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Introduction Type 2 diabetes mellitus (T2DM) is a highly heterogeneous and complex metabolic disease harbouring different metabolic characteristics. Adequate characterisation of subjects is essential to allow the implementation of precision medicine for the prevention, diagnosis, prognosis and treatment of this condition.Methods and analysis This prospective observational cohort study aims to identify and characterise relevant clinical clusters that are reproducibly associated with various clinical outcomes in T2DM in our Mediterranean region. The COPERNICAN study will include 1200 subjects with newly diagnosed T2DM from 28 primary care centres from the city of Barcelona and the healthcare district of Lleida in Catalonia (Spain). Participants will undergo a comprehensive phenotypic evaluation including, among others, six relevant variables: age, antibodies against glutamic acid decarboxylase, body mass index, glycated haemoglobin (HbA1c), indexes of insulin sensibility (HOMA2-IR) and secretion (HOMA2-beta). We will collect additional comprehensive data on glucose-lowering and other drug treatments, clinical evaluation (including complications), laboratory parameters, advanced lipoprotein profile, dietary habits and physical activity. The linkage with the population database will be done to perform a pragmatic follow-up of participants as part of their usual clinical care. A state-of-the-art cluster analysis (k-means and hierarchical clustering) will be performed.Ethics and dissemination The present study complies with all the ethical aspects and protection of participant subjects complying with all current local and European Union legislation. All Ethics Committees from the institutions involved in the study (IR Sant Pau Ethics Committee, Ethics Committee for Drug Research at IDIAP Jordi Gol and University Hospital of Bellvitge Ethics Committee for Research) approved this protocol. Confidentiality and anonymity of the data are ensured according to the current Spanish Organic Law 3/2018 of 05 December.Trial registration number ClinicalTrials.gov. registration number NCT05333718, 27 January 2023.

BackgroundThe increasing use of non-specific immunoglobulins (NSIGs) and their current shortage show a need for NSIGs’ use prioritization. Data from a clinical perspective are necessary, mainly for pediatric patients.ObjectivesThe aim of the study was to assess the level of clinical evidence (LoE) of the indications that NSIGs are used for, the reasons for discontinuation, and the costs invested.MethodsA retrospective multicentric study was conducted on NSIG incident users between September 2019 and December 2021 retrieved from the Registry of Patients and Treatments (RPT) from Catalonia (Spain). LoE was categorized as A) authorized indications, B) unauthorized with scientific support, C) unauthorized without support, and D) unknown (UNK), following local and the United Kingdom’s guidelines as a sensitivity analysis. We also estimated overall spending and costs per patient visit.ResultsA total of 400 patients were included (17.3% pediatric), with a mean follow-up of 122.1/person-years for adults. The most frequent indications were nervous system and blood diseases. Almost all pediatric patients (56; 81.2%) were treated under A-level indications, as for 217 (65.6%) adults. In the sensitivity analysis, the A-level usage rate decreased to one-third and the B-level usage rate increased by 2–3 times. Furthermore, 37.8% (151) of individuals discontinued. This was predominantly due to remission or no response. The total costs were 868,462.6€/year, with median spending per visit amounting to 1,500€ for adults and 700€ for pediatric patients.ConclusionNSIGs are used in clinical practice mainly for approved indications; however, non-approved indications are still an important issue. This could represent a significant economic burden on the healthcare system, focusing on the pediatric population and those at risk for discontinuation with alternative therapeutic options.

Background & Aims: Patients with vascular liver diseases (VLD) are at higher risk of both severe courses of COVID-19 disease and thromboembolic events. The impact of SARS-CoV-2 vaccination in patients with VLD has not been described and represents the aim of our study. Methods: International, multicenter, prospective observational study in patients with VLD analyzing the incidence of COVID-19 infection after vaccination, severity of side effects, occurrence of thromboembolic events and hepatic decompensation. In a subgroup of patients, the humoral and cellular responses to vaccination were also analyzed. Results: A total of 898 patients from 14 European centers – part of the VALDIG network – were included, 872 (97.1%) patients received two vaccine doses (fully vaccinated), and 674 (75.1%) three doses. Of the total cohort, 151/898 had a COVID-19 infection prior to vaccination, of whom 9/151 (5.9%) were re-infected. Of the 747/898 patients who were not previously infected, 11.2% (84/747) were diagnosed with a COVID-19 infection during the study period. Two infected patients required intensive care unit admission and infection was fatal in two fully vaccinated patients. Adverse effects were reported in around 40% of patients, with local side effects being the most frequent. During the study period, 31 (3.5%) patients had thromboembolic events and 21 (2.3%) hepatic decompensations. No cases of vaccine-induced thrombocytopenia were reported. Vaccine immunogenicity was assessed in 36 patients; seroconversion reached 100% and IFNy T-cell responses significantly increased post two mRNA-1273 vaccine doses. Conclusion: Patients with VLD seem to have a preserved immune response to SARS-CoV-2 vaccination, which appears to be safe and effective in preventing severe COVID-19 infection. Our study cannot definitively establish a direct link between vaccination and thrombotic events, though the contribution of vaccination as a cofactor in VLD remains to be elucidated. Impact and implications:: Patients with vascular liver disease (VLD) are at increased risk of both SARS-CoV-2 infection and severe COVID-19 disease. The potential risks associated with vaccination against this infection need thorough investigation. Our research enhances the understanding of the effects of COVID-19 vaccination in patients with VLD, highlighting its good tolerability. Moreover, patients with VLD appear to have a preserved immune response to SARS-CoV-2 vaccination, providing protection against severe COVID-19 infection. Our study cannot definitively establish a direct link between vaccination and thrombotic events, and no cases of vaccine-induced thrombocytopenia were reported.

Background: Inflammatory bowel disease (IBD) affects 5%–10% of ankylosing spondylitis (AS) patients. Prior data suggest AS patients with IBD may have more severe disease and lower HLA-B27 prevalence. Yet, little is known about potential distinctions in AS with IBD compared to those without IBD. Objective: To investigate the clinical characteristics and radiographic differences between patients with (AS) with and without concurrent IBD. Design: This multicenter, observational, cross-sectional study included patients meeting European Spondyloarthropathy Study Group criteria from the Registry of Spondyloarthritis of Spanish Rheumatology (REGISPONSER) and Ibero-American Registry of Spondyloarthropathies (RESPONDIA) registries. Methods: Characteristics and disease burden were compared between patients with and without IBD. Multivariate logistic regression identified factors independently associated with IBD presence in patients with AS. Results: We included a total of 2766 patients with AS (1254 from REGISPONSER and 1512 from RESPONDIA), among whom 142 patients (5.13%) presented with concomitant IBD. AS patients with concurrent IBD were less frequently male, had a lower prevalence of HLA-B27 positivity, experienced a lower prolonged diagnostic delay, had a lower frequency of enthesitis, and received more commonly intensified treatment compared to those without IBD. In terms of structural damage, the Bath Ankylosing Spondylitis Radiology Index (BASRI) score for the sacroiliac joints (SIJs), cervical spine, and lumbar spine was lower in patients with AS and IBD than in those without IBD. In the multivariable analysis, the presence of IBD was significantly associated with a lower prevalence of HLA-B27 and enthesitis, with odds ratios (OR) of 0.32 (95% confidence interval (CI): 0.20–0.52) and 0.58 (95% CI: 0.33–0.97), respectively. Furthermore, structural damage in SIJs (BASRI) was significantly decreased in patients with IBD, with an OR of 0.79 (95% CI: 0.64–0.99). Conclusion: The presence of IBD in AS is associated with lower HLA-B27 positivity, less enthesitis, and less radiographic damage in this large population study.

ObjectivesAnti-PD-(L)1 agents changed the landscape of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treatment. Previous studies showed improved response rates to salvage chemotherapy (SCT) after progression to anti-PD-(L)1 agents. This study aims to evaluate the outcomes of SCT and to identify predictors of response and survival in patients with R/M HNSCC.Materials and methodsRetrospective cohort analysis of 63 R/M patients treated with SCT after antiPD-(L1)-based therapy between January 2015 and August 2022. The overall response rate (ORR) was evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated with Kaplan–Meier method. Progression-free survival 2 was calculated from anti-PD-(L)1-therapy start until progression to SCT (PFS2-I). Logistic regression and Cox regression analyses were performed to identify predictors of outcome.ResultsA total of 63 patients were included: 76% were men, and median age was 60 years. PD-L1 status was available in 68% (61% positive). Up to 71% received SCT as third line or beyond. ORR to SCT was 49% with higher rates in PD-L1 positive tumors, 71% vs. 18% (p=0.001), and cetuximab-containing regimens, 68% vs. 39% (p=0.026). PD-L1 status was the only predictor of ORR in the adjusted model (OR=8.6, 95% CI 1.7–43.0). OS and PFS were 9.3 months (95% CI, 6.5–12.3) and 4.1 months (95% CI, 3.0–5.8) respectively. PFS2-I was 8.6 months (95% CI, 6.6–10.5). In the multivariate analysis, PD-L1 was the only independent factor for OS (HR=0.3; 95% CI, 0.1–0.7), PFS (HR=0.2; 95% CI, 0.1–0.5; p

Summary: The blood enzyme glutamate-oxaloacetate transaminase (GOT) has been postulated as an effective therapeutic to protect the brain during stroke. To demonstrate its potential clinical utility, a new human recombinant form of GOT (rGOT) was produced for medical use.We tested the pharmacokinetics and evaluated the protective efficacy of rGOT in rodent and non-human primate models that reflected clinical stroke conditions.We found that continuous intravenous administration of rGOT within the first 8 h after ischemic onset significantly reduced the infarct size in both severe (30%) and mild lesions (48%). Cerebrospinal fluid and proteomics analysis, in combination with positron emission tomography imaging, indicated that rGOT can reach the brain and induce cytoprotective autophagy and induce local protection by alleviating neuronal apoptosis.Our results suggest that rGOT can be safely used immediately in patients suspected of having a stroke. This study requires further validation in clinical stroke populations.

Background: Altered bacterial translocation is associated with changes in hepatic function and the progression from compensated to decompensated cirrhosis. Child-Turcotte-Pugh (CTP) score is an essential indicator of liver severity. Thus, we aimed to study differences in the blood microbiome together with metabolome profile between HCV-infected patients with CTP class B (CTP-B, significant functional compromise) and patients with CTP class A (CTP-A, well-compensated cirrhosis). Methods: We conducted a cross-sectional study in patients with advanced HCV-related cirrhosis (n = 88) stratified by CTP-B and CTP-A. Bacterial 16S rRNA sequencing was sequenced by MiSeq Illumina technology and non-targeted metabolomics was performed by GC-MS and LC-MS ESI+ and ESI- to complement the analysis. Results: Patients with CTP-B had lower levels of richness (Chao1), and alpha diversity (Shannon and Simpson indexes) at phylum level than patients with CTP-A. Likewise, we observed significant differences in beta diversity between groups at phylum, class, and order levels, showing lower diversity in patients with CTP-B. Higher relative abundance of Proteobacteria (p = 0.012), Alphaproteobacteria (p = 0.005), Sphingomonadales (p = 0.012) and Sphingomonadaceae (p = 0.016) were significantly associated with CTP-B. The phylum Proteobacteria was positively correlated with ethanolamine and oleic acid (p = 0.005 and p = 0.004, respectively) and negatively with p-cresol (p = 0.006). In addition, the order Sphingomonadales and the family Sphingomonadaceae was also negatively correlated with p-cresol (p = 0.001 and p = 0.001). Conclusions: Blood microbial diversity was significantly decreased in patients with CTP-B, who presented an enrichment of Proteobacteria, Alphaproteobacteria, Sphingomonadales and Sphingomonadaceae compared to patients with CTP-A.

Human exposure to mycotoxins is a global concern since several mycotoxins, such as enniatins and aflatoxins, have shown carcinogenic and neurotoxic effects, and the toxicologic mechanisms of most of them still need to be clarified. This study aims to investigate the metabolic pathways affected by mycotoxin exposure by evaluating metabolite alterations in urine. The participants were 540 women from the Spanish Childhood and Environment Project (INMA). For metabolite identification, a dilute and shoot extraction, followed by HPLC-Q-TOF-MS identification analysis, was performed. Data were processed using Agilent Mass Hunter Workstation with the METLIN database, Agilent Mass Profiler Professional 10.0, and Metaboanalyst 6.0. Over 2000 metabolites were obtained in each sample after feature extraction, and the most significant metabolites (p-value ≤ 0.05, fold change ≥ 2.0) were considered for pathway analysis. Enrichment analysis and topology showed that the most significantly affected pathway was the biosynthesis of unsaturated fatty acids (adjusted p-value = 0.007), with four metabolomic hits associated: linoleic acid, octadecanoic acid/stearic acid, an arachidonic acid metabolite, and (9Z)-octadecenoic acid/oleic acid. Other related pathways (unadjusted p-value ≤ 0.1) included fatty acid biosynthesis, glycerophospholipid metabolism, and ether lipid metabolism. The present study highlights the importance of metabolomics in increasing knowledge of the toxicity mechanisms and health effects of mycotoxins, especially emerging ones.

Introducción: El bruxismo del sueño es una actividad parafuncional en la que se produce el apretamiento y/o rechinamiento dentario tanto en la población infantil como en la adulta. Objetivo: Recoger el conocimiento actual disponible sobre las causas, diagnóstico y tratamiento del bruxismo del sueño en niños para facilitar al odontólogo y/u odontopediatra su identificación y adecuado manejo en la clínica diaria. Material y métodos: Se realizó una búsqueda bibliográfica electrónica de artículos publicados en inglés entre los años 1986 y 2023 sobre bruxismo del sueño en menores de 14 años. Se seleccionaron 36 artículos. Resultados: La prevalencia del bruxismo del sueño en niños oscila entre el 5 y el 46%. De etiología multifactorial, sus manifestaciones clínicas son tanto intraorales como extraorales. El diagnóstico, en la mayoría de los casos, no resulta fácil y debe realizarse evaluando no solo sus consecuencias sino también los elementos etiológicos implicados. El tratamiento integral requiere de un abordaje temprano y multidisciplinar combinando técnicas psicológicas y odontológicas. La evidencia disponible no avala el uso de férulas de descarga rígidas en niños. Conclusión: El conocimiento actual sobre el bruxismo del sueño en niños busca centrarse en el disgnóstico temprano y en el tratamiento etiológico, pero todavía en necesario seguir realizando estudios para generar un protocolo estandarizado para el diagnóstico precoz que ayude en la toma de decisiones del clínico y mejore la calidad de vida del paciente a corto, mediano y largo plazo.

Although bone transport by means of distraction osteogenesis has become the standard of care for massive segmental bone defects, the technique faces limitations such as the lengthy period of time during which patients must wear an external fixator. Thus, other techniques may be more appropriate in certain circumstances.Capanna developed a combination of vascularized fibular grafts and strut allografts in a way that the strut allograft provides with significant initial mechanical stability, which facilitates incorporation of a vascularized fibular graft and promotes long-term survival of the reconstruction.The case presented in this report is the first in the medical literature where a circular external fixator is used as a stabilization method in a patient with a structural bone deficiency treated by means of the Capanna technique. It is also one of the few reported cases where the underlying condition does not originate in a tumor and where the joint is involved.

The initial excitement generated more than two decades ago by the discovery of drugs targeting fatty acid synthase (FASN)‐catalyzed de novo lipogenesis for cancer therapy was short‐lived. However, the advent of the first clinical‐grade FASN inhibitor (TVB‐2640; denifanstat), which is currently being studied in various phase II trials, and the exciting advances in understanding the FASN signalome are fueling a renewed interest in FASN‐targeted strategies for the treatment and prevention of cancer. Here, we provide a detailed overview of how FASN can drive phenotypic plasticity and cell fate decisions, mitochondrial regulation of cell death, immune escape and organ‐specific metastatic potential. We then present a variety of FASN‐targeted therapeutic approaches that address the major challenges facing FASN therapy. These include limitations of current FASN inhibitors and the lack of precision tools to maximize the therapeutic potential of FASN inhibitors in the clinic. Rethinking the role of FASN as a signal transducer in cancer pathogenesis may provide molecularly driven strategies to optimize FASN as a long‐awaited target for cancer therapeutics.

Abstract Rheumatoid arthritis (RA) is a fluctuating progressive disease requiring frequent symptom assessment for appropriate management. Continuous tracking using digital technologies may provide greater insights of a patient’s experience. This prospective study assessed the feasibility, reliability, and clinical utility of using novel digital technologies to remotely monitor participants with RA. Participants with moderate to severe RA and non-RA controls were monitored continuously for 14 days using an iPhone with an integrated bespoke application and an Apple Watch. Participants completed patient-reported outcome measures and objective guided tests designed to assess disease-related impact on physical function. The study was completed by 28 participants with RA, 28 matched controls, and 2 unmatched controls. Completion rates for all assessments were > 97% and were reproducible over time. Several guided tests distinguished between RA and control cohorts (e.g., mean lie-to-stand time [seconds]: RA: 4.77, control: 3.25; P

Resumen: La ecografía en el punto de atención (POCUS) se refiere a la utilización del ultrasonido (US) mediante dispositivos ultrasonográficos de bolsillo, al pie de la cama del paciente, con el objetivo de establecer un diagnóstico o dirigir un procedimiento y responder a una cuestión clínica de forma inmediata, su finalidad es ampliar la exploración física, no sustituir la evaluación ultrasonográfica convencional. POCUS ha evolucionado como un complemento del examen físico siendo adoptado por distintas especialidades médicas, incluyendo la hepatología. Se elaboró una síntesis de evidencia narrativa sobre las aplicaciones de POCUS en hepatología, describiendo la utilidad de POCUS en el diagnóstico de cirrosis hepática, enfermedad hepática esteatósica asociada a disfunción metabólica (MASLD, por sus siglas en inglés), cirrosis descompensada y el diagnóstico de hipertensión portal, así como las más recientes aplicaciones de POCUS en la evaluación hemodinámica del paciente con cirrosis hepática en estado crítico, otras enfermedades hepáticas y guía ultrasonográfica de procedimientos.POCUS podría formar parte de la práctica clínica diaria de gastroenterólogos y hepatólogos, simplificando la evaluación inicial de los pacientes y optimizando el manejo clínico. Su accesibilidad, facilidad de uso y bajo perfil de efectos adversos la hacen una herramienta útil para el médico propiamente entrenado en el escenario clínico adecuado, por lo que el objetivo de esta revisión fue describir la evidencia que existe sobre la utilidad de POCUS en la práctica clínica diaria de gastroenterólogos y hepatólogos. Abstract: Point-of-care ultrasound (POCUS) refers to the use of ultrasound imaging through pocket-sized sonographic devices at the patient's bedside, to make a diagnosis or direct a procedure and immediately answer a clinical question. Its goal is to broaden the physical examination, not to replace conventional ultrasound studies. POCUS has evolved as a complement to physical examination and has been adopted by different medical specialties, including hepatology. A narrative synthesis of the evidence on the applications of POCUS in hepatology was carried out, describing its usefulness in the diagnosis of cirrhosis of the liver, metabolic dysfunction-associated steatotic liver disease (MASLD), decompensated cirrhosis, and portal hypertension. The review also encompasses more recent applications in the hemodynamic evaluation of the critically ill patient with cirrhosis of the liver, patients with other liver diseases, as well as in the ultrasound guidance of procedures.POCUS could make up part of the daily clinical practice of gastroenterologists and hepatologists, simplifying the initial evaluation of patients and optimizing clinical management. Its accessibility, ease of use, and low adverse event profile make POCUS a useful tool for the properly trained physician in the adequate clinical setting. The aim of this review was to describe the available evidence on the usefulness of POCUS in the daily clinical practice of gastroenterologists and hepatologists.