SARS-CoV-2 S protein activates NLRP3 inflammasome and deregulates coagulation factors in endothelial and immune cells.

BACKGROUND: Hyperinflammation, hypercoagulation and endothelial injury are major findings in acute and post-COVID-19. The SARS-CoV-2 S protein has been detected as an isolated element in human tissues reservoirs and is the main product of mRNA COVID-19 vaccines. We investigated whether the S protein alone triggers pro-inflammatory and pro-coagulant responses in primary cultures of two cell types deeply affected by SARS-CoV-2, such are monocytes and endothelial cells. METHODS: In human umbilical vein endothelial cells (HUVEC) and monocytes, the components of NF-κB and the NLRP3 inflammasome system, as well as coagulation regulators, were assessed by qRT-PCR, Western blot, flow cytometry, or indirect immunofluorescence. RESULTS: S protein activated NF-κB, promoted pro-inflammatory cytokines release, and triggered the priming and activation of the NLRP3 inflammasome system resulting in mature IL-1ß formation in both cell types. This was paralleled by enhanced production of coagulation factors such as von Willebrand factor (vWF), factor VIII or tissue factor, that was mediated, at least in part, by IL-1ß. Additionally, S protein failed to enhance ADAMTS-13 levels to counteract the pro-coagulant activity of vWF multimers. Monocytes and HUVEC barely expressed angiotensin-converting enzyme-2. Pharmacological approaches and gene silencing showed that TLR4 receptors mediated the effects of S protein in monocytes, but not in HUVEC. CONCLUSION: S protein behaves both as a pro-inflammatory and pro-coagulant stimulus in human monocytes and endothelial cells. Interfering with the receptors or signaling pathways evoked by the S protein may help preventing immune and vascular complications driven by such an isolated viral element. Video Abstract.

Mental health inequalities in times of crisis: evolution between 2005 and 2021 among the Spanish salaried population.

BACKGROUND: Studying the working population's mental health in times of crisis (such as the 2008 recession or the COVID-19 pandemic) is very relevant. This study aims to assess the prevalence of poor mental health among the Spanish salaried population, according to the labour market inequality axes (2005-2021). METHODS: Repeated cross-sectional study by comparing different surveys from 2005, 2010, 2016 and 2021 on workers residing in Spain who had been working in a salaried job during the week preceding the survey. n=7197 (2005), n=4985 (2010), n=1807 (2016) and n=18 870 (2021). OUTCOME VARIABLE: poor mental health (Mental Health Inventory of the 36-item Short Form Health Survey scale). Explanatory variables: gender, age, occupational class and type of contract. Prevalence of poor mental health was estimated for each year by means of logistic regression models with robust clustered SEs, stratifying by the explanatory variables. Additionally, prevalence ratios (PR) were estimated by means of robust Poisson regression models to assess differences between the explanatory variables' categories. All analyses were weighted to address unrepresentativeness. RESULTS: Poor mental health significantly increased in 2021 (55.92%), compared with the previous years of study (15%-17.72%). Additionally, pattern changes were identified on inequality axes in 2021, with better mental health status among older workers (oldest group PR: 0.76; 95% CI 0.71 to 0.8) and permanent workers (PR: 0.9; 95% CI 0.85 to 0.94). CONCLUSION: This study shows a steep worsening of mental health among the salaried population in 2021 compared with previous periods. In 2021, health inequalities have apparently narrowed, although not by improving the disadvantaged groups' mental health but by worsening the typically advantaged groups' mental health.

Relación entre exposición a riesgos psicosociales y salud: un estudio de cohorte mediante el COPSOQ-Istas21 / Relationship between psychosocial risks exposure and health: a cohort study using the COPSOQ-Istas21

Objetivo: Estimar las relaciones prospectivas entre la exposición a las dimensiones de riesgos psicosociales incluidas en el COPSOQ-Istas21 y el deterioro de la salud general, la salud mental y los problemas del sueño entre personas trabajadoras residentes en España. Método: Cohorte cuya línea base corresponde a la Encuesta de Riesgos Psicosociales de 2016, con una nueva medición al cabo de 1 año. Resultados: Las dimensiones de capital social y de relaciones interpersonales y liderazgo, así como el conflicto trabajo-vida, se relacionaron con todas las variables de salud. Las de organización y contenido del trabajo lo hicieron especialmente con la salud mental, las exigencias cuantitativas con la salud general y las emocionales con la salud mental. Las dimensiones relacionadas con la inseguridad laboral no mostraron relación con la salud. Conclusiones: Los resultados obtenidos refuerzan el papel del COPSOQ-Istas21 como un instrumento útil para la evaluación y la prevención de los riesgos psicosociales en el trabajo. (AU)

Objective: To estimate the prospective relationships between exposure to psychosocial risks dimensions included in the COPSOQ-Istas21 and the deterioration of general and mental health and sleep problems among workers residing in Spain. Method: Social capital and interpersonal relations and leadership dimensions, as well as work-Cohort whose baseline corresponds to the 2016 Psychosocial Risks Survey with a new measurement after one year. Results: life conflict, were related to all health variables. Dimensions of work organization and job contents did it especially with the mental health, the quantitative demands with the general health and the emotional ones with the mental health. The dimensions related to job insecurity did not show relationships with health. Conclusions: The results obtained reinforce the role of the COPSOQ-Istas21 as a useful instrument for the evaluation and prevention of psychosocial risks at work. (AU)

Nitric oxide favours tumour-promoting inflammation through mitochondria-dependent and -independent actions on macrophages.

Production of nitric oxide (NO) has been demonstrated in several malignancies, however its role remains not fully understood, specifically in relation to the metabolic and functional implications that it may have on immune cells participating in tumorigenesis. Here, we show that inducible NO synthase (iNOS) is expressed in cancers of the colon and the prostate, mainly by tumour cells, and NO generation is evidenced by widespread nitrotyrosine (NT) staining in tumour tissue. Furthermore, presence of NT is observed in the majority of tumour-associated macrophages (TAMs), despite low iNOS expression by these cells, suggesting that NO from the tumour microenvironment affects TAMs. Indeed, using a co-culture model, we demonstrate that NO produced by colon and prostate cancer cells is sufficient to induce NT formation in neighbouring macrophages. Moreover, exposure to exogenous NO promotes mitochondria-dependent and -independent changes in macrophages, which orientate their polarity towards an enhanced pro-inflammatory phenotype, whilst decreasing antigen-presenting function and wound healing capacity. Abrogating endogenous NO generation in murine macrophages, on the other hand, decreases their pro-inflammatory phenotype. These results suggest that the presence of NO in cancer may regulate TAM metabolism and function, favouring the persistence of inflammation, impairing healing and subverting adaptive immunity responses.

Validation of the medium and short version of CENSOPAS-COPSOQ: a psychometric study in the Peruvian population.

BACKGROUND: The presence of psychosocial risks at work are associated with mental and physical health issues in workers. The study aim was to adapt the COPSOQ-ISTAS21 (Spanish version of the Copenhagen Psychosocial Questionnaire and Union Institute of Work, Environment and Health) Medium-Version to the Peruvian context and to develop a Short-Version of the instrument. METHOD: Cross-sectional design study. The COPSOQ-ISTAS21 Medium Version was used. A confirmatory factor analysis was performed to determine the internal structure of each subdimension (first-order) and dimension (second-order) using the Robust Maximum Likelihood estimation method, and classic fit indices in the literature (CFI, SRMR, RMSEA). Internal consistency was evaluated using the alpha and omega coefficients. A short version was developed based on the items with the highest factorial load and that reduce the factorial complexity. RESULTS: A total of 1707 participants were evaluated. In the confirmatory factor analysis, the goodness-of-fit indices for seventeen of the 20 one-dimensional models (subdimensions) were identified; two subdimensions could not be evaluated because they presented only two items. When conducting a multidimensional analysis, we identified that all second-order models presented optimal goodness-of-fit indices, except "psychological demands at work". Finally, a short version of only 31 items was designed from the items with optimal fit indices. CONCLUSIONS: The new adapted versions of COPSOQ-ISTAS21 were renamed CENSOPAS-COPSOQ (National center of occupational health and environment protection for health -in Spanish- and Copenhagen Psychosocial Questionnaire). The CENSOPAS-COPSOQ is an instrument with sufficient evidence of validity and reliability in its medium and short version, which is why its use is recommended in Peruvian work centers to identify the evaluation and prevention of psychosocial risks at work in Peru.

ß-cell-specific deletion of PFKFB3 restores cell fitness competition and physiological replication under diabetogenic stress.

HIF1α and PFKFB3 play a critical role in the survival of damaged ß-cells in type-2 diabetes while rendering ß-cells non-responsive to glucose stimulation. To discriminate the role of PFKFB3 from HIF1α in vivo, we generated mice with conditional ß-cell specific disruption of the Pfkfb3 gene on a human islet pancreatic polypeptide (hIAPP+/-) background and a high-fat diet (HFD) [PFKFB3ßKO + diabetogenic stress (DS)]. PFKFB3 disruption in ß-cells under DS led to selective purging of hIAPP-damaged ß-cells and the disappearance of insulin- and glucagon positive bihormonal cells. PFKFB3 disruption induced a three-fold increase in ß-cell replication as evidenced by minichromosome maintenance 2 protein (MCM2) expression. Unlike high-, lower DS or switch to restricted chow diet abolished HIF1α levels and reversed glucose intolerance of PFKFB3ßKO DS mice. Our data suggest that replication and functional recovery of ß-cells under DS depend on ß-cell competitive and selective purification of HIF1α and PFKFB3-positive ß-cells.

[Relationship between psychosocial risks exposure and health: a cohort study using the COPSOQ-Istas21]. / Relación entre exposición a riesgos psicosociales y salud: un estudio de cohorte mediante el COPSOQ-Istas21.

OBJECTIVE: To estimate the prospective relationships between exposure to psychosocial risks dimensions included in the COPSOQ-Istas21 and the deterioration of general and mental health and sleep problems among workers residing in Spain. METHOD: Cohort whose baseline corresponds to the 2016 Psychosocial Risks Survey with a new measurement after one year. RESULTS: Social capital and interpersonal relations and leadership dimensions, as well as work̶life conflict, were related to all health variables. Dimensions of work organization and job contents did it especially with the mental health, the quantitative demands with the general health and the emotional ones with the mental health. The dimensions related to job insecurity did not show relationships with health. CONCLUSIONS: The results obtained reinforce the role of the COPSOQ-Istas21 as a useful instrument for the evaluation and prevention of psychosocial risks at work.

Persistent inequality: evolution of psychosocial exposures at work among the salaried population in Spain between 2005 and 2016.

PURPOSE: To assess the prevalence of poor mental health and of exposure to psychosocial risks among the working population in Spain in 2005, 2010 and 2016; to analyse the associations between workplace psychosocial exposures and mental health problems according to gender and occupation. METHODS: Three representative samples of the Spanish working population were analysed, in 2005 (n = 7,023), 2010 (n = 4,979), and 2016 (n = 1,807). Prevalence ratios between mental health and the five dimensions - job demands, job control, social support, employment insecurity and insecurity over working conditions-were estimated using multilevel mixed-effects Poisson regressions. All the analyses were separated by gender and occupation. RESULTS: In 2016, there were improvements in job control, job demands and social support, and deteriorations in employment insecurity and insecurity over working conditions. The risk of poor mental health among manual workers rose if they were exposed to high demands, low social support and high employment insecurity; among non-manual workers, the risk increased if they were exposed to high demands, low control, low social support and high insecurity over working conditions. There were no differences according to gender. CONCLUSION: The new findings shed light on the evolution of the working conditions and health of the wage-earning population in Spain over the last 11 years. The stratification by gender and occupational group is relevant, since it allows a detailed analysis of the social disparities in the associations between psychosocial risks and mental health. The most vulnerable groups can be identified and preventive measures developed at source.

Job insecurity, economic hardship, and sleep problems in a national sample of salaried workers in Spain.

OBJECTIVE: To check for associations between various types of job insecurity and self-reported sleeping problems. DESIGN: A population-based, cross-sectional study. SETTING: Spain, 2016. PARTICIPANTS: Salaried workers included in the third Psychosocial Risks Survey (n = 1807). MEASUREMENTS: We investigated the association between 6 subjective and 2 attributed indicators of job insecurity (exposure) with 5 sleep problem variables (difficulty falling sleep, difficulty sleeping through the night, waking up too early, sleeping restlessly, and a composite variable summing all the sleeping problems) using Poisson regression, and controlling for socioeconomic, occupational, and demographic factors. RESULTS: Anticipating a salary decrease or working at a company where staff restructuring had occurred in the preceding year were associated with sleeping problems. Having a temporary or informal employment contract and most domains of perceived job insecurity were not a significant factor in adjusted models. CONCLUSIONS: Recent or anticipated economic hardship within a worker's household was the main predictor of sleeping problems. More research is needed to elucidate the exact mechanisms through which the experience of aspects of downsizing might manifest in disruptions to employees' sleep. Sleep health should be an active part of all employee wellness programs.

A comparison between cognitive and affective job insecurities.

BACKGROUND: Cognitive and affective job insecurity are compared in six aspects related to employment: job loss, worsening of tasks, schedule, salary and workplace, and difficulties over finding an alternative job (also known as labor market insecurity). Methods: Cross-sectional study. Data comes from the third Spanish Psychosocial Risks Survey (2016) which is a representative sample of the Spanish salaried population. Results: Affective responses are more variable than cognitive ones resulting in a low degree of answer concordance (IC95% Kappa = 0.08-0.13 to 0.18-0.23). There is a significant percentage of workers (22.5-50.3%) highly concerned about their future despite perceiving low probabilities of experiencing the specific insecurity threat, except for the labor market insecurity question. Conclusion: The differences observed in the degree of insecurity between the affective and the cognitive forms confirm that they are measuring different components of the insecurity construct. These differences are partly due to the economic situation of their households.

Sickness presenteeism: Are we sure about what we are studying? A research based on a literature review and an empirical illustration.

BACKGROUND: There has been an increasing interest in studying sickness presenteeism (SP). An ever-increasing amount of scientific literature is published using this term, yet there appears to be considerable heterogeneity in how it is assessed, which could result in substantial differences in the definition and interpretation of the phenomenon really being studied. We aim to discuss what really is being studied, depending on how the phenomenon is operationalized, measured, and analyzed. METHODS: A study based on a literature review and an empirical illustration using data of the third Spanish Psychosocial Risks Survey (2016). RESULTS: Differences are observed based on the population in which SP is measured, the cut-off points used to define a worker as presenteeist, the reasons for an SP episode and even an analysis of the phenomenon treated as a count or as a dichotomous. CONCLUSIONS: Without being completely exclusive, it seems that restricting the population of analysis to only those workers who consider that they should not have gone to work due to their health, and/or establishing low cut-off points to define someone as presenteeist, would more clearly delimit the study of SP to the exercise of a right to sick leave. In contrast, working with the entire population or using high cut-off points appears to relate the study of SP more with health status and less with the exercise of rights. On the other hand, taking the reasons for SP into account would probably help to improve interpretation of the phenomenon.

The Third Version of the Copenhagen Psychosocial Questionnaire.

INTRODUCTION: A new third version of the Copenhagen Psychosocial Questionnaire (COPSOQ III) has been developed in response to trends in working life, theoretical concepts, and international experience. A key component of the COPSOQ III is a defined set of mandatory core items to be included in national short, middle, and long versions of the questionnaire. The aim of the present article is to present and test the reliability of the new international middle version of the COPSOQ III. METHODS: The questionnaire was tested among 23,361 employees during 2016-2017 in Canada, Spain, France, Germany, Sweden, and Turkey. A total of 26 dimensions (measured through scales or single items) of the middle version and two from the long version were tested. Psychometric properties of the dimensions were assessed regarding reliability (Cronbach α), ceiling and floor effects (fractions with extreme answers), and distinctiveness (correlations with other dimensions). RESULTS: Most international middle dimensions had satisfactory reliability in most countries, though some ceiling and floor effects were present. Dimensions with missing values were rare. Most dimensions had low to medium intercorrelations. CONCLUSIONS: The COPSOQ III offers reliable and distinct measures of a wide range of psychosocial dimensions of modern working life in different countries; although a few measures could be improved. Future testing should focus on validation of the COPSOQ items and dimensions using both qualitative and quantitative approaches. Such investigations would enhance the basis for recommendations using the COPSOQ III.

Cognitive and Affective Insecurity Related to Remaining Employed and Working Conditions: Their Associations With Mental and General Health.

OBJECTIVE: The present study aims to tackle in detail the associations of insecurity with mental and self-rated health by using cognitive and affective measures of insecurity that focus on different aspects such as job loss, difficulties in finding an alternative job, and worsening the working conditions. METHODS: Data come from a representative sample of the Spanish salaried working population (n = 1807) obtained by the 2016 Psychosocial Risks Survey. RESULTS: Cognitive measures yield stronger associations between job loss and labor market insecurity and health, whereas the association between insecurity over worsening job conditions and health is stronger when using affective measures, the associations with mental health being stronger in both cases than those involving self-rated health. CONCLUSION: Association with health varies, in strength and at times in direction, depending on how insecurity is measured and conceptualized.

Prevalence, associated factors and reasons for sickness presenteeism: a cross-sectional nationally representative study of salaried workers in Spain, 2016.

OBJECTIVES: The aim of this study was to estimate the prevalence of sickness presenteeism (SP), its associated factors and the reasons given for SP episodes, among the overall salaried population and excluding the 'healthy' workers. DESIGN: Population-based cross-sectional study. SETTING: Salaried population in Spain. PARTICIPANTS: Data were obtained from the third Spanish Psychosocial Risks Survey (2016), carried out between October and December 2016, n=1615. MAIN OUTCOME MEASURES: Self-reported episodes of SP and their reasons. RESULTS: 23.0% (95% CI 19.2 to 26.8) of the workers exhibit SP, whereas among those manifesting having had some health problem in the preceding year, the figure was 53.0% (95% CI 46.9 to 59.1). The factors associated with SP when we study all workers are age, seniority, salary structure, working more than 48 hours, the contribution of worker's wage to the total household income and downsizing; factors among the 'unhealthy' workers are working more than 48 hours and not having a contract. The most common reason for SP is 'did not want to burden my colleagues', 45.7% (95% CI 37.3 to 54.4), whereas 'I could not afford it for economic reasons' ranked third, 35.9% (29.4% to 42.9%), and 27.5% (21.3% to 34.6%) of the workers report 'worried about being laid off' as a reason for going to work despite being ill. CONCLUSIONS: The estimated frequency of SP in Spain is lower than certain other countries, such as the Scandinavian countries. The factors associated vary depending on the population analysed (all workers or excluding 'healthy' workers). The reason 'I was worried about being laid off' was much more common than the estimates for Sweden or Norway.

Specific psychosocial exposures for workers' mental health: A population-based study.

BACKGROUND: In order to plan interventions it is important to obtain evidence on the relation between a health outcome and specific exposures. However, there are few studies that identify the effect of specific psychosocial work exposures on poor mental health. This is the aim of this study. METHODS: Population-based cross-sectional study in Catalonia. We estimated prevalence ratios (PR) of minor psychiatric disorder associated with several psychosocial work exposures. RESULTS: The items with highest PR were "Are there times when you need to be at work and at home at the same time?" (PR = 1.81), "Are you worried about a variation in your salary?" (PR = 1.77), "Is your work emotionally demanding?" (PR = 1.65) and "Are you worried about it being difficult for you to find another job if you became unemployed?" (PR = 1.51). CONCLUSIONS: This study could be useful in order to begin planning interventions on specific psychosocial exposures to protect mental health in the workplace.

Modulation of the conformational state of mitochondrial complex I as a target for therapeutic intervention.

In recent years, there have been significant advances in our understanding of the functions of mitochondrial complex I other than the generation of energy. These include its role in generation of reactive oxygen species, involvement in the hypoxic tissue response and its possible regulation by nitric oxide (NO) metabolites. In this review, we will focus on the hypoxic conformational change of this mitochondrial enzyme, the so-called active/deactive transition. This conformational change is physiological and relevant to the understanding of certain pathological conditions including, in the cardiovascular system, ischaemia/reperfusion (I/R) damage. We will discuss how complex I can be affected by NO metabolites and will outline some potential mitochondria-targeted therapies in I/R damage.

Nitric oxide and pulmonary arterial hypertension.

The pathogenesis of pulmonary arterial hypertension remains undefined. Changes in the expression and effects mediated by a number of vasoactive factors have been implicated to play a role in the onset and progression of the disease. The source of many of these mediators, such as nitric oxide (NO), prostacyclin and endothelin-1 (ET-1), is the pulmonary endothelium. This article focus in the role of nitric oxide in PAH, reviewing the evidence for its involvement in regulation of pulmonary a vascular tone under physiological conditions, the mechanisms by which it can contribute to the pathological changes seen in PAH and strategies for the use of NO as a therapy for treatment of the disease.