Socioeconomic and gender inequalities in mental disorders among adolescents and young adults.

BACKGROUND: Socioeconomic status (SES) and gender play a key role in mental health. The objective of this study was to assess socioeconomic and gender mental health inequalities in adolescents and young adults using a population-based registry. MATERIALS AND METHODS: We conducted a lifetime follow-up study of all residents in the Basque Country between 1 and 30 years old (n=609,381) as of 31 December 2018. Primary care, specialized outpatient, and hospital care records were searched for diagnoses. SES was assessed based on household income. We estimated disaggregated lifetime prevalence of substance use, behaviour, anxiety, depression, psychosis, and attention deficit hyperactivity disorder. The local Institute of Statistics validated the mortality data. The likelihood of risks was estimated using logistic regression. RESULTS: Overall, 96,671 individuals (15.9%) had a diagnosed mental disorder, with clear gradients by gender and SES. Females of medium-to-high SES had the lowest prevalence of all mental disorders, except anxiety and depression. This group was followed by males of the same SES and females of low SES, while the highest prevalence of mental disorders was observed in low-SES males. The lower income categories had higher risks of psychiatric admission (adjusted odds ratio [AOR]: 3.64 for females; 6.66 for males) and death (AOR: 5.42). People with a mental health diagnosis had higher mortality (AOR: 2.38). CONCLUSIONS: Our work evidenced important SES and gender inequalities in the mental health and premature mortality of adolescents and young adults, findings that should drive the development and implementation of early preventive interventions.

Transforming health care systems towards high-performance organizations: qualitative study based on learning from COVID-19 pandemic in the Basque Country (Spain).

BACKGROUND: The COVID-19 pandemic is one of the worst health catastrophes of the last century, which caused severe economic, political, and social consequences worldwide. Despite these devastating consequences, lessons learned provide a great opportunity that can drive the reform of health systems to become high-performing, effective, equitable, accessible, and sustainable organisations. This work identifies areas in which changes must be encouraged that will enable health systems to deal effectively with current and future challenges, beyond COVID-19. METHODS: A realist design was chosen, based on qualitative data collection techniques, content analysis and triangulation to identify key domains of organizational interventions behind the changes implemented to react to the COVID-19 pandemic in the Basque Country. Twenty key informants were used as an expert source of information. Thematic analysis was done using the Framework Method. RESULTS: The analysis of the interviews resulted in the identification of 116 codes, which were reviewed and agreed upon by the researchers. Following the process of methodological analysis, these codes were grouped into domains: seven themes and 23 sub-themes. Specifically, the themes are: responsiveness, telehealth, integration, knowledge management, professional roles, digitisation, and organisational communication. The detailed description of each theme and subtheme is presented. CONCLUSIONS: The findings of this work pretend to guide the transformation of health systems into organisations that can improve the health of their populations and provide high quality care. Such a multidimensional and comprehensive reform encompasses both strategic and operational actions in diverse areas and requires a broad and sustained political, technical, and financial commitment.

European value-based healthcare benchmarking: moving from theory to practice.

BACKGROUND: Value-based healthcare (VBHC) is a conceptual framework to improve the value of healthcare by health, care-process and economic outcomes. Benchmarking should provide useful information to identify best practices and therefore a good instrument to improve quality across healthcare organizations. This paper aims to provide a proof-of-concept of the feasibility of an international VBHC benchmarking in breast cancer, with the ultimate aim of being used to share best practices with a data-driven approach among healthcare organizations from different health systems. METHODS: In the VOICE community-a European healthcare centre cluster intending to address VBHC from theory to practice-information on patient-reported, clinical-related, care-process-related and economic-related outcomes were collected. Patient archetypes were identified using clustering techniques and an indicator set following a modified Delphi was defined. Benchmarking was performed using regression models controlling for patient archetypes and socio-demographic characteristics. RESULTS: Six hundred and ninety patients from six healthcare centres were included. A set of 50 health, care-process and economic indicators was distilled for benchmarking. Statistically significant differences across sites have been found in most health outcomes, half of the care-process indicators, and all economic indicators, allowing for identifying the best and worst performers. CONCLUSIONS: To the best of our knowledge, this is the first international experience providing evidence to be used with VBHC benchmarking intention. Differences in indicators across healthcare centres should be used to identify best practices and improve healthcare quality following further research. Applied methods might help to move forward with VBHC benchmarking in other medical conditions.

GATEKEEPER's Strategy for the Multinational Large-Scale Piloting of an eHealth Platform: Tutorial on How to Identify Relevant Settings and Use Cases.

BACKGROUND: The World Health Organization's strategy toward healthy aging fosters person-centered integrated care sustained by eHealth systems. However, there is a need for standardized frameworks or platforms accommodating and interconnecting multiple of these systems while ensuring secure, relevant, fair, trust-based data sharing and use. The H2020 project GATEKEEPER aims to implement and test an open-source, European, standard-based, interoperable, and secure framework serving broad populations of aging citizens with heterogeneous health needs. OBJECTIVE: We aim to describe the rationale for the selection of an optimal group of settings for the multinational large-scale piloting of the GATEKEEPER platform. METHODS: The selection of implementation sites and reference use cases (RUCs) was based on the adoption of a double stratification pyramid reflecting the overall health of target populations and the intensity of proposed interventions; the identification of a principles guiding implementation site selection; and the elaboration of guidelines for RUC selection, ensuring clinical relevance and scientific excellence while covering the whole spectrum of citizen complexities and intervention intensities. RESULTS: Seven European countries were selected, covering Europe's geographical and socioeconomic heterogeneity: Cyprus, Germany, Greece, Italy, Poland, Spain, and the United Kingdom. These were complemented by the following 3 Asian pilots: Hong Kong, Singapore, and Taiwan. Implementation sites consisted of local ecosystems, including health care organizations and partners from industry, civil society, academia, and government, prioritizing the highly rated European Innovation Partnership on Active and Healthy Aging reference sites. RUCs covered the whole spectrum of chronic diseases, citizen complexities, and intervention intensities while privileging clinical relevance and scientific rigor. These included lifestyle-related early detection and interventions, using artificial intelligence-based digital coaches to promote healthy lifestyle and delay the onset or worsening of chronic diseases in healthy citizens; chronic obstructive pulmonary disease and heart failure decompensations management, proposing integrated care management based on advanced wearable monitoring and machine learning (ML) to predict decompensations; management of glycemic status in diabetes mellitus, based on beat to beat monitoring and short-term ML-based prediction of glycemic dynamics; treatment decision support systems for Parkinson disease, continuously monitoring motor and nonmotor complications to trigger enhanced treatment strategies; primary and secondary stroke prevention, using a coaching app and educational simulations with virtual and augmented reality; management of multimorbid older patients or patients with cancer, exploring novel chronic care models based on digital coaching, and advanced monitoring and ML; high blood pressure management, with ML-based predictions based on different intensities of monitoring through self-managed apps; and COVID-19 management, with integrated management tools limiting physical contact among actors. CONCLUSIONS: This paper provides a methodology for selecting adequate settings for the large-scale piloting of eHealth frameworks and exemplifies with the decisions taken in GATEKEEPER the current views of the WHO and European Commission while moving forward toward a European Data Space.

Cost-utility analysis of the UPRIGHT intervention promoting resilience in adolescents.

BACKGROUND: As mental health in adulthood is related to mental status during adolescence, school-based interventions have been proposed to improve resilience. The objective of this study was to build a simulation model representing the natural history of mental disorders in childhood, adolescence and youth to estimate the cost-effectiveness of the UPRIGHT school-based intervention in promoting resilience and mental health in adolescence. METHODS: We built a discrete event simulation model fed with real-world data (cumulative incidence disaggregated into eight clusters) from the Basque Health Service database (609,381 individuals) to calculate utilities (quality-adjusted life years [QALYs]) and costs for the general population in two scenarios (base case and intervention). The model translated changes in the wellbeing of adolescents into different risks of mental illnesses for a time horizon of 30 years. RESULTS: The number of cases of anxiety was estimated to fall by 5,125 or 9,592 and those of depression by 1,269 and 2,165 if the effect of the intervention lasted 2 or 5 years respectively. From a healthcare system perspective, the intervention was cost-effective for all cases considered with incremental cost-utility ratios always lower than €10,000/QALY and dominant for some subgroups. The intervention was always dominant when including indirect and non-medical costs (societal perspective). CONCLUSIONS: Although the primary analysis of the trial did not did not detect significant differences, the UPRIGHT intervention promoting positive mental health was dominant in the economic evaluation from the societal perspective. Promoting resilience was more cost-effective in the most deprived group. Despite a lack of information about the spillover effect in some sectors, the economic evaluation framework developed principally for pharmacoeconomics can be applied to interventions to promote resilience in adolescents. As prevention of mental health disorders is even more necessary in the post-coronavirus disease-19 era, such evaluation is essential to assess whether investment in mental health promotion would be good value for money by avoiding costs for healthcare providers and other stakeholders.

Assessment of the Effectiveness, Socio-Economic Impact and Implementation of a Digital Solution for Patients with Advanced Chronic Diseases: The ADLIFE Study Protocol.

Due to population ageing and medical advances, people with advanced chronic diseases (ACD) live longer. Such patients are even more likely to face either temporary or permanent reduced functional reserve, which typically further increases their healthcare resource use and the burden of care on their caregiver(s). Accordingly, these patients and their caregiver(s) may benefit from integrated supportive care provided via digitally supported interventions. This approach may either maintain or improve their quality of life, increase their independence, and optimize the healthcare resource use from early stages. ADLIFE is an EU-funded project, aiming to improve the quality of life of older people with ACD by providing integrated personalized care via a digitally enabled toolbox. Indeed, the ADLIFE toolbox is a digital solution which provides patients, caregivers, and health professionals with digitally enabled, integrated, and personalized care, supporting clinical decisions, and encouraging independence and self-management. Here we present the protocol of the ADLIFE study, which is designed to provide robust scientific evidence on the assessment of the effectiveness, socio-economic, implementation, and technology acceptance aspects of the ADLIFE intervention compared to the current standard of care (SoC) when applied in real-life settings of seven different pilot sites across six countries. A quasi-experimental trial following a multicenter, non-randomized, non-concurrent, unblinded, and controlled design will be implemented. Patients in the intervention group will receive the ADLIFE intervention, while patients in the control group will receive SoC. The assessment of the ADLIFE intervention will be conducted using a mixed-methods approach.

Incidence of mental disorders in the general population aged 1-30 years disaggregated by gender and socioeconomic status.

PURPOSE: The objective of this study was to estimate the incidence and age of onset of mental disorders diagnosed by gender and socioeconomic status (SES) in children, adolescents, and young adults up to 30 years of age in the whole population of the Basque Country (Spain). METHODS: All mental health diagnoses documented in Basque Health Service records from 1 January 2003 to 31 December 2018, were classified into eight clusters: anxiety, attention deficit hyperactivity disorder (ADHD), conduct disorders, depression, psychosis/personality disorders, substance use, eating disorders, and self-harm. We calculated incidence and cumulative incidence for each cluster, disaggregated by gender, and socioeconomic status (SES). Poisson regression analyses were performed. RESULTS: Overall, 9,486,853 person-years of observation were available for the 609,281 individuals included. ADHD and conduct disorders were diagnosed in the first decade, anxiety and depression disorders in the second and third decades, and psychosis/personality and substance use in the third. The cumulative incidence at 18 years of age for any type of disorder was 15.5%. The group with low SES had a statistically significantly higher incidence of all eight clusters. The incidence of ADHD, conduct disorders, depression, psychosis/personality disorders, and substance use was higher in males and that of anxiety, eating disorders and self-harm was higher in females. CONCLUSIONS: The incidence of mental disorders is high among children, adolescents, and young adults in the Basque Country underlining the need for preventive interventions. Marked differences by gender and SES highlight mental health inequalities, especially for depression and psychosis in low SES males.

Relevance of well-being, resilience, and health-related quality of life to mental health profiles of European adolescents: results from a cross-sectional analysis of the school-based multinational UPRIGHT project.

PURPOSE: The existing evidence suggests that a complete evaluation of mental health should incorporate both psychopathology and mental well-being indicators. However, few studies categorize European adolescents into subgroups based on such complete mental health data. This study used the data on mental well-being and symptoms of mental and behavioral disorders to explore the mental health profiles of adolescents in Europe. METHODS: Data collected from adolescents (N = 3767; mean age 12.4 [SD = 0.9]) from five European countries supplied the information on their mental well-being (personal resilience, school resilience, quality of life, and mental well-being) and mental and behavioral disorder symptoms (anxiety, depression, stress, bullying, cyber-bullying, and use of tobacco, alcohol, or cannabis). Multiple correspondence analysis and cluster analysis were combined to classify the youths into mental health profiles. RESULTS: Adolescents were categorized into three mental health profiles. The "poor mental health" profile (6%) was characterized by low levels of well-being and moderate symptoms of mental disorders. The "good mental health" profile group (26%) showed high well-being and few symptoms of mental disorders, and the "intermediate mental health" profile (68%) was characterized by average well-being and mild-to-moderate symptoms of mental disorders. Groups with higher levels of well-being and fewer symptoms of mental disorders showed lower rates of behavioral problems. Mental well-being indicators strongly contributed to this classification. CONCLUSION: Adolescents with the "intermediate" or "poor" mental health profiles may benefit from interventions to improve mental health. Implications for school-based interventions are discussed. TRIAL REGISTRATION NUMBER (TRN) AND DATE OF REGISTRATION: ClinicalTrials.gov Identifier: NCT03951376. Registered 15 May 2019.

Impact of the CareWell integrated care model for older patients with multimorbidity: a quasi-experimental controlled study in the Basque Country.

BACKGROUND: Older patients with multimorbidity have complex health and social care needs, associated with elevated use of health care resources. The aim of this study is to evaluate the impact of CareWell integrated care model for older patients with multimorbidity in the Basque Country. METHODS: The CareWell program for older patients with multimorbidity, based on the coordination between health providers, home-based care and patient empowerment, supported by information and communication technology tools. The program was deployed in four healthcare areas in the Basque Country. The control group was formed by two organizations in which the program had not been deployed and regular care procedures were applied. Participants, older patients (aged ≥65) with two or more chronic conditions (at least one being chronic obstructive pulmonary disease, chronic heart failure, or diabetes mellitus), categorized as complex according to a risk stratification algorithm, were followed up to 12 months. The impact of the program on the use of health resources, clinical effectiveness, and satisfaction was evaluated using a mixed-method approach. Semi-structured interviews were performed to assess satisfaction with the newly deployed model and mixed regression models to measure the effect of the intervention throughout the follow-up period. RESULTS: Two hundred patients were recruited (101 intervention and 99 control), mostly males (63%) with a mean age of 79 years and age-adjusted Charlson Comorbidity Index of 9.7 on average. Relevant differences between the groups were observed for all dimensions. In the intervention group, the number of hospitalizations and visits to emergency centers was reduced, and the number of primary care contacts increased. Clinical changes were also observed, such as a decrease in the body mass index and blood glucose levels. The satisfaction level was high for all stakeholders. CONCLUSION: The implementation of CareWell integrated care model changed the profile of health resource utilization, strengthening the key role of primary care and reducing the number of emergency visits and hospitalizations. The satisfaction with this model of care was high. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03042039 . Registered 3 February 2017 - Retrospectively registered.

Impact Assessment of an Innovative Integrated Care Model for Older Complex Patients with Multimorbidity: The CareWell Project.

OBJECTIVES: To evaluate the impact in terms of use of health services, clinical outcomes, functional status, and patient's satisfaction of an integrated care program, the CareWell program, for complex patients with multimorbidity, supported by information and communication technology platforms in six European regions. DATA SOURCES: Primary data were used and the follow-up period ranged between 8 and 12 months. STUDY DESIGN: A quasi-experimental study, targeting chronic patients aged 65 or older, with 2 or more conditions - one of them necessarily being diabetes, congestive heart failure or congestive obstructive pulmonary disease. The intervention group received the integrated care program and the control group received usual care. Generalized mixed regression models were used. DATA COLLECTION: Data were obtained from individual interviews and electronic clinical records. PRINCIPAL FINDINGS: Overall, 856 patients were recruited (475 intervention and 381 control). In the intervention group, the number of visits to emergency rooms was significantly lower, and the number of visits to the general practitioners and primary care nurses was higher than in the control group. CONCLUSION: The CareWell program resulted in improvements in the use of health services, strengthening the role of PC as the cornerstone of care provision for complex patients with multimorbidity.

A Methodological Approach for Implementing an Integrated Multimorbidity Care Model: Results from the Pre-Implementation Stage of Joint Action CHRODIS-PLUS.

Patients with multimorbidity (defined as the co-occurrence of multiple chronic diseases) frequently experience fragmented care, which increases the risk of negative outcomes. A recently proposed Integrated Multimorbidity Care Model aims to overcome many issues related to fragmented care. In the context of Joint Action CHRODIS-PLUS, an implementation methodology was developed for the care model, which is being piloted in five sites. We aim to (1) explain the methodology used to implement the care model and (2) describe how the pilot sites have adapted and applied the proposed methodology. The model is being implemented in Spain (Andalusia and Aragon), Lithuania (Vilnius and Kaunas), and Italy (Rome). Local implementation working groups at each site adapted the model to local needs, goals, and resources using the same methodological steps: (1) Scope analysis; (2) situation analysis-"strengths, weaknesses, opportunities, threats" (SWOT) analysis; (3) development and improvement of implementation methodology; and (4) final development of an action plan. This common implementation strategy shows how care models can be adapted according to local and regional specificities. Analysis of the common key outcome indicators at the post-implementation phase will help to demonstrate the clinical effectiveness, as well as highlight any difficulties in adapting a common Integrated Multimorbidity Care Model in different countries and clinical settings.

UPRIGHT, a resilience-based intervention to promote mental well-being in schools: study rationale and methodology for a European randomized controlled trial.

BACKGROUND: Adolescence is crucial period for laying the foundations for healthy development and mental well-being. The increasing prevalence of mental disorders amongst adolescents makes promotion of mental well-being and prevention interventions at schools important. UPRIGHT (Universal Preventive Resilience Intervention Globally implemented in schools to improve and promote mental Health for Teenagers) is designed as a whole school approach (school community, students and families) to promote a culture of mental well-being and prevent mental disorders by enhancing resilience capacities. The present article aims at describing the rationale, conceptual framework, as well as methodology of implementation and evaluation of the UPRIGHT intervention. METHODS: UPRIGHT project is a research and innovation project funded by the European Union's Horizon 2020 Research and Innovation programme under grant agreement No. 754919 (Duration: 48 months). The theoretical framework has been developed by an innovative and multidisciplinary approach using a co-creation process inside the UPRIGHT Consortium (involving seven institutions from Spain, Italy, Poland, Norway, Denmark, and Iceland). Resulted is the UPRIGHT programme with 18 skills related to 4 components: Mindfulness, Coping, Efficacy and Social and Emotional Learning. Among the five Pan-European regions, 34 schools have been currently involved (17 control; 17 intervention) and around 6000 adolescents and their families are foreseen to participate along a 3-year period of evaluation. Effectiveness of the intervention will be evaluated as a randomized controlled trial including quantitative and qualitative analysis in the five Pan-European regions representative of the cultural and socioeconomic diversity. The cost-effectiveness assessment will be performed by simulation modelling methods. DISCUSSION: We expect a short- to medium-term improvement of mental well-being in adolescents by enhancing resilience capacities. The study may provide robust evidence on intrapersonal, familiar and social environmental resilience factors promoting positive mental well-being. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03951376 . Registered 15 May 2019.

Impact of stratification on the effectiveness of a comprehensive patient-centered strategy for multimorbid patients.

OBJECTIVE: The objective of this work was to assess the effectiveness of a population-level patient-centered intervention for multimorbid patients based on risk stratification for case finding in 2014 compared with the baseline scenario in 2012. DATA SOURCE: Clinical and administrative databases. STUDY DESIGN: This was an observational cohort study with an intervention group and a historical control group. A propensity score by a genetic matching approach was used to minimize bias. Generalized linear models were used to analyze relationships among variables. DATA COLLECTION: We included all eligible patients at the beginning of the year and followed them until death or until the follow-up period concluded (end of the year). The control group (2012) totaled 3558 patients, and 4225 patients were in the intervention group (2014). PRINCIPAL FINDING: A patient-centered strategy based on risk stratification for case finding and the implementation of an integrated program based on new professional roles and an extensive infrastructure of information and communication technologies avoided 9 percent (OR: 0.91, CI: 0.86-0.96) of hospitalizations. However, this effect was not found in nonprioritized groups whose probability of hospitalization increased (OR: 1.19, CI = 1.09-1.30). CONCLUSIONS: In a before-and-after analysis using propensity score matching, a comprehensive, patient-centered, integrated care intervention was associated with a lower risk of hospital admission among prioritized patients, but not among patients who were not prioritized to receive the intervention.

Economic Evaluation of an Integrated Health and Social Care Program for Heart Failure Through 2 Different Modeling Techniques.

INTRODUCTION: An integrated health and social care program for patients with heart failure (HF) was implemented at the Friuli-Venezia Giulia deployment site as part of the SmartCare European project. The objective of this study was to validate 2 different decision modeling techniques used to perform the economic evaluation. METHODS: Data were collected during the SmartCare project which enrolled 108 patients with HF and followed for more than 6 months. The techniques used were Markov and discrete event simulation models. In both cases, a cost-effectiveness analysis and a budget impact analysis were carried out. The former was used to assign priority to the intervention and the latter to assess its sustainability. Analyses were conducted from the perspective of the Regional Health Authority. RESULTS: Results were similar with both types of model. Cost-effectiveness analysis found no significant differences in quality of life, but the intervention generated significant cost savings, becoming the dominant option. Data extrapolation showed no benefits in terms of mortality or hospital admissions, but budget impact analysis also predicted annual savings, as a significant number of in-hospital days were avoided. In budget analysis, both models predicted early, increasing and cumulative annual savings. DISCUSSION: The integrated program was dominant as it provided better outcomes and lower total costs, and thus, decision-makers should prioritize it. Besides, the work demonstrates the capacity of decision modeling to become a complementary tool in managing integrated health and social care models.

Prelamin A accumulation and stress conditions induce impaired Oct-1 activity and autophagy in prematurely aged human mesenchymal stem cell.

Aging, a time-dependent functional decline of biological processes, is the primary risk factor in developing diseases such as cancer, cardiovascular or degenerative diseases. There is a real need to understand the human aging process in order to increase the length of disease-free life, also known as "health span". Accumulation of progerin and prelamin A are the hallmark of a group of premature aging diseases but have also been found during normal cellular aging strongly suggesting similar mechanisms between healthy aging and LMNA-linked progeroid syndromes. How this toxic accumulation contributes to aging (physiological or pathological) remains unclear. Since affected tissues in age-associated disorders and in pathological aging are mainly of mesenchymal origin we propose a model of human aging based on mesenchymal stem cells (hMSCs) which accumulate prelamin A. We demonstrate that prelamin A-accumulating hMSCs have a premature aging phenotype which affects their functional competence in vivo. The combination of prelamin A accumulation and stress conditions enhance the aging phenotype by dysregulating the activity of the octamer binding protein Oct-1This experimental model has been fundamental to identify a new role for Oct-1 in hMSCs aging.

Whole transcriptome analysis of Acinetobacter baumannii assessed by RNA-sequencing reveals different mRNA expression profiles in biofilm compared to planktonic cells.

Acinetobacterbaumannii has emerged as a dangerous opportunistic pathogen, with many strains able to form biofilms and thus cause persistent infections. The aim of the present study was to use high-throughput sequencing techniques to establish complete transcriptome profiles of planktonic (free-living) and sessile (biofilm) forms of A. baumannii ATCC 17978 and thereby identify differences in their gene expression patterns. Collections of mRNA from planktonic (both exponential and stationary phase cultures) and sessile (biofilm) cells were sequenced. Six mRNA libraries were prepared following the mRNA-Seq protocols from Illumina. Reads were obtained in a HiScanSQ platform and mapped against the complete genome to describe the complete mRNA transcriptomes of planktonic and sessile cells. The results showed that the gene expression pattern of A. baumannii biofilm cells was distinct from that of planktonic cells, including 1621 genes over-expressed in biofilms relative to stationary phase cells and 55 genes expressed only in biofilms. These differences suggested important changes in amino acid and fatty acid metabolism, motility, active transport, DNA-methylation, iron acquisition, transcriptional regulation, and quorum sensing, among other processes. Disruption or deletion of five of these genes caused a significant decrease in biofilm formation ability in the corresponding mutant strains. Among the genes over-expressed in biofilm cells were those in an operon involved in quorum sensing. One of them, encoding an acyl carrier protein, was shown to be involved in biofilm formation as demonstrated by the significant decrease in biofilm formation by the corresponding knockout strain. The present work serves as a basis for future studies examining the complex network systems that regulate bacterial biofilm formation and maintenance.

Sp1 transcription factor interaction with accumulated prelamin a impairs adipose lineage differentiation in human mesenchymal stem cells: essential role of sp1 in the integrity of lipid vesicles.

Lamin A (LMNA)-linked lipodystrophies may be either genetic (associated with LMNA mutations) or acquired (associated with the use of human immunodeficiency virus protease inhibitors [PIs]), and in both cases they share clinical features such as anomalous distribution of body fat or generalized loss of adipose tissue, metabolic alterations, and early cardiovascular complications. Both LMNA-linked lipodystrophies are characterized by the accumulation of the lamin A precursor prelamin A. The pathological mechanism by which prelamin A accumulation induces the lipodystrophy associated phenotypes remains unclear. Since the affected tissues in these disorders are of mesenchymal origin, we have generated an LMNA-linked experimental model using human mesenchymal stem cells treated with a PI, which recapitulates the phenotypes observed in patient biopsies. This model has been demonstrated to be a useful tool to unravel the pathological mechanism of the LMNA-linked lipodystrophies, providing an ideal system to identify potential targets to generate new therapies for drug discovery screening. We report for the first time that impaired adipogenesis is a consequence of the interaction between accumulated prelamin A and Sp1 transcription factor, sequestration of which results in altered extracellular matrix gene expression. In fact, our study shows a novel, essential, and finely tuned role for Sp1 in adipose lineage differentiation in human mesenchymal stem cells. These findings define a new physiological experimental model to elucidate the pathological mechanisms LMNA-linked lipodystrophies, creating new opportunities for research and treatment not only of LMNA-linked lipodystrophies but also of other adipogenesis-associated metabolic diseases.

Regulation of Drosophila-virus interaction.

Drosophila melanogaster is a useful model system for deciphering mammalian biological processes including development, innate immunity and cancer. Most genetic studies conducted in Drosophila have focused on the immune response against microbial infection and the results obtained have been extrapolated to other organisms. During the last decade the issue of the antiviral response attracted a great deal of interest. In this review we highlight recent discoveries in the role of RNA interference pathway in antiviral response in Drosophila with a focus on the role of miRNAs as both host defense elements and helpers of viral replication.

Identification of putative miRNA involved in Drosophila melanogaster immune response.

MicroRNAs (miRNAs) are small endogenous non-coding RNAs that post-transcriptionally regulate gene expression in eukaryotes. They are known to play diverse roles in physiological processes such as homeostasis, development, cancer and immune response. In Drosophila melanogaster up to 176 miRNAs have been identified; yet, their biological functions remain unknown. Here, we describe an in silico screening strategy to identify miRNAs involved in a specific immune signaling pathway that is based on: (i) the potential capability of miRNAs to target mRNAs of a given pathway; (ii) the sequence conservation of miRNAs across species and (iii) the expression profile of miRNAs. Using this strategy, we have defined a subset of seven Drosophila miRNAs that are likely to participate in the immune response. Interestingly, some of these miRNAs target peptidoglycan receptor proteins (PGRPs) for which no regulators are known yet. miRNA-mediated regulation may explain how PGRPs are controlled in the immune signaling pathway.

Spn1 regulates the GNBP3-dependent Toll signaling pathway in Drosophila melanogaster.

The Drosophila genome encodes 29 serpins, most of unknown function. We show here that Spn1 is an active protease inhibitor of the serpin superfamily. Spn1 inhibits trypsin in vitro and regulates the Toll-mediated immune response in vivo. Expression of the Toll-dependent transcripts Drosomycin and IM1 is increased in Spn1 null mutants. Overexpression of Spn1 reduces the induction of Drosomycin upon immune challenge with fungi but not Gram-positive bacteria. Similar reductions in Drosomycin levels are observed in the psh, spz, and grass mutants of the Toll signaling pathway. These results support a role of Spn1 as a repressor of Toll activation upon fungal infection. Epistatic analysis places Spn1 upstream of Spätzle processing enzyme and Grass, in the fungal cell wall-activated side branch of the pathway. Overexpression of the pattern recognition receptor GNBP3 activates the ß-1,3-glucan-sensitive side branch of the Toll pathway. The resultant increased Drosomycin level is reduced by concomitant overexpression of Spn1, confirming that Spn1 regulates the fungal cell wall side branch. Spn1 null mutants show altered susceptibility to fungal infection compared to the wild type, demonstrating a requirement for Spn1 in the fine regulation of the immune response.