitted from home (OR 0.47) than from assisted living (OR 2.24), indicating functional impairment. These patients were more severely ill, as indicated by emergency (OR 3.25) vs. elective admission (OR 0.3), requirement for intensive care management (OR 2.12) and ventilation (OR 5.56-8.33). At discharge, one-third did not return home (OR 0.22) and almost half were transferred to assisted living (OR 2.63), or deceased (OR 47.76). SIGNIFICANCE OF RESULTS: At age older than 90 years, the prevalence and sequelae of delirium are substantial. In particular, functional impairment and pre-existent dementia predicted delirium and subsequently, the loss of independence and death were imminent.

Assessing delirium with nursing care instruments: Evaluation of the cognitive and associated domains.

OBJECTIVE: Nursing instruments have the potential for daily screening of delirium; however, they have not yet been evaluated. Therefore, after assessing the functional domains of the electronic Patient Assessment - Acute Care (ePA-AC), this study evaluates the cognitive and associated domains. METHODS: In this prospective cohort study in the intensive care unit, 277 patients were assessed and 118 patients were delirious. The impacts of delirium on the cognitive domains, consciousness and cognition, communication and interaction, in addition to respiration, pain, and wounds were determined with simple logistic regressions and their respective odds ratios (ORs). RESULTS: Delirium was associated with substantial impairment throughout the evaluated domains. Delirious patients were somnolent (OR 6), their orientation (OR 8.2-10.6) and ability to acquire knowledge (OR 5.5-11.6) were substantially impaired, they lost the competence to manage daily routines (OR 8.2-22.4), and their attention was compromised (OR 12.8). In addition, these patients received psychotropics (OR 3.8), were visually impaired (OR 1.8), unable to communicate their needs (OR 5.6-7.6), displayed reduced self-initiated activities (OR 6.5-6.9) and challenging behaviors (OR 6.2), as well as sleep-wake disturbances (OR 2.2-5), Furthermore, delirium was associated with mechanical ventilation, abdominal/thoracic injuries or operations (OR 4.2-4.4), and sensory perception impairment (OR 3.9-5.8). SIGNIFICANCE OF RESULTS: Delirium caused substantial impairment in cognitive and associated domains. In addition to the previously described functional impairments, these findings will aid the implementation of nursing instruments in delirium screening.

The p38 Mitogen-Activated Protein Kinase Critically Regulates Human Keratinocyte Inflammasome Activation.

Inflammasomes are key intracellular signaling platforms involved in innate immune responses to micro-organisms and danger signals. Extracellular signal-regulated kinase, Jun N-terminal kinase, and p38 mitogen-activated protein kinase family members are activated by numerous environmental stresses. Recently, it has been reported that Jun N-terminal kinase is involved in inflammasome activation in myeloid immune cells. To date, the role of mitogen-activated protein kinase in inflammasome activity in keratinocytes has not been investigated. Here, we show that, in primary human keratinocytes, p38 mitogen-activated protein kinase is required for inflammasome activation and IL-1ß secretion. Using selective small molecule inhibitors, small interfering RNA gene silencing, and CRISPR/Cas9-based deletion, we demonstrate the above and identify p38α and p38δ as critical regulators of ASC oligomerization, inflammasome activation, and IL-1ß secretion in keratinocytes. Furthermore, our data suggest that the nature of the mitogen-activated protein kinase regulating inflammasome activity exhibits a certain cell specificity, with p38 playing a predominant role in keratinocytes and Jun N-terminal kinase 1 in cells of myeloid origin.

Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages.

Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood. Here we show that the damage-associated molecular pattern High-Mobility Group Box 1 protein (HMGB1) is released by melanoma tumour cells as a consequence of hypoxia and promotes M2-like tumour-associated macrophage accumulation and an IL-10 rich milieu within the tumour. Furthermore, we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products (RAGE). Finally, we show that HMGB1 has an important role in murine B16 melanoma growth and metastasis, whereas in humans its serum concentration is significantly increased in metastatic melanoma. Collectively, our findings identify a mechanism by which hypoxia affects tumour growth and metastasis in melanoma and depict HMGB1 as a potential therapeutic target.

IL-1ß drives inflammatory responses to propionibacterium acnes in vitro and in vivo.

Acne vulgaris is potentially a severe skin disease associated with colonization of the pilo-sebaceous unit by the commensal bacterium Propionibacterium acnes and inflammation. P. acnes is considered to contribute to inflammation in acne, but the pathways involved are unclear. Here we reveal a mechanism that regulates inflammatory responses to P. acnes. We show that IL-1ß mRNA and the active processed form of IL-1ß are abundant in inflammatory acne lesions. Moreover, we identify P. acnes as a trigger of monocyte-macrophage NLRP3-inflammasome activation, IL-1ß processing and secretion that is dependent on phagocytosis, lysosomal destabilization, reactive oxygen species, and cellular K+ efflux. In mice, inflammation induced by P. acnes is critically dependent on IL-1ß and the NLRP3 inflammasome of myeloid cells. These findings show that the commensal P. acnes-by activating the inflammasome-can trigger an innate immune response in the skin, thus establishing the NLRP3-inflammasome and IL-1ß as possible therapeutic targets in acne.

Epidermal IL-15Rα acts as an endogenous antagonist of psoriasiform inflammation in mouse and man.

Stromal cells at epithelial surfaces contribute to innate immunity by sensing environmental danger signals and producing proinflammatory cytokines. However, the role of stromal cells in controlling local inflammation is unknown. We show that endogenous soluble IL-15 receptor α (IL-15Rα) derived from epidermal stroma, notably keratinocytes, protects against dendritic cell/IL-15-mediated, T cell-driven skin inflammation in vivo, and is relevant to human psoriasis. Selective lack of IL-15Rα on stromal epidermal cells exacerbated psoriasiform inflammation in animals. Epidermal IL-15Rα was shed by keratinocytes via proteolytic cleavage by matrix metalloproteinases upon stimulation with proinflammatory cytokines to counteract IL-15-induced proliferation of IL-17(+) αß and γδ T cells and production of TNF, IL-23, IL-17, and IL-22 during skin inflammation. Notably, administration of soluble IL-15Rα was able to repress secretion of IL-1ß, IL-6, and TNF by keratinocytes, dampen expansion of IL-17(+) αß and γδ T cells in vivo, and prevent psoriasis in two mouse models, including human xenograft AGR mice. Serum levels of soluble IL-15Rα negatively correlated with disease severity, and levels rose upon successful treatment of psoriasis in patients. Thus, stressed epidermal stromal cells use soluble IL-15Rα to dampen chronic inflammatory skin disease.

Carcinogen treatment in mouse selectively expressing activated N-Ras Q61K in melanocytes recapitulates metastatic cutaneous melanoma development.

The incidence of melanoma has significantly increased, and a better understanding of its pathogenesis and development of new therapeutic strategies are urgently needed. Here, we describe a murine model of metastatic cutaneous melanoma using C57BL/6 mice expressing a mutated human N-Ras gene under the control of a tyrosinase promoter (TyrRas). These mice were topically exposed to 7,12- dimethylbenzanthracene (DMBA) for brief exposure periods. Cutaneous melanoma developed at the site of exposure on average by 19 weeks of age and in 80% of mice. Importantly, as in humans, melanoma development was associated with subsequent metastasis to tumor-draining lymph nodes. Critically, such metastatic behavior is transplantable, as intradermal inoculation of melanoma cells from TyrRas-DMBA mice into non-transgenic mice led to the growth of melanoma and, again, metastasis to skin-draining lymph nodes. This metastatic melanoma model closely mimics human pathology and should be a useful tool for studying melanoma pathogenesis and developing new therapies.

Dermoscopy of Pitted Keratolysis.

Irritated hyperhidrotic soles with multiple small pits are pathognomonic for pitted keratolysis (PK). Here we show the dermatoscopic view of typical pits that can ensure the diagnosis. PK is a plantar infection caused by Gram-positive bacteria, particularly Corynebacterium. Increases in skin surface pH, hyperhidrosis, and prolonged occlusion allow these bacteria to proliferate. The diagnosis is fundamentally clinical and treatment generally consists of a combination of hygienic measures, correcting plantar hyperhidrosis and topical antimicrobials.

Danger signaling through the inflammasome acts as a master switch between tolerance and sensitization.

Efficient priming of adaptive immunity depends on danger signals provided by innate immune pathways. As an example, inflammasome-mediated activation of caspase-1 and IL-1beta is crucial for the development of reactive T cells targeting sensitizers like dinitrofluorobenzene (DNFB). Surprisingly, DNFB and dinitrothiocyanobenzene provide cross-reactive Ags yet drive opposing, sensitizing vs tolerizing, T cell responses. In this study, we show that, in mice, inflammasome-signaling levels can be modulated to turn dinitrothiocyanobenzene into a sensitizer and DNFB into a tolerizer, and that it correlates with the IL-6 and IL-12 secretion levels, affecting Th1, Th17, and regulatory T cell development. Hence, our data provide the first evidence that the inflammasome can define the type of adaptive immune response elicited by an Ag, and hint at new strategies to modulate T cell responses in vivo.