Generative Modeling of RNA Sequence Families with Restricted Boltzmann Machines.

In this chapter, we discuss the potential application of Restricted Boltzmann machines (RBM) to model sequence families of structured RNA molecules. RBMs are a simple two-layer machine learning model able to capture intricate sequence dependencies induced by secondary and tertiary structure, as well as mechanisms of structural flexibility, resulting in a model that can be successfully used for the design of allosteric RNA such as riboswitches. They have recently been experimentally validated as generative models for the SAM-I riboswitch aptamer domain sequence family. We introduce RBM mathematically and practically, providing self-contained code examples to download the necessary training sequence data, train the RBM, and sample novel sequences. We present in detail the implementation of algorithms necessary to use RBMs, focusing on applications in biological sequence modeling.

La aplicación del saber médico. Hipertensión y daño cognitivo

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Introduction: High blood pressure (HBP) is the leading cause of death from cardiovascular disease. Despite the advances, the percentage of undiagnosed and untreated hypertensive patients is 58.4%. The evaluation of cognitive damage in HBP focuses on preventing stroke, while functional damage is ignored. This inadequate management may be multifactorial. The objective was to analyze the opinions that doctors have about the relationship between high blood pressure and cognitive damage. Methodology: Observational, descriptive, cross-sectional study developed in the period between August 2020 and August 2023. Analysis of data obtained from a self-administered, anonymous and voluntary questionnaire. Revealing information on the professional profile, knowledge of HBP, its link with cognitive impairment (CD), diagnosis and treatment. Results: 222 professionals were included, 215 (96.8%) agree with the existence of a link between HBP and other cardiovascular risk factors in CD, and 218 (98.1%) acknowledge assisting patients at risk of suffering from CD. The CD evaluation is carried out in selected cases by 132 (59.4%) participants and 59 (26.7%) always do it. Of those who perform evaluation, 103 (54%) use the Mini Mental State Examination (MMSE), 10 (5.2%) use the Montreal Cognitive Assessment (MoCA) and 9 (4.7%) use the Clock Drawing Test. Regarding the decrease in blood pressure in elderly patients and the link with risk of CD: 54 (24.3%) do not recognize risk and 65 (29.2%) recognize a moderate-high risk. In reference to the implication of the treatment of cardiovascular disease and CD: 217 (97.7%) recognized a beneficial effect. Discussion: Given the recognition of the link between HBP and CD, it would be expected that CD would be investigated in the vast majority, however only 26.7% always evaluate it. There is no consensus on the method, the MMSE being the most used, with a low application of the MoCA test and/or Clock Drawing Test, the latter being the ones that evaluate executive function, mostly altered in CD linked to HBP. Although the treatment of cardiovascular disease is recognized as beneficial with respect to CD, the control of HBP in older adults is considered risky. A diagnosis is made of a situation where a disparity is evident between what one recognizes as knowing and what one claims to do. Conclusions: The role of vascular disease in functional brain damage is recognized, considering it necessary to know the cognitive status of patients, however there is a low application of screening tests that evaluate executive function. In this context, a gap between medical knowledge and practice is shown.

Introdução: A hipertensão arterial (HA) é a principal causa de morte por doenças cardiovasculares. Apesar dos avanços, o percentual de hipertensos não diagnosticados e não tratados é de 58,4%. A avaliação do dano cognitivo na hipertensão concentra-se na prevenção do acidente vascular cerebral, enquanto o dano funcional é ignorado. Esse manejo inadequado pode ser multifatorial. É objetivo fue analisar a opinião dos médicos sobre a relação entre hipertensão arterial e danos cognitivos. Metodologia: Estudo observacional, descritivo, transversal desenvolvido no período entre agosto de 2020 e agosto de 2023. Análise de dados obtidos a partir de questionário autoaplicável, anônimo e voluntário. Revelar informações sobre o perfil profissional, conhecimento sobre a HA, sua ligação com o comprometimento cognitivo (DC), diagnóstico e tratamento. Resultados: Foram incluídos 222 profissionais, 215 (96,8%) concordam com a existência de ligação entre hipertensão e outros fatores de risco cardiovascular na DC e 218 (98,1%) reconhecem ajudar pacientes com risco de sofrer de D.C. A avaliação da DC é realizada em casos selecionados por 132 (59,4%) participantes e 59 (26,7%) a fazem sempre. Dos que realizam avaliação, 103 (54%) utilizam o Mini Exame do Estado Mental (MEEM), 10 (5,2%) utilizam a Avaliação Cognitiva de Montreal (MoCA) e 9 (4,7%) utilizam o Clock Drawing Test. Em relação à diminuição da pressão arterial em pacientes idosos e a ligação com o risco de DC: 54 (24,3%) não reconhecem risco e 65 (29,2%) reconhecem risco moderado-alto. Em referência à implicação do tratamento de doenças cardiovasculares e DC: 217 (97,7%) reconheceram o efeito benéfico. Discussão: Dado o reconhecimento da ligação entre hipertensão e DC, seria de esperar que a DC fosse investigada na grande maioria, no entanto apenas 26,7% sempre a avaliam. Não há consenso sobre o método, sendo o MEEM o mais utilizado, com baixa aplicação do teste MoCA e/ou Clock Drawing Test, sendo estes últimos os que avaliam a função executiva, majoritariamente alterada nos DC vinculados à HA. Embora o tratamento das doenças cardiovasculares seja reconhecido como benéfico em relação à DC, o controle da HA em idosos é considerado arriscado. É feito um diagnóstico de uma situação em que é evidente uma disparidade entre o que se reconhece como saber e o que se afirma fazer. Conclusões: O papel da doença vascular no dano cerebral funcional é reconhecido, considerando-se necessário conhecer o estado cognitivo dos pacientes, porém há baixa aplicação de testes de triagem que avaliam a função executiva. Nesse contexto, evidencia-se uma lacuna entre o conhecimento e a prática médica.

Studying the Humoral Response against SARS-CoV-2 in Cuban COVID-19 Recovered Patients.

Understanding the immune response generated by SARS-CoV-2 is critical for assessing efficient therapeutic protocols and gaining insights into the durability of protective immunity. The current work was aimed at studying the specific humoral responses against SARS-CoV-2 in Cuban COVID-19 convalescents. We developed suitable tools and methods based on ELISA methodology, for supporting this evaluation. Here, we describe the development of an ELISA for the quantification of anti-RBD IgG titers in a large number of samples and a similar test in the presence of NH4SCN as chaotropic agent for estimating the RBD specific antibody avidity. Additionally, a simple and rapid ELISA based on antibody-mediated blockage of the binding RBD-ACE2 was implemented for detecting, as a surrogate of conventional test, the levels of anti-RBD inhibitory antibodies in convalescent sera. In a cohort of 273 unvaccinated convalescents, we identified higher anti-RBD IgG titer (1 : 1,330, p < 0.0001) and higher levels of inhibitory antibodies blocking RBD-ACE2 binding (1 : 216, p < 0.05) among those who had recovered from severe illness. Our results suggest that disease severity, and not demographic features such as age, sex, and skin color, is the main determinant of the magnitude and neutralizing ability of the anti-RBD antibody response. An additional paired longitudinal assessment in 14 symptomatic convalescents revealed a decline in the antiviral antibody response and the persistence of neutralizing antibodies for at least 4 months after the onset of symptoms. Overall, SARS-CoV-2 infection elicits different levels of antibody response according to disease severity that declines over time and can be monitored using our homemade serological assays.

Sequencing vs. amplification for the estimation of allele dosages in sugarcane (Saccharum spp.).

Premise: Detecting single-nucleotide polymorphisms (SNPs) in a cost-effective way is fundamental in any plant breeding pipeline. Here, we compare three genotyping techniques for their ability to reproduce the allele dosage of SNPs of interest in sugarcane (Saccharum spp.). Methods: To identify a reproducible technique to estimate allele dosage for the validation of SNP markers, the correlation between Flex-Seq, kompetitive allele-specific PCR (KASP), and genotyping-by-sequencing and restriction site-associated DNA sequencing (GBS+RADseq) was determined for a set of 76 SNPs. To find alternative methodologies for allele dosage estimation, the KASP and Flex-Seq techniques were compared for the same set of SNPs. For the three techniques, a population of 53 genotypes from the diverse sugarcane panel of the Centro de Investigación de la Caña de Azúcar (Cenicaña), Colombia, was selected. Results: The average Pearson correlation coefficients between GBS+RADseq and Flex-Seq, GBS+RADseq and KASP, and Flex-Seq and KASP were 0.62 ± 0.27, 0.38 ± 0.27, and 0.38 ± 0.30, respectively. Discussion: Flex-Seq reproduced the allele dosages determined using GBS+RADseq with good levels of precision because of its depth of sequencing and ability to target specific positions in the genome. Additionally, Flex-Seq outperformed KASP by allowing the conversion of a higher number of SNPs and a more accurate estimation of the allele dosage. Flex-Seq has therefore become the genotyping methodology of choice for marker validation at Cenicaña.

Premisa: Detectar polimorfismos de un único nucleótido (SNP) de forma costo­efectiva es fundamental en cualquier programa de mejoramiento genético. En este artículo nosotros comparamos tres técnicas de genotipado para medir su habilidad en reproducir las dosis alélicas de SNPs de interés en caña de azúcar (Saccharum spp.). Métodos: Para identificar una técnica reproducible para la estimación de dosis alélicas durante los pasos de validación de marcadores, la correlación entre Flex­Seq, kompetitive allele­specific PCR (KASP), y genotyping­by­sequencing and restriction site­associated DNA sequencing (GBS+RADseq) fue determinada para un set de 76 SNPs. Para identificar metodologías alternativas en la estimación de las dosis alélicas, las tecnologías KASP y Flex­Seq fueron comparadas para el mismo grupo de SNPs. Para las tres técnicas, una población de 53 genotipos fue seleccionados de la población diversa de caña de azúcar del Centro de Investigación de la Caña de Azúcar (Cenicaña), Colombia. Resultados: El promedio del coeficiente de correlación de Pearson entre GBS+RADseq y Flex­Seq, GBS+RADseq y KASP, y Flex­Seq y KASP fue de 0.62 ± 0.27, 0.38 ± 0.27, y 0.38 ± 0.30, respectivamente. Discusión: Flex­Seq reprodujo las dosis alélicas determinadas usando GBS+RADseq con buenos niveles de precisión debido a su profundidad de secuenciación y habilidad de secuenciar posiciones especificas en el genoma. Adicionalmente, Flex­Seq superó a KASP al permitir la conversión de un número mayor de SNPs y al estimar las dosis alélicas de forma más precisa. Flex­Seq por tanto se convierte en la metodología de genotipado de elección para la validación de marcadores en Cenicaña.

Intrinsic cardiomyopathy in pediatric Marfan syndrome: predictive factors and risk assessments.

BACKGROUND: Marfan syndrome (MFS) is associated with cardiovascular complications, particularly valvulopathies; however, its association with primary cardiomyopathy remains unclear. METHODS: This retrospective cohort study examined the cardiomyopathy characteristics (CMCs) in pediatric patients with MFS. CMCs were defined as meeting at least one of the following echocardiography or clinical parameters: (1) cardiac index (CI) too low for patient's age, (2) ejection fraction (EF) <50%, and (3) diastolic dysfunction. The predictive factors for CMCs were determined using a multivariable logistic regression model. RESULTS: Among 83 patients with MFS (age, median [range], 12.5 [0.4-22.3] years), 39.8% exhibited CMCs. Only 4 patients (5%) showed heart failure symptoms (NYHA > 1). Independent predictors for CMCs included a systemic score of ≥7 (revised Ghent criteria) and likely pathogenic or pathogenic variants in FBN1, including variants that introduce a premature stop codon, splice site variants, and missense variants involving cysteine. A multivariable score was constructed with an AUC of 0.733. CONCLUSION: This study offers valuable insights into the prevalence and predictors of CMC in pediatric patients with MFS and presents potential strategies for risk assessment of cardiomyopathy. IMPACT: The objective of this study was to elucidate the contentious issue of intrinsic cardiomyopathy in Marfan syndrome and demonstrate its notable occurrence even in pediatric patients who do not exhibit heart failure symptoms or valvular complications. We highlighted the importance of specific FBN1 variants and higher systemic scores in identifying the potential for intrinsic cardiomyopathy in pediatric patients with Marfan syndrome.

Assessment of inbreeding coefficients and inbreeding depression on complex traits from genomic and pedigree data in Nelore cattle.

BACKGROUND: Nelore cattle play a key role in tropical production systems due to their resilience to harsh conditions, such as heat stress and seasonally poor nutrition. Monitoring their genetic diversity is essential to manage the negative impacts of inbreeding. Traditionally, inbreeding and inbreeding depression are assessed by pedigree-based coefficients (F), but recently, genetic markers have been preferred for their precision in capturing the inbreeding level and identifying animals at risk of reduced productive and reproductive performance. Hence, we compared the inbreeding and inbreeding depression for productive and reproductive performance traits in Nelore cattle using different inbreeding coefficient estimation methods from pedigree information (FPed), the genomic relationship matrix (FGRM), runs of homozygosity (FROH) of different lengths (> 1 Mb (genome), between 1 and 2 Mb - FROH 1-2; 2-4 Mb FROH 2-4 or > 8 Mb FROH >8) and excess homozygosity (FSNP). RESULTS: The correlation between FPed and FROH was lower when the latter was based on shorter segments (r = 0.15 with FROH 1-2, r = 0.20 with FROH 2-4 and r = 0.28 with FROH 4-8). Meanwhile, the FPed had a moderate correlation with FSNP (r = 0.47) and high correlation with FROH >8 (r = 0.58) and FROH-genome (r = 0.60). The FROH-genome was highly correlated with inbreeding based on FROH>8 (r = 0.93) and FSNP (r = 0.88). The FGRM exhibited a high correlation with FROH-genome (r = 0.55) and FROH >8 (r = 0.51) and a lower correlation with other inbreeding estimators varying from 0.30 for FROH 2-4 to 0.37 for FROH 1-2. Increased levels of inbreeding had a negative impact on the productive and reproductive performance of Nelore cattle. The unfavorable inbreeding effect on productive and reproductive traits ranged from 0.12 to 0.51 for FPed, 0.19-0.59 for FGRM, 0.21-0.58 for FROH-genome, and 0.19-0.54 for FSNP per 1% of inbreeding scaled on the percentage of the mean. When scaling the linear regression coefficients on the standard deviation, the unfavorable inbreeding effect varied from 0.43 to 1.56% for FPed, 0.49-1.97% for FGRM, 0.34-2.2% for FROH-genome, and 0.50-1.62% for FSNP per 1% of inbreeding. The impact of the homozygous segments on reproductive and performance traits varied based on the chromosomes. This shows that specific homozygous chromosome segments can be signs of positive selection due to their beneficial effects on the traits. CONCLUSIONS: The low correlation observed between FPed and genomic-based inbreeding estimates suggests that the presence of animals with one unknown parent (sire or dam) in the pedigree does not account for ancient inbreeding. The ROH hotspots surround genes related to reproduction, growth, meat quality, and adaptation to environmental stress. Inbreeding depression has adverse effects on productive and reproductive traits in Nelore cattle, particularly on age at puberty in young bulls and heifer calving at 30 months, as well as on scrotal circumference and body weight when scaled on the standard deviation of the trait.

Water deficit and aphid resilience on wheat: examining Sitobion avenae F. and their bacterial symbionts interplay under controlled laboratory conditions.

BACKGROUND: Climate change has far-reaching effects on food security and agriculture, affecting crop yields and food distribution. Agriculture relies heavily on water for irrigation and production, making it vulnerable to water scarcity. Additionally, climate change can affect crop pest insects, leading to increased global crop losses, particularly in cereals, an important component of the human diet. Aphids are major crop pests and have a symbiotic relationship with bacterial endosymbionts that can contribute to their success as pests under a climate change scenario. To test the effect of drought on aphids, we examined varying levels of water deficit and endosymbiont composition on the grain aphid (Sitobion avenae) performance on wheat under controlled laboratory conditions. We measured the intrinsic rate of population increase (rm), the body weight of adult aphids, and the pre-reproductive period for different genotypes of the grain aphid (including Chilean superclones) under different irrigation regimes. We also analyzed the relative abundance of their endosymbionts under the different water treatments. RESULTS: Our findings revealed that water deficit affects each aphid genotype differently, impacting various traits. For instance, the body weight of adult aphids was notably affected by different water treatments, with aphids grown under intermediate water deficit (IW) being significantly bigger. The relative abundance of endosymbionts also varied among genotypes and water treatments-specifically Regiella insecticola had a noticeably higher abundance under IW (P < 0.05). CONCLUSION: This study provides valuable insights into the impact of water deficit on aphid performance and the role of endosymbionts in mitigating the effects of water deficit. © 2024 Society of Chemical Industry.

Sirtuin Expression in Insulin-Sensitive Tissues of Rats with Impaired Glucose Tolerance is not Affected by Resistance Training or Zinc Supplementation.

While physical activity and zinc supplementation have shown benefits in diabetes management, little is known about their effect on less severe glucose homeostasis disorders, such as impaired glucose tolerance. On the other hand, sirtuins have an important role in glucose metabolism and insulin sensitivity, but to date, there is no information about the impact of zinc supplementation or physical activity on their regulation in individuals with impaired glucose homeostasis. The aim of this study was to assess the effect of supplemental zinc, muscle-resistance training, and their combination on the expression of selected sirtuins in insulin-sensitive tissues of rats with impaired glucose tolerance. Thirty male Wistar rats with impaired glucose tolerance were fed a high-fat diet for 12 weeks while subjected to zinc supplementation, resistance training, both, or none. Morphometric and metabolic evaluations were performed at the end of the experimental period, and gene expression of sirtuins 1, 2, 4, and 7 was assessed in liver, gastrocnemius muscle, and white adipose tissue. Results showed that zinc supplementation and/or resistance training did not improve metabolic parameters of rats with impaired glucose tolerance, nor did they affect the expression of selected sirtuins in any of the tissues evaluated. However, the expression of some sirtuins was associated with metabolic parameters in a tissue-specific manner. Additional studies are needed to evaluate whether zinc supplementation and/or resistance training can improve metabolic status or modulate sirtuins expression in advanced stages of impaired glucose homeostasis.

Responses to Exercise with Low Carbohydrate Availability on Muscle Glycogen and Cell Signaling: A Systematic Review and Meta-analysis.

BACKGROUND: The growing interest in how exercise and carbohydrate (CHO) restriction may modify molecular responses that promote endurance adaptations has led to many interesting controversies. OBJECTIVE: We conducted a systematic review and a meta-analysis regarding the effect of low-carbohydrate availability (LOW) pre-, during, or post-exercise, on the mRNA content of commonly measured genes involved in mitochondrial biogenesis (PGC-1α, TFAM mRNA) and metabolism (PDK4, UCP3 and GLUT4 mRNA), and on muscle glycogen levels, compared with a high-CHO (CON) condition. METHODS: MEDLINE, Scopus, and Web of Science databases were searched following the PRISMA 2020 guidelines (with an end date of November 2023). In total, 19 randomized-controlled studies were considered for inclusion. We evaluated the methodological quality of all studies using the Cochrane Risk of Bias tool for randomized clinical studies. A meta-analysis was performed using a random effects model to calculate the standardized mean difference (SMD), estimated by Hedges' g, and 95% confidence intervals (CIs). RESULTS: The LOW condition was associated with an increased mRNA content of several genes during the early recovery period post-exercise, such as PDK4 (SMD 1.61; 95% CI 0.80-2.42), GLUT4 (SMD 1.38; 95% CI 0.46-2.30), and UCP3 (SMD 2.05; 95% CI 0.40-3.69). However, overall, there was no significant effect on the mRNA content of PGC-1α or TFAM. Finally, CHO restriction and exercise significantly reduced muscle glycogen levels (SMD 3.69; 95% CI 2.82-5.09). A meta-analysis of subgroups from studies with a difference in muscle glycogen concentration of > 200 mmol kg dw-1 between the LOW and CON conditions showed an increase in exercise-induced PGC-1α mRNA (SMD 2.08; 95% CI 0.64-3.52; p = 0.005; I2 = 75%) and a greater effect in PDK4 and GLUT4 mRNA. CONCLUSION: The meta-analysis results show that CHO restriction was associated with an increase in the exercise-induced mRNA content of PDK4, UCP3, and GLUT4, but not the exercise-induced mRNA content of PGC-1ɑ and TFAM. However, when there were substantial differences in glycogen depletion between CON and LOW CHO conditions (> 200 mmol kg dw-1), there was a greater effect of CHO restriction on the exercise-induced mRNA content of metabolic genes, and an increase in exercise-induced PGC-1α mRNA.

Comment to "An unusual "linitis plastica" like breast cancer bladder metastasis".

Dear Editor, We read with interest the recently published article by Farci et al., titled "An unusual 'linitis plastica' like breast cancer bladder metastasis" and we congratulate the authors for the very interesting topic and case presented...

Cytokine-Based Validation of the Inflammation-Based Risk Score in Patients with ST-Segment Elevation Myocardial Infarction.

This study aimed to validate an inflammation-based risk score in patients with ST-segment elevation myocardial infarction (STEMI) by examining their cytokine profiles. Upon admission, patients were evaluated for systemic inflammation using a risk score that assigned points based on specific biomarkers: 1 point for leukocyte count ≥9.3 × 10³ cells/µL, 2 points for high-sensitivity C-reactive protein (hsCRP) ≥13.0 mg/L, and 3 points for serum albumin ≤3.6 g/dL. Patients were categorized into three groups: no inflammation (0 points, n = 13), mild inflammation (1-2 points, n = 35), and severe inflammation (3-6 points, n = 26). Serum levels of 16 key cytokines were measured. Patients with higher risk scores showed elevated interleukin (IL)-6 levels (19.6 vs. 8.5 vs. 6.8 pg/mL; P = 0.021) and decreased interferon-γ-induced protein-10 (IP-10) levels (73.4 vs. 68.8 vs. 112.2 pg/mL; P = 0.011). IL-6 was positively correlated with hsCRP (ρ 0.307) and negatively correlated with albumin (ρ -0.298), while IP-10 was negatively correlated with leukocyte count (ρ -0.301). No other cytokines showed significant association with the risk score. Higher inflammation scores were also associated with an increased incidence of major adverse cardiovascular events, particularly acute heart failure. This study underscores the association between the inflammation-based risk score and cytokine levels, specifically IL-6 and IP-10, in patients with STEMI.

Mexican Clinical Practice Guidelines for Adult Overweight and Obesity Management.

PURPOSE: To develop Mexico's first methodologically rigorous clinical practice guideline for the management of adult overweight and obesity. The target audiences are interdisciplinary healthcare professionals across healthcare systems who are the first point of contact for patients with obesity in Mexico, patients, and health system decision makers. RECENT FINDINGS: A review of recent international obesity clinical practice guidelines and an expert consensus process identified: i) common recommendations appropriate for implementation in Mexico and ii) knowledge gaps requiring the formulation of new recommendations. In all, 20 new recommendations and 20 good practice statements were developed using the GRADE Evidence-to-Decision Framework and expert consensus. Overweight and obesity negatively impact the health and well-being of individuals and populations in Mexico. This guideline aims to establish a new evidence-based, patient-centered, non-stigmatizing, and practical treatment and management framework, based on the fundamental principles of chronic disease prevention and management.

Phase Ib Study for the Combination of Doxorubicin, Dacarbazine, and Nivolumab as the Upfront Treatment in Patients With Advanced Leiomyosarcoma: A Study by the Spanish Sarcoma Group (GEIS).

PURPOSE: Doxorubicin, alongside a select group of cytotoxic agents, is capable of inducing an adaptive immune response via a well-established peculiar type of tumor cell death called immunogenic cell death (ICD). We hypothesize that combining doxorubicin and dacarbazine with nivolumab may enhance therapeutic efficacy by exerting synergy in the ICD circuit. We hereby present a phase Ib trial with this combination. PATIENTS AND METHODS: Patients with advanced leiomyosarcoma and anthracycline-naïve were eligible. The initial dose level consisted of doxorubicin 75 mg/m2 once on day 1, once every three weeks, followed by dacarbazine 400 mg/m2 once on days 1 and 2, once every three weeks, plus nivolumab 360 mg once on day 2, once every 3 weeks, for six courses and then 1 year of nivolumab. A (-1) dose level was the same regimen but with nivolumab 240 mg. A classic 3 + 3 phase-I design was used to determine the recommended phase-II dose (RP2D). Secondary end points included overall response rate, safety profile, survival, and translational research. RESULTS: From January 2002 to July 2023, 24 patients were enrolled and 23 were evaluable for efficacy, excluding one patient because of noncompliant dose. All patients were treated with the initial dose level, then the RP2D. Toxicity was mild, with the most frequent being grade 4 toxicity neutropenia (16.7%) and thrombocytopenia (8.3%), while no grade 5 toxicity occurred. The centrally reviewed objective response rate was as follows: partial response 56.5%, stable disease 39.1%, and progression 4.4%. The 6-month progression-free survival (PFS) rate was 80% (95% CI, 63 to 98). Dynamic increases of HMGB1 in blood significantly correlated with longer PFS. CONCLUSION: This scheme of doxorubicin, dacarbazine, and nivolumab is feasible and well tolerated. Clinical activity is encouraging and the prognostic impact of HMGB1 supports the relevance of ICD activation. Further clinical research is already underway with this concept in leiomyosarcoma.

Novel risk loci for COVID-19 hospitalization among admixed American populations.

The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations (BAZ2B and DDIAS). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP. Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.

Engineering bacterial biocatalysts for the degradation of phthalic acid esters.

Phthalic acid esters (PAEs) are synthetic diesters derived from o-phthalic acid, commonly used as plasticizers. These compounds pose significant environmental and health risks due to their ability to leach into the environment and act as endocrine disruptors, carcinogens, and mutagens. Consequently, PAEs are now considered major emerging contaminants and priority pollutants. Microbial degradation, primarily by bacteria and fungi, offers a promising method for PAEs bioremediation. This article highlights the current state of microbial PAEs degradation, focusing on the major bottlenecks and associated challenges. These include the identification of novel and more efficient PAE hydrolases to address the complexity of PAE mixtures in the environment, understanding PAEs uptake mechanisms, characterizing novel o-phthalate degradation pathways, and studying the regulatory network that controls the expression of PAE degradation genes. Future research directions include mitigating the impact of PAEs on health and ecosystems, developing biosensors for monitoring and measuring bioavailable PAEs concentrations, and valorizing these residues into other products of industrial interest, among others.

Systematic review in relation to support of diversity in nursing homes.

Introduction: Given the increasing global population of older adults, it is essential and inevitable that healthcare centers and nursing homes address and accommodate diversity in their support systems as interventions for healthy aging. The active aging and the inclusion of all people regardless of their religion, origin, and/or sexual orientation is essential to create a climate of safety. Discrimination must be addressed from all angles, at the social level, at the business level and by all workers in nursing homes. Methodology and results: This study provides a comprehensive review of existing literature to systematize information on diversity among older adults in healthcare centers and nursing homes. Out of 1.458 articles identified, 10 were analyzed in depth, revealing that addressing diversity among older adults is crucial to overall mental and physical healthy aging. The findings underscore the need for a multidisciplinary approach and effective management through the Person-Centered Care Model (PCCM). Discussion and conclusion: This study highlights the critical role of the Person-Centered Care Model (PCCM) in addressing diversity in aging needs. It highlights the necessity of tailoring care based on individual life histories and experiences. Additionally, it calls for the implementation of inclusive policies in nursing homes and emphasizes the need for professional training on diversity to ensure these facilities are safe and supportive for all residents.

Liver fibrosis screening increases alcohol abstinence.

Background & Aims: Individuals with alcohol use disorder (AUD) are at risk of liver disease. There is scarce information on the effectiveness of screening for liver fibrosis on alcohol consumption. Thus, we evaluated the efficacy of a screening program for liver fibrosis on alcohol consumption in individuals with AUD. Methods: We performed a prospective interventional study in the Hospital Clinic of Barcelona. The screening cohort included individuals with AUD from the addiction unit who underwent screening for liver fibrosis with transient elastography and counselling on lifestyle habits in the liver unit. The control cohort included individuals with similar characteristics who attended the same unit in a previous period but did not undergo screening. Effects on alcohol consumption were evaluated at 6 months, after clinical follow-up, with clinical assessment by addiction specialists and urine ethyl glucuronide monitoring. Results: In the screening cohort, 149/334 (45%) individuals were abstinent at 6 months (68% confirmed with urine ethyl glucuronide). Alcohol abstinence was higher in the screening cohort than in the control cohort (40/137 [29%], p = 0.002). Factors associated with alcohol abstinence in the multivariate analysis of the two combined cohorts (n = 471) were: receiving AUD medications (odds ratio [OR] 1.72, 95% CI 1.11-2.67), absence of illicit drug use (OR 0.50, 95% CI 0.31-0.80) and participating in the screening program (OR 1.77, 95% CI 1.14-2.74). In the screening cohort, 40 (12%) individuals had increased liver stiffness (≥8 kPa), which was associated with obesity (p = 0.03), arterial hypertension (p = 0.03), gamma-glutamyltransferase (p <0.001) and platelet levels (p = 0.001). Conclusions: This study shows that an integrated screening program for liver fibrosis associated with counselling on alcohol consumption in individuals with AUD allows for early diagnosis of alcohol-associated liver disease and is associated with alcohol abstinence. Impact and implications: Individuals with high alcohol consumption are at higher risk of liver disease compared to the general population. The potential beneficial effects of screening for liver disease in this population have scarcely been studied. We show that a screening program for liver fibrosis together with a lifestyle counselling intervention favoured alcohol abstinence among individuals with alcohol use disorder attending an addiction unit at 6 months, compared to a matched cohort who did not undergo screening. These findings suggest that screening programs for liver fibrosis have a therapeutic role in individuals with alcohol use disorder, supporting the implementation of these programs in addiction units.

Repeatability and Reproducibility of a Modified Lekholm and Zarb Bone Quality Classification Based on Cone Beam Computed Tomography: An Observatsion Study.

Aim: We propose a modified Lekholm and Zarb classification that considers all possible combinations of cortical and cancellous bone to provide parameters that favor greater repeatability and reproducibility. Materials and Methods: This observational and analytical study consisted of a sample of 50 cone beam computed tomography (CBCT) scans. Two new types (V and VI), three subtypes to type II (II-A, II-B, and II-C), and two subtypes to type III (III-A and III-B) were added to the original bone quality classification. The new types refer to regenerated bone (type V) and bone with some pathology (type VI). The subtypes are described as type II-A: thick cortical surrounding the abundant cancellous bone with sharp trabeculae throughout the image and presence of small and visible medullary spaces; type II-B: thick cortical surrounding the abundant cancellous bone with predominance of diffuse trabeculae in the basal bone and predominant presence of wide and visible medullary spaces; type II-C: thick cortical surrounding the abundant cancellous bone with predominance of very thick and sharp trabeculae in the basal third as well as presence of small and visible medullary spaces; type III-A: thin cortical surrounding the abundant cancellous bone with sharp trabeculae throughout the image and presence of small and visible medullary spaces; type III-B: thin cortical surrounding the abundant cancellous bone with predominance of diffuse trabeculae and presence of diffuse medullary spaces. Five dental specialists were trained in the use of the modified classification and were provided with CBCT-sectioned images of edentulous jaws for classification. Each specialist classified the images twice at a 7-day interval. The strength of intra-examiner and inter-examiner agreement was measured with Cohen's and Fleiss' kappa index, respectively. In addition, the agreement between both classifications was analyzed. All data were analyzed at a 95% confidence level, considering a P-value <0.05. Results: According to the modified Lekholm and Zarb classification, an almost perfect intra-examiner agreement was significant (P < 0.05) in all five specialists, with the kappa index [k] ranging from 0.91 [95% confidence interval (CI): 0.82-0.99) to 0.95 (95% CI: 0.89-1.00). Furthermore, substantial inter-examiner concordance (k=0.76; 95% CI: 0.73-0.79) was significant (P < 0.05). Conclusion: The high repeatability and reproducibility of the modified Lekholm and Zarb classification on CBCT suggest its applicability to distinguish between the various combinations of cortical and cancellous bone and help to define treatment appropriately to optimize results.

Cardiac coherence and medical hypnosis: a feasibility study of a new combined approach for managing preoperative anxiety in patients with breast or gynaecological cancer.

Background: Non-pharmaceutical approaches can help manage preoperative anxiety, but few studies have evaluated psychoeducational programmes, especially for cancer surgery. We assessed the feasibility of the COHErence Cardiaque (COHEC) programme where cardiac coherence and medical hypnosis are combined to manage preoperative anxiety in patients undergoing breast or gynaecological cancer surgical interventions (BGCSI). Methods: Patients undergoing BGCSI were enrolled and followed a daily home programme with cardiac coherence and medical hypnosis sessions, starting 7 days before the procedure. The primary endpoint was optimal patient adherence (i.e. completion of ≥14 sessions). Secondary endpoints were anxiety levels, measured using the Visual Analogue Scale (VAS) and the Amsterdam Preoperative Anxiety and Information Scale (APAIS), satisfaction (EVAN-G), and quality of postoperative recovery (QoR-15). Results: In total, 53 patients [mean age: 55 (34-82) yr] were included; 83.7% had breast cancer and 15.1% had gynaecological cancer. Optimal adherence was achieved by 64.2% (95% confidence interval: 49.8-76.9%) of the intention-to-treat population. Among the 43 patients who completed at least one session, exploratory analysis showed that anxiety on the day before (P=0.02) and the morning of the intervention (P=0.04) was decreased in patients with severe anxiety at baseline (VAS ≥70). The median VAS satisfaction score for the programme was 10 (4-10). Overall, 94% of patients were willing to include the COHEC programme in their daily routine. Conclusions: The implementation of a psychoeducational programme combining cardiac coherence and medical hypnosis is feasible and might potentially help patients undergoing BGCSI to manage preoperative anxiety. A randomised trial is underway to assess the efficacy of the COHEC programme. Clinical trial registration: NCT03981731.