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Objective: The cardioprotective enzyme paraoxonase-1 (PON1) suffers an important influence from genetic polymorphisms and nutritional factors. The aim of this study was to investigate the influence of diet, nutritional status, and the C(-107)T polymorphism on PON1 arylesterase activity in children. Methods: This was a cross-sectional study with 97 children, aged between 5 and 8 years, of both genders, from a pediatric outpatient clinic in southern Brazil. A sociodemographic, behavioral, and food consumption questionnaire was applied, and anthropometric measurements and laboratory blood samples were taken. PON1 arylesterase activity was measured by phenol extinction (U/mL), and DNA extraction and analysis of the PON1 C(-107)T polymorphism were performed. The Hardy–Weinberg equilibrium was tested with the chi-squared test and linear regression was used to estimate PON1 activity according to four adjustment models, with an acceptable error of 5%. Results: In the sample, the male gender accounted for 50.5%, 39.2% were 6 years of age, 54.5% had normal weight, and 51.5% had PON1 activity below the median (90.0, 15–30 U/mL). Genotype frequency was 54.6% (53/97), 31.0% (30/97), and 14.4% (14/97), respectively, for CT, CC, and TT, consistent with the Hardy–Weinberg equilibrium (p = 0.22). In the regression analysis, the model that included sociodemographic variables as well as frequency of consumption of fruits, vegetables, legumes, dairy products, and beans estimated a variability of 14.8% in PON1 activity combined with the PON1 C(-107)T polymorphism. Conclusions: During childhood, a good-quality diet with greater inclusion of healthy foods was important to predict the activity of the cardioprotective enzyme PON1 combined with the C(-107)T polymorphism of the PON1 gene. Resumo: Objetivo: A enzima cardioprotetora Paraoxonase 1 (PON1) sofre importante influência de polimorfismos genéticos e fatores nutricionais. O objetivo deste estudo foi investigar a influência da alimentação, do estado nutricional e do polimorfismo C(-107)T sobre a atividade arilesterase da PON1 em crianças. Métodos: Estudo transversal com 97 crianças entre 5 e 8 anos, de ambos os sexos, de um ambulatório de pediatria no sul do Brasil. Realizou-se questionário sociodemográfico, de comportamento e de consumo alimentar, medidas antropométricas e coleta de sangue em laboratório. A atividade arilesterase da PON1 foi mensurada pela extinção de fenol (U/mL), realizada extração do DNA e análise do polimorfismo PON1 C(-107)T. O equilíbrio de Hardy-Weinberg foi testado com qui-quadrado e usada regressão linear para estimar a atividade da PON1 segundo quatro modelos de ajuste, erro aceitável de 5%. Resultados: Na amostra o sexo masculino representou 50,5%, 39,2% tinham 6 anos, 54,5% eram eutróficos e 51,5% tinha atividade da PON1 inferior à mediana (90,0;15-30 U/ml). A frequência dos genótipos foi 54,6% (53/97), 31,0% (30/97) e 14,4% (14/97), respectivamente, para CT, CC e TT, estiveram em equilíbrio de Hardy-Weinberg (p = 0,22). Na análise de regressão o modelo que incluiu variáveis sociodemográficas, de frequência do consumo de frutas, verduras, legumes, laticínios e feijões estimou uma variabilidade de 14,8% na atividade da PON1 combinada ao polimorfismo PON1 C(-107)T. Conclusões: Na infância uma alimentação de boa qualidade, com maior participação de alimentos saudáveis foi importante para predizer a atividade da enzima cardioprotetora PON1 combinada ao polimorfismo C(-107)T do gene da PON1.

ABSTRACT: Objectives: Klebsiella spp. are leading causes of nosocomial infections. Their ability to harbour antimicrobial resistance genes makes them an important public health threat. This study aimed to report the genomic background of carbapenemase-producing Klebsiella quasipneumoniae (HV55B) and Klebsiella michiganensis (HV55D) strains isolated from fresh vegetables destined for hospitalized inpatients. Methods: Microbiological and molecular methods were used to isolate and identify the strains, which were submitted to the antimicrobial susceptibility test and pH tolerance assays. Whole genome sequencing was performed on MiSeq and NextSeq platforms, and online available tools were applied to bioinformatic analysis of clinically relevant information. Results: Both isolates were considered multidrug-resistant and tolerated pH ≥ 4 for 24 h. HV55B belonged to sequence type (ST) ST668, and presented a broad resistome and plasmids from four incompatibility groups. HV55D belonged to ST40. Both strains HV55B and HV55D were genetically close to isolates responsible for human infections around the world, which stands for the plausibility of such bacteria to cause disease in patients of the studied institution. Conclusions: Our results confirm the presence of carbapenemase-producing Klebsiella spp. in fresh foodstuffs intended for hospitalized inpatients’ consumption. The genomes characterized here also provide clinically and genomically relevant information to forthcoming epidemiological surveillance studies.

TDP-43 is aggregated in patients with ALS and FLTD through mechanisms still incompletely understood. Since aggregation in the cytosol is most probably responsible for the delocalization and loss of proper RNA-binding function of TDP-43 in the nucleus, interception of the formation of aggregates may represent a useful therapeutic option.In this study, we investigated the relative importance of the N-terminal and C-terminal moieties of TDP-43 in the aggregation process and the weight of each of the six cysteine residues in determining unfolding and aggregation of the different domains. We report that cytoplasmic inclusions formed by WT and mutant TDP-43 in motor neuron-like NSC34 cells are redox-sensitive only in part, and contain at least two components, i.e. oligomers and large aggregates, that are made of different molecular species.The two N-terminal cysteine residues contribute to the seeding for the first step in oligomerization, which is then accomplished by mechanisms depending on the four cysteines in the RNA-recognition motifs. Cysteine-independent large aggregates contain unfolded isoforms of the protein, held together by unspecific hydrophobic interactions. Interestingly, truncated isoforms are entrapped exclusively in oligomers. Ab initio modeling of TDP-43 structure, molecular dynamics and molecular docking analysis indicate a differential accessibility of cysteine residues that contributes to aggregation propensity.We propose a model of TDP-43 aggregation involving cysteine-dependent and cysteine-independent stages that may constitute a starting point to devise strategies counteracting the formation of inclusions in TDP-43 proteinopathies.

Background: Paediatric Inflammatory Crohn's MRE Index (PICMI) is a multi-point index of intestinal inflammation (mucosal and transmural) for children with CD. The present study aims to assess whether PICMI at diagnosis may predict the course of CD and to test the inter-reader agreement., Methods: CD children with a ≥ 1-year follow-up were retrospectively enrolled. Three radiologists calculated PICMI at diagnosis and association between PICMI and Paediatric Crohn's Disease Activity Index (PCDAI) and CD Endoscopic Index of Severity (CDEIS) was tested., Results: 68 children (median age 13 years IQR: 11-14) with CD with PICMI at diagnosis: remission 6 (8.8 %), mild 29 (42.6 %), moderate 24 (35.3 %), severe 9 (13.2 %), were enrolled. PICMI score significantly correlated with PCDAI at diagnosis (p: 0.036). Steroid-free remission at 1, 3 and 5 years was comparable between PICMI groups (p: 0.606). Higher PICMI at diagnosis was associated with higher biologic introduction at 1 year: incidence rate ratio IRR: 2.17 (1.09-4.42); p = 0.019, 3-year IRR: 2.12 (1.15-3.96); p = 0.011, and 5 years: 2.21 (1.20-4.08); p = 0.007., Conclusions: PICMI score is a reliable and almost reproducible index to score activity in children with CD. Children with higher PICMI scores of disease activity at diagnosis required more biologic treatment to achieve comparable rates of steroid-free remission if compared with lower PICMI scores., Competing Interests: Conflict of interest AR, CV, AG, PAB, DI, NS, MC, GZ, PM, LDA, LN: none related to the paper., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Infertility is recognized as a multifaceted condition affecting approximately 15% of couples globally, influenced by various factors including genetic predisposition and environmental exposures. Among these environmental factors, bisphenol A (BPA) emerges as a prominent Endocrine-disrupting chemical (EDCs) widely distributed, leading to chronic human exposure in daily life. As regulations on BPA became more stringent, alternative substances such as bisphenol S (BPS) and bisphenol F (BPF) have emerged. Animal studies have demonstrated a dose-dependent decline in fertility and embryotoxicity following chronic exposure to BPA. However, literature data on human studies are limited and heterogeneous. Additionally, even less is known about the relationship between exposure to the BPA analogues (BPS and BPF) and sperm quality. Therefore, the present study aimed to examine the association between urinary concentrations of BPA, BPF, and BPS and semen quality parameters among 195 adult Spanish men from the Led-Fertyl study cohort using multiple linear regression models adjusted by potential confounding variables. Our results revealed an inverse association between log-transformed creatinine-adjusted concentration (ng/mg) of BPA and BPF levels and the percentage of sperm vitality (β: 3.56 %; 95%CI: 6.48 to -0.63 and β: 4.14 %; 95%CI: 6.97 to -1.31; respectively). Furthermore, participants in the highest quartile of BPA and BPF urinary concentration exhibited lower sperm vitality compared to those in the lowest quartile (β: 6.90 %; 95%CI: 11.60 to -2.15 and β: 9.68 %; 95%CI: 14.43 to -4.94; respectively). These results supply epidemiological evidence establishing a relationship between bisphenols urine exposure and sperm quality, suggesting that a re-evaluation of the overall safety of BPA alternatives is warranted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The underlying mechanisms and clinical impact of portal microthrombosis in severe COVID-19 are unknown. Intrapulmonary vascular dilation (IPVD)-related hypoxia has been described in severe liver diseases. We hypothesised that portal microthrombosis is associated with IPVD and fatal respiratory failure in COVID-19., Methods: Ninety-three patients who died from COVID-19 were analysed for portal microvascular damage (histology), IPVD (histology and chest-computed tomography, CT), and hypoxemia (arterial blood gas). Seventeen patients who died from COVID-19-unrelated pneumonia served as controls. Vascular lesions and microthrombi were phenotyped for endothelial (vWF) and pericyte (αSMA/PDGFR-β) markers, tissue factor (TF), viral spike protein and nucleoprotein (SP, NP), fibrinogen, and platelets (CD41a). Viral particles in vascular cells were assessed by transmission electron microscopy. Cultured pericytes were infected with SARS-CoV-2 to measure TF expression and tubulisation of human pulmonary microvascular endothelial cells was assessed upon vWF treatment., Results: IPVD was present in 16/66 patients with COVID-19, with available liver and lung histology, and was associated with younger age (62 vs. 78 years-old), longer illness (25 vs. 14 days), worsening hypoxemia (PaO 2 /FiO 2 from 209 to 89), and an increased requirement for ventilatory support (63% vs. 22%) compared to COVID-19/Non-IPVD. IPVD, absent in controls, was confirmed by chest CT. COVID-19/IPVD liver histology showed portal microthrombosis in >82.5% of portal areas, with a thicker wall of αSMA/PDGFR-β + /SP + /NP + pericytes compared with COVID-19/Non-IPVD. Thrombosed portal venules correlated with αSMA + area, whereas infected SP + /NP + pericytes expressed TF. SARS-CoV-2 viral particles were observed in portal pericytes. In vitro SARS-CoV-2 infection of pericytes upregulated TF and induced endothelial cells to overexpress vWF, which expanded human pulmonary microvascular endothelial cell tubules., Conclusions: SARS-CoV-2 infection of liver pericytes elicits a local procoagulant response associated with extensive portal microthrombosis, IPVD and worsening respiratory failure in fatal COVID-19., Impact and Implications: Vascular involvement of the liver represents a serious complication of COVID-19 infection that must be considered in the work-up of patients with long-lasting and progressively worsening respiratory failure, as it may associate with the development of intrapulmonary vascular dilations. This clinical picture is associated with a procoagulant phenotype of portal venule pericytes, which is induced by SARS-CoV-2 infection of pericytes. Both observations provide a model that may apply, at least in part, to other vascular disorders of the liver, featuring obliterative portal venopathy, similarly characterised at the clinical level by development of hypoxemia and at the histological level by phlebosclerosis and reduced calibre of the portal vein branches in the absence of cirrhosis. Moreover, our findings shed light on an overlooked player in the pathophysiology of thrombosis, i.e. pericytes, which may present a novel therapeutic target., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Nuts are nutrient-dense foods touted for their health-promoting effects, especially regarding cardiovascular health, yet inconsistencies in the literature remain in relation to their effect on blood lipids. Hence, a systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to determine the effect of nut intake on blood lipids., Data Synthesis: MEDLINE-PubMed and Cochrane databases were searched. 113 unique trials met eligibility criteria (n = 8060 adults with various health status) assessing the effect of a median daily dose of 45.5 g/d of nuts compared to a non-nut control on blood lipid outcomes met inclusion criteria. Overall, nut consumption resulted in moderate reductions in total cholesterol (mean difference, -0.14 mmol/L [95 % confidence interval, -0.18 to -0.10 mmol/L]) and LDL-C (-0.12 mmol/L [-0.14 to -0.09 mmol/L]), with small reductions in triglycerides (-0.05 mmol/L [-0.07 to -0.03 mmol/L]), TC:HDL-C (-0.11 [-0.16 to -0.06]), LDL-C:HDL-C (-0.19 [-0.24 to -0.12]), and apolipoprotein B (-0.04 g/L [-0.06 to -0.02 g/L]). There was no significant impact on HDL-cholesterol or other assessed measures. Certainty of evidence was high for apolipoprotein A, and generally moderate/low for all other outcomes. Sensitivity analysis did not change the evidence on the main outcomes. Significant effect modifications in subgroup analysis were shown for most of the lipid parameters assessed. None of these subgroup effects altered the evidence of heterogeneity for any primary outcome., Conclusions: Current evidence provides a good indication that consuming nuts may advantageously affect blood lipids in adults with a mix of health status., Prospero Registration: PROSPERO identifier, CRD42022358688., Competing Interests: Declaration of competing interest S.K.N. is a volunteer member of the not-for-profit group Plant-Based Canada. J.S.-S. reported receiving research support from the Instituto de Salud Carlos III, Ministerio de Educación y Ciencia, the European Commission, the USA National Institutes of Health; receiving consulting fees or travel expenses from Instituto Danone and Abbott Laboratories, receiving nonfinancial support from Patrimonio Comunal Olivarero, the Almond Board of California, Pistachio Growers and Borges S.A; serving on the board of and receiving grant support through his institution from the International Nut and Dried Foundation; and personal fees from Instituto Danone; Serving in the Board of Danone Institute International. None of these organizations had any role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. All other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Ultra-processed food (UPF) consumption has increased dramatically over the last decades worldwide. Although it has been linked to some cardiometabolic comorbidities, there is limited evidence regarding kidney function. This study aimed to cross-sectionally and longitudinally assess the association between UPF consumption and estimated-glomerular filtration rate (eGFR) based on Cystatin C (CysC)., Methods: Older adults (mean age 65 ± 5.0 years, 46% women) with overweight/obesity and metabolic syndrome (MetS) who had available data of CysC at baseline (n = 1909), at one-year and at 3-years of follow-up (n = 1700) were analyzed. Food consumption was assessed using a validated 143-item semi-quantitative food frequency questionnaire and UPF consumption (% of g/d) at baseline and changes after one-year of follow-up were estimated according to NOVA classification system. Multivariable-adjusted linear and logistic regression models were performed to evaluate the cross-sectional associations between UPF consumption with eGFR levels and decreased kidney function (eGFR <60 ml/min/1.73 m2) at baseline. Multivariable-adjusted mixed-effects linear regression models were fitted to investigate the associations between one-year changes in UPF and eGFR over 3-years of follow-up., Results: Individuals with the highest baseline UPF consumption showed lower eGFR (β: -3.39 ml/min/1.73 m 2 ; 95% CI: -5.59 to -1.20) and higher odds of decreased kidney function (OR: 1.64; 95% CI: 1.21 to 2.22) at baseline, compared to individuals in the lowest tertile. Participants in the highest tertile of one-year changes in UPF consumption presented a significant decrease in eGFR after one-year of follow-up (β: -1.45 ml/min/1.73 m 2 ; 95% CI: -2.90 to -0.01) as well as after 3-years of follow-up (β: -2.18 ml/min/1.73 m 2 ; 95% CI: -3.71 to -0.65) compared to those in the reference category., Conclusions: In a Mediterranean population of older adults with overweight/obesity and MetS, higher UPF consumption at baseline and one-year changes towards higher consumption of UPF were associated with worse kidney function at baseline and over 3-years of follow-up, respectively., Clinical Trial Registry Number: ISRCTN89898870., Competing Interests: Conflict of interest JS-S reported receiving research support from the California Walnut Commission, Patrimonio Comunal Olivarero, La Morella Nuts, and Borges S.A; receiving consulting fees or travel expenses from Instituto Danone, Abbott Laboratories and Mundifarma, receiving nonfinancial support from Hojiblanca, Patrimonio Comunal Olivarero, and Almond Board of California; serving on the board of and receiving grant support through his institution from the International Nut and Dried Foundation and the Eroski Foundation. All other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Short telomeres have been observed in chronic disease patients. Identifying environmental and lifestyle factors that could reduce telomere attrition is crucial for disease prevention. The aim of this work was to determine whether weight-loss induced by an energy-reduced Mediterranean diet (erMedDiet) and physical activity (PA) could modify telomere length (TL)., Methods: In 317 randomized non-smoker participants (mean age, 65.8 ± 4.98 years) with metabolic syndrome from two "Prevención con Dieta Mediterránea-Plus" (PREDIMED-Plus) trial centers, we evaluated MedDiet adherence, PA, anthropometric variables and TL at baseline and after a 3-year intervention using an intensive lifestyle program (IG) with an erMedDiet and PA or an unrestricted MedDiet without PA promotion (CG)., Results: Participants in the IG displayed greater 3-year weight reductions (-3.7 ± 4 kg, P < 0.001) compared to those in the CG. No differences in TL changes between groups were observed in the cohort as a whole. However, an interaction was observed between the intervention group and sex for TL changes (p interaction  = 0.039). Women in the IG showed an increase in TL after 3-y (+0.25 ± 0.9, relative units) compared to women in the CG (-0.07 ± 1.0) (p ANCOVA  = 0.036), whereas no differences between groups were observed in men. Women in the IG had a lower risk of telomere shortening after the intervention (OR = 0.17, 95%CI: 0.05-0.64, p = 0.008) compared to women in the CG., Conclusions: A 3-year lifestyle intervention based on an erMedDiet and PA slowed telomere shortening in women but not in men., Trial Registration: ISRCTN, ISRCTN89898870. Registered 24 July 2014- Retrospectively registered, https://www.isrctn.com/ISRCTN89898870., Competing Interests: Conflict of interest All authors declare that they have no conflict of interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers., Patients and Methods: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies., Results: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation., Conclusions: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research., Competing Interests: Disclosure AJ: Honoraria: AstraZeneca. CH: Honoraria: Roche, Novartis; research funding: Boehringer Ingelheim; consulting or advisory board: Boehringer Ingelheim. CVG: Employed by Illumina since August 2021. LM reports non-financial support from Celgene outside the submitted work (travel expenses). MAu: Consulting or advisory board membership: Bristol-Myers Squibb, Ipsen, Merck KGaA, MSD Sharp & Dohme, Novartis, Pfizer, Roche, PharmaMar; research funding: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Exelixis, Ipsen, Merck KGaA, Novartis, Pfizer, PharmaMar, Roche; honoraria: Blueprint Medicines, Bristol-Myers Squibb, Ipsen, Janssen-Cilag, Merck KGaA, Pfizer, PharmaMar. PHoh: Advisory board membership: Roche, Deciphera, PharmaMar, Pfizer, BluMedicine, GSK; honoraria: Bristol-Meyers-Squibb, Astrazeneca; research funding: Novartis, Siemens. MK: Honoraria: Bayer, MSD, Eisai, Ipsen, Eli Lilly; research funding: Eli Lilly, Ipsen, Loxo Oncology. RFS: Consulting or advisory board membership: Astellas, Bristol-Myers Squibb, Celgene, Pfizer; research funding: AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, PharmaMar, Roche; honoraria: Daiichi Sankyo, Pfizer. GF: Honoraria: Amgen, Armo Biosciences, Bayer, Bristol-Myers Squibb, Eli Lilly, HRA Pharma, Merck KGaA, MSD Sharp & Dohme, Pierre Fabre, Roche, Sanofi, Servier, Shire; research funding: Merck KGaA. SB: Consulting or advisory board membership: ADC Therapeutics, Blueprint Medicines, Daichii-Sankyo, Deciphera, Eli Lilly, Exelixis, Janssen-Cilag, Mundipharma, Novartis, Plexxikon; honoraria: Bayer, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, PharmaMar; research funding: Blueprint Medicines, Incyte, Novartis. JTS: Consulting or advisory board membership: AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Immunocore, Novartis, Roche, Shire; honoraria: AstraZeneca, Aurikamed, Baxalta, Bristol Myers Squibb, Celgene, Falk Foundation, iomedico, Immunocore, Novartis, Roche, Shire; research funding: Bristol-Myers Squibb, Celgene, Roche; minor equity in iTheranostics and Pharma15; member of the Board of Directors for Pharma15, all outside the submitted work. ALI: Honoraria: Bristol-Myers Squibb, Janssen-Cilag, Takeda, Roche. NvB: Consulting or advisory board membership: Novartis; honoraria: Novartis, Takeda. PJJ: Consulting or advisory board membership, honoraria, research funding, travel or accommodation expenses: Abbvie, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Novartis, Pfizer, Roche, Servier. KHM: Consulting: Celgene/BMS, Novartis, Jazz Pharmaceuticals, Pfizer; honoraria: Celgene/BMS, Daiichi Sankyo, Astellas, AbbVie, Novartis; research funding: Celgene. AS: Consulting or advisory board membership, honoraria: AGCT, AstraZeneca, Bayer, Bristol-Myers Squibb, Chugai, Eli Lilly, Illumina, Janssen, MSD Sharp & Dohme, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, Thermo Fisher; research funding: Bayer, Bristol-Myers Squibb, Chugai. WW: Consulting or advisory board membership, honoraria: Agilent, Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Illumina, Merck, MSD Sharp & Dohme, Pfizer, NewOncology, Novartis, Roche, Takeda; research funding: AstraZeneca, Bristol-Myers Squibb, MSD Sharp & Dohme, Roche. SF: Consulting or advisory board membership: Bayer, Illumina, Roche; honoraria: Amgen, Eli Lilly, PharmaMar, Roche; research funding: AstraZeneca, Pfizer, PharmaMar, Roche; travel or accommodation expenses: Amgen, Eli Lilly, Illumina, PharmaMar, Roche. ES: Honoraria: AstraZeneca, Illumina. All other authors have declared no conflicts of interest. Data sharing All evaluated germline variants can be found in Supplementary Table S5, available at https://doi.org/10.1016/j.annonc.2022.07.008. Sequencing data have been deposited in the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/datasets) under accession EGAS00001005537., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In an active motor unit (MU), the time intervals between the firings of its muscle fibers vary across successive MU activations. This variability is called jitter and is increased in pathological processes that affect the neuromuscular junctions or terminal axonal segments of MUs. Traditionally, jitter has been measured using single fiber electrodes (SFEs) and a difficult and subjective manual technique. SFEs are expensive and reused, implying a potential risk of patient infection; so, they are being gradually substituted by safer, disposable, concentric needle electrodes (CNEs). As CNEs are larger, voltage contributions from individual fibers of a MU are more difficult to detect, making jitter measurement more difficult. This paper presents an automatic method to estimate jitter from trains of motor unit potentials (MUPs), for both SFE and CNE records. For a MUP train, segments of MUPs generated by single muscle fibers (SF MUP segments) are found and jitter is measured between pairs of these segments. Segments whose estimated jitter values are not reliable, according to several SF MUP segment characteristics, are excluded. The method has been tested in several simulation studies that use mathematical models of muscle fiber potentials. The results are very satisfactory in terms of jitter estimation error (less than 10% in most of the cases studied) and mean number of valid jitter estimates obtained per simulated train (greater than 1.0 in many of the cases and less than 0.5 only in the most complicated). A preliminary study with real signals was also performed, using 19 MUP trains from 3 neuropathic patients. Jitter measurements obtained by the automatic method were compared with those extracted from a commercial system (Keypoint) and the edition and supervision of an expert electromyographer. From these measurements 63% were taken from equivalent interval pair sites within the time span of the MUP trains and, as such, were considered as compatible measurements. Differences in jitter of these compatible measurements were very low (mean value of 1.3 μs, mean of absolute differences of 2.97 μs, 25% and 75% percentile intervals of -0.85 and 3.82 μs, respectively). Although new tests with larger number of real recordings are still required, the method seems promising for clinical practice., Competing Interests: Declaration of competing interest No conflicts of interests related to the manuscript are declared., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In the Bay of Biscay, regional monitoring programmes and data on abundance and distribution of floating marine litter are scarce, contrary to many other European marine regions. Here, a joint analysis of multiyear observations (2017-2019) of floating micro and macrolitter and oceanographic conditions was conducted for the Bay of Biscay by combining microlitter samplings with neuston nets and vessel-based macrolitter observations. Results show spatiotemporal abundance and distribution patterns. The density of floating microlitter increased from 26,056 items/km 2 in 2017 to 1,802,4611 items/km 2 in 2019; floating macrolitter densities barely varied amongst year (2.52 items/km 2 in 2017 and 3.70 items/km 2 in 2019). No significant correlation was found between densities of micro and macrolitter, neither for the oceanographic variables. We conclude that longer micro and macrolitter monitoring periods and standardized datasets based on the cross-border cooperation are needed to collect more comparable information, evaluate trends, and support decision making in the area., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This paper proposes a novel method for offline outlier detection in nonlinear dynamical systems using an input-output dataset of a Topical Negative Pressure Wound Therapy Device, NPWT. The fundamental characteristics of an NPWT describe a chaotic system whose states vary over time and may result in unpredictable and possibly anomalous divergent behavior in the presence of perturbations and other unmodeled system dynamics, despite a quasi-stable controller. Bacterial Memetic Algorithm, BMA, is used to generate fuzzy rule-based models of the input-output dataset. The error definition in the fuzzy rule extraction features a novel application of the Canberra Distance. The optimal number of rules for identifying the outliers, validated against both artificial and real system datasets, is calculated from the sample of inferred fuzzy models. The optimal number of rules is two in both cases based on the maximum average-error-drop. Using three or more rules results in better error performance; however, the algorithm learns the nuances of the outlier patterns instead. Novel methods for creating the outlier list and determining the optimal number of rules for the outlier detection problem are proposed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 ISA. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19., Methods: Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism., Results: Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling., Conclusion: IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism behind liver injury in these patients., Lay Summary: Patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in patients with COVID-19. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The environmental impact of desalination is the most important concern related to its sustainable development. We present the results of a long-term environmental plan to monitor brine discharge (BD) from a desalination plant located in a high environmental value area in Spain. Generalized additive models were used to analyze the biological parameters of biological communities. Results of 17 years of BD monitoring show how its environmental impact can be minimized through well-planned decision-making between scientists and industry. The brine dilution prior to its discharge into an artificial channel of low ecological value significantly reduced the brine influence area. P. oceanica shoot production and echinoderms abundances were relatively stable across historical series and similar values in control and impacts locations were observed. Conversely, there was a higher abundance and species richness of fishes in the BD area. The important findings reported here should be considered for future applications in similar projects., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In 2019, a new coronavirus (2019-nCoV) infecting Humans has emerged in Wuhan, China. Its genome has been sequenced and the genomic information promptly released. Despite a high similarity with the genome sequence of SARS-CoV and SARS-like CoVs, we identified a peculiar furin-like cleavage site in the Spike protein of the 2019-nCoV, lacking in the other SARS-like CoVs. In this article, we discuss the possible functional consequences of this cleavage site in the viral cycle, pathogenicity and its potential implication in the development of antivirals., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Prediction of metastatic outcome in sarcomas is challenging for clinical management since they are aggressive and carry a high metastatic risk. A 67-gene expression signature, the Complexity INdex in SARComas (CINSARC), has been identified as a better prognostic factor than the reference pathological grade. Since it cannot be applied easily in standard laboratory practice, we assessed its prognostic value using nanoString on formalin-fixed, paraffin-embedded (FFPE) blocks to evaluate its potential in clinical routine practice and guided therapeutic management., Methods: A code set consisting of 67 probes derived from the 67 genes of the CINSARC signature was built and named NanoCind®. To compare the performance of RNA-seq and nanoString (NanoCind®), we used expressions of various sarcomas (n = 124, frozen samples) using both techniques and compared predictive values based on CINSARC risk groups and clinical annotations. We also used nanoString on FFPE blocks (n = 67) and matching frozen and FFPE samples (n = 45) to compare their level of agreement. Metastasis-free survival and agreement values in classification groups were evaluated., Results: CINSARC strongly predicted metastatic outcome using nanoString on frozen samples (HR = 2.9, 95% CI: 1.23-6.82) with similar risk-group classifications (86%). While more than 50% of FFPE blocks were not analyzable by RNA-seq owing to poor RNA quality, all samples were analyzable with nanoString. When similar (risk-group) classifications were measured with frozen tumors (RNA-seq) compared with FFPE blocks (84% agreement), the CINSARC signature was still a predictive factor of metastatic outcome with nanoString on FFPE samples (HR = 4.43, 95% CI: 1.25-15.72)., Conclusion: CINSARC is a material-independent prognostic signature for metastatic outcome in sarcomas and outperforms histological grade. Unlike RNA-seq, nanoString is not influenced by the poor quality of RNA extracted from FFPE blocks. The CINSARC signature can potentially be used in combination with nanoString (NanoCind®) in routine clinical practice on FFPE blocks to predict metastatic outcome.

Background and Aims: Several epidemiological studies highlighted the association between folate and B-vitamins low intake and cardiovascular diseases (CVD) risk. Contrasting results were reported on the relationship between folate intake and DNA-methylation. Folate and B-vitamins may modulate DNA-methylation of specific enzymes which are included in the One-Carbon Metabolism (OCM) and in the homocysteine (Hcy) pathways. The aim of the study was to evaluate whether DNA-methylation profiles of OCM and Hcy genes could modulate the myocardial infarction (MI) risk conferred by a low B-vitamins intake., Methods and Results: Study sample (206 MI cases and 206 matched controls) is a case-control study nested in the prospective EPIC cohort. Methylation levels of 33 candidate genes where extracted by the whole epigenome analysis (Illumina-HumanMethylation450K-BeadChip). We identified three differentially methylated regions in males (TCN2 promoter, CBS 5'UTR, AMT gene-body) and two in females (PON1 gene-body, CBS 5'UTR), each of them characterized by an increased methylation in cases. Functional in silico analysis suggested a decreased expression in cases. A Recursively Partitioned Mixture Model cluster algorithm identified distinct methylation profiles associated to different MI risk: high-risk vs. low-risk methylation profile groups, OR = 3.49, p = 1.87 × 10(-)(4) and OR = 3.94, p = 0.0317 in males and females respectively (multivariate logistic regression adjusted for classical CVD risk factors). Moreover, a general inverse relationship between B-vitamins intake and DNA-methylation of the candidate genes was observed., Conclusions: Our findings support the hypothesis that DNA-methylation patterns in specific regions of OCM and Hcy pathways genes may modulate the CVD risk conferred by folate and B-vitamins low intake., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A laboratory strain of Schistosoma mansoni subjected to repeated in vivo praziquantel (PZQ) treatments for several generations has been previously found to have lesser sensitivity to the drug than the original unselected strain. In this study we have collected evidence on the mode of inheritance of the partial insensitivity exhibited by the PZQ-selected schistosomes. A single male and a single female worm of the two strains, assorted in the four possible combinations, were introduced into the mesenteric veins of mice and the eggs produced by each pair were used as the source of the F(1) progeny. PZQ sensitivity was assessed using both in vivo and in vitro methods. In the first approach, the PZQ ED(50) was determined by infecting mice with cercariae of the strains to be tested, treating at seven weeks with different drug doses and counting the number of surviving worms three weeks later. For the in vitro approach, adult schistosomes kept in culture were exposed overnight to different PZQ concentrations and their survival was monitored during the subsequent 7 days. Results from both approaches lead to the conclusion that hybrid schistosomes of the F(1) generation have a drug sensitivity intermediate between those of the two parental strains and are thus suggestive of a pattern of partial dominance for the trait under study.

Marine protected areas (MPAs) could be useful as fisheries management tools for the exportation of pelagic eggs, larvae and adult fish. A decreasing gradient of fish biomass across MPAs boundary may indicate export. We determine whether gradients of decreasing biomass of fish assemblage occurred in Tabarca Marine Reserve over two habitats with different continuity across the boundaries, to test if the patchy nature of the marine environment might act as a barrier for the fish export. In general, significant decreasing gradients in total fish biomass and biomass of some species were observed on P. oceanica and rocky substrates, independently of their different continuity through the reserve boundaries. Changes in the multivariate structure of the fish assemblage were correlated with the distance from integral reserve. All of these results support the hypothesis that the exportation of adult fish from Tabarca Marine Reserve occurs, and this process may influence the surrounding fished areas.

Background: Diet-induced weight reduction promotes a decrease in resting energy expenditure that could partly explain the difficulty in maintaining reduced body mass. Whether this reduction remains after stabilized weight loss is still controversial, and the molecular mechanisms are unknown., Objective: The objective was to investigate the effect of a stabilized 10% weight loss on body composition, metabolic profile, and skeletal muscle gene expression profiling., Design: Obese women were assigned to a 4-wk very-low-calorie diet, a 3-6-wk low-calorie diet, and a 4-wk weight-maintenance program to achieve a 10% weight loss. Resting energy expenditure, body composition, plasma variables, and skeletal muscle transcriptome were compared before weight loss and during stabilized weight reduction., Results: Energy restriction caused an 11% weight loss. Stabilization to the new weight was accompanied by an 11% decrease in the resting metabolic rate normalized to the body cellular mass. A large number of genes were regulated with a narrow range of regulation. The main regulated genes were slow/oxidative fiber markers, which were overexpressed, and the gene encoding the glucose metabolism inhibitor PDK4, which tended to be down-regulated. The knowledge-based approach gene set enrichment analysis showed that a set of genes related to long-term calorie restriction was up-regulated, whereas sets of genes related to insulin, interleukin 6, and ubiquitin-mediated proteolysis were down regulated., Conclusions: Weight loss-induced decreases in resting metabolic rate persist after weight stabilization. Changes in skeletal muscle gene expression indicate a shift toward oxidative metabolism.

Mice given 10-weekly injections (i.m.) of 20 mumol of isopropyl methanesulfonate (IPMS) in trioctanoin exhibited depressed hematopoiesis as manifested by reduced peripheral blood counts and by reduced thymic and bone marrow cellularities. The treatments were particularly toxic to erythroid populations and ultimately induced signs of splenic erythropoiesis. Bone marrow cellularity recovered during the latter stages of the treatments indicating that subpopulations of hematopoietic cells were resistant to the treatments. This recovery of bone marrow cellularity may bear on the recently discovered leukemogenic potential of IPMS.