Validity of the PARADISE24 questionnaire in people with substance use disorders : A measure to assess psychosocial difficulties

Objectives: Psychosocial difficulties (PSDs) are common in people with substance use disorders (SUDs). The PARADISE24 has been shown to be an adequate tool for measuring PSDs in inpatients with SUDs. The aim of this study is to evaluate the psychometric properties of the PARADISE24 in a sample of patients with SUDs. Methods: 2637 participants with SUDs completed the PARADISE24 questionnaire during their treatment. The latent structure of the PARADISE24 questionnaire was analyzed in the outpatient sample by means of exploratory and confirmatory factor analysis (EFA and CFA). Metric invariance was then assessed in relation to the inpatient sample using multiple group CFA. Finally, evidences of known-groups validity were checked to test the ability of the questionnaire to differentiate between socio-demographic and clinical groups. Results: The one-factor model presented an adequate fit in both the EFA (CFI = 0.98; TLI = 0.98; RMSEA = 0.07) and the CFA (CFI = 0.98; TLI = 0.98; RMSEA = 0.07) solutions. The reliability of the scale was found to be high (alpha = 0.93). Strict metric invariance between inpatients and outpatients was achieved (RMSEA = 0.063; TLI = 0.983; CFI = 0.981). The PARADISE24 was able to discriminate between the inpatients and outpatients at both latent (d = 0.98) and observed levels (d = 0.86). Conclusions: The PARADISE24 is a unidimensional tool that is reliable for assessing and comparing PSDs in both outpatients and inpatients with SUDs. Further research is required for evaluating the ability of the PARADISE24 to quantify longitudinal changes in PSDs.Peer reviewe

Health and happiness : cross-sectional household surveys in Finland, Poland and Spain

OBJECTIVE: To explore the associations between health and how people evaluate and experience their lives. METHODS: We analysed data from nationally-representative household surveys originally conducted in 2011–2012 in Finland, Poland and Spain. These surveys provided information on 10 800 adults, for whom experienced well-being was measured using the Day Reconstruction Method and evaluative well-being was measured with the Cantril Self-Anchoring Striving Scale. Health status was assessed by questions in eight domains including mobility and self-care. We used multiple linear regression, structural equation models and multiple indicators/multiple causes models to explore factors associated with experienced and evaluative well-being. FINDINGS: The multiple indicator/multiple causes model conducted over the pooled sample showed that respondents with younger age (effect size, β = 0.19), with higher levels of education (β = −0.12), a history of depression (β = −0.17), poor health status (β = 0.29) or poor cognitive functioning (β = 0.09) reported worse experienced well-being. Additional factors associated with worse evaluative well-being were male sex (β = −0.03), not living with a partner (β = 0.07), and lower occupational (β = −0.07) or income levels (β = 0.08). Health status was the factor most strongly correlated with both experienced and evaluative well-being, even after controlling for a history of depression, age, income and other sociodemographic variables. CONCLUSION: Health status is an important correlate of well-being. Therefore, strategies to improve population health would also improve people’s well-being

Which Are the Most Burdensome Functioning Areas in Depression? A Cross-National Study

Background: The study aimed to identify the most burdensome functioning domains in depression and their differential impact on the quality of life (QoL) of individuals from nine countries in Asia, Africa, Europe, and Latin America. Materials and Methods: Data from two multi-country projects-the World Health Organization’s Study on Global Ageing and Adult Health (SAGE) and the Collaborative Research on Ageing in Europe (COURAGE) - were analyzed. Eight functioning domains (pain, mobility, self-care, cognition, interpersonal activities, domestic life, and work, sleep and energy, and affect) and QoL were assessed in 4051 individuals with depression. Results: The analyses of the pooled sample showed that affect (ß = -0.21, p < 0.001), domestic life and work (ß = -0.16, p < 0.001) and interpersonal activities (ß = -0.15, p < 0.001) were the most affected functioning domains. When the analysis was stratified by gender, women showed similar patterns to the total sample, whereas mobility, self-care, cognition and pain were not significant amongst men. The cross-national analysis revealed that difficulties in affect and interpersonal activities were common across countries, whereas the rest of the domains showed country variability. In addition, being a woman (ß = -0.05), being older (ß = 0.07), being married (ß = 0.05), not having a comorbid condition (ß = -0.03) and having a higher education (ß = 0.04) were all factors associated with higher levels of QoL. Conclusion: There was a variation in the level of decrements in different functioning domains across countries. This is in line with the growing evidence that reporting functioning sum-scores obscures potential differences among people. Functioning tools should capture the distinctiveness among individuals in order to provide tailored responses

The role of unhealthy lifestyles in the incidence and persistence of depression: A longitudinal general population study in four emerging countries

Background: Unhealthy lifestyles and depression are highly interrelated: depression might elicit and exacerbate unhealthy lifestyles and people with unhealthy lifestyles are more likely to become depressed over time. However, few longitudinal evidence of these relationships has been collected in emerging countries. The present study aims i) to analyse whether people with unhealthy lifestyles are more likely to develop depression, and ii) to examine whether depressed people with unhealthy lifestyles are more likely to remain depressed. A total of 7908 participants from Ghana, India, Mexico and Russia were firstly evaluated in the World Health Organization's Study on Global AGEing and Adult Health (SAGE) Wave 0 (2002-2004) and re-evaluated in 2007-2010 (Wave 1). Data on tobacco use, alcohol drinking and physical activity, were collected. Logistic regressions models were employed to assess whether baseline unhealthy lifestyles were related to depression in Wave 1, among people without 12-month depression in Wave 0 and any previous lifetime diagnosis of depression, and to 12-month depression at both study waves (persistent depression). Results: Baseline daily and non-daily smoking was associated with depression in Wave 1. Low physical activity and heavy alcohol drinking were associated with persistent depression. Conclusions: Unhealthy lifestyles and depression are also positively related in emerging countries. Smoking on a daily and non-daily basis was longitudinally related to depression. Depressed people with low physical activity and with heavy drinking patterns were more likely to become depressed over time. Several interpretations of these results are given. Further studies should check whether a reduction of these unhealthy lifestyles leads to lower depression rates and/or to a better clinical prognosis of depressed people.This paper uses data from the WHO's Study on Global AGEing and Adult Health (SAGE). SAGE is supported by the US National Institute on Aging through Interagency Agreements (OGHA 04034785; YA1323-08-CN-0020; Y1- AG-1005-01) and through a research grant (R01-AG034479). The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2007 – 2013 under grant agreement n° 316795 (MARATONE project). The present work was also supported by the Centro de Investigacion Biomédica en Red en Salud Mental (CIBERSAM) and by the Instituto de Salud Carlos III - FIS research grant PI13/00059, which has been co-funded by the European Union European Regional Development Fund (ERDF) "A Way to Build Europe". This study was also supported by the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 305968 (EMERALD project)

Inhibition of NAE-dependent protein hyper-NEDDylation in cystic cholangiocytes halts cystogenesis in experimental models of polycystic liver disease

Background Polycystic liver diseases (PLDs) are genetic inherited disorders characterized by the progressive growth of numerous intrahepatic biliary cysts, which are the main cause of morbidity. Previous studies revealed that cystic cholangiocytes are characterized by endoplasmic reticulum stress and aberrant posttranslational modification (PTM) of proteins, in particular hyper-SUMOylation, that promote PLD pathobiology. Protein NEDDylation is a newly characterized PTM that modulates a plethora of biological processes and its dysregulation is associated with the development and progression of several human diseases. However, the role of NEDDylation in PLD remains elusive. Objective To explore the role of protein NEDDylation in PLD and its potential therapeutic regulatory value. Methods Levels and functional effects of NEDDylation, including response to Pevonedistat (first-in-class selective inhibitor of the NEDDylation E1 enzyme NAE), were assessed in vitro, in vivo, and/or in patients with PLD. NEDDylated protein levels in normal and cystic human cholangiocytes were assessed by immunoprecipitation, and the proteomic profile was further analyzed by mass spectrometry. Results and Conclusion The genes involved in the NEDDylation pathway were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture, compared to controls. Elevated levels of NEDDylated proteins were further confirmed in cystic cholangiocytes in vitro, which diminished under Pevonedistat incubation. Pevonedistat promoted apoptotic cell death and reduced proliferation in cystic cholangiocytes in vitro. Comparative proteomic profiling of NEDD8-immunoprecipitated proteins between normal and cystic cholangiocytes in culture reported candidate proteins involved in cystogenesis, mostly associated with protein biogenesis and quality control. All these data indicate that cystic cholangiocytes display increased protein NEDDylation, contributing to cell survival and proliferation, ultimately supporting hepatic cystogenesis. Targeting of protein hyper-NEDDylation in cystic cholangiocytes inhibits cystogenesis in experimental models, representing a novel therapeutic opportunity in PLD.Spanish Carlos III Health Institute (ISCIII), Grant/Award Numbers: CON14/00129, CPII19/00008, FIS PI12/00380, FIS PI14/ 00399, FIS PI15/01132, FIS PI17/00022, FIS PI18/01075, FIS PI20/00186, Sara Borrell CD19/00254; Diputacion Foral de Gipuzkoa, Grant/Award Numbers: DFG15/010, DFG16/004; Department of Health of the Basque Country, Grant/Award Numbers: 2015111100, 2017111010, 2019111024; Euskadi RIS3, Grant/Award Numbers: 2016222001, 2017222014, 2018222029, 2019222054, 2020333010; Department of Industry of the Basque Country, Grant/Award Number: KK-2020/00008; Spanish Ministry of Economy and Competitiveness, Grant/Award Number: RYC-2015-17755; Ministerio de Ciencia, Innovacion y Universidades, Grant/ Award Number: SAF2017-87301-R; Ayudas para apoyar grupos de investigacion del Sistema Universitario Vasco, Grant/Award Number: IT971-16; Universita Politecnica delle Marche, Grant/Award Number: PSA2017_UNIVPM; European Association for the Study of the Liver, Grant/Award Number: Sheila Sherlock Award 2017; Spanish Ministry of Science and Innovation, Grant/Award Number: BES-2014-069148; Basque Government, Grant/Award Number: PRE_2016_1_0269; Basque Foundation for Innovation and Health Research, Grant/Award Number: BIO15/CA/016/BD; Fundacion Cientifica de la Asociacion Espanola Contra el Cancer; La Caixa Scientific Foundation, Grant/ Award Number: HR17-00601; CIBERehd; Fondo Europeo de Desarrollo Regional Documen

Targeting UBC9-Mediated Protein Hyper-SUMOylation in Cystic Cholangiocytes Halts Polycystic Liver Disease in Experimental Models

BACKGROUND & AIMS: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple fluid-filled biliary cysts. Most PLD-causative genes participate in protein biogenesis and/or transport. Post-translational modifications (PTMs) are implicated in protein stability, localization and activity, contributing to human pathobiology; however, their role in PLD is unknown. Herein, we aimed to unveil the role of protein SUMOylation in PLD and its potential therapeutic targeting. METHODS: Levels and functional effects of SUMOylation, along with response to S-adenosylmethionine (SAMe, inhibitor of the SUMOylation enzyme UBC9) and/or short-hairpin RNAs (shRNAs) against UBE2I (UBC9), were evaluated invitro, invivo and/or in patients with PLD. SUMOylated proteins were determined by immunoprecipitation and proteomic analyses by mass spectrometry. RESULTS: Most SUMOylation-related genes were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture compared to controls. Increased SUMOylated protein levels were also observed in cystic human cholangiocytes in culture, which decreased after SAMe administration. Chronic treatment of polycystic (PCK: Pkdh1-mut) rats with SAMe halted hepatic cystogenesis and fibrosis, and reduced liver/body weight ratio and liver volume. Invitro, both SAMe and shRNA-mediated UBE2I knockdown increased apoptosis and reduced cell proliferation of cystic cholangiocytes. High-throughput proteomic analysis of SUMO1-immunoprecipitated proteins in cystic cholangiocytes identified candidates involved in protein biogenesis, ciliogenesis and proteasome degradation. Accordingly, SAMe hampered proteasome hyperactivity in cystic cholangiocytes, leading to activation of the unfolded protein response and stress-related apoptosis. CONCLUSIONS: Cystic cholangiocytes exhibit increased SUMOylation of proteins involved in cell survival and proliferation, thus promoting hepatic cystogenesis. Inhibition of protein SUMOylation with SAMe halts PLD, representing a novel therapeutic strategy. LAY SUMMARY: Protein SUMOylation is a dynamic post-translational event implicated in numerous cellular processes. This study revealed dysregulated protein SUMOylation in polycystic liver disease, which promotes hepatic cystogenesis. Administration of S-adenosylmethionine (SAMe), a natural UBC9-dependent SUMOylation inhibitor, halted polycystic liver disease in experimental models, thus representing a potential therapeutic agent for patients.Spanish Carlos III Health Institute (ISCIII) [J.M. Banales (FIS PI12/00380, PI15/01132, PI18/01075 and Miguel Servet Program CON14/00129 and CPII19/00008); M.J. Perugorria (FIS PI14/00399, PI17/00022 and PI20/00186); P.M. Rodrigues (Sara Borrell CD19/00254)] cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER); Ministerio de Ciencia, Innovación y Universidades (MICINN; M.L. Martinez-Chantar: SAF2017-87301-R); “Instituto de Salud Carlos III” [CIBERehd: J.M. Banales, M.J. Perugorria, M.L. Martinez-Chantar and L. Bujanda], Spain; “Diputación Foral Gipuzkoa” (J.M. Banales: DFG15/010, DFG16/004), Department of Health of the Basque Country (M.J. Perugorria: 2019111024, 2015111100 and J.M. Banales: 2017111010), “Euskadi RIS3” (J.M. Banales: 2016222001, 2017222014, 2018222029, 2019222054, 2020333010), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to J.M. Banales and M.L. Martinez-Chantar) and Department of Industry of the Basque Country (J.M. Banales: Elkartek: KK-2020/00008). La Caixa Scientific Foundation (J.M. Banales and M.L. Martinez-Chantar: HR17-00601). “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation, to J.M. Banales and M.L. Martinez-Chantar). “Ayudas para apoyar grupos de investigación del Sistema Universitario Vasco” (IT971-16 to P.A.). Università Politecnica delle Marche PSA2017_UNIVPM grant (to M. Marzioni). National Institutes of Health (NIH) of United States of America (DK24031 to N.F. LaRusso). MJ Perugorria was funded by the Spanish Ministry of Economy and Competitiveness (MINECO: “Ramón y Cajal” Program RYC-2015-17755), P.Y. Lee-Law by the European Association for the Study of the Liver (EASL; Sheila Sherlock Award 2017), F.J. Caballero-Camino by the Spanish Ministry of Science and Innovation (BES-2014-069148), and P. Olaizola and A. Santos-Laso by the Basque Government (PRE_2016_1_0269, PRE_2015_1_0126). We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644). The funding sources had no involvement in study design, data collection and analysis, decision to publish, or preparation of the article

Targeting NAE1-mediated protein hyper-NEDDylation halts cholangiocarcinogenesis and impacts on tumor-stroma crosstalk in experimental models.

[EN] BACKGROUND & AIMS: Cholangiocarcinoma (CCA) comprises a heterogeneous group of malignant tumors associated with dismal prognosis. Alterations in post-translational modifications (PTMs), including NEDDylation, result in abnormal protein dynamics, cell disturbances and disease. Herein, we investigate the role of NEDDylation in CCA development and progression. METHODS: Levels and functions of NEDDylation, together with response to pevonedistat (NEDDylation inhibitor) or CRISPR/Cas9 against NAE1 were evaluated invitro, invivo and/or in patients with CCA. The development of preneoplastic lesions in Nae1+/- mice was investigated using an oncogene-driven CCA model. The impact of NEDDylation in CCA cells on tumor-stroma crosstalk was assessed using CCA-derived cancer-associated fibroblasts (CAFs). Proteomic analyses were carried out by mass-spectrometry. RESULTS: The NEDDylation machinery was found overexpressed and overactivated in human CCA cells and tumors. Most NEDDylated proteins found upregulated in CCA cells, after NEDD8-immunoprecipitation and further proteomics, participate in the cell cycle, proliferation or survival. Genetic (CRISPR/Cas9-NAE1) and pharmacological (pevonedistat) inhibition of NEDDylation reduced CCA cell proliferation and impeded colony formation invitro. NEDDylation depletion (pevonedistat or Nae1+/- mice) halted tumorigenesis in subcutaneous, orthotopic, and oncogene-driven models of CCA invivo. Moreover, pevonedistat potentiated chemotherapy-induced cell death in CCA cells invitro. Mechanistically, impaired NEDDylation triggered the accumulation of both cullin RING ligase and NEDD8 substrates, inducing DNA damage and cell cycle arrest. Furthermore, impaired NEDDylation in CCA cells reduced the secretion of proteins involved in fibroblast activation, angiogenesis, and oncogenic pathways, ultimately hampering CAF proliferation and migration. CONCLUSION: Aberrant protein NEDDylation contributes to cholangiocarcinogenesis by promoting cell survival and proliferation. Moreover, NEDDylation impacts the CCA-stroma crosstalk. Inhibition of NEDDylation with pevonedistat may represent a potential therapeutic strategy for patients with CCA. LAY SUMMARY: Little is known about the role of post-translational modifications of proteins in cholangiocarcinoma development and progression. Herein, we show that protein NEDDylation is upregulated and hyperactivated in cholangiocarcinoma, promoting tumor growth. Pharmacological inhibition of NEDDylation halts cholangiocarcinogenesis and could be an effective therapeutic strategy to tackle these tumors.This article is based upon work from the COST Action CA18122 European Cholangiocarcinoma Network supported by COST (European Cooperation in Science and Technology: www.cost.eu)

International Consensus Document on Obstructive Sleep Apnea

El objetivo principal de este documento internacional de consenso sobre apnea obstructiva del sueno es proporcionar unas directrices que permitan a los profesionales sanitarios tomar las mejores decisiones en la asistencia de los pacientes adultos con esta enfermedad según un resumen crítico de la literatura más actualizada. El grupo de trabajo de expertos se ha constituido principalmente por 17 sociedades científicas y 56 especialistas con amplia representación geográfica (con la participación de 4 sociedades internacionales), además de un metodólogo experto y un documentalista del Centro Cochrane Iberoamer icano. El documento consta de un manuscrito principal, con las novedades más relevantes del DIC, y una serie de manuscritos online que recogen las búsquedas bibliográficas sistemáticas de cada uno de los apartados del DIC. Este documento no cubre la edad pediátrica ni el manejo del paciente en ventilación mecánica crónica no invasiva (que se publicarán en sendos documentos de consenso aparte)