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Dementia represents a key impending global health challenge. The aim of this systematic review was to evaluate the current evidence on nutritional interventions for the prevention of dementia in developing economies in East-Asia. Four comprehensive databases were searched from inception until January 2020: MEDLINE, Embase, PsycInfo, and Scopus. The search was restricted to randomized controlled trials [RCTs] in adult humans, assessing the effect of nutritional interventions on global and domain specific cognitive performance and dementia risk. Meta-analysis of data was conducted for each domain and sub-categorized according to the type of nutritional intervention. Twenty-four RCTs were included, of which, fifteen studies showed significant beneficial effects on cognition. Eighteen studies were included in the meta-analysis. Significant beneficial effects were found for essential fatty acids (EPA/DHA) and micronutrient supplementation on specific cognitive domains including attention and orientation, perception, verbal functions and language skills. The effect size of the interventions appeared to be greater in older subjects with cognitive impairment. Supplementation with B-vitamins and essential fatty acids may represent promising strategies to minimize age-related cognitive decline in Asian populations. Large, high-quality, long-term trials are needed to confirm these findings. Refereed/Peer-reviewed

Acquired elastotic hemangioma (AEH) is a rare variant of hemangioma that usually presents as an asymptomatic, solitary, slow-growing red plaque on a sun-exposed site of an adult. Ultraviolet radiation can contribute to the pathogenesis of this hemangioma. Lichen sclerosus (LS), a scarring disease, may present a prominent accumulation of elastic fibers in the reticular dermis reflecting a reparative process. Vulvar elastosis, a novel diagnostic entity with fibers similar to solar elastosis, is more common in women 45 yr and older and is related to aging and/or hormonal changes. We herein report for the first time a case of AEH-like change located in the vulva, a sun-protected area, associated with genital LS. An 81-yr-old woman presented with a painful vulvar lesion of 1-yr duration. Clinical examination revealed vulvar LS and 1 cm-flat, erythematous, well-defined plaque with increased consistency located on the left labium minus. Histopathology showed a non-neoplastic proliferation of WT1-positive, small vascular channels surrounded and intertwined by intense elastosis in the reticular dermis. Alpha-smooth muscle actin positive pericytes encircled the vascular channels. The lesion can be understood as a reparative process within an LS with the appearance of epidermal hyperplasia, proliferation of small vascular channels, and hyperplastic elastosis. There is a close link between epidermal hyperplasia and angiogenesis in the formation of this reparative lesion. Recognition of this lesion is crucial to avoid confusion with other significant processes especially Kaposi sarcoma and well-differentiated angiosarcoma.

[Objective] The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD., [Design] The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI), [Results] Lean patients represented 14.4% of the cohort and were predominantly of Italian origin (89%). They had less severe histological disease (lean vs non-lean: non-alcoholic steatohepatitis 54.1% vs 71.2% p10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069)., [Conclusions] Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and PNPLA3 genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds. [Lay summary] NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD., This study has been supported by the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413 and the Newcastle NIHR Biomedical Research Centre. The authors are contributing members of The European NAFLD Registry. The study was also supported by the Italian Ministry of Health, grant RF-2016-02364358 (Ricerca Finalizzata, Ministero della Salute). ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206, APP1149976) and Project grants (APP1107178 and APP1108422).

Editor’s note: This article was written before the publication by the EU Commission of its proposal for an artificial intelligence (AI) regulation [29] . In a first and provisional analysis of the proposed regulation, we observe that the proposed regulation incorporates some of the basic principles laid down in our article: it prioritizes fundamental rights and incorporates some human rights principles, such as accountability, and the inclusion of governance through supervisory authorities to implement and enforce the regulation. Nevertheless, we still feel that many of the suggestions present in our article, which would help to operationalize the regulation, are not addressed. One example is the reduced scope of the regulation to a list of “high risk applications,” leaving without a legal framework all other AI applications. We believe that the principles that inspire the regulation should also be applied in “lower risk applications.” Defining only the compliance process for AI developers, but leaving open the specific technical requirements that these high risk applications shall meet leaves untouched the existing gap between legal language and engineering practice. There are no described mechanisms by which all stakeholders (other than developers and implementers) can influence AI development, monitor their performance or claim redress if harmed. These shortcomings and other issues presented in our article leave the door open to loopholes that we hope the European Parliament can fix during the legislative process.

BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) is an increasingly important cause of liver cirrhosis and subsequent complications. We retrospectively developed and validated a model to predict hepatic decompensation in patients with NAFLD and cirrhosis and compared this with currently available models. APPROACH AND RESULTS Baseline variables from an international cohort of 299 patients with biopsy-proven NAFLD with compensated cirrhosis were examined to construct a model using competing risk multivariate regression and Akaike/Bayesian information criteria. Validation was performed in 244 patients with biopsy-proven NAFLD cirrhosis from the United States. Prognostic accuracy was compared with the NAFLD fibrosis score (NFS), fibrosis-4 (FIB-4), Model for End-Stage Liver Disease (MELD), Child-Turcotte-Pugh (CTP), and albumin-bilirubin (ALBI)-FIB-4 score using time-dependent area under the curve (tAUC) analysis. During a median follow-up of 5.6 years (range 2.4-14.1) and 5.4 years (range 1.5-13.8), hepatic decompensation occurred in 81 and 132 patients in the derivation and validation cohorts, respectively. In the derivation cohort, independent predictors of hepatic decompensation (Aspartate aminotransferase/alanine aminotransferase ratio, Bilirubin, International normalized ratio, type 2 Diabetes, and Esophageal varices) were combined into the ABIDE model. Patients with a score ≥4.1 compared with those with a score

Introduction Severe novel corona virus disease 2019 (COVID-19) causes dysregulation of the coagulation system with arterial and venous thromboembolism (VTE). We hypothesize that validated VTE risk scores would have prognostic ability in this population. Methods Retrospective observational cohort with severe COVID-19 performed in NorthShore University Health System. Patients were >18 years of age and met criteria for inpatient or intensive care unit (ICU) care. The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) and Caprini scores were calculated and patients were stratified. Results This study includes 184 patients, mostly men (63.6%), Caucasian (54.3%), 63 years old (interquartile range [IQR]: 24–101), and 57.1% of them required ICU care. Twenty-seven (14.7%) thrombotic events occurred: 12 (6.5%) cases of disseminated intravascular coagulation (DIC), 9 (4.9%) of pulmonary embolism, 5 (2.7%) of deep vein thrombosis, and 1 (0.5%) stroke. Among them, 86 patients (46.7%) died, 95 (51.6%) were discharged, and 3 (1.6%) were still hospitalized. “Moderate risk for VTE” and “High risk for VTE” by IMPROVE score had significant mortality association: (hazard ratio [HR]: 5.68; 95% confidence interval [CI]: 2.93–11.03; p Conclusion The IMPROVE and Caprini risk scores were independent predictors of mortality and thrombotic events in severe COVID-19. With larger validation, this can be useful prognostic information.

Background: Mild cognitive impairment (MCI) is a cognitive state associated with increased risk of dementia. Little research on MCI exists from low-and middle-income countries (LMICs), despite high prevalence of dementia in these settings. Objective: This systematic review aimed to review epidemiological reports to determine the prevalence of MCI and its associated risk factors in LMICs. Methods: Medline, Embase, and PsycINFO were searched from inception until November 2019. Eligible articles reported on MCI in population or community-based studies from LMICs and were included as long as MCI was clearly defined. Results: 5,568 articles were screened, and 78 retained. In total, n = 23 different LMICs were represented; mostly from China (n = 55 studies). Few studies were from countries defined as lower-middle income (n = 14), low income (n = 4), or from population representative samples (n = 4). There was large heterogeneity in how MCI was diagnosed; with Petersen criteria the most commonly applied (n = 26). Prevalence of amnesic MCI (aMCI) (Petersen criteria) ranged from 0.6%to 22.3%. Similar variability existed across studies using the International Working Group Criteria for aMCI (range 4.5%to 18.3%) and all-MCI (range 6.1%to 30.4%). Risk of MCI was associated with demographic (e.g., age), health (e.g., cardio-metabolic disease), and lifestyle (e.g., social isolation, smoking, diet and physical activity) factors. Conclusion: Outside of China, few MCI studies have been conducted in LMIC settings. There is an urgent need for population representative epidemiological studies to determine MCI prevalence in LMICs. MCI diagnostic methodology also needs to be standardized. This will allow for cross-study comparison and future resource planning.

Introduction Spontaneous subarachnoid haemorrhage is a rare cause of stroke, but it causes great socioeconomic impact and high morbidity and mortality. The aim of this study is to describe the clinical profile and evolution of a series of patients with SAH admitted to a tertiary hospital, as well as the diagnostic and therapeutic management. Material and methods Retrospective study of 536 patients diagnosed with SAH admitted to the ICU of the Hospital Universitario de A Coruna between 2003 and 2013 (Age: 56.9 ± 14.1 years, female/male ratio: 1.5:1). Demographic characteristics, risk factors, aetiologies and clinical signs, prognostic scales, diagnostic tests and treatment were collected. A comparative analysis was made between the general series and subgroups of patients with aneurysmal (SAH-A) and idiopathic (SAH-I) subarachnoid haemorrhage. Results There were 49.0 ± 15.1 patients/year (2013 incidence: 4.3/100,000 inhabitants). 60.3% presented Glasgow Coma Scale (GCS) 14-15, with scarce symptomatology (Hunt-Hess I-II 61.9%, World Federation Neurosurgeons Scale I-II 60.4%). 50.7% presented Fisher IV. SAH-A was diagnosed in 78.3% (n = 396); perimesencephalic subarachnoid haemorrhage (SAH-PM) in 3.2%; and SAH-I in 17.9%. During the study period there was an increase in the prevalence of aneurysms, causing an increased number of surgeries in recent years. Both SAH-A and SAH-I presented greater severity upon admission. Patients with SAH-A had higher percentage of complications and mortality, with lesser degree of independence at 6 and 12 months. Conclusions The incidence of SAH appears to have decreased in recent years, with SAH-I comprising 17.9% of the cases. Patients with SAH-I have better prognosis and lower risk of complications, highlighting the benignity of SAH-PM.

Resumen Introduccion La hemorragia subaracnoidea espontanea (HSA) es una causa poco frecuente de ictus que ocasiona gran impacto socioeconomico y elevada morbimortalidad. El objetivo de este estudio es describir el perfil clinico y la evolucion de una serie de pacientes con HSA ingresados en un hospital terciario, asi como el manejo diagnostico-terapeutico. Material y metodos Estudio retrospectivo de 536 pacientes diagnosticados de HSA ingresados en la Unidad de Cuidados Intensivos del Hospital Universitario de A Coruna de 2003 a 2013 (edad: 56,9 ± 14,1 anos, ratio mujer/hombre: 1,5:1). Se recogieron caracteristicas demograficas, factores de riesgo, etiologia y clinica, escalas pronosticas, pruebas diagnosticas y tratamiento. Se realizo un analisis comparativo entre la serie general y subgrupos de pacientes con HSA aneurismatica (HSA-A) e idiopatica (HSA-I). Resultados Se registraron 49,0 ± 15,1 pacientes/ano (incidencia 2013: 4,3/100.000 habitantes). El 60,3% presentaba Glasgow Coma Scale 14-15, con escasa sintomatologia (escala de Hunt-Hess [H-H] I-II 61,9%; World Federation Neurosurgeons Scale [WFNS] I-II 60,4%). El 50,7% presentaba Fisher IV. En el 78,3% (n = 396) se diagnostico HSA-A, el 3,2% presentaba sangrado perimesencefalico (HSA-PM) y HSA-I 17,9%. Durante el periodo de estudio se registro un aumento de la prevalencia de aneurismas, incrementandose en los ultimos anos la cirugia. Tanto la HSA-A como HSA-I presentaban mayor gravedad al ingreso. Los pacientes con HSA-A presentaron mayor porcentaje de complicaciones y mortalidad, con menor grado de independencia a 6 y 12 meses. Conclusiones La incidencia de HSA tiende a descender en los ultimos anos, representando la HSA-I el 17,9% de los casos. Los pacientes con HSA-I tienen mejor pronostico y menor riesgo de complicaciones, destacando la benignidad de la HSA-PM.

Introduction Few studies conducted in primary care setting report about age-adjusted prevalence rates of erectile dysfunction (ED). Aims of SIMETAP-ED study were to determine crude and age-adjusted prevalence rates of ED diagnosis, to compare these rates with other similar studies, and to compare prevalence rates of cardiovascular risk factors (CVRF), cardiovascular diseases (CVD), metabolic diseases and chronic kidney disease (CKD) between populations with and without ED. Methods Cross-sectional observational study conducted in primary care setting. Population-based random sample: 2934 adult men. Response rate: 66%. A clinical interview was conducted to diagnose ED using a question derived from ED definition. The medical records of patients were reviewed to identify their CVRF and diseases associated with ED. The age-adjustments were standardized to Spanish population. Results The prevalence rates of metabolic diseases, CVD, CVRF, and CKD in population with ED were higher than population without ED, highlighting the CVD. The crude prevalence of ED was 17.2% (95% confidence interval: 15.8•18.6). The age-adjusted prevalence rates of ED were 0.71% in men under 40 years, 12.4% in men over 18 years, 10.8% in men aged 40•69 years, 18.9% in men over 40 years, and 48.6% in men over 70 years. Conclusions SIMETAP-ED study showed association of ED with metabolic diseases, CKD, CVRF, and highlighting CVD. The age-adjusted prevalence of ED was 12.4% in adult men, 19% in men over 40 years, and almost 50% in men over 70 years.

Aim To determine in the adult population the crude and the sex- and age-adjusted prevalence rates of hypertriglyceridaemia (HTG) and to assess its association with cardiovascular risk factors, chronic kidney disease, cardiovascular and cardiometabolic diseases. Methods Cross-sectional observational study conducted in Primary Care, with 6,588 adult study subjects, randomly selected on base-population. Patients had HTG if the triglyceride level was ≥150 mg/dL (≥1.7 mmol/L), or were on lipid-lowering therapy to lower triglyceride. Associations were assessed by univariate and multivariate analysis, and crude and sex- and age-adjusted prevalence rates were determined. Results The arithmetic and geometric means of triglyceride levels were respectively 120.5 and 104.2 mg/dL in global population, 135.7 and 116.0 mg/dL in men, and 108.6 and 95.7 mg/dL in women. The crude HTG prevalence rates were 29.6% in global population, 36.9% in men and 23.8% in women. The sex- and age-adjusted HTG prevalence rates were 27.0% in global population, 34.6% in men and 21.4% in women. The independent variables that were most associated with HTG were hypercholesterolemia (OR: 4.6), low HDL-C (OR: 4.1), hepatic steatosis (OR: 2.8), diabetes (OR: 2.0), and obesity. (OR: 1.9). Conclusions The means of triglyceride levels and HTG prevalence rates are intermediate between those of other national and international studies. A fifth of the female adult population and more than a third of the male population had HTG. The independent factors associated with HTG were hypercholesterolemia and low HDL-C, and the cardiometabolic variables diabetes, hepatic steatosis and obesity.

Background Health care trends including advanced technology, higher patient acuity, and shorter employment orientation have impacted the environment in which new-graduate nurses are entering the workforce. These issues are contributing to new nurses leaving the workforce prematurely. Theoretical foundations for nursing education need to be updated to better prepare graduates for entry into this burdened environment. Purpose The purpose of this study was to explore, from the student perspective, the process of educational development into professional licensure-ready graduates. Method Grounded theory was used to explore the developmental process of undergraduate nursing education. Results Two simultaneous developmental processes emerged: decision-making and self-doubt/self-efficacy. Early in the nursing program, students made very few patient care decisions and were plagued with self-doubt. As knowledge and experience were gained, decisions became based on patient conditions, self-doubt decreased, self-efficacy emerged, and students relayed increased comfort, confidence, and competence. Conclusion A contemporary nursing education framework has been developed for testing.

RESUMEN Objetivo: Evaluar la prevalencia y los factores asociados a la infección por SARS-CoV-2 en médicos y enfermeras de centros de atención primaria y residencias de ancianos del área de salud de León (España). Material y métodos: Estudio observacional realizado en una muestra de conveniencia de profesionales de 30 centros de salud y 30 residencias de ancianos, de la Gerencia de Atención Primaria del área de salud de León. Se recogió información del centro de trabajo, tipo de profesión, infección por COVID-19, nivel de exposición, cumplimiento de medidas preventivas, aislamiento (si fue requerido) y test diagnósticos realizados. La determinación de infección fue llevada a cabo mediante prueba de diagnóstico rápido diferenciado (PDRd), usando muestra de sangre capilar. La asociación de las variables con la infección se evaluó mediante regresión logística multivariable no condicional. La prevalencia real de infección por SARS-CoV-2 fue calculada de acuerdo a dos escenarios para el PDRd (Sensibilidad=0,6 y Especificidad=0,985; Sensibilidad=0,8 y Especificidad=1). Resultados: La prevalencia real de infección por SARS-CoV-2 se encontró entre 4,9%-11,0%. La prevalencia observada fue de 5,9%, siendo mayor en trabajadores de residencias de ancianos que de centros de salud de atención primaria (9,5% vs 5,5%). No hubo diferencias estadísticamente significativas por sexo, tipo de profesional, nivel de exposición o cumplimiento de medidas preventivas. Conclusiones: La prevalencia de la infección por el SARS-CoV-2 en este grupo es baja. Un gran número de profesionales siguen siendo susceptibles a la infección por el SARS-CoV-2 y, por lo tanto, medidas de protección deben ser adoptadas, especialmente en los profesionales de las residencias de ancianos.

Resumen Introduccion y objetivos Analizar el impacto pronostico de la infeccion por citomegalovirus (CMV) durante el primer ano tras el trasplante cardiaco (TC) y describir factores de riesgo. Metodos Se realizo un estudio retrospectivo unicentrico que incluyo 222 receptores de TC. La identificacion de factores de riesgo de infeccion por CMV se llevo a cabo mediante la regresion multivariable de Cox. A traves de los metodos de Kaplan-Meier y Cox se analizo la influencia de la infeccion por CMV durante el primer ano sobre la supervivencia e incidencia de eventos clinicos adversos en el seguimiento a largo plazo. Resultados En el analisis multivariante, el estado serologico donante/receptor frente a CMV (hazard ratio [HR] 1,92, intervalo de confianza 95% [IC 95%] 1,2-3,09; p = 0,007), la edad del receptor (HR 1,02, IC 95%: 1,00-1,1; p = 0,02), la diabetes (HR 1,86, IC 95%: 1,4-3,05; p = 0,01), el soporte circulatorio mecanico (HR 1,59, IC 95%: 1,06-2,38; p = 0,03) y el uso de tacrolimus (HR 1,64, IC 95%: 1,13-2,36; p = 0,009) resultaron predictores independientes de infeccion por CMV postrasplante. No se detecto una influencia significativa de la infeccion por CMV durante el primer ano postrasplante sobre la mortalidad, la incidencia de insuficiencia cardiaca, enfermedad vascular del injerto o rechazo agudo. Conclusiones La infeccion por CMV durante el primer ano postrasplante no se asocio a un peor pronostico a largo plazo.

A cohort of 172 patients diagnosed clinically with nonsyndromic retinal dystrophies, from 110 families underwent full ophthalmologic examination, including retinal imaging, electrophysiology, and optical coherence tomography, when feasible. Molecular analysis was performed using targeted next-generation sequencing (NGS). Variants were filtered and prioritized according to the minimum allele frequency, and finally classified according to the American College of Medical Genetics and Genomics guidelines. Multiplex ligation-dependent probe amplification and array comparative genomic hybridization were performed to validate copy number variations identified by NGS. The diagnostic yield of this study was 62% of studied families. Thirty novel mutations were identified. The study found phenotypic intra- and interfamilial variability in families with mutations in C1QTNF5, CERKL, and PROM1; biallelic mutations in PDE6B in a unilateral retinitis pigmentosa patient; interocular asymmetry RP in 50% of the symptomatic RPGR-mutated females; the first case with possible digenism between CNGA1 and CNGB1; and a ROM1 duplication in two unrelated retinitis pigmentosa families. Ten unrelated cases were reclassified. This study highlights the clinical utility of targeted NGS for nonsyndromic inherited retinal dystrophy cases and the importance of full ophthalmologic examination, which allows new genotype-phenotype associations and expands the knowledge of this group of disorders. Identifying the cause of disease is essential to improve patient management, provide accurate genetic counseling, and take advantage of gene therapy-based treatments.

The prevalence of the non-alcoholic fatty liver disease (NAFLD) in developed countries is up to 30% of the general population, and 50% of patients present type 2 diabetes mellitus (DM2). Fibrosis is the most important prognostic factor in NAFLD. The aim of this study was to search evidence for an early diagnosis of liver fibrosis in subjects with DM2 and to evaluate potential risk and protective factors. This study was conducted among 160 diabetic patients with NAFLD proven biopsy. Anthropometric assessments, laboratory test, liver histological features and follow-up of a Mediterranean diet were evaluated. Diabetic patients with liver fibrosis showed a greater number of positive metabolic criteria than diabetic patients without liver fibrosis. Patients with hepatic fibrosis have a lower score on the PREDIMED test (9.0 (2.4) vs. 6.2 (2.3); p

Observational study [Abstract] Background: Infection is a major cause of morbidity and mortality after heart transplantation (HT). Little information about its importance in the immediate post-operative period is available. The aim of this study was to analyze the characteristics, incidence, and outcomes of in-hospital post-operative infections after HT. Methods: We conducted an observational, single-center study based on 677 adults who underwent HT from 1991 to 2015 and who survived the surgical intervention. In-hospital post-operative infections were identified retrospectively according to the medical finding in the clinical records. Results: Over a mean hospital stay of 24.5 days, 239 patients (35.3%) developed 348 episodes of infection (2 episodes per 100 patient-days). The most common sources of infection were those related to invasive procedures (respiratory infections, 115 [33%]; urinary tract infections, 47 [13.5%]; bacteremia, 42 [12.1%]; surgical site infections, 25 [7.2%]), in addition to abdominal focus (33, 9.5%). Enterobacteriaceae (76, 21.8%) and gram-positive cocci (58, 16.7%) were the predominant germs, although opportunistic infections were not infrequent (69, 19.8%). Ninety-five septic episodes were detected with a mean Sequential Organ Failure Assessment Score of 9.5 ± 5.3 points, with hemodynamic failure being the most severe organ dysfunction and renal dysfunction the most frequent one. Management included broad-spectrum antibiotics in 48.8% of episodes and surgical management in 13.8%. The overall antimicrobial success rate was 96.3%. Higher in-hospital mortality was observed among infected patients (15.1% vs. 10.3%), but this difference was not statistically significant (p = 0.067). The one-year survival and events were not different between patients suffering from a post-operative infection and those who did not. Conclusions: In-hospital infections were frequent in the post-operative period after HT and were associated with a poor short-term outcome. Patients who survived sepsis had a similar one-year morbidity and mortality compared with patients who did not develop an infection.

Resumen En los pacientes con Hipertensión Arterial Pulmonar (HAP) de alto riesgo, en clase funcional (CF)IV, la terapia específica debe ser combinada y debe incluir una prostaciclina (PGI2) de uso sistémico en espera de trasplante bipulmonar (TBP). En el sistema público la única PGI2 disponible para asociar a Sildenafil y algún inhibidor de endotelina (Ambrisentan o Bosentan) es Iloprost nebulizado, que si bien es efectiva, no logra estabilizar los casos graves con severa disfunción del ventrículo derecho (VD). Se presenta el primer caso en el Instituto del Tórax, centro de referencia nacional de HAP, del uso de treprostinil en una paciente de 24 años con HAP grave e indicación de TBP. Treprostinil es un análogo sintético de PGI2 de uso subcutáneo en dosis desde 1 a 40 ng/kg/min. La paciente presentaba una situación de extrema gravedad: CF IV, distancia recorrida en el test de caminata de 6 min (DRTC 6 min) < 300 m,derrame pericárdico y severa disfunción del VD con TAPSE (índice de disfunción del VD) de 13 cm/s asociado a ProBNP >2.500 pg/ml. Luego de 6 meses de hospitalización en intermedio, terapia triple (Sildenafil, Ambrisentan e Iloprost nebulizado) asociado a O2,diuréticos y milrinona, logró ser dada de alta a las 3 semanas del inicio de treprostinil, regresando al trabajo a los 2 meses y estabilizando su condición en CF III, con DRTC 6 min > 440 m, mejoría de la función del VD(TAPSE 19). El ProBNP persistió elevado, 1.491 pg/ml, indicando que su enfermedad es grave y progresiva; sin embargo, ha logrado un nivel de estabilidad clínica que le permite una adecuada vida de relación familiar y laboral.

The Ripple Modulation (RM) is a technique that provides a variable output voltage by using the output voltage ripple of a Switching-Mode Power Converter (SMPC). It was proposed to reproduce the communication signal of a Visible Light Communication (VLC) transmitter, thus avoiding the use of power inefficient Linear Power Amplifiers (LPAs). However, the RM has a major drawback: it has not been reported how to reproduce Multi-Carrier Modulation (MCM) schemes, which are the preferred modulation schemes due to their high performance in wireless communications. In this work, it is demonstrated that the RM can be used to reproduce MCM schemes by considering the envelope and the instantaneous phase of the communication signal. Moreover, the control system of the power stage is described in detailed, explaining how to modulate both the width and the phase of the gate signals, the calculation of the phase-shift that is required for tracking the envelope, etc., This work was supported by the Spanish Government under the Project MINECO-17-DPI2016-75760-R, the scholarship FPU14/03268, the Principality of Asturias under the Project IDI/2018/000179, the grant BP17-91 and by European Regional Development Fund (ERDF)

The Frankfurt Kunstbuchlin is a handbook for a wide range of professions and crafts, such as metalwork (etching, alloying, gilding) and the production of colors for dyeing clothes and painting. Pri...

The risk allele (G) of rs10830963 in the melatonin receptor 1 B (MTNR1B) gene presents an association with obesity. We study the effect of this SNP on cardiovascular risk factors and weight loss secondary to 2hypocaloric diets.361 obese subjects were randomly allocated during 3 months (Diet M - high monounsaturated fat hypocaloric diet vs. Diet P - high polyunsaturated fat hypocaloric diet). Anthropometric parameters, fasting blood glucose, C-reactive protein (CRP), insulin concentration, insulin resistance (HOMA-IR), lipid profile and adipocytokines levels were measured. Genotype of MTNR1B gene polymorphism (rs10830963) was evaluated.All anthropometric parameters, systolic blood pressure and leptin levels decreased in all subjects after both diets. This improvement of anthropometric parameters was higher in non G allele carriers than G allele carriers. After dietary intervention with Diet M, (CC vs. CG + GG); total cholesterol (delta: -10.4 ± 2.1mg/dl vs. -6.4 ± 1.2mg/dl: P.05), LDL-cholesterol (delta:-7.1 ± 0.9mg/dl vs. -2.8 ± 0.8mg/dl: P.05), insulin (delta:-3.0 ± 0.8 UI/L vs. -2.0 ± 1.0 UI/L: P.05) and HOMA-IR (delta:-3.4 ± 1.0 units vs. -2.9 ± 0.9 units: P.05) improved in no G allele carriers. After Diet P, in the group of subjects without G allele CC, insulin levels (delta: -2.9 ± 1.0 UI/L vs. -0.6 ± 0.2 UI/L: P.05) and HOMA-IR (delta (CC vs. CG + GG): -0.8 ± 0.2 units vs. -0.4 ± 0.3 units: P.05) decreased, too.Our study detected a relationship of rs10830963 MTNR1B SNP with body weight loss and insulin resistance modification induced by 2different hypocaloric. Only monounsaturated enriched hypocaloric diet and in no-G allele carriers showed a significant effect on lipoproteins.

An 11-month-old intact female Golden Retriever presented for a 3- to 4-week history of right thoracic limb lameness. Computed tomography of the limb showed a sequestrum with a periosteal and endosteal reaction at the level of the nutrient foramen of the radius. Septic osteomyelitis was suspected based on cytology. Repeat examination and imaging revealed improvement in the lesion and resolution of the lameness. This lesion is similar to reports of radioulnar ischaemic necrosis, but is the first report with concurrent osteomyelitis and sequestration.

Lava caves are the result of a geological process related to the cooling of basaltic lava flows. On the Moon, this process may lead to caves several kilometers long and diameters of hundreds of meters. Access to lava tubes can be granted through skylights, a vertical pit between the lava tube and the lunar surface. This represents an outstanding opportunity for long-term missions, for future permanent human settlements, and for accessing pristine samples of lava, secondary minerals and volatiles. Given this, the ESA launched a campaign through the Open Space Innovation Platform calling for ideas that would tackle the many challenges of exploring lava pits. Five projects, including Robocrane, were selected. Solar light and direct line of sight (for communications) with the lunar surface are not available inside lava tubes. This is a problem for any robot (or swarm of robots) exploring the lava tubes. Robocrane tackles both problems by deploying an element (called the Charging head, or CH) at the bottom of the skylight by means of a crane. This CH behaves as a battery charger and a communication relay for the exploring robots. The required energy is extracted from the crane’s solar panel (on the surface) and driven to the bottom of the skylight through an electrical wire running in parallel to the crane hoisting wire. Using a crane allows the system to deal with unstable terrain around the skylight rim and protect the wires from abrasion from the rocky surface and the pit rim. The charger in the CH is wireless so that the charging process can begin as soon as any of the robots get close enough to the CH. This avoids complex and time-consuming docking operations, aggravated by the skylight floor orography. The crane infrastructure can also be used to deploy the exploring robots inside the pit, reducing their design constraints and mass budget, as the robots do not need to implement their own self-deployment system. Finally, RoboCrane includes all the sensors and actuators for remote operation from a ground station. RoboCrane has been designed in a parametric tool so it can be dynamically and rapidly adjusted to input-variable changes, such as the number of exploring robots, their electrical characteristics, and crane reach, etc., This work was supported in part by the Spanish Government under the Project MCIU-19-RTI2018-099682-A-I00 and by ESA under project CN-UE-20-ROBOCRANE.

Alcohol-related liver disease (ARLD) is the most prevalent cause of advanced liver disease and liver cirrhosis in Europe, including Spain. According to the World Health Organization the fraction of liver cirrhosis attributable to alcohol use in Spain is 73.8% among men and 56.3% among women. ARLD includes various stages such as steatohepatitis, cirrhosis and hepatocellular cancer. In addition, patients with underlying ARLD and heavy alcohol intake may develop alcoholic hepatitis, which is associated with high mortality. To date, the only effective treatment to treat ARLD is prolonged withdrawal. There are no specific treatments, and the only treatment that increases life expectancy in alcoholic hepatitis is prednisolone. For patients with alcoholic hepatitis who do not respond to treatment, some centres offer the possibility of an early transplant. These clinical practice guidelines aim to propose recommendations on ARLD taking into account their relevance as a cause of advanced chronic liver disease and liver cirrhosis in our setting. This paper aims to answer the key questions for the clinical practice of Gastroenterology, Hepatology, as well as Internal Medicine and Primary Health Centres, making the most up-to-date information regarding the management and treatment of ARLD available to health professionals. These guidelines provide evidence-based recommendations for the clinical management of this disease.

Metabolic associated fatty liver disease (MAFLD) is the most prevalent liver disease in Western nations, with high heritability. A recent study of Japanese patients with the disease suggested that TLL1 rs17047200 is associated with fibrosis; whether a similar association is observed in Caucasian patients with MAFLD is unknown. We investigated the association of the TLL1 rs17047200 polymorphism with liver fibrosis in a cohort of Caucasian patients with MAFLD (n = 728). We also investigated whether TLL1 expression is altered during liver injury in humans, in murine models of fibrosis, and in in-vitro. While TLL1 expression is upregulated in the liver of humans with MAFLD and in mice, the rs17047200 variant was not associated with fibrosis or any other histological features, or with hepatic TLL1 expression. In conclusion, the TLL1 rs17047200 variant is not a risk variant for fibrosis in Caucasian patients with MAFLD. However, TLL1 could be involved in the pathogenesis of liver fibrosis., ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; National Health and Medical Research Council of Australia (NHMRC) Program Grants (1053206 and 1149976) and Project grants (1107178 and 1108422). EB is supported by Horizon 2020 under grant 634413 for the project EPoS. AB is supported by an Australian Government Research Training Program (RTP) scholarship.

Background: Hospitals have constituted the limiting resource of the healthcare systems for the management of the COVID-19 pandemic. As the pandemic progressed, knowledge of the disease improved, and healthcare systems were expected to be more adapted to provide a more efficient response. The objective of this research was to compare the flow of COVID-19 patients in emergency rooms and hospital wards, between the pandemic's first and second waves at the University Hospital of Vall d’Hebron (Barcelona, Spain), and to compare the profiles, severity and mortality of COVID-19 patients between the two waves. Methods: A retrospective observational analysis of COVID-19 patients attending the hospital from February 24 to April 26, 2020 (first wave) and from July 24, 2020, to May 18, 2021 (second wave) was carried out. We analysed the data of the electronic medical records on patient demographics, comorbidity, severity, and mortality. Results: The daily number of COVID-19 patients entering the emergency rooms (ER) dropped by 65% during the second wave compared to the first wave. During the second wave, patients entering the ER were significantly younger (61 against 63 years old p Conclusions: Changes in the flow, severity and mortality of COVID-19 patients entering this tertiary hospital during the two waves may reflect a better adaptation of the health care system and the improvement of knowledge on the disease.

This paper presents the modeling of a Wind Energy Conversion System (WECS) using a self-excited induction generator (SEIG) coupled to the grid with a predictive Direct Power Controller (DPC), applying an optimal space vector selection technique. The self-excitation of the induction generator is obtained with a Direct Torque Controller (DTC) which allows controlling the machine's space vector flux and electric torque. On the other hand, the power system coupling is with a Direct Power Controller (DPC), that selects the voltage space vectors required to minimize the active and reactive power errors to the reference. The advantage of the optimum DPC scheme proposed in this work is the fast adjustment of the active and reactive powers to the references, compared with speed obtained using the inverter's PLL synchronization method.

Background Oxidative stress may be a key player in COVID-19 pathogenesis due to its significant role in response to infections. A defective redox balance has been related to viral pathogenesis developing a massive induction of cell death provoked by oxidative stress. The aim of this study is to perform a complete oxidative stress profile evaluation regarding antioxidant enzymes, total antioxidant capacity and oxidative cell damage in order to characterize its role in diagnosis and severity of this disease. Methods Blood samples were obtained from 108 COVID-19 patients and 28 controls and metabolites representative of oxidative stress were assessed. The association between lipid peroxidation and 28-day intubation/death risk was evaluated by multivariable regression analysis. Probability of intubation/death to day-28 was analyzed by using Kaplan-Meier curves and tested with the log-rank test. Results Antioxidant enzymes (Superoxide dismutase (SOD) and Catalase) and oxidative cell damage (Carbonyl and Lipid peroxidation (LPO)) levels were significantly higher in COVID-19 patients while total antioxidant capacity (ABTS and FRAP) levels were lower in these patients. The comparison of oxidative stress molecules’ levels across COVID-19 severity revealed that only LPO was statistically different between mild and intubated/death COVID-19 patients. COX multivariate regression analysis identified LPO levels over the OOP (LPO>1948.17 μM) as an independent risk factor for 28-day intubation/death in COVID-19 patients [OR: 2.57; 95% CI: 1.10–5.99; p = 0.029]. Furthermore, Kaplan-Meier curve analysis revealed that COVID-19 patients showing LPO levels above 1948.17 μM were intubated or died 8.4 days earlier on average (mean survival time 15.4 vs 23.8 days) when assessing 28-day intubation/death risk (p, Graphical abstract Image 1

Introduction/Background* The accelerated US Food and Drug Administration approval of pembrolizumab validated the efficacy of anti-PD-(L)1 therapy for patients with recurrent/metastatic cervical cancer; however, the objective response rate (ORR) with pembrolizumab was 14.3% in patients with PD-L1–expressing tumours. Human papillomavirus infection is implicated in >95% of cervical cancers and is linked to upregulation of TGF-β signalling. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β ‘trap’) fused to a human immunoglobulin G1 monoclonal antibody blocking PD-L1. We report pooled safety and efficacy in patients with pretreated, immune checkpoint inhibitor-naive, recurrent/metastatic cervical cancer treated with bintrafusp alfa in phase 1 (INTR@PID 001; NCT02517398) and phase 2 (study 012; NCT03427411) studies. Methodology Patients received bintrafusp alfa 0.3-30 mg/kg (phase 1 dose escalation) or 1200 mg every 2 weeks (phase 1 dose expansion and phase 2) until progressive disease, unacceptable toxicity, or withdrawal. Treatment past progression was allowed. Primary endpoints were safety (phase 1 dose escalation) and best overall response per RECIST 1.1 (phase 1 dose expansion and phase 2). Result(s)* As of May 15, 2020 (phase 1) and December 22, 2020 (phase 2), 39 patients had received bintrafusp alfa for a median duration of 2.8 months (range, 0.5-19.3). The median follow-up to data cutoff was 35.0 months and 24.1 months for the phase 1 and phase 2 studies, respectively. All patients had received prior anticancer therapy; 16 (41.0%) had received ≥3 regimens. Confirmed ORR was 28.2% (table 1); responses occurred irrespective of Moore criteria (phase 1), tumour histology, prior bevacizumab treatment, or radiation treatment. Median overall survival was 13.4 months. No new safety signals and no treatment-related deaths were observed; side effects were manageable. Conclusion* Bintrafusp alfa had a manageable safety profile and demonstrated clinical activity in patients with heavily pretreated, immune checkpoint inhibitor-naive recurrent/metastatic cervical cancer. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved.

© 2020 The Author(s)., Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS ‘Liver Investigation: Testing Marker Utility in Steatohepatitis’ consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace., The European NAFLD Registry is supported by the LITMUS (Liver Investigation: Testing Biomarker Utility in Steatohepatitis) consortium funded by the European Union Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement 777377, which receives support from the Horizon 2020 Framework Program of European Union and EFPIA. It has also received support from the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413, the FLIP consortium funded by the Framework Program 7 of the European Union under grant agreement 241762, and an EASL Registry Grant from the European Association for the Study of the Liver.

[Background & Aims] Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain., [Methods] The most common NSS (NFS, FIB-4, BARD, APRI) and the Hepamet fibrosis score (HFS) were assessed in 1,173 European patients with NAFLD from tertiary centres. Performance for fibrosis risk stratification and for the prediction of long-term hepatic/extrahepatic events, hepatocarcinoma (HCC) and overall mortality were evaluated in terms of AUC and Harrell’s c-index. For longitudinal data, NSS-based Cox proportional hazard models were trained on the whole cohort with repeated 5-fold cross-validation, sampling for testing from the 607 patients with all NSS available., [Results] Cross-sectional analysis revealed HFS as the best performer for the identification of significant (F0-1 vs. F2-4, AUC = 0.758) and advanced (F0-2 vs. F3-4, AUC = 0.805) fibrosis, while NFS and FIB-4 showed the best performance for detecting histological cirrhosis (range AUCs 0.85-0.88). Considering longitudinal data (follow-up between 62 and 110 months), NFS and FIB-4 were the best at predicting liver-related events (c-indices>0.7), NFS for HCC (c-index = 0.9 on average), and FIB-4 and HFS for overall mortality (c-indices >0.8). All NSS showed limited performance (c-indices, [Conclusions] Overall, NFS, HFS and FIB-4 outperformed APRI and BARD for both cross-sectional identification of fibrosis and prediction of long-term outcomes, confirming that they are useful tools for the clinical management of patients with NAFLD at increased risk of fibrosis and liver-related complications or death., [Lay summary] Non-invasive scoring systems are increasingly being used in patients with non-alcoholic fatty liver disease to identify those at risk of advanced fibrosis and hence clinical complications. Herein, we compared various non-invasive scoring systems and identified those that were best at identifying risk, as well as those that were best for the prediction of long-term outcomes, such as liver-related events, liver cancer and death., This study has been supported by the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413 and the Newcastle NIHR Biomedical Research Centre. The authors are contributing members of The European NAFLD Registry. The study was also supported by the Italian Ministry of Health, grant RF-2016-02364358 (Ricerca Finalizzata, Ministero della Salute), and the Italian Ministry for Education, University and Research (Ministero dell’Istruzione, dell’Università e della Ricerca - MIUR) under the programme “Dipartimenti di Eccellenza 2018 – 2022” Project code D15D18000410001.

[Background] Liver fibrosis risk is a heritable trait, the outcome of which is the net deposition of extracellular matrix by hepatic stellate cell-derived myofibroblasts. Whereas nucleotide sequence variations have been extensively studied in liver fibrosis, the role of copy number variations (CNV) in which genes exist in abnormal numbers of copies (mostly due to duplication or deletion) has had limited exploration., [Methods] The impact of the XPO4 CNV on histological liver damage was examined in a cohort comprised 646 Caucasian patients with biopsy-proven MAFLD and 170 healthy controls. XPO4 expression was modulated and function was examined in human and animal models., [Findings] Here we demonstrate in a cohort of 816 subjects, 646 with biopsy-proven metabolic associated liver disease (MAFLD) and 170 controls, that duplication in the exportin 4 (XPO4) CNV is associated with the severity of liver fibrosis. Functionally, this occurs via reduced expression of hepatic XPO4 that maintains sustained activation of SMAD3/SMAD4 and promotes TGF-β1-mediated HSC activation and fibrosis. This effect was mediated through termination of nuclear SMAD3 signalling. XPO4 demonstrated preferential binding to SMAD3 compared to other SMADs and led to reduced SMAD3-mediated responses as shown by attenuation of TGFβ1 induced SMAD transcriptional activity, reductions in the recruitment of SMAD3 to target gene promoters following TGF-β1, as well as attenuation of SMAD3 phosphorylation and disturbed SMAD3/SMAD4 complex formation., [Interpretation] We conclude that a CNV in XPO4 is a critical mediator of fibrosis severity and can be exploited as a therapeutic target for liver fibrosis., ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206) and Project and ideas grants (APP2001692, APP1107178 and APP1108422). AB is supported by an Australian Government Research Training Program (RTP) scholarship. EB is supported by Horizon 2020 under grant 634413 for the project EPoS.

Antigen tests or polymerase chain reaction (PCR) amplification are currently COVID-19 diagnostic tools. However, developing complementary diagnosis tools is mandatory. Thus, we performed a plasma cytokine array in COVID-19 patients to identify novel diagnostic biomarkers. A discovery–validation study in two independent prospective cohorts was performed. The discovery cohort included 136 COVID-19 and non-COVID-19 patients recruited consecutively from 24 March to 11 April 2020. Forty-five cytokines’ quantification by the MAGPIX system (Luminex Corp., Austin, TX, USA) was performed in plasma samples. The validation cohort included 117 patients recruited consecutively from 15 to 25 April 2020 for validating results by ELISA. COVID-19 patients showed different levels of multiple cytokines compared to non-COVID-19 patients. A single chemokine, IP-10, accurately identified COVID-19 patients who required hospital admission (AUC: 0.962, 95%CI (0.933–0.992), p &lt, 0.001)). The results were validated in an independent cohort by multivariable analysis (OR: 25.573, 95%CI (8.127–80.469), 0.001) and AUROC (AUC: 0.900, 95%CI (0.846–0.954), 0.001). Moreover, showing IP-10 plasma levels over 173.35 pg/mL identified COVID-19 with higher sensitivity (86.20%) than the first SARS-CoV-2 PCR. Our discover–validation study identified IP-10 as a robust biomarker in clinical practice for COVID-19 diagnosis at hospital. Therefore, IP-10 could be used as a complementary tool in clinical practice, especially in emergency departments.

Aim: to translate and evaluate psychometric properties of the BCLE SEI Spanish version among Spanish-speaking breast cancer patients in Spain. Methods: cross-sectional, known-group comparison, and test-retest study design. To ensure the semantic equivalence and content validity, an integrative translation method was employed to translate the English version into Spanish. 286 patients were recruited, from 2018 to 2020, from the Asturias Central University Hospital, Spain. Data analysis included descriptive statistics, Cronbach’s alpha and test-retest reliability, and factor analysis, and the receiver operating characteristic (ROC) curves. Results: No semantic modifications to items were needed. The Spanish version of the instrument demonstrated excellent reliability (Cronbach's alpha= 0.93–0.97) and test-retest reliability (r = 0.78 – 0.87, n = 29). A significant difference was observed between the lymphedema group and non-lymphedema group (p < 0.001) in terms of total scale, symptom occurrence (p < 0.001), symptom distress of physical-functional (p Conclusions: This study provided initial evidence to support the psychometric properties and patient acceptance of the BCLE SEI Spanish version.

[Objective] To prove that 7-day courses of antibiotics for bloodstream infections caused by members of the Enterobacterales (eBSIs) allow a reduction in patients' exposure to antibiotics while achieving clinical outcomes similar to those of 14-day schemes., [Methods] A randomized trial was performed. Adult patients developing eBSI with appropriate source control were assigned to 7 or 14 days of treatment, and followed 28 days after treatment cessation; treatments could be resumed whenever necessary. The primary endpoint was days of treatment at the end of follow-up. Clinical outcomes included clinical cure, relapse of eBSI and relapse of fever. A superiority margin of 3 days was set for the primary endpoint, and a non-inferiority margin of 10% was set for clinical outcomes. Efficacy and safety were assessed together with a DOOR/RADAR (desirability of outcome ranking and response adjusted for duration of antibiotic risk) analysis., [Results] 248 patients were assigned to 7 (n = 119) or 14 (n = 129) days of treatment. In the intention-to-treat analysis, median days of treatment at the end of follow-up were 7 and 14 days (difference 7, 95%CI 7–7). The non-inferiority margin was also met for clinical outcomes, except for relapse of fever (–0.2%, 95%CI –10.4 to 10.1). The DOOR/RADAR showed that 7-day schemes had a 77.7% probability of achieving better results than 14-day treatments., [Conclusions] 7-day schemes allowed a reduction in antibiotic exposure of patients with eBSI while achieving outcomes similar to those of 14-day schemes. The possibility of relapsing fever in a limited number of patients, without relevance to final outcomes, may not be excluded, but was overcome by the benefits of shortening treatments., This work received technical support from the Spanish Network of Research in Infectious Diseases (REIPI) and the Spanish Clinical Research Network (SCReN) of the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spanish Government (PT13/0002/0010).

Spastic paraplegia type 7 (SPG7) is one of the most common hereditary spastic paraplegias. SPG7 mutations most often lead to spastic paraparesis (HSP) and/or hereditary cerebellar ataxia (HCA), frequently with mixed phenotypes. We sought to clinically and genetically characterize a Spanish cohort of SPG7 patients. Patients were recruited from our HCA and HSP cohorts. We identified twenty-one patients with biallelic pathogenic SPG7 mutations. Mean age at onset was 37.4 years (SD ± 14.3). The most frequent phenotype was spastic ataxia (57%), followed by pure spastic paraplegia (19%) and complex phenotypes (19%). Isolated patients presented with focal or multifocal dystonia, subclinical myopathy or ophthalmoplegia. p.Ala510Val was the most frequent pathogenic variant encountered. Compound heterozygous for p.Ala510Val displayed younger onset (p 0.05) and more complex phenotypes (p 0.05) than p.Ala510Val homozygotes. Two novel variants were found: p.Lys559Argfs*33 and p.Ala312Glu. In conclusion, spastic ataxia is the most common phenotype found in Spanish patients. Nonetheless, SPG7 analysis should also be considered in patients with less frequent clinical findings such as dystonia or ophthalmoplegia especially when these symptoms are associated with mild spastic ataxia.

Sepsis is a major health problem worldwide. It is a time-dependent disease, with a high rate of morbidity and mortality. In this sense, an early diagnosis is essential to reduce these rates. The progressive increase of both the incidence and prevalence of sepsis has translated into a significant socioeconomic burden for health systems. Currently, it is the leading cause of noncoronary mortality worldwide and represents one of the most prevalent pathologies both in hospital emergency services and in intensive care units. In this article, we review the role of both endothelial dysfunction and neutrophil dysregulation in the physiopathology of this disease. The lack of a key symptom in sepsis makes it difficult to obtain a quick and accurate diagnosis of this condition. Thus, it is essential to have fast and reliable diagnostic tools. In this sense, the use of biomarkers can be a very important alternative when it comes to achieving these goals. Both new biomarkers and treatments related to endothelial dysfunction and neutrophil dysregulation deserve to be further investigated in order to open new venues for the diagnosis, treatment and prognosis of sepsis.

Background: The role of ADIPOQ gene variants in weight loss after different dietary fat amounts remains unclear. Objective: Our aim was to analyze the effects of ADIPOQ gene polymorphism rs266729 on metabolic changes after two different amounts of dietary fat in two hypocaloric diets. Design: A population of 283 obese patients was recruited in a randomized clinical trial with two diets: Diet HF (high-fat diet: 38% carbohydrates, 24% proteins, and 38% fats) versus Diet LF (low-fat diet: 53% carbohydrates, 20% proteins, and 27% fats). Before and after 3 months, an anthropometric evaluation, an assessment of nutritional intake, and a biochemical analysis were carried out. The variant of the ADIPOQgene was assessed by real-time PCR. Results: Weight loss was similar with both diets in both genotypes (CC vs. CG+GG). After dietary intervention with Diet HF, only subjects with CC genotype showed a significant improvement in insulin levels (–3.3 ± 0.6 vs. –1.8 ± 0.9 mU/L; p = 0.03) and the homeostasis model assessment for insulin resistance (HOMA-IR) (–1.3 ± 0.1 vs. –0.8 ± 0.2 units; p = 0.02). After Diet LF, subjects with CC genotype showed a significant improvement in total cholesterol levels (CC vs. CG+GG) (–15.3 ± 1.4 vs. –6.4 ± 1.3 mg/dL; p = 0.01), LDL cholesterol (–14.6 ± 1.8 vs. –6.4 ± 1.3 mg/dL; p = 0.01), insulin levels (–4.6 ± 1.0 vs. –1.6 ± 0.5 mU/L; p = 0.01), and HOMA-IR (–1.6 ± 0.1 vs. –1.0 ± 0.2 units; p = 0.02). Only subjects with CC genotype showed a significant increase of adiponectin levels after both diets (CC vs. CG+GG): Diet HF (10.6 ± 2.0 vs. 1.8 ± 1.0 ng/dL; p = 0.01) and Diet LF (16.1 ± 2.8 vs. 1.3 ± 1.0 ng/dL: p = 0.03). Conclusion: CC genotype of ADIPOQgene variantrs266729 was associated with a better metabolic response after both diets. Additionally, Diet LF produced a significant improvement in lipid profile in noncarriers of allele G.

Objective Some adiponectin gene (ADIPOQ) single-nucleotide polymorphisms (SNPs) have been related to basal and adiponectin levels and metabolic parameters. The aim of this study was to evaluate the effect of the genetic variant rs1501299 ADIPOQ gene on biochemical changes after weight loss secondary to a high-protein and low-carbohydrate diet versus a standard severe hypocaloric diet over 9 mo as the primary endpoint. Methods A white population of 270 obese patients was enrolled in a randomized clinical trial with two hypocaloric diets (high-protein and low carbohydrate diet [HP] versus standard diet [S]) over 9 mo of intervention. The statistical analysis was performed for the combined GT and TT as a group (T-allele carriers) and GG as second group (non–T-allele carriers). Before and after 12 wk on each hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake, and a biochemical analysis were realized. Results With both dietary interventions, body weight, body mass index (BMI), fat mass, waist circumference, systolic blood pressure, and leptin levels decreased. In non–T-allele carriers after both diets, the decrease in total cholesterol levels –12.3 ± 2.2 mg/dL (T-allele carriers –6.9 ± 2.1 mg/dL; P = 0.01 diet HP) and 12.2 ± 3.1 mg/dL (T-allele carriers –4.7 ± 1.2 mg/dL; P = 0.02 after diet S), low-density lipoprotein cholesterol –13.2 ± 2.7 mg/dL (T-allele carriers –6.1 ± 2.1 mg/dL; P = 0.02 after diet HP) and –9.3 ± 1.8 mg/dL (T-allele carriers –4.8 ± 2.9 mg/dL; P = 0.01 after diet S), triacylglycerol levels –12.7 ± 6.1 mg/dL (T-allele carriers –6 ± 2.9 mg/dL; P = 0.01 after diet HP) and –16.3 ± 7.2 mg/dL (T-allele carriers –5.3 ± 1.4 mg/dL; P = 0.03 after diet S), insulin levels –5 ± 1.1 mUI/L (in T-allele –1.7 ± 0.9 mUI/L; P = 0.02 after diet HP) and –3.2 1.1 mUI/L (T-allele carriers –0.7 ± 0.7 mUI/L; P = 0.02 after diet S), and homeostatic model assessment of insulin resistance levels –0.4 ± 0.2 units (T-allele group –0.1 ± 0.1; P = 0.04 after diet HP) and –0.7 ± 0.1 units (T-allele carriers –0.1 ± 0.5 mg/dL; P = 0.01 after diet S) was higher than T-allele carriers. Only no T-allele carriers showed an increase in adiponectin levels after both diets. Conclusion After two different hypocaloric diets during 9 mo of intervention, the GG genotype of an ADIPOQ gene variant (rs1501299) is related to better improvement in adiponectin levels, insulin resistance, and lipid profile than T-allele carriers.

The project that we present develops a mobile application (ArtAlive®) for the generation of augmented reality experiences on museum sculptural objects. The novelty of our application is that we eliminate the markers that other applications need to run. We do this turning the sculptures into their own markers, based on the recognition of anamorphic images of these sculptures: two-dimensional images of three-dimensional objects. So we eliminate the intermediate elements of the process making the experience easier. The aim is to transform the experience of visiting a museum into a more interactive and intuitive experience. The possibility of accessing the information contained in the augmented reality experiences linked specifically to each work, from the comfort of the smartphone, gives the process greater accessibility and flexibility. The recognition of the objects is developed with Vuforia, an augmented reality software development kit (SDK) for mobile devices. ArtAlive® has been registered in the Spanish Intellectual Property Registry, and a possible business model has been defined in a very basic way.

The following clinical question is posed: is pneumococcal vaccination effective for prevention of pneumonia and invasive pneumococcal disease in immunosuppressed patients or with immunosuppressive, immunomodulatory or biological drugs? In spite of the current recommendations to administer the pneumococcal vaccine to adults with immunosuppression, the data to support this approach in this population group are scarce. The evidence indicates that current vaccination in patients older than 65 years is more effective in the prevention of invasive pneumococcal disease than preventing the development of pneumococcal pneumonia and pneumonia from all causes. In the absence of further evidence, the health teams, follow the recommendations given by the scientific societies and by the Spanish Ministry of Health, Consumption and Social Welfare on pneumococcal vaccination to patients with immunosuppression who advise sequential vaccination of patients with immunosuppression with VNC13 + VNP23, with 8 weeks of difference and revaccination at 5 years.

Objective: To evaluate the burden of diabetes mellitus (DM) in adult patients with acromegaly treated with second-line pharmacotherapy, from the perspective of the Spanish National Health System (NHS). Methods: A Markov model was developed including three states: normal glucose metabolism, DM and death. The evolution of a hypothetical cohort of acromegaly patients requiring second-line pharmacological treatment (pegvisomant or pasireotide) after first generation somatostatin analogues therapy was analyzed. Direct healthcare costs regarding acromegaly management, diabetes management and drugs costs were obtained from Spanish sources. Transition probabilities between health states were obtained from published studies. Deterministic and probabilistic sensitivity analyses were undertaken. Results: Compared to pasireotide, pegvisomant increased the likelihood of glucose normalization and reduced the likelihood of DM. Consequently, in a cohort of 1,000 patients with acromegaly, treatment with pegvisomant compared to pasireotide would prevent 243, 413 and 453 cases of DM after 1, 2 and 5 years, respectively, and would reduce mortality by 0.1% after 5 years of treatment. This would result in 1 million euros savings for the NHS in 5 years. These health benefits would be obtained with savings of €1,512, €3,422 and €10,162 per patient treated with pegvisomant, after 1, 2 and 5 years, respectively. After 5 years of treatment, the probability that pegvisomant generated savings versus pasireotide would be 65.3%. Conclusion: The favorable effects of pegvisomant on glucose metabolism would allow a considerable number of cases of DM to be avoided compared to pasireotide, resulting in savings for the NHS in Spain.

Chronic inflammatory liver disease with an acute deterioration of liver function is named acute-on-chronic inflammation and could be regulated by the metabolic impairments related to the liver dysfunction. In this way, the experimental cholestasis model is excellent for studying metabolism in both types of inflammatory responses. Along the evolution of this model, the rats develop biliary fibrosis and an acute-on-chronic decompensation. The acute decompensation of the liver disease is associated with encephalopathy, ascites, acute renal failure, an acute phase response and a splanchnic increase of pro- and anti-inflammatory cytokines. This multiorgan inflammatory dysfunction is mainly associated with a splanchnic and systemic metabolic switch with dedifferentiation of the epithelial, endothelial and mesothelial splanchnic barriers. Furthermore, a splanchnic infiltration by mast cells occurs, which suggests that these cells could carry out a compensatory metabolic role, especially through the modulation of hepatic and extrahepatic mitochondrial-peroxisome crosstalk. For this reason, we propose the hypothesis that mastocytosis in the acute-on-chronic hepatic insufficiency could represent the development of a survival metabolic mechanisms that mitigates the noxious effect of the hepatic functional deficit. A better understanding the pathophysiological response of the mast cells in liver insufficiency and portal hypertension would help to find new pathways for decreasing the high morbidity and mortality rate of these patients.

We propose that the circulatory impairments produced, in both portal hypertension and liver cirrhosis, to a certain degree resemble those characterizing prenatal life in the fetus. In fact, the left-right circulatory syndrome is common in cirrhotic patients and in the fetus. Thus, in patients with portal hypertension and chronic liver failure, the re-expression of a blood circulation comparable to fetal circulation is associated with the development of similar amniotic functions, i.e., ascites production and placenta functions, and portal vascular enteropathy. Therefore, these re-expressed embryonic functions are extra-embryonic and responsible for prenatal trophism and development.

Objectives The role of ADIPOQ gene variants on weight loss after a dietary intervention remain unclear. The aim of this study was to analyze the effects of rs266729 of the ADIPOQ gene on cardiovascular risk factors and adiposity parameters after adherence to a Mediterranean-type hypocaloric diet. Method Eighty-three obese patients were studied before and after 12 wk on a Mediterranean-type hypocaloric diet. Anthropometric parameters and biochemical profiles were measured. The variant of ADIPOQ gene rs266729 was assessed at basal time by polymerase chain reaction at real time. Results Two genotype groups were realized (CC versus CG + GG). The final genotype distribution was 48 patients CC (57.8%), 30 patients CG (36.2%) and 5 patients GG (6%). After dietary intervention with a moderate calorie restriction and in both genotypes, body mass index (BMI), weight, fat mass, systolic blood pressure, and waist circumference decreased. After dietary intervention and in non-G allele carriers (CC versus CG+ GG), glucose (δ: –6.2 ± 1.1 versus –2.9 ± 1.2 mg/dL; P = 0.02), total cholesterol (δ:-15.2 ± 3.1 versus –3.4 ± 2 mg/dL; P = 0.02), low-density lipoprotein cholesterol (δ, –14.9 ± 3.1 versus –4.9 ± 1.2 mg/dL; P = 0.01), insulin levels (δ, –4± 0.6 versus 0.7 ± 0.3 UI/L;P = 0.01), homeostasis model assessment for insulin resistance (δ, –1.6 ± 0.4 versus –0.2 ± 0.4 units; P = 0.01), and adiponectin (δ, –10.4 ± 3.1 versus –1.3 ± 1.0 ng/dL; P = 0.01) improved. Conclusion After weight loss, the CC genotype of ADIPOQ gene variant (rs266729) is associated with increases in adiponectin levels and decreases of low-density lipoprotein cholesterol, insulin and homeostasis model assessment for insulin resistance after weight loss.

Background and rationale This study was intended to assess the influence of the rs16147 variant of the NPY gene on liver histology in patients with non-alcoholic fatty liver disease (NAFLD). Material and methods Eighty-nine patients with NAFLD were recruited into the study. Serum chemistry tests were done including lipid profile, transaminases, adipokines, and insulin resistance. Genotype of polymorphism (rs161477) of the NPY gene was studied. Results Twenty-three patients (25.0%) had the GG genotype (wild type) and sixty-six patients (75%) the GA (n = 39) or AA (n = 27) (mutant) types. Patients with A allele had a lower percentage of lobular inflammation and steatohepatitis (lobular inflammation plus ballooning) than those with wild genotype. Patients with A allele showed lower SAF (Steatosis, Activity, Fibrosis) scores than non-A allele carriers (5.4 ± 2.7 points vs. 4.1 ± 1.1 points; p = 0.01). In the analysis without fibrosis (NAS score), the same differences were detected (4.5 ± 1.8 points vs. 3.4 ± 1.8 points; p = 0.01). In the logistic regression analysis A allele carriers showed lower odds for inflammation (OR 0.11, 95% CI 0.02–0.84, p = 0.03) and steatohepatitis (OR 0.39, 95% CI 0.14–0.86, p = 0.04) after adjusting for age, sex, and body mass index. Conclusions A variant of polymorphism rs16147 of the NPY gene is independently associated to a lower percentage of steatohepatitis and lobular inflammation in obese subjects with biopsy-proven NAFLD.

Objective The objective of this study was to effectuate a consensus of emergency physicians on minimum requirements for facility, diagnostic, and medical specialist availability as a first step toward minimum operational standards for 24/7 available emergency departments (EDs) in the Netherlands.Patients and methods A two-part e-Delphi through online survey was performed between January 2015 and May 2016, using a panel of 20 experts in emergency medicine. The aim of part I was to reach an agreement on a list of possible ED elements and their definitions. The second part addressed the actual study objective to reach consensus on operational standards. Successive rounds were submitted to the members of the panel online using SurveyMonkey. Results of each survey round were discussed and interpreted in agreement with all authors in preparation for the next round. Reaching consensus, defined as 70% or more agreement or disagreement among the panel, on the level of all items was the endpoint of this study.Results Both parts I and II required five rounds. The dropout rate of the expert panel remained zero. The availability of 52 facilities and diagnostic functionalities and the manner in which 17 medical specialties should be available to every 24/7 ED were agreed upon by the expert panel.Conclusion An expert panel agreed upon minimum operational standards for EDs in the Netherlands. These results are helpful as a first step toward a more widely supported standard for future 24/7 available EDs in the Netherlands and in addition to this other urgent care facilities.

Background & aims A common G-to-A transition located 75 base pairs upstream (rs670) from transcription start site of the APOA1 gene has been related with some metabolic parameters. Our aim was to analyze the effects of rs670 APOA1 gene polymorphism on lipid profile and metabolic changes after two different hypocaloric diets. Methods 282 obese subjects were randomly allocated during 12 weeks (Diet HF – high fat diet vs. Diet LF – low fat diet). Anthropometric and biochemical status were evaluated. Results Body mass index, weight, fat mass, waist circumference, systolic blood pressure, leptin levels and waist circumference decreased in all patients in average after both diets. In A allele carriers after 12 weeks with both diets, insulin levels (Delta diet HF: −5.3 + 1.2 UI/L; P = 0.02 and Delta diet LF: −5.8 + 1.3 UI/L; P = 0.02) and HOMA-IR (Delta diet HF: −2.9 + 0.8 units; P = 0.01 and Delta diet LF: −2.2 + 0.9 units; P = 0.03) improved in a significant way. With the low fat diet, A allele carriers showed a statistical improvement in HDL-cholesterol levels (Delta: 4 + 1 mg/dl; P = 0.03). Conclusions Our study showed the association of rs670 ApoA1 polymorphism with a decrease of insulin resistance induced by both diets and provided additional evidence on HDL-cholesterol increase after a LF hypocaloric diet in A allele carriers.