Key epidemiological indicators and spatial autocorrelation patterns across five waves of COVID-19 in Catalonia

Epidemiology; StatisticsEpidemiología; EstadísticasEpidemiologia; EstadístiquesThis research studies the evolution of COVID-19 crude incident rates, effective reproduction number R(t) and their relationship with incidence spatial autocorrelation patterns in the 19 months following the disease outbreak in Catalonia (Spain). A cross-sectional ecological panel design based on n = 371 health-care geographical units is used. Five general outbreaks are described, systematically preceded by generalized values of R(t) > 1 in the two previous weeks. No clear regularities concerning possible initial focus appear when comparing waves. As for autocorrelation, we identify a wave’s baseline pattern in which global Moran’s I increases rapidly in the first weeks of the outbreak to descend later. However, some waves significantly depart from the baseline. In the simulations, both baseline pattern and departures can be reproduced when measures aimed at reducing mobility and virus transmissibility are introduced. Spatial autocorrelation is inherently contingent on the outbreak phase and is also substantially modified by external interventions affecting human behavior.All the authors acknowledge funding from the Social Observatory of the “la Caixa” Foundation as part of the project LCF/PR/SR20/52550011. Partial funding was also received from the Spanish Ministry of Science and Innovation (PID2020-117029RB-I00). Joan Benach gratefully acknowledges the financial support by ICREA under the ICREA Academia programme. J. Fernández-Gracia was supported by Direcció General de Política Universitària i Recerca from the government of the Balearic Islands through the postdoctoral program Vicenç Mut. J. P. Rodríguez is supported by Juan de la Cierva Formacion program (Ref. FJC2019-040622-I) funded by MCIN/AEI/ https://doi.org/10.13039/501100011033

Review article: The need for more efficient and patient-oriented drug development pathways in NASH—setting the scene for platform trials

Drug development; Non-alcoholic steatohepatitis; Study designsDesenvolupament de fàrmacs; Esteatohepatitis no alcohòlica; Dissenys d'estudiDesarrollo de fármacos; Esteatohepatitis no alcohólica; Diseños de estudioBackground and Aims Non-alcoholic steatohepatitis (NASH) constitutes a significant unmet medical need with a burgeoning field of clinical research and drug development. Platform trials (PT) might help accelerate drug development while lowering overall costs and creating a more patient-centric environment. This review provides a comprehensive and nuanced assessment of the NASH clinical development landscape. Methods Narrative review and expert opinion with insight gained during the EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project. Results Although NASH represents an opportunity to use adaptive trial designs, including master protocols for PT, there are barriers that might be encountered owing to distinct and sometimes opposing priorities held by these stakeholders and potential ways to overcome them. The following aspects are critical for the feasibility of a future PT in NASH: readiness of the drug pipeline, mainly from large drug companies, while there is not yet an FDA/EMA-approved treatment; the most suitable design (trial Phase and type of population, e.g., Phase 2b for non-cirrhotic NASH patients); the operational requirements such as the scope of the clinical network, the use of concurrent versus non-concurrent control arms, or the re-allocation of participants upon trial adaptations; the methodological appraisal (i.e. Bayesian vs. frequentist approach); patients' needs and patient-centred outcomes; main regulatory considerations and the funding and sustainability scenarios. Conclusions PT represent a promising avenue in NASH but there are a number of conundrums that need addressing. It is likely that before a global NASH PT becomes a reality, ‘proof-of-platform’ at a smaller scale needs to be provided.JMP reports having received consulting fees from Boehringer-Ingelheim, MSD and Novo Nordisk. He has received speaking fees from Gilead, Intercept, and Novo Nordisk, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has received educational and research support from Madrigal, Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD. Funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898. NAdP works for Janssen. QMA is Coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multistakeholder consortium includes industry partners. He reports research Grant Funding: Allergan/Tobira, AstraZeneca, Boehringer-Ingelheim, Glaxo SmithKline, Glympse Bio, Intercept, Novartis Pharma AG, Pfizer Ltd. Consultancy: 89Bio, Abbvie/Allergan, Akero, Altimentiv, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Boehringer-Ingelheim, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genentech, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Johnson & Johnson, Madrigal, MedImmune, Medpace, Merck, Metacrine, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, PathAI, Pfizer Ltd., Poxel, ProSciento, Raptor Pharma, Roche, Servier, Shionogi, Terns, The Medicines Company, Viking Therapeutics. Speaker: Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, Kenes, Medscape. Royalties: Elsevier Ltd. PM works for Novartis. MSK is an employee of and a shareholder in Novo Nordisk A/S. JG has received consulting fees from Boehringer-Ingelheim, speaking fees from Echosens and travel expenses from Gilead and Abbie. Funds from ISCIII PI18/00947 and PI21/00691. JRE has received speaking fees from Gilead. FT lab’ work has been supported by the German Research Foundation (DFG, CRC/TR 362) and research grants from Gilead, Allergan, Bristol-Myers Squibb and Inventiva. VR consults for and Intercept, Novo Nordisk, Galmed, Poxel, NGM, Madrigal, Enyo, Sagimet, 89 Bio, Prosciento, Terns, and Theratechnologies, and received grants from Intercept and Gilead

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis

Homeostasis; PathogenesisHomeostasis; PatogénesisHomeòstasi; PatogènesiProgressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS−/−) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS−/− mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS−/− livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.This work was supported by the MICINN Retos RTI2018-095673-B-I00, PID2020-11782RB-I00, PID2020-117941RB-I00, all of which were co-funded with FEDER funds, AMMF 2018/117, COST Action CA17112 and Comunidad de Madrid S2022/BMD-7409. This project has received funding from the European Horizon’s research and innovation program HORIZON-HLTH-2022-STAYHLTH-02 under agreement No. 101095679. The research group belongs to the validated Research Groups Ref. 970935 Liver Pathophysiology, 920631 Lymphocyte Immunobiology and IBL-6 (imas12-associated). KZ was supported by the China Scholarship Council. SM-G was supported by a predoctoral scholarship from Complutense University

Prevalence and Risk Factors of MASLD and Liver Fibrosis amongst the Penitentiary Population in Catalonia: The PRISONAFLD Study

Metabolic dysfunction-associated steatotic liver disease; Metabolic syndrome; PrisonMalaltia hepàtica esteatòtica associada a disfunció metabòlica; Síndrome metabòlica; PresóEnfermedad hepática esteatósica asociada a disfunción metabólica; Síndrome metabólico; PrisiónBackground and Aims: The prevalence of chronic non-communicable diseases, particularly metabolic syndrome (MetS), has increased among the prison population. Nevertheless, we have limited data on metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of this syndrome. We aimed to investigate the prevalence and risk factors of MASLD and MASLD-associated liver fibrosis in the penitentiary population in Catalonia, Spain. Method: A cross-sectional observational study involving eight penitentiary centers. Participants had at least one metabolic disorder and were at a closed-regimen penitentiary. Individuals with concomitant liver diseases and/or alcohol risk consumption were excluded. Significant fibrosis and MASLD were defined as liver stiffness ≥8 kPa and a controlled attenuation parameter ≥275 dB/m by vibration-controlled transient elastography (VCTE), respectively. After exclusions, metabolic inmates with VCTE were analyzed. Logistic regression analysis was performed to identify predictors of MASLD and MASLD-associated significant fibrosis. Results: Out of the 4338 inmates studied, 1290 (29.7%) had metabolic disorders, and 646 (14.9%) underwent VCTE. The mean age was 48.0 years (SD 12.1), and 89.5% were male. MASLD prevalence was 33.9%. Significant fibrosis and MASLD-associated significant fibrosis were found in 16.4% and 9.4% of inmates, respectively. In the multivariate analysis, T2D, waist circumference, MetS, and higher ALT values were identified as independent risk factors for MASLD and MASLD-associated significant fibrosis amongst the prison population. Conclusions: Metabolic disorders including MASLD are highly prevalent among inmates. The prevalence of significant fibrosis seems notably higher than that of the general population, underscoring the need for targeted screening programs and therapeutic interventions in the incarcerated population

Proteomic Analysis of Dysfunctional Liver Sinusoidal Endothelial Cells Reveals Substantial Differences in Most Common Experimental Models of Chronic Liver Diseases

Animal models; Chronic liver disease; Endothelial dysfunctionModels animals; Malaltia hepàtica crònica; Disfunció endotelialModelos animales; Enfermedad hepática crónica; Disfunción endotelialMolecular markers of dedifferentiation of dysfunctional liver sinusoidal endothelial cells (LSEC) have not been fully elucidated. We aimed at deciphering the molecular profile of dysfunctional LSEC in different pathological scenarios. Flow cytometry was used to sort CD11b−/CD32b+ and CD11b−/CD32b− LSEC from three rat models of liver disease (bile duct ligation-BDL; inhaled carbon tetrachloride-CCl4; and high fat glucose/fructose diet-HFGFD). A full proteomic profile was performed applying nano-scale liquid chromatography tandem mass spectrometry (nLC-MS) and analyzed with PEAKS software. The percentage of CD32b− LSEC varied across groups, suggesting different capillarization processes. Both CD32+ and CD32b− LSEC from models are different from control LSEC, but differently expressed proteins in CD32b− LSEC are significantly higher. Heatmaps evidenced specific protein expression patterns for each model. Analysis of biological significance comparing dysfunctional CD32b− LSEC with specialized CD32b+ LSEC from controls showed central similarities represented by 45 common down-regulated proteins involved in the suppression of the endocytic machinery and 63 common up-regulated proteins associated with the actin-dependent cytoskeleton reorganization. In summary; substantial differences but also similarities in dysfunctional LSEC from the three most common models of liver disease were found, supporting the idea that LSEC may harbor different protein expression profiles according to the etiology or disease stage.This work was supported by grants PI18/00947 and AC18/00033 (ENM3 2018) and PI21/00691 from Instituto de Salud Carlos III (ISCIII) and cofounded by the European Union (ERDF/ESF, “Investing in your future”). J.G. is the recipient of a clinical intensification award and D.H. of a Sara Borrell grant, both from ISCIII. M.G. and A.B. have predoctoral fellowships from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) and ISCIII respectively. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) is supported by ISCIII. The APC was funded by ISCIII

LiverScreen project: study protocol for screening for liver fibrosis in the general population in European countries

Background: The development of liver cirrhosis is usually an asymptomatic process until late stages when complications occur. The potential reversibility of the disease is dependent on early diagnosis of liver fibrosis and timely targeted treatment. Recently, the use of non-invasive tools has been suggested for screening of liver fibrosis, especially in subjects with risk factors for chronic liver disease. Nevertheless, large population-based studies with cost-effectiveness analyses are still lacking to support the widespread use of such tools. The aim of this study is to investigate whether non-invasive liver stiffness measurement in the general population is useful to identify subjects with asymptomatic, advanced chronic liver disease. Methods: This study aims to include 30,000 subjects from eight European countries. Subjects from the general population aged ≥ 40 years without known liver disease will be invited to participate in the study either through phone calls/letters or through their primary care center. In the first study visit, subjects will undergo bloodwork as well as hepatic fat quantification and liver stiffness measurement (LSM) by vibration-controlled transient elastography. If LSM is ≥ 8 kPa and/or if ALT levels are ≥1.5 x upper limit of normal, subjects will be referred to hospital for further evaluation and consideration of liver biopsy. The primary outcome is the percentage of subjects with LSM ≥ 8kPa. In addition, a health economic evaluation will be performed to assess the cost-effectiveness and budget impact of such an intervention. The project is funded by the European Commission H2020 program. Discussion: This study comes at an especially important time, as the burden of chronic liver diseases is expected to increase in the coming years. There is consequently an urgent need to change our current approach, from diagnosing the disease late when the impact of interventions may be limited to diagnosing the disease earlier, when the patient is asymptomatic and free of complications, and the disease potentially reversible. Ultimately, the LiverScreen study will serve as a basis from which diagnostic pathways can be developed and adapted to the specific socio-economic and healthcare conditions in each country

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Differential clinical characteristics and prognosis of intraventricular conduction defects in patients with chronic heart failure

Intraventricular conduction defects (IVCDs) can impair prognosis of heart failure (HF), but their specific impact is not well established. This study aimed to analyse the clinical profile and outcomes of HF patients with LBBB, right bundle branch block (RBBB), left anterior fascicular block (LAFB), and no IVCDs. Clinical variables and outcomes after a median follow-up of 21 months were analysed in 1762 patients with chronic HF and LBBB (n = 532), RBBB (n = 134), LAFB (n = 154), and no IVCDs (n = 942). LBBB was associated with more marked LV dilation, depressed LVEF, and mitral valve regurgitation. Patients with RBBB presented overt signs of congestive HF and depressed right ventricular motion. The LAFB group presented intermediate clinical characteristics, and patients with no IVCDs were more often women with less enlarged left ventricles and less depressed LVEF. Death occurred in 332 patients (interannual mortality = 10.8%): cardiovascular in 257, extravascular in 61, and of unknown origin in 14 patients. Cardiac death occurred in 230 (pump failure in 171 and sudden death in 59). An adjusted Cox model showed higher risk of cardiac death and pump failure death in the LBBB and RBBB than in the LAFB and the no IVCD groups. LBBB and RBBB are associated with different clinical profiles and both are independent predictors of increased risk of cardiac death in patients with HF. A more favourable prognosis was observed in patients with LAFB and in those free of IVCDs. Further research in HF patients with RBBB is warranted

Misconduct Policies in High-Impact Biomedical Journals

<div><h3>Background</h3><p>It is not clear which research misconduct policies are adopted by biomedical journals. This study assessed the prevalence and content policies of the most influential biomedical journals on misconduct and procedures for handling and responding to allegations of misconduct.</p> <h3>Methods</h3><p>We conducted a cross-sectional study of misconduct policies of 399 high-impact biomedical journals in 27 biomedical categories of the Journal Citation Reports in December 2011. Journal websites were reviewed for information relevant to misconduct policies.</p> <h3>Results</h3><p>Of 399 journals, 140 (35.1%) provided explicit definitions of misconduct. Falsification was explicitly mentioned by 113 (28.3%) journals, fabrication by 104 (26.1%), plagiarism by 224 (56.1%), duplication by 242 (60.7%) and image manipulation by 154 (38.6%). Procedures for responding to misconduct were described in 179 (44.9%) websites, including retraction, (30.8%) and expression of concern (16.3%). Plagiarism-checking services were used by 112 (28.1%) journals. The prevalences of all types of misconduct policies were higher in journals that endorsed any policy from editors’ associations, Office of Research Integrity or professional societies compared to those that did not state adherence to these policy-producing bodies. Elsevier and Wiley-Blackwell had the most journals included (22.6% and 14.8%, respectively), with Wiley journals having greater a prevalence of misconduct definition and policies on falsification, fabrication and expression of concern and Elsevier of plagiarism-checking services.</p> <h3>Conclusions</h3><p>Only a third of top-ranking peer-reviewed journals had publicly-available definitions of misconduct and less than a half described procedures for handling allegations of misconduct. As endorsement of international policies from policy-producing bodies was positively associated with implementation of policies and procedures, journals and their publishers should standardize their policies globally in order to increase public trust in the integrity of the published record in biomedicine.</p> </div