Role of retinal pigment epithelium-derived exosomes and autophagy in new blood vessel formation

Autophagy and exosome secretion play important roles in a variety of physiological and disease states, including the development of age‐related macular degeneration. Previous studies have demonstrated that these cellular mechanisms share common pathways of activation. Low oxidative damage in ARPE‐19 cells, alters both autophagy and exosome biogenesis. Moreover, oxidative stress modifies the protein and genetic cargo of exosomes, possibly affecting the fate of surrounding cells. In order to understand the connection between these two mechanisms and their impact on angiogenesis, stressed ARPE‐19 cells were treated with a siRNA‐targeting Atg7, a key protein for the formation of autophagosomes. Subsequently, we observed the formation of multivesicular bodies and the release of exosomes. Released exosomes contained VEGFR2 as part of their cargo. This receptor for VEGF—which is critical for the development of new blood vessels—was higher in exosome populations released from stressed ARPE‐19. While stressed exosomes enhanced tube formation, exosomes became ineffective after silencing VEGFR2 in ARPE‐19 cells and were, consequently, unable to influence angiogenesis. Moreover, vessel sprouting in the presence of stressed exosomes seems to follow a VEGF‐independent pathway. We propose that abnormal vessel growth correlates with VEGFR2‐expressing exosomes release from stressed ARPE‐19 cells, and is directly linked to autophagy

Chronological and biological aging of the human left ventricular myocardium: Analysis of microRNAs contribution

Aging is the main risk factor for cardiovascular diseases. In humans, cardiac aging remains poorly characterized. Most studies are based on chronological age (CA) and disregard biological age (BA), the actual physiological age (result of the aging rate on the organ structure and function), thus yielding potentially imperfect outcomes. Deciphering the molecular basis of ventricular aging, especially by BA, could lead to major progresses in cardiac research. We aim to describe the transcriptome dynamics of the aging left ventricle (LV) in humans according to both CA and BA and characterize the contribution of microRNAs, key transcriptional regulators. BA is measured using two CA-associated transcriptional markers: CDKN2A expression, a cell senescence marker, and apparent age (AppAge), a highly complex transcriptional index. Bioinformatics analysis of 132 LV samples shows that CDKN2A expression and AppAge represent transcriptomic changes better than CA. Both BA markers are biologically validated in relation to an aging phenotype associated with heart dysfunction, the amount of cardiac fibrosis. BA-based analyses uncover depleted cardiac-specific processes, among other relevant functions, that are undetected by CA. Twenty BA-related microRNAs are identified, and two of them highly heart-enriched that are present in plasma. We describe a microRNA-gene regulatory network related to cardiac processes that are partially validated in vitro and in LV samples from living donors. We prove the higher sensitivity of BA over CA to explain transcriptomic changes in the aging myocardium and report novel molecular insights into human LV biological aging. Our results can find application in future therapeutic and biomarker research

Management of acute diverticulitis with pericolic free gas (ADIFAS). an international multicenter observational study

Background: There are no specific recommendations regarding the optimal management of this group of patients. The World Society of Emergency Surgery suggested a nonoperative strategy with antibiotic therapy, but this was a weak recommendation. This study aims to identify the optimal management of patients with acute diverticulitis (AD) presenting with pericolic free air with or without pericolic fluid. Methods: A multicenter, prospective, international study of patients diagnosed with AD and pericolic-free air with or without pericolic free fluid at a computed tomography (CT) scan between May 2020 and June 2021 was included. Patients were excluded if they had intra-abdominal distant free air, an abscess, generalized peritonitis, or less than a 1-year follow-up. The primary outcome was the rate of failure of nonoperative management within the index admission. Secondary outcomes included the rate of failure of nonoperative management within the first year and risk factors for failure. Results: A total of 810 patients were recruited across 69 European and South American centers; 744 patients (92%) were treated nonoperatively, and 66 (8%) underwent immediate surgery. Baseline characteristics were similar between groups. Hinchey II-IV on diagnostic imaging was the only independent risk factor for surgical intervention during index admission (odds ratios: 12.5, 95% CI: 2.4-64, P =0.003). Among patients treated nonoperatively, at index admission, 697 (94%) patients were discharged without any complications, 35 (4.7%) required emergency surgery, and 12 (1.6%) percutaneous drainage. Free pericolic fluid on CT scan was associated with a higher risk of failure of nonoperative management (odds ratios: 4.9, 95% CI: 1.2-19.9, P =0.023), with 88% of success compared to 96% without free fluid ( P <0.001). The rate of treatment failure with nonoperative management during the first year of follow-up was 16.5%. Conclusion: Patients with AD presenting with pericolic free gas can be successfully managed nonoperatively in the vast majority of cases. Patients with both free pericolic gas and free pericolic fluid on a CT scan are at a higher risk of failing nonoperative management and require closer observation

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.info:eu-repo/semantics/publishedVersio

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

L’execució de les mesures penals alternatives a les comarques de Tarragona. Anàlisi comparativa entre Tarragona, Lleida i Girona

La finalitat d’aquest estudi és conèixer quines són les singularitats en el treball amb adults en mesures penals alternatives a la província de Tarragona. Es vol saber si hi ha diferències respecte Lleida i Girona en relació amb les característiques de les persones ateses, del seu entorn sociofamiliar, dels agents que intervenen, dels fets delictius comesos, de les mesures imposades i quina és la taxa de reincidència. Aquesta és la segona part d’una recerca que vam començar amb el recull dels resultats de justícia juvenil i que completa el coneixement en clau territorial del funcionament de l’execució penal a Catalunya. L’encàrrec el va fer el Centre d’Estudis Jurídics i Formació Especialitzada i els Serveis Territorials de Justícia a Tarragona a la Universitat Rovira i Virgili. L’estudi descriu, delimita i interpreta les diferències de Tarragona, Lleida i Girona en els següents conjunts de variables : a) les característiques socioeconòmiques; b) el perfil delictiu dels penats que compleixen una MPA; c) la reincidència d’aquests penats; d) la imposició de les penes; i e) l’evolució dels indicadors del sistema d’execució de les MPA en el període 2010-2013. La població objecte d’estudi són els penats que a l’any 2010 havien finalitzat completament una causa penal (N=2.485) a MPA a Tarragona, Lleida i Girona, i se’ls ha seguit fins el 2013 per saber si han tornat a reincidir. S’han recollit també dades de l’evolució dels indicadors del sistema d’execució penal dels anys 2010 fins el 2013 i dades macrosocials dels diferents àmbits socials. Juntament amb la part quantitativa, l’estudi té una part qualitativa feta a partir de les entrevistes amb informants clau: 32 juristes, 22 tècnics dels serveis territorials de Justícia, 11 professionals de recursos col·laboradors de les MPA, 2 jutges, 1 fiscal, 5 Mossos d’Esquadra i 3 delegats de MPA. Els resultats donen molta informació comuna i particular de cadascun dels 3 territoris estudiats i permeten una amplia visió del fenomen amb la possibilitat d’entendre i atendre les singularitats i particularitats de cada territori.The purpose of this research is to know the singularities of the development of community sanctions and measures (CSM) with adult offenders in the Catalan province of Tarragona, and to analyze if there are differences regarding other provinces: Lleida and Girona (which should be comparable to Tarragona). The research compares the characteristics of people serving a CSM, their socio-family environment, the agents involved, the offenses committed, the measures imposed and the rate of recidivism. This is the second part of a research that began with the analysis of the juvenile justice system in Tarragona. The task was requested by the Center for Legal Studies and Specialized Training and the Territorial Justice Services in Tarragona to the University Rovira i Virgili. The study describes, delimits and interprets the differences between Tarragona, Lleida and Girona in the following sets of variables: A) socio-economic characteristics of Tarragona; B) criminal profile of the offenders serving a CSM; C) the recidivism of these offenders; D) the imposition of penalties; and E) the evolution of the indicators of the CSM in the period 2010-2013. The population under study are those offenders that in 2010 had completely finished a CSM (N = 2,485) in Tarragona, Lleida and Girona. They were followed until 2013 to find out if they re-offended. The study also collected data on the evolution of the indicators of the criminal justice system from 2010 to 2013 and macro-social data from the different social spheres. Besides the quantitative part, the study has a qualitative part based on interviews with key informants: 32 jurists, 22 civil servants from the territorial justice services, 11 professionals from NGO carrying out CSM, 2 judges, 1 prosecutor, 5 policemen and 3 probation officers. The results give a lot of information of each of the 3 studied territories and allow a broad vision of the CSM in all of them, with the possibility of understanding the singularities and particularities of each territory.La finalidad de este estudio es conocer cuáles son las singularidades en el trabajo con adultos en medidas penales alternativas en la provincia de Tarragona. Pretendemos esclarecer también si hay diferencias respecto a Lleida y Girona en relación con las características de las personas atendidas, de su entorno sociofamiliar, los agentes que intervienen, los hechos delictivos cometidos, las medidas que se les imponen y cuál es la tasa de reincidencia. Ésta es la segunda parte de una investigación que empezamos con la recopilación de los resultados de justicia juvenil y que completa el conocimiento en clave territorial del funcionamiento de la ejecución penal en Cataluña. El encargo lo hicieron el Centro de Estudios Jurídicos y Formación Especializada y los Servicios Territoriales de Justicia en Tarragona a la Universidad Rovira i Virgili de Tarragona. El estudio describe, delimita e interpreta las diferencias de Tarragona, Lleida y Girona en los siguientes conjuntos de variables: a) las características socioeconómicas; b) el perfil delictivo de los penados que cumplen una MPA; c) la reincidencia de estos penados; d) la imposición de las penas; y e) la evolución de los indicadores del sistema de ejecución de las MPA en el periodo 2010-2013. La población objeto de estudio son los penados que el año 2010 habían finalizado completamente una causa penal (N = 2.485) en MPA en Tarragona, Lleida y Girona, y se les ha seguido hasta el 2013 para saber si han vuelto a reincidir. Se han recogido también datos de la evolución de los indicadores del sistema de ejecución penal de los años 2010 hasta 2013 y datos macrosociales de los diferentes ámbitos sociales. Junto con la parte cuantitativa, el estudio tiene una parte cualitativa realizada a partir de las entrevistas con informantes clave: 32 juristas, 22 técnicos de los servicios territoriales de Justicia, 11 profesionales de recursos colaboradores de las MPA, 2 jueces, 1 fiscal, 5 Mossos d’Esquadra (policía catalana) y 3 delegados de MPA. Los resultados dan mucha información común y particular de cada uno de los 3 territorios estudiados y permiten una amplia visión del fenómeno con la posibilidad de entender y atender las singularidades y particularidades de cada territorio

La ejecución de las medidas penales alternativas en las comarcas de Tarragona. Análisis comparativo entre Tarragona, Lleida y Girona

La finalidad de este estudio es conocer cuáles son las singularidades en el trabajo con adultos en medidas penales alternativas en la provincia de Tarragona. Pretendemos esclarecer también si hay diferencias respecto a Lleida y Girona en relación con las características de las personas atendidas, de su entorno sociofamiliar, los agentes que intervienen, los hechos delictivos cometidos, las medidas que se les imponen y cuál es la tasa de reincidencia. Ésta es la segunda parte de una investigación que empezamos con la recopilación de los resultados de justicia juvenil y que completa el conocimiento en clave territorial del funcionamiento de la ejecución penal en Cataluña. El encargo lo hicieron el Centro de Estudios Jurídicos y Formación Especializada y los Servicios Territoriales de Justicia en Tarragona a la Universidad Rovira i Virgili de Tarragona. El estudio describe, delimita e interpreta las diferencias de Tarragona, Lleida y Girona en los siguientes conjuntos de variables: a) las características socioeconómicas; b) el perfil delictivo de los penados que cumplen una MPA; c) la reincidencia de estos penados; d) la imposición de las penas; y e) la evolución de los indicadores del sistema de ejecución de las MPA en el periodo 2010-2013. La población objeto de estudio son los penados que el año 2010 habían finalizado completamente una causa penal (N = 2.485) en MPA en Tarragona, Lleida y Girona, y se les ha seguido hasta el 2013 para saber si han vuelto a reincidir. Se han recogido también datos de la evolución de los indicadores del sistema de ejecución penal de los años 2010 hasta 2013 y datos macrosociales de los diferentes ámbitos sociales. Junto con la parte cuantitativa, el estudio tiene una parte cualitativa realizada a partir de las entrevistas con informantes clave: 32 juristas, 22 técnicos de los servicios territoriales de Justicia, 11 profesionales de recursos colaboradores de las MPA, 2 jueces, 1 fiscal, 5 Mossos d’Esquadra (policía catalana) y 3 delegados de MPA. Los resultados dan mucha información común y particular de cada uno de los 3 territorios estudiados y permiten una amplia visión del fenómeno con la posibilidad de entender y atender las singularidades y particularidades de cada territorio.La finalitat d’aquest estudi és conèixer quines són les singularitats en el treball amb adults en mesures penals alternatives a la província de Tarragona. Es vol saber si hi ha diferències respecte Lleida i Girona en relació amb les característiques de les persones ateses, del seu entorn sociofamiliar, dels agents que intervenen, dels fets delictius comesos, de les mesures imposades i quina és la taxa de reincidència. Aquesta és la segona part d’una recerca que vam començar amb el recull dels resultats de justícia juvenil i que completa el coneixement en clau territorial del funcionament de l’execució penal a Catalunya. L’encàrrec el va fer el Centre d’Estudis Jurídics i Formació Especialitzada i els Serveis Territorials de Justícia a Tarragona a la Universitat Rovira i Virgili. L’estudi descriu, delimita i interpreta les diferències de Tarragona, Lleida i Girona en els següents conjunts de variables : a) les característiques socioeconòmiques; b) el perfil delictiu dels penats que compleixen una MPA; c) la reincidència d’aquests penats; d) la imposició de les penes; i e) l’evolució dels indicadors del sistema d’execució de les MPA en el període 2010-2013. La població objecte d’estudi són els penats que a l’any 2010 havien finalitzat completament una causa penal (N=2.485) a MPA a Tarragona, Lleida i Girona, i se’ls ha seguit fins el 2013 per saber si han tornat a reincidir. S’han recollit també dades de l’evolució dels indicadors del sistema d’execució penal dels anys 2010 fins el 2013 i dades macrosocials dels diferents àmbits socials. Juntament amb la part quantitativa, l’estudi té una part qualitativa feta a partir de les entrevistes amb informants clau: 32 juristes, 22 tècnics dels serveis territorials de Justícia, 11 professionals de recursos col·laboradors de les MPA, 2 jutges, 1 fiscal, 5 Mossos d’Esquadra i 3 delegats de MPA. Els resultats donen molta informació comuna i particular de cadascun dels 3 territoris estudiats i permeten una amplia visió del fenomen amb la possibilitat d’entendre i atendre les singularitats i particularitats de cada territori.The purpose of this research is to know the singularities of the development of community sanctions and measures (CSM) with adult offenders in the Catalan province of Tarragona, and to analyze if there are differences regarding other provinces: Lleida and Girona (which should be comparable to Tarragona). The research compares the characteristics of people serving a CSM, their socio-family environment, the agents involved, the offenses committed, the measures imposed and the rate of recidivism. This is the second part of a research that began with the analysis of the juvenile justice system in Tarragona. The task was requested by the Center for Legal Studies and Specialized Training and the Territorial Justice Services in Tarragona to the University Rovira i Virgili. The study describes, delimits and interprets the differences between Tarragona, Lleida and Girona in the following sets of variables: A) socio-economic characteristics of Tarragona; B) criminal profile of the offenders serving a CSM; C) the recidivism of these offenders; D) the imposition of penalties; and E) the evolution of the indicators of the CSM in the period 2010-2013. The population under study are those offenders that in 2010 had completely finished a CSM (N = 2,485) in Tarragona, Lleida and Girona. They were followed until 2013 to find out if they re-offended. The study also collected data on the evolution of the indicators of the criminal justice system from 2010 to 2013 and macro-social data from the different social spheres. Besides the quantitative part, the study has a qualitative part based on interviews with key informants: 32 jurists, 22 civil servants from the territorial justice services, 11 professionals from NGO carrying out CSM, 2 judges, 1 prosecutor, 5 policemen and 3 probation officers. The results give a lot of information of each of the 3 studied territories and allow a broad vision of the CSM in all of them, with the possibility of understanding the singularities and particularities of each territory

Chronological and biological aging of the human left ventricular myocardium: Analysis of microRNAs contribution

Aging is the main risk factor for cardiovascular diseases. In humans, cardiac aging remains poorly characterized. Most studies are based on chronological age (CA) and disregard biological age (BA), the actual physiological age (result of the aging rate on the organ structure and function), thus yielding potentially imperfect outcomes. Deciphering the molecular basis of ventricular aging, especially by BA, could lead to major progresses in cardiac research. We aim to describe the transcriptome dynamics of the aging left ventricle (LV) in humans according to both CA and BA and characterize the contribution of microRNAs, key transcriptional regulators. BA is measured using two CA-associated transcriptional markers: CDKN2A expression, a cell senescence marker, and apparent age (AppAge), a highly complex transcriptional index. Bioinformatics analysis of 132 LV samples shows that CDKN2A expression and AppAge represent transcriptomic changes better than CA. Both BA markers are biologically validated in relation to an aging phenotype associated with heart dysfunction, the amount of cardiac fibrosis. BA-based analyses uncover depleted cardiac-specific processes, among other relevant functions, that are undetected by CA. Twenty BA-related microRNAs are identified, and two of them highly heart-enriched that are present in plasma. We describe a microRNA-gene regulatory network related to cardiac processes that are partially validated in vitro and in LV samples from living donors. We prove the higher sensitivity of BA over CA to explain transcriptomic changes in the aging myocardium and report novel molecular insights into human LV biological aging. Our results can find application in future therapeutic and biomarker research

Stoma-free Survival After Rectal Cancer Resection With Anastomotic Leakage: Development and Validation of a Prediction Model in a Large International Cohort.

Objective:To develop and validate a prediction model (STOMA score) for 1-year stoma-free survival in patients with rectal cancer (RC) with anastomotic leakage (AL).Background:AL after RC resection often results in a permanent stoma.Methods:This international retrospective cohort study (TENTACLE-Rectum) encompassed 216 participating centres and included patients who developed AL after RC surgery between 2014 and 2018. Clinically relevant predictors for 1-year stoma-free survival were included in uni and multivariable logistic regression models. The STOMA score was developed and internally validated in a cohort of patients operated between 2014 and 2017, with subsequent temporal validation in a 2018 cohort. The discriminative power and calibration of the models' performance were evaluated.Results:This study included 2499 patients with AL, 1954 in the development cohort and 545 in the validation cohort. Baseline characteristics were comparable. One-year stoma-free survival was 45.0% in the development cohort and 43.7% in the validation cohort. The following predictors were included in the STOMA score: sex, age, American Society of Anestesiologist classification, body mass index, clinical M-disease, neoadjuvant therapy, abdominal and transanal approach, primary defunctioning stoma, multivisceral resection, clinical setting in which AL was diagnosed, postoperative day of AL diagnosis, abdominal contamination, anastomotic defect circumference, bowel wall ischemia, anastomotic fistula, retraction, and reactivation leakage. The STOMA score showed good discrimination and calibration (c-index: 0.71, 95% CI: 0.66-0.76).Conclusions:The STOMA score consists of 18 clinically relevant factors and estimates the individual risk for 1-year stoma-free survival in patients with AL after RC surgery, which may improve patient counseling and give guidance when analyzing the efficacy of different treatment strategies in future studies

Stoma-free survival after anastomotic leak following rectal cancer resection: worldwide cohort of 2470 patients

Background: The optimal treatment of anastomotic leak after rectal cancer resection is unclear. This worldwide cohort study aimed to provide an overview of four treatment strategies applied. Methods: Patients from 216 centres and 45 countries with anastomotic leak after rectal cancer resection between 2014 and 2018 were included. Treatment was categorized as salvage surgery, faecal diversion with passive or active (vacuum) drainage, and no primary/secondary faecal diversion. The primary outcome was 1-year stoma-free survival. In addition, passive and active drainage were compared using propensity score matching (2: 1). Results: Of 2470 evaluable patients, 388 (16.0 per cent) underwent salvage surgery, 1524 (62.0 per cent) passive drainage, 278 (11.0 per cent) active drainage, and 280 (11.0 per cent) had no faecal diversion. One-year stoma-free survival rates were 13.7, 48.3, 48.2, and 65.4 per cent respectively. Propensity score matching resulted in 556 patients with passive and 278 with active drainage. There was no statistically significant difference between these groups in 1-year stoma-free survival (OR 0.95, 95 per cent c.i. 0.66 to 1.33), with a risk difference of -1.1 (95 per cent c.i. -9.0 to 7.0) per cent. After active drainage, more patients required secondary salvage surgery (OR 2.32, 1.49 to 3.59), prolonged hospital admission (an additional 6 (95 per cent c.i. 2 to 10) days), and ICU admission (OR 1.41, 1.02 to 1.94). Mean duration of leak healing did not differ significantly (an additional 12 (-28 to 52) days). Conclusion: Primary salvage surgery or omission of faecal diversion likely correspond to the most severe and least severe leaks respectively. In patients with diverted leaks, stoma-free survival did not differ statistically between passive and active drainage, although the increased risk of secondary salvage surgery and ICU admission suggests residual confounding