Circular statistics for analyzing changes in retinal nerve fiber layer.

OBJECTIVE: To evaluate the use of circular statistics to analyze retinal nerve fibre layer (RNFL) thickness in eyes with and without a prior history of optic neuritis (ON). DESIGN: Single-centre consecutive study. PARTICIPANTS: Twenty-two multiple sclerosis patients and 20 healthy control subjects. METHODS: Data on 28 eyes with a history of ON of 22 multiple sclerosis patients and 40 eyes of 20 healthy control subjects collected in 2010 and 2015. RNFL thickness was measured separately in 12 sectors around the optic nerve head. We used circular statistics to calculate the mean weighted vector of RNFL thickness for each sector and eye in 2 measurements made 5 years apart (2010 and 2015). Comparisons of weighted mean vectors between groups were made using a paired Mardia-Watson-Wheeler test. RESULTS: The directions of the mean weighted vectors for ON eyes were 45.8º in 2010 and 56.0º in 2015, whereas in control eyes the directions were 319.4º in 2010 and 188.9º in 2015. No significant differences were found between 2010 and 2015 in any of the 2 groups. However, significant differences were found between ON and control eyes in 2010 and 2015. CONCLUSIONS: This paper provides an example of how to use circular statistics in cases of directional data in ophthalmology and demonstrates that circular statistics are a suitable tool for this purpose.

Grain Products: Traditional and Innovative Technologies.

The current knowledge regarding various cereals, their composition, and their processing methods is extensive [...].

The biochemical pattern defines MASLD phenotypes linked to distinct histology and prognosis.

BACKGROUND: MASLD can manifest as hepatocellular damage, which can result in mild elevation of aminotransferases. However, in some patients, MASLD presents with cholestatic pattern. OBJECTIVE: To assess the impact of the biochemical pattern on the natural course of MASLD, including liver damage in histology, the accuracy of non-invasive tests(NITs), and prognosis. METHODS: Multicenter study enrolling 2156 patients with biopsy-proven MASLD, who were classified based on their[ALT/ULN)]/[(ALP/ULN)] levels at the time of biopsy: (a) hepatocellular pattern(H), > 5; (b) mixed pattern(M),2-5; (c) cholestatic pattern(C), < 2. OUTCOMES: (a) histological evaluation of the single components of NAS, MASH, and fibrosis; (b) NITs and transient elastography assessing advanced fibrosis; (c) prognosis determined by the appearance of decompensated cirrhosis and death. RESULTS: Out of the 2156 patients, 22.9% exhibited the H-pattern, whilst 31.7% exhibited the C-pattern. Severe steatosis, ballooning, lobular inflammation, and MASH (56.4% H vs. 41.9% M vs. 31.9% C) were more common in H-pattern (p = 0.0001),whilst C-pattern was linked to cirrhosis (5.8% H vs. 5.6% M vs. 10.9% C; p = 0.0001). FIB-4(0.74(95% CI 0.69-0.79) vs. 0.83 (95% CI 0.80-0.85); p = 0.005) and Hepamet Fibrosis Score(0.77 (95% CI 0.69-0.85) vs. 0.84 (95% CI 0.80-0.87); p = 0.044)exhibited lower AUROCs in the H-pattern. The C-pattern[HR 2.37 (95% CI 1.12-5.02); p = 0.024], along with age, diabetes, and cirrhosis were independently associated with mortality. Most patients maintained their initial biochemical pattern during the second evaluation. CONCLUSIONS: The H-pattern exhibited greater necro-inflammation in the histology than the C-pattern, whereas the latter showed more cirrhosis. The accuracy of NITs in detecting fibrosis was decreased in H-pattern. The occurrence of decompensated events and mortality was predominant in C-pattern. Therefore, identifying MASLD phenotypes based on the biochemical presentation could be relevant for clinical practice.

The Janus of a disease: Diabetes and metabolic dysfunction-associated fatty liver disease.

Metabolic Dysfunction-Associated Fatty Liver Disease and Diabetes Mellitus are two prevalent metabolic disorders that often coexist and synergistically contribute to the progression of each other. Several pathophysiological pathways are involved in the association, including insulin resistance, inflammation, and lipotoxicity, providing a foundation for understanding the complex interrelationships between these conditions. The presence of MASLD has a significant impact on diabetes risk and the development of microvascular and macrovascular complications, and diabetes significantly contributes to an increased risk of liver fibrosis progression in MASLD and the development of hepatocellular carcinoma. Moreover, both pathologies have a synergistic effect on cardiovascular events and mortality. Therapeutic interventions targeting MASLD and diabetes are discussed, considering lifestyle modifications, pharmacological agents, and emerging treatment modalities. The review also addresses the challenges in managing these comorbidities, such as the need for personalized approaches and the potential impact on cardiovascular health. The insights gleaned from this analysis can inform clinicians, researchers, and policymakers in developing integrated strategies for preventing, diagnosing, and managing these metabolic disorders.

Joint environmental and social benefits from diversified agriculture.

Agricultural simplification continues to expand at the expense of more diverse forms of agriculture. This simplification, for example, in the form of intensively managed monocultures, poses a risk to keeping the world within safe and just Earth system boundaries. Here, we estimated how agricultural diversification simultaneously affects social and environmental outcomes. Drawing from 24 studies in 11 countries across 2655 farms, we show how five diversification strategies focusing on livestock, crops, soils, noncrop plantings, and water conservation benefit social (e.g., human well-being, yields, and food security) and environmental (e.g., biodiversity, ecosystem services, and reduced environmental externalities) outcomes. We found that applying multiple diversification strategies creates more positive outcomes than individual management strategies alone. To realize these benefits, well-designed policies are needed to incentivize the adoption of multiple diversification strategies in unison.

Is There a Safe Alcohol Consumption Limit for the General Population and in Patients with Liver Disease?

Excessive alcohol consumption represents an important burden for health systems worldwide and is a major cause of liver- and cancer-related deaths. Alcohol consumption is mostly assessed by self-report that often underestimates the amount of drinking. While alcohol use disorders identification test - version C is the most widely used test for alcohol use screening, in patients with liver disease the use of alcohol biomarker could help an objective assessment. The amount of alcohol that leads to significant liver disease depends on gender, genetic background, and coexistence of comorbidities (i.e., metabolic syndrome factors). All patients with alcohol-associated liver disease are recommended to follow complete abstinence and they should be treated within multidisciplinary teams. Abstinence slows down and even reverses the progression of liver fibrosis and can help recompensate patients with complicated cirrhosis. Whether there is a safe amount of alcohol in the general population is a matter of intense debate. Large epidemiological studies showed that the safe amount of alcohol to avoid overall health-related risks is lower than expected even in the general population. Even one drink per day can increase cancer-related death. In patients with any kind of chronic liver disease, especially in those with metabolic-associated steatotic liver disease, no alcohol intake is recommended. This review article discusses the current evidence supporting the deleterious effects of small-to-moderate amounts of alcohol in the general population and in patients with underlying chronic liver disease.

Fibrosis avanzada asociada a esteatohepatitis no alcohólica (NASH) en España: resultados de un estudio Delphi / Advanced fibrosis associated with non-alcoholic steatohepatitis (NASH) in Spain: results of a Delphi study

Objetivo: Describir de manera detallada la epidemiología, diagnóstico, manejo clínico, opciones de tratamiento, impacto en la calidad de vida y necesidades no cubiertas de los pacientes con fibrosis hepática avanzada (F3-F4) asociada a esteatohepatitis no alcohólica (NASH) en España. Metodología: Estudio Delphi de dos rondas de consulta con 41 hepatólogos expertos de 16 comunidades autónomas para recoger su experiencia en práctica clínica. Resultados: La prevalencia estimada de pacientes adultos diagnosticados de fibrosis F3-F4 asociada a NASH en España es de 0,019% (intervalo de confianza [IC] 95%: 0,019-0,020%). Aproximadamente 7.588 adultos con este padecimiento están actualmente diagnosticados y son manejados en los Servicios de Aparato Digestivo de los hospitales españoles, y alrededor de 1.881 nuevos pacientes son diagnosticados cada año. El manejo es multidisciplinar e incluye las especialidades de Aparato Digestivo, Endocrinología y Medicina interna, considerando las frecuentes comorbilidades metabólicas asociadas (obesidad, diabetes mellitus tipo 2 o sobrecarga férrica dismetabólica). A pesar del claro impacto en la calidad de vida, este no se evalúa rutinariamente en la práctica clínica. Las técnicas diagnósticas no invasivas más utilizadas son la elastografía de transición y el índice de fibrosis hepática 4 (FIB-4). La ausencia de tratamientos eficaces y seguros se presenta como la principal necesidad no cubierta para el manejo de estos pacientes. Conclusiones: Este estudio proporciona una representación de la situación actual de los pacientes diagnosticados con fibrosis F3-F4 asociada a NASH en España, incrementando la evidencia disponible y contribuyendo a la toma de decisiones informadas por parte de los profesionales y el sistema sanitario. (AU)

Objective: To describe in detail the epidemiology, diagnosis, clinical management, treatment options, impact on quality of life and unmet needs of patients with advanced liver fibrosis (F3-F4) associated with non-alcoholic steatohepatitis (NASH) in Spain. Methodology: Delphi study of two rounds of consultation rounds with 41 expert hepatologists from 16 autonomous communities to collect their experience in clinical practice. Results: The estimated prevalence of adult patients diagnosed with F3-F4 fibrosis associated with NASH in Spain is 0.019% (95% confidence interval [CI]: 0.019-0.020%). Approximately 7,588 adults with this condition are currently diagnosed and managed in the Digestive System Services of Spanish hospitals, and around 1,881 new patients are diagnosed each year. Management is multidisciplinary and includes the specialties of Digestive System, Endocrinology and Internal Medicine, considering the frequently associated metabolic comorbidities (obesity, type 2 diabetes mellitus or dysmetabolic iron overload). Despite a clear impact on quality of life, this it is not routinely evaluated in clinical practice. The most widely used non-invasive diagnostic techniques are transitional elastography and liver fibrosis index 4 (FIB-4). The absence of effective and safe treatments appears as the main unmet need for the management of these patients. Conclusions: This study provides a representation of the current situation of patients diagnosed with F3-F4 fibrosis associated with NASH in Spain, increasing the evidence available and contributing to informed decision-making by professionals and the health system. (AU)

Multidisciplinary approach for locally advanced non-small cell lung cancer (NSCLC): 2023 expert consensus of the Spanish Lung Cancer Group GECP.

INTRODUCTION: Recent advances in the treatment of locally advanced NSCLC have led to changes in the standard of care for this disease. For the selection of the best approach strategy for each patient, it is necessary the homogenization of diagnostic and therapeutic interventions, as well as the promotion of the evaluation of patients by a multidisciplinary oncology team. OBJECTIVE: Development of an expert consensus document with suggestions for the approach and treatment of locally advanced NSCLC leaded by Spanish Lung Cancer Group GECP. METHODS: Between March and July 2023, a panel of 28 experts was formed. Using a mixed technique (Delphi/nominal group) under the guidance of a coordinating group, consensus was reached in 4 phases: 1. Literature review and definition of discussion topics 2. First round of voting 3. Communicating the results and second round of voting 4. Definition of conclusions in nominal group meeting. Responses were consolidated using medians and interquartile ranges. The threshold for agreement was defined as 85% of the votes. RESULTS: New and controversial situations regarding the diagnosis and management of locally advanced NSCLC were analyzed and reconciled based on evidence and clinical experience. Discussion issues included: molecular diagnosis and biomarkers, radiologic and surgical diagnosis, mediastinal staging, role of the multidisciplinary thoracic committee, neoadjuvant treatment indications, evaluation of response to neoadjuvant treatment, postoperative evaluation, and follow-up. CONCLUSIONS: Consensus clinical suggestions were generated on the most relevant scenarios such as diagnosis, staging and treatment of locally advanced lung cancer, which will serve to support decision-making in daily practice.

Characterization of a Fermented Beverage from Discarded Bread Flour Using Two Commercial Probiotics Starters.

The aim of this study was to develop a plant-based fermented beverage from discarded bread flour and to analyze its characteristics as a novel functional product. Eight cereal-based probiotic beverages were produced by inoculating discarded bread flour with a monoculture of Lactobacillus rhamnosus or a co-culture consisting of lactic acid bacteria and Bifidobacterium. Two additional factors, namely, the addition of amylolytic enzymes and matrix desalting, were studied alongside the type of culture. The organic acid content and microbial growth were monitored during fermentation and storage (15 and 21 days). Proximal composition, gamma-aminobutyric acid, and volatile compounds were measured in the final product. Sensory analysis was only conducted on the enzymatically treated samples. The estimated shelf life of the bread beverage was 15 days. The variables studied significantly influenced the amountof organic acids and specific volatile compounds responsible for the aroma of fermented beverages. The beverage produced via co-culturing was preferred by consumers in the sensory test.

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. Results: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

Chronic liver disease-associated severe thrombocytopenia in Spain: Results from a retrospective study using machine learning and natural language processing / Trombocitopenia grave asociada a enfermedad hepática crónica en España: Resultados de un estudio retrospectivo utilizando aprendizaje automático y procesamiento de lenguaje natural

Background Patients with chronic liver disease (CLD) often develop thrombocytopenia (TCP) as a complication. Severe TCP (platelet count<50×109/L) can increase morbidity and complicate CLD management, increasing bleeding risk during invasive procedures. Objectives To describe the real-world scenario of CLD-associated severe TCP patients’ clinical characteristics. To evaluate the association between invasive procedures, prophylactic treatments, and bleeding events in this group of patients. To describe their need of medical resource use in Spain. Methods This is a retrospective, multicenter study including patients who had confirmed diagnosis of CLD and severe TCP in four hospitals within the Spanish National Healthcare Network from January 2014 to December 2018. We analyzed the free-text information from Electronic Health Records (EHRs) of patients using Natural Language Processing (NLP), machine learning techniques, and SNOMED-CT terminology. Demographics, comorbidities, analytical parameters and characteristics of CLD were extracted at baseline and need for invasive procedures, prophylactic treatments, bleeding events and medical resources used in the follow up period. Frequency tables were generated for categorical variables, whereas continuous variables were described in summary tables as mean (SD) and median (Q1–Q3). Results Out of 1,765,675 patients, 1787 had CLD and severe TCP; 65.2% were male with a mean age of 54.7 years old. Cirrhosis was detected in 46% (n=820) of patients and 9.1% (n=163) had hepatocellular carcinoma. Invasive procedures were needed in 85.6% of patients during the follow up period. Patients undergoing procedures compared to those patients without invasive procedures presented higher rates of bleeding events (33% vs 8%, p<0.0001) and higher number of bleedings. While prophylactic platelet transfusions were given to 25.6% of patients undergoing procedures, TPO receptor agonist use was only detected in 3.1% of them... (AU)

Antecedentes Los pacientes con enfermedad hepática crónica (EHC) a menudo desarrollan trombocitopenia (TCP) como agravante de su enfermedad. La TCP grave (definida por un recuento de plaquetas < 50 x 109/L) puede aumentar la morbilidad y complicar el manejo de la EPC, incrementando el riesgo de hemorragia durante los procedimientos invasivos. Objetivos Describir el escenario de mundo real de las características clínicas de los pacientes con TCP grave asociado a EHC. Evaluar la asociación entre procedimientos invasivos, tratamientos profilácticos y eventos hemorrágicos en este grupo de pacientes, así como describir el uso de recursos médicos en España. Métodos Se plantea un estudio multicéntrico retrospectivo que incluye pacientes con diagnóstico confirmado de EHC y TCP grave en cuatro hospitales de la Red Nacional de Salud de España desde enero de 2014 hasta diciembre de 2018. Analizamos la información de texto libre de la Historia Clínica Electrónica (HCE) de pacientes que utilizan procesamiento de lenguaje natural (PLN), técnicas de aprendizaje automático y terminología de SNOMED-CT. Los datos demográficos, las comorbilidades, los parámetros analíticos y las características de la EHC se extrajeron al inicio del estudio, así como la necesidad de procedimientos invasivos, tratamientos profilácticos, eventos hemorrágicos y recursos médicos utilizados en el periodo de seguimiento. Se generaron tablas de frecuencia para las variables categóricas, mientras que las variables continuas se describieron en tablas resumen como media (SD) y mediana (Q1-Q3). Resultados De 1.765.675 pacientes identificados, 1.787 tenían EHC y TCP grave, siendo el 65,2% varones con una edad media de 54,7 años. Se detectó cirrosis en el 46% (n = 820) de los pacientes y el 9,1% (n = 163) de ellos presentaron un diagnóstico de carcinoma hepatocelular... (AU)

Modulation of early gene expression responses to water deprivation stress by the E3 ubiquitin ligase ATL80: implications for retrograde signaling interplay.

BACKGROUND: Primary response genes play a pivotal role in translating short-lived stress signals into sustained adaptive responses. In this study, we investigated the involvement of ATL80, an E3 ubiquitin ligase, in the dynamics of gene expression following water deprivation stress. We observed that ATL80 is rapidly activated within minutes of water deprivation stress perception, reaching peak expression around 60 min before gradually declining. ATL80, despite its post-translational regulation role, emerged as a key player in modulating early gene expression responses to water deprivation stress. RESULTS: The impact of ATL80 on gene expression was assessed using a time-course microarray analysis (0, 15, 30, 60, and 120 min), revealing a burst of differentially expressed genes, many of which were associated with various stress responses. In addition, the diversity of early modulation of gene expression in response to water deprivation stress was significantly abolished in the atl80 mutant compared to wild-type plants. A subset of 73 genes that exhibited a similar expression pattern to ATL80 was identified. Among them, several are linked to stress responses, including ERF/AP2 and WRKY transcription factors, calcium signaling genes, MAP kinases, and signaling peptides. Promoter analysis predicts enrichment of binding sites for CAMTA1 and CAMTA5, which are known regulators of rapid stress responses. Furthermore, we have identified a group of differentially expressed ERF/AP2 transcription factors, proteins associated with folding and refolding, as well as pinpointed core module genes which are known to play roles in retrograde signaling pathways that cross-referenced with the early ATL80 transcriptome. CONCLUSIONS: Based on these findings, we propose that ATL80 may target one or more components within the retrograde signaling pathways for degradation. In essence, ATL80 serves as a bridge connecting these signaling pathways and effectively functions as an alarm signal.

Mortalidad asociada al trastorno neurocognitivo y dependencia en personas mayores de 55 años. Revisión sistemática / Mortality associated with neurocognitive disorder and dependence in people over 55 years of age. Systematic review

Introducción El creciente envejecimiento poblacional trae consigo un aumento de la incidencia del trastorno neurocognitivo (TNC) así como diversas situaciones generadoras de dependencia. Objetivo Analizar mediante una revisión sistemática la relación que existe entre TNC y dependencia con el riesgo de mortalidad en personas mayores. Métodos Se realizó una búsqueda bibliográfica de los estudios longitudinales publicados en Pubmed y Scopus abordando la relación entre TNC, dependencia para las actividades básicas de la vida diaria (ABVD) y mortalidad publicados entre los años 1995 y 2021 De los 1040 artículos encontrados, se seleccionaron 10 estudios. Resultados Se observó que las cohortes de personas mayores con TNC presentaron riesgo de mortalidad asociado a la afectación de las ABVD (test de Barthel) y a las puntuaciones de Mini-Mental State Examination siguiendo una tendencia lineal significativa. Otros factores asociados al riesgo de mortalidad fueron: niveles bajos de educación, vivir solo y presentar fragilidad. Es clara la vinculación entre los tres términos utilizados en la búsqueda de este trabajo y, sin embargo, destaca que haya pocos estudios longitudinales que los analicen conjuntamente. Conclusiones Los resultados hallados subrayan la importancia de realizar evaluaciones del estado cognitivo y funcional mediante escalas validadas, ya que ambas áreas se asocian con la mortalidad. La evaluación de la dependencia y de la función cognitiva en adultos mayores debe considerarse tanto en la investigación como en la práctica clínica, ya que aportarían información sobre su posible relación con la mortalidad. (AU)

Introduction The increasing aging of the population brings with it an increase in the incidence of neurocognitive disorder (NCD) as well as various situations that generate dependence. Objective To analyze by means of a systematic review the relationship between NCD and dependence with the risk of mortality in the elderly. Methods A bibliographic search of longitudinal studies published in Pubmed and Scopus addressing the relationship between NCI, dependence for basic activities of daily living (ADL) and mortality published between 1995 and 2021 was performed. Of the 1040 articles found, 10 studies were selected. Results It was observed that cohorts of elderly people with NCI presented mortality risk associated with ABVD impairment (Barthel test) and Mini-Mental State Examination scores following a significant linear trend. Other factors associated with mortality risk were low levels of education, living alone, and frailty. Conclusions The results underline the importance of performing assessments of cognitive and functional status using validated scales, since both areas are associated with mortality. The link between the three terms used in the search for this work is clear, but it is noteworthy that there are few longitudinal studies that analyze them together. The assessment of dependence and cognitive function in older adults should be considered in both research and clinical practice as it would provide information on their possible relationship with mortality. (AU)

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death.

The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways.

Isocyanide-Based Multicomponent Reactions Coupled One-Pot Process: Efficient Tools to Diversity-Oriented Synthesis of Structural Peptidomimetics.

Multicomponent diversity-oriented synthesis (DOS) of conformationally anchored structural peptidomimetics like 2,5-diketopiperazines (2,5-DKP) containing heterocyclic bioisosteres of the amide bond, such as 1,2,3-triazoles and 1,5-disubstituted tetrazoles (1,5-DS-T) is described. Structural peptidomimetics are synthesized from similar available starting materials, via a strategy based on isocyanide-based multicomponent reactions (IMCRs): Ugi-4CR and Ugi-Azide (UA), followed by a one-pot process: SN 2/intramolecular alkyne-azide cycloaddition (IAAC). The sequential aligning of two powerful synthetic tools (IMCR and IAAC) has parallelly contributed to generate anchored conformation and complexity in target molecules, which are considered structural peptidomimetics of 2,5-DKP. Herein, the 1,2,3-triazole ring plays a key role in the preference for the boat conformation. Furthermore, the use of UA reaction generates scaffold diversity at the N-1 α-carbon of the pyrazinone ring, replacing a linear amide bond with a heterocyclic bioisostere such as 1,5-DS-T leading to the synthesis of novel tricyclic peptidomimetics. The DFT calculations confirmed the boat conformation of the synthesized molecules.

Machine learning approaches to enhance diagnosis and staging of patients with MASLD using routinely available clinical information.

AIMS: Metabolic dysfunction Associated Steatotic Liver Disease (MASLD) outcomes such as MASH (metabolic dysfunction associated steatohepatitis), fibrosis and cirrhosis are ordinarily determined by resource-intensive and invasive biopsies. We aim to show that routine clinical tests offer sufficient information to predict these endpoints. METHODS: Using the LITMUS Metacohort derived from the European NAFLD Registry, the largest MASLD dataset in Europe, we create three combinations of features which vary in degree of procurement including a 19-variable feature set that are attained through a routine clinical appointment or blood test. This data was used to train predictive models using supervised machine learning (ML) algorithm XGBoost, alongside missing imputation technique MICE and class balancing algorithm SMOTE. Shapley Additive exPlanations (SHAP) were added to determine relative importance for each clinical variable. RESULTS: Analysing nine biopsy-derived MASLD outcomes of cohort size ranging between 5385 and 6673 subjects, we were able to predict individuals at training set AUCs ranging from 0.719-0.994, including classifying individuals who are At-Risk MASH at an AUC = 0.899. Using two further feature combinations of 26-variables and 35-variables, which included composite scores known to be good indicators for MASLD endpoints and advanced specialist tests, we found predictive performance did not sufficiently improve. We are also able to present local and global explanations for each ML model, offering clinicians interpretability without the expense of worsening predictive performance. CONCLUSIONS: This study developed a series of ML models of accuracy ranging from 71.9-99.4% using only easily extractable and readily available information in predicting MASLD outcomes which are usually determined through highly invasive means.

Mortalidad asociada al trastorno neurocognitivo y dependencia en personas mayores de 55 años. Revisión sistemática / Mortality associated with neurocognitive disorder and dependence in people over 55 years of age. Systematic review

Introducción El creciente envejecimiento poblacional trae consigo un aumento de la incidencia del trastorno neurocognitivo (TNC) así como diversas situaciones generadoras de dependencia. Objetivo Analizar mediante una revisión sistemática la relación que existe entre TNC y dependencia con el riesgo de mortalidad en personas mayores. Métodos Se realizó una búsqueda bibliográfica de los estudios longitudinales publicados en Pubmed y Scopus abordando la relación entre TNC, dependencia para las actividades básicas de la vida diaria (ABVD) y mortalidad publicados entre los años 1995 y 2021 De los 1040 artículos encontrados, se seleccionaron 10 estudios. Resultados Se observó que las cohortes de personas mayores con TNC presentaron riesgo de mortalidad asociado a la afectación de las ABVD (test de Barthel) y a las puntuaciones de Mini-Mental State Examination siguiendo una tendencia lineal significativa. Otros factores asociados al riesgo de mortalidad fueron: niveles bajos de educación, vivir solo y presentar fragilidad. Es clara la vinculación entre los tres términos utilizados en la búsqueda de este trabajo y, sin embargo, destaca que haya pocos estudios longitudinales que los analicen conjuntamente. Conclusiones Los resultados hallados subrayan la importancia de realizar evaluaciones del estado cognitivo y funcional mediante escalas validadas, ya que ambas áreas se asocian con la mortalidad. La evaluación de la dependencia y de la función cognitiva en adultos mayores debe considerarse tanto en la investigación como en la práctica clínica, ya que aportarían información sobre su posible relación con la mortalidad. (AU)

Introduction The increasing aging of the population brings with it an increase in the incidence of neurocognitive disorder (NCD) as well as various situations that generate dependence. Objective To analyze by means of a systematic review the relationship between NCD and dependence with the risk of mortality in the elderly. Methods A bibliographic search of longitudinal studies published in Pubmed and Scopus addressing the relationship between NCI, dependence for basic activities of daily living (ADL) and mortality published between 1995 and 2021 was performed. Of the 1040 articles found, 10 studies were selected. Results It was observed that cohorts of elderly people with NCI presented mortality risk associated with ABVD impairment (Barthel test) and Mini-Mental State Examination scores following a significant linear trend. Other factors associated with mortality risk were low levels of education, living alone, and frailty. Conclusions The results underline the importance of performing assessments of cognitive and functional status using validated scales, since both areas are associated with mortality. The link between the three terms used in the search for this work is clear, but it is noteworthy that there are few longitudinal studies that analyze them together. The assessment of dependence and cognitive function in older adults should be considered in both research and clinical practice as it would provide information on their possible relationship with mortality. (AU)

Novel insights into metabolic-associated steatotic liver disease preclinical models.

Metabolic-associated steatotic liver disease (MASLD) encompasses a wide spectrum of metabolic conditions associated with an excess of fat accumulation in the liver, ranging from simple hepatic steatosis to cirrhosis and hepatocellular carcinoma. Finding appropriate tools to study its development and progression is essential to address essential unmet therapeutic and staging needs. This review discusses advantages and shortcomings of different dietary, chemical and genetic factors that can be used to mimic this disease and its progression in mice from a hepatic and metabolic point of view. Also, this review will highlight some additional factors and considerations that could have a strong impact on the outcomes of our model to end up providing recommendations and a checklist to facilitate the selection of the appropriate MASLD preclinical model based on clinical aims.

Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease.

OBJECTIVE: Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death. DESIGN: We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell's C-index and its improvement by including ferritin as a covariate. RESULTS: Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 µg/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 µg/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 µg/L and 272 µg/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65). CONCLUSIONS: This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD.