The 4G/4G genotype of PAI-1 polymorphism is associated with higher plasma PAI-1 concentrations and mortality in patients with severe sepsis

Objective: Two studies have reported that patients with the 4G/4G genotype of the plasminogen activator inhibitor-1 (PAI-1) genetic polymorphism had higher plasma PAI-1 concentrations and higher risk of death than those with the 4G/5G or 5G/5G genotypes; one study involved 175 children with meningococcal disease, and the other included 88 adult patients with septic shock. Thus, the objective of this study was to determine whether there is an association between carriage of the 4G/4G genotype, plasma PAI-1 concentrations and mortality in a large series of adult septic patients. Methods: An observational, prospective, multicenter study was carried out in six Spanish Intensive Care Units including severe septic patients. We determined the PAI-1 4G/5G polymorphism and plasma PAI-1 concentrations in all patients. The end-points of the study were 30-day and 6-month mortality. Results: We included a total of 260 patients, 82 (31.5%) with 4G/4G, 126 (48.5%) with 4G/5G and 52 (20.0%) with 5G/5G genotype. Multivariate logistic regression analysis showed that the 4G/4G genotype was associated with higher mortality at 30 days (Odds Ratio = 1.95; 95% CI = 1.063-3.561; p = 0.03) and at 6 months (Odds Ratio = 2.19; 95% CI = 1.221-3.934; p = 0.01), and that higher plasma PAI-1 concentrations were associated with higher mortality at 30 days (Odds Ratio = 1.01; 95% CI = 1.002-1.022; p = 0.02) at 6 months (Odds Ratio = 1.01; 95% CI = 1.003-1.023; p = 0.01). Multivariate linear regression analysis showed that increased plasma PAI-1 concentrations were associated with the PAI-1 4G/4G genotype (regression coefficient = 4.82; 95% CI = 3.227 to 6.406; p<0.001). Conclusions: The major findings of our study, to our knowledge the largest series reporting data about 4G/5G polymorphism of the PAI-1 gene, plasma PAI-1 concentrations and mortality in septic patients, were that septic patients with the 4G/4G genotype had higher plasma PAI-1 concentrations and higher risk of death than those with 4G/5G or 5G/5G genotypes

Multimorbidity Patterns in Elderly Primary Health Care Patients in a South Mediterranean European Region: A Cluster Analysis.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tThis is the final version of the article. Available from Public Library of Science via the DOI in this record.OBJECTIVE: The purpose of this study was to identify clusters of diagnoses in elderly patients with multimorbidity, attended in primary care. DESIGN: Cross-sectional study. SETTING: 251 primary care centres in Catalonia, Spain. PARTICIPANTS: Individuals older than 64 years registered with participating practices. MAIN OUTCOME MEASURES: Multimorbidity, defined as the coexistence of 2 or more ICD-10 disease categories in the electronic health record. Using hierarchical cluster analysis, multimorbidity clusters were identified by sex and age group (65-79 and ≥80 years). RESULTS: 322,328 patients with multimorbidity were included in the analysis (mean age, 75.4 years [Standard deviation, SD: 7.4], 57.4% women; mean of 7.9 diagnoses [SD: 3.9]). For both men and women, the first cluster in both age groups included the same two diagnoses: Hypertensive diseases and Metabolic disorders. The second cluster contained three diagnoses of the musculoskeletal system in the 65- to 79-year-old group, and five diseases coincided in the ≥80 age group: varicose veins of the lower limbs, senile cataract, dorsalgia, functional intestinal disorders and shoulder lesions. The greatest overlap (54.5%) between the three most common diagnoses was observed in women aged 65-79 years. CONCLUSION: This cluster analysis of elderly primary care patients with multimorbidity, revealed a single cluster of circulatory-metabolic diseases that were the most prevalent in both age groups and sex, and a cluster of second-most prevalent diagnoses that included musculoskeletal diseases. Clusters unknown to date have been identified. The clusters identified should be considered when developing clinical guidance for this population.This study was supported by a grant from the Ministry of Science and Innovation through the Instituto Carlos III (ISCiii) in the 2012 call for Strategic Health Action proposals under the National Plan for Scientific Research, Development and Technological Innovation 2008–2011; by the European Union through the European Regional Development Fund (IP12/00427), as part of the Primary Care Prevention and Health Promotion Research Network (rediAPP), by ISCiii-RETICS (RD12/0005), by a 2011–2013 scholarship that aims to promote research in Primary Health Care by health professionals who have completed their specialty training, awarded by Institut Universitari d’Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), by a National Institute for Health Research Clinician Scientist Award (Jose M Valderas, NIHR/CS/010/024) and by a grant from the XIX call for research projects in the elderly population by Agrupació Mútua Foundation (Premio ámbito para las personas mayores, 2012). The funders had no role in the study design, collection, analysis and interpretation of data, writing of the manuscript or decision to submit for publication

Multimorbidity patterns with K-means nonhierarchical cluster analysis

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials: The datasets are not available because researchers have signed an agreement with the Information System for the Development of Research in Primary Care (SIDIAP) concerning confidentiality and security of the dataset that forbids providing data to third parties. This organization is subject to periodic audits to ensure the validity and quality of the data.BACKGROUND: The purpose of this study was to ascertain multimorbidity patterns using a non-hierarchical cluster analysis in adult primary patients with multimorbidity attended in primary care centers in Catalonia. METHODS: Cross-sectional study using electronic health records from 523,656 patients, aged 45-64 years in 274 primary health care teams in 2010 in Catalonia, Spain. Data were provided by the Information System for the Development of Research in Primary Care (SIDIAP), a population database. Diagnoses were extracted using 241 blocks of diseases (International Classification of Diseases, version 10). Multimorbidity patterns were identified using two steps: 1) multiple correspondence analysis and 2) k-means clustering. Analysis was stratified by sex. RESULTS: The 408,994 patients who met multimorbidity criteria were included in the analysis (mean age, 54.2 years [Standard deviation, SD: 5.8], 53.3% women). Six multimorbidity patterns were obtained for each sex; the three most prevalent included 68% of the women and 66% of the men, respectively. The top cluster included coincident diseases in both men and women: Metabolic disorders, Hypertensive diseases, Mental and behavioural disorders due to psychoactive substance use, Other dorsopathies, and Other soft tissue disorders. CONCLUSION: Non-hierarchical cluster analysis identified multimorbidity patterns consistent with clinical practice, identifying phenotypic subgroups of patients.The project has been funded by the Instituto de Salud Carlos III of the Ministry of Economy and Competitiveness (Spain) through the Network for Prevention and Health Promotion in Primary Health Care (redIAPP, RD12/0005), by a grant for research projects on health from ISCiii (PI12/00427) and co-financed with European Union ERDF funds). Jose M. Valderas was supported by the National Institute for Health Research Clinician Scientist Award NIHR/CS/010/024

Association between interleukin-6 promoter polymorphism (-174 G/C), serum interleukin-6 levels and mortality in severe septic patients

The association between interleukin (IL)-6 promoter polymorphism (-174 G/C), circulating IL-6 levels and mortality in septic patients has scarcely been addressed, and then only in studies of small sample size, and a direct association among them has not been previously reported. Therefore, the purpose of our study was to determine whether this association exists. An observational, prospective and multicenter study including severe septic patients was undertaken and serum IL-6 levels at severe sepsis diagnosis and IL-6 promoter polymorphism (-174 G/C) were determined. The end-point of the study was 30-day mortality. The study included 263 patients with the following genotypes of IL-6 promoter polymorphism (-174 G/C): 123 (46.8%) GG, 110 (41.8%) GC and 30 (11.4%) CC. CC homozygous patients showed lower sepsis-related organ failure assessment (SOFA) score, serum IL-6 levels and mortality at 30 days compared to those with other genotypes (GC or GG). On regression analysis, CC homozygous patients showed lower 30-day mortality than those with genotype GG (odds ratio = 0.21; 95% CI = 0.053-0.838; p = 0.03) or GC (hazard ratio = 0.28; 95% CI = 0.074-1.037; p = 0.06). The most important results of our study were that CC might be a favorable genotype in septic patients showing lower serum IL-6 levels and lower risk of death within 30 days

Five-year trajectories of multimorbidity patterns in an elderly Mediterranean population using Hidden Markov Models

This is the final version. Available on open access from Nature Research via the DOI in this recordThis study aimed to analyse the trajectories and mortality of multimorbidity patterns in patients aged 65 to 99 years in Catalonia (Spain). Five year (2012–2016) data of 916,619 participants from a primary care, population-based electronic health record database (Information System for Research in Primary Care, SIDIAP) were included in this retrospective cohort study. Individual longitudinal trajectories were modelled with a Hidden Markov Model across multimorbidity patterns. We computed the mortality hazard using Cox regression models to estimate survival in multimorbidity patterns. Ten multimorbidity patterns were originally identified and two more states (death and drop-outs) were subsequently added. At baseline, the most frequent cluster was the Non-Specific Pattern (42%), and the least frequent the Multisystem Pattern (1.6%). Most participants stayed in the same cluster over the 5 year follow-up period, from 92.1% in the Nervous, Musculoskeletal pattern to 59.2% in the Cardio-Circulatory and Renal pattern. The highest mortality rates were observed for patterns that included cardio-circulatory diseases: Cardio-Circulatory and Renal (37.1%); Nervous, Digestive and Circulatory (31.8%); and Cardio-Circulatory, Mental, Respiratory and Genitourinary (28.8%). This study demonstrates the feasibility of characterizing multimorbidity patterns along time. Multimorbidity trajectories were generally stable, although changes in specific multimorbidity patterns were observed. The Hidden Markov Model is useful for modelling transitions across multimorbidity patterns and mortality risk. Our findings suggest that health interventions targeting specific multimorbidity patterns may reduce mortality in patients with multimorbidity.Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain)European Regional Development FundDepartment of Health of the Catalan GovernmentCatalan Governmen

Serum levels of caspase-cleaved cytokeratin-18 and mortality are associated in severe septic patients: Pilot study

Objective: Apoptosis is increased in sepsis. Cytokeratin 18 (CK-18), a protein of the intermediate filament group present in most epithelial and parenchymal cells, is cleaved by the action of caspases and released into the blood as caspase-cleaved CK (CCCK)-18 during apoptosis. Circulating levels of CCCK-18 have scarcely been explored in septic patients. In one study with 101 severe septic patients, the authors reported higher serum CCCK-18 levels in non-survivors than in survivors; however, the sample size was too small to demonstrate an association between serum CCCK-18 levels and early mortality and whether they could be used as a biomarker to predict outcomes in septic patients. Thus, these were the objectives of this study with a large series of patients. Methods: We performed a prospective, multicenter, observational study in six Spanish Intensive Care Units with 224 severe septic patients. Blood samples were collected at the time that severe sepsis was diagnosed to determine serum levels of CCCK-18, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-10. The end point was 30-day mortality. Results: Non-surviving patients (n = 80) showed higher serum CCCK-18 levels (P391 u/L were associated with 30-day survival (Odds ratio = 2.687; 95% confidence interval = 1.449-4.983; P = 0.002), controlling for SOFA score, serum lactic acid levels and age. Kaplan-Meier survival analysis showed that the risk of death in septic patients with serum CCCK-18 levels >391 u/L was higher than in patients with lower values (Hazard Ratio = 3.1; 95% CI = 1.96-4.84; P<0.001). Serum CCCK-18 levels were positively associated with serum levels of IL-6 and lactic acid, and with SOFA and APACHE scores. Conclusions: The major novel finding of our study, the largest cohort of septic patients providing data on circulating CCCK-18 levels, was that serum CCCK-18 levels are associated with mortality in severe septic patients

La participación ciudadana en la investigación desde la perspectivade investigadores de atención primaria

Objetivo: Explorar las debilidades, amenazas, fortalezas y oportunidades (DAFO) para el desarrollo de la participación de la ciudadanía en los proyectos de investigación gestionados por el Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAPJGol) según los investigadores de atención primaria de salud de Catalu ̃na.Método: Estudio transversal realizado en 2017 con 36 equipos de investigación de atención primaria de salud acreditados por el IDIAPJGol y su personal de gestión. Se dise ̃nó y pilotó un cuestionario abierto(papel y online) para desarrollar una técnica DAFO. Se obtuvieron 65 respuestas (14 en papel y 51 online).Se realizó un análisis de contenido temático.Resultados: La mayoría de informantes considera la participación de la ciudadanía en la investigació nuna estrategia útil, innovadora, viable e imprescindible, pero exige un cambio de mentalidad y un alejamiento del paradigma jerárquico. Puede ser difícil su ejecución y complicar los estudios. Les preocupa a qué ciudadanos implicar, cómo seleccionarlos, los posibles conflictos de intereses y las necesidades deformación. Las principales propuestas para su implementación son difundir estrategias previas, fomentar la motivación y las sinergias entre ciudadanos, investigadores e instituciones, y clarificar los roles delos actores implicados. El IDIAPJGol debería elaborar recomendaciones para la participación de la ciudadanía en la investigación, incentivar su inclusión, disponer de un referente y asesorar a los equipos investigadores. Conclusiones: A pesar de los retos, desarrollar la participación de la ciudadanía en la investigación en atención primaria de salud es imprescindible y factible, pero partiendo de una estrategia participativa con todos los actores. La ciudadanía puede participar en cualquier dise ̃no y fase de la investigación adaptando cada proyecto, siendo la atención primaria un ámbito privilegiado para desarrollar la participación ciudadana en la investigación.Objective: Explore the strengths, weaknesses, opportunities and threats (SWOT) for development of public involvement in research by Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAPJGol) according to primary health care researchers in Catalonia (Spain). Methods: Cross-sectional study carried out in 2017 with 36 primary health care research teams accredited by IDIAPJGol and its management staff. An open questionnaire (paper and online) was designed and piloted to develop a SWOT technique, and 65 answers were obtained (14 in paper and 51 online). A thematic content analysis was carried out. Results: Most informants consider public involvement in research a useful, innovative, viable and essential strategy, but it requires a change of mentality and a move away from the hierarchical paradigm. It can be difficult to execute and can complicate studies. They are concerned about which citizens should be involve, how to select them, possible conflicts of interest and training needs. The main proposals for its implementation are to disseminate previous strategies, encourage motivation and synergies among citizens, researchers and institutions, and to clarify the roles of the actors involved. IDIAPJGol should develop recommendations for the public involvement in research, encourage their inclusion, have a mentor and advise the research teams. Conclusions: Despite the challenges, developing public involvement in research in primary health care is essential and feasible, what it is more should be based on a participatory strategy with all actors. The citizens can participate in any kind of design and phase of the research, adapting each project, being the primary health care a privileged area to develop the public involvement in research

Sustained high serum caspase-3 concentrations and mortality in septic patients

Caspase-3 is the main executor of the apoptotic process. Higher serum caspase-3 concentrations in non-survivor compared to survivor septic patients have been found. The objectives of this work (with the increase of sample size to 308 patients, and the determination of serum caspase-3 concentrations also on days 4 and 8 of diagnosis of severe sepsis) were to know whether an association between serum caspase-3 concentrationss during the first week, degree of apoptosis, sepsis severity, and sepsis mortality exists. We collected serum samples of 308 patients with severe sepsis from eight intensive care units on days 1, 4 and 8 to measure concentrations of caspase-3 and caspase-cleaved cytokeratin (CCCK)-18 (to assess degree of apoptosis). End point was 30-day mortality. We found higher serum concentrations of caspase-3 and CCCK-18 in non-survivors compared to survivors on days 1 (p < 0.001), 4 (p < 0.001), and 8 (p < 0.001). We found an association between serum caspase-3 concentrations on days 1, 4 and 8 of severe sepsis diagnosis and serum CCCK-18 concentrations (p < 0.001), SOFA (p < 0.001), serum acid lactic concentrations (p < 0.001), and 30-day sepsis mortality (p < 0.001). The new findings of this work were that an association between serum caspase-3 concentrations during the first week, apoptosis degree, sepsis severity, and sepsis mortality exists

Disease networks identify specific conditions and pleiotropy influencing multimorbidity in the general population

Multimorbidity is an emerging topic in public health policy because of its increasing prevalence and socio-economic impact. However, the age- and gender-dependent trends of disease associations at fine resolution, and the underlying genetic factors, remain incompletely understood. Here, by analyzing disease networks from electronic medical records of primary health care, we identify key conditions and shared genetic factors influencing multimorbidity. Three types of diseases are outlined: "central", which include chronic and non-chronic conditions, have higher cumulative risks of disease associations; "community roots" have lower cumulative risks, but inform on continuing clustered disease associations with age; and "seeds of bursts", which most are chronic, reveal outbreaks of disease associations leading to multimorbidity. The diseases with a major impact on multimorbidity are caused by genes that occupy central positions in the network of human disease genes. Alteration of lipid metabolism connects breast cancer, diabetic neuropathy and nutritional anemia. Evaluation of key disease associations by a genome-wide association study identifies shared genetic factors and further supports causal commonalities between nervous system diseases and nutritional anemias. This study also reveals many shared genetic signals with other diseases. Collectively, our results depict novel population-based multimorbidity patterns, identify key diseases within them, and highlight pleiotropy influencing multimorbidity