University of Padua

Objective This study was undertaken to describe a cohort of pediatric patients with status epilepticus (SE) in Italy over the past decade, focusing on the variability of treatment protocols among centers, adherence to guidelines, and potential predictors of refractoriness. Methods This is a multicenter retrospective observational cohort study including patients aged 1 month to 18 years who experienced convulsive SE (CSE) between January 2010 and June 2022. Variables analyzed included age at CSE onset, etiology, and treatment. Results We included 1374 CSE episodes in 1071 patients (median age = 3.3 years); 46% occurred in the first 3 years of life. The prominent etiology was remote symptomatic (32%). Resolution was obtained only with benzodiazepine administration in 19.2% of SE episodes. Phenytoin, phenobarbital, and midazolam by infusion were the drugs most frequently used. Maximum therapeutic response occurred with low‐dose (<.2 mg/kg/h) midazolam infusion administered at an early stage, following a single dose of benzodiazepine or an antiseizure medication (ASM; 59%). Midazolam effectiveness decreased to 37% when it was used after multiple ASMs, even at high doses. CSE was refractory in 39% of cases. Predictors of refractoriness included nonadherence to current guidelines, type of CSE, and etiology. Significance This study emphasizes that low‐dose midazolam infusion, not requiring endotracheal intubation and administered at an early phase, appears to be effective in permanently stopping seizure and preventing the evolution toward a refractory CSE. Given its proven efficacy and widespread use in many hospitals, early midazolam infusion could be considered in the management of pediatric CSE. Adherence to treatment protocols, specific etiologies, and type of CSE are correlated with refractoriness; thus, when facing SE in infants, these factors should guide treatment protocol selection, including medication choice and timing.

BACKGROUND Thresholds to define prognosis with hs-cTnI (high-sensitivity cardiac troponin I) have not been systematically addressed in wild-type transthyretin amyloid cardiomyopathy, in part because of the multiplicity of hs-cTnI assays. The aims of this study were, first, to assess the prognostic performance of hs-cTnI measured with different assays in patients with wild-type transthyretin amyloid cardiomyopathy and, second, to identify assay-specific hs-cTnI thresholds for prognosis that could be integrated into staging systems for risk stratification. METHODS Observational multicenter study of stable wild-type transthyretin amyloid cardiomyopathy patients from different cohorts using the Abbott Architect Stat hs-cTnI assay and the Beckman Coulter Access hs-cTnI assay (testing cohorts) and the Siemens Centaur XPT hs-cTnI assay (validation cohort). Outcome was all-cause mortality. RESULTS In the Abbott cohort (n=136; median follow-up, 22 [13–41] months; 31 [23%] deaths) and Beckman cohort (n=98; median follow-up, 19 [12–28] months; 16 [16%] deaths), natural log-transformed hs-cTnI was an independent predictor of mortality (age- and sex-adjusted hazard ratio, 1.62 [95% CI, 1.11–2.35]; P =0.012 and 2.47 [95% CI, 1.48–4.14]; P <0.001, respectively). The best hs-cTnI threshold for 18-month mortality of the combined Abbott/Beckman cohorts (n=234) was 81 ng/L, rounded to 80 ng/L for simplicity of clinical use. A 2-variable staging system (based on the Mayo Clinic system) using hs-cTnI (>80 ng/L) and NPs (natriuretic peptides, NT-proBNP [N-terminal pro-B-type NP] >3000 ng/L or BNP (B-type natriuretic peptide) >250 ng/L) identified 3 groups with progressively worse prognosis. The staging system (using hs-cTnI >80 ng/L and NT-proBNP>3000 ng/L) was then applied to an independent cohort evaluated with the hs-cTnI Siemens assay (n=345, median follow-up 32 (24-42) months, 119 (34%) deaths). The significant differences between the groups were maintained. CONCLUSIONS In patients with wild-type transthyretin amyloid cardiomyopathy, hs-cTnI is a strong and independent predictor of mortality. A threshold of hs-cTnI of 80 ng/L for these 3 assays provides effective risk stratification alone and in a staging system with NP.

Biological heart valves (BHVs) are currently the main prosthetic substitute used to treat patients with severe valvular heart diseases. Unlike mechanical valves, BHVs provide better hemodynamic profile and lower thrombogenicity. However, their durability remains one of the main concerns in the field. Structural bioprosthetic valve degeneration (SVD) is a progressive phenomenon occurring early postimplantation and characterized by the fibro-calcification of the BHV leaflets, which leads to BHV failure over ∼10 years. SVD is currently an unpreventable and untreatable condition occurring in all BHV. The pathophysiological mechanisms leading to the development and progression of SVD remain largely unknown. However, a better understanding of these mechanisms will provide valuable data to improve BHV durability via the development of preventive treatments and/or newly engineered biological tissues. In this review, we provide a contemporary overview of the complex and interrelated pathophysiological mechanisms leading to SVD. We discussed the relevant studies in the fields, addressing the role of (i) the biomaterial structure and manufacturing processes, (ii) the active cell-mediated fibro-calcific processes, (iii) the residual immunogenicity of the currently animal-derived biomaterial, and (iv) the subclinical thrombosis, in the development and progression of SVD.

Metacognition– namely the capacity to reflect on one’s own cognitive processes - provides animals with numerous evolutionary advantages. Metacognition abilities encompass enhanced decision-making in uncertain situations, more efficient resource management, error detection and correction, and improved problem-solving skills. Here, we investigate how Eurasian jays, Garrulus glandarius, monitor uncertainty through a working memory food-retrieval task. In this task, a desirable food item is hidden under one of two cups, which are then shuffled either once (easy treatment) or several times (difficult treatment). The jays then choose to either engage in locating the food or opt out by selecting a third cup that offers a less preferred food reward. Our findings reveal that the difficulty of the task significantly influenced the jays’ choice, with a higher tendency to opt out during difficult trials. Individual performance analysis revealed that when jays that typically opted out of difficult trials chose to engage instead, they exhibited significant accuracy. This suggests their decisions were guided by a confidence assessment of their knowledge. Overall, our study indicates that Eurasian jays possess metacognitive abilities that enable them to evaluate their own certainty and make strategic decisions based on perceived task difficulty and confidence in their knowledge. These capabilities likely confer advantages in natural settings, such as caching behaviours, allowing jays to make well-informed decisions about when to store or retrieve food based on environmental cues and internal assessments of uncertainty.

Background Most forms of obesity are associated with chronic diseases that remain a global public health challenge. Aims Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation. Materials and Methods This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long‐term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity‐related cardiometabolic risks. Moreover, the socio‐economic drivers of obesity and its transition across phenotypes remain poorly understood. Results The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community‐level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies. Discussion The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity. Conclusion This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio‐economic model not compatible with optimal human health.

Myosin is the primary motor protein in skeletal muscle, responsible for adenosine triphosphate (ATP) hydrolysis that drives muscle contraction. In addition to force production, resting myosin consumes ATP in futile cycles at two rates, the slower one being associated with the Super Relaxed State (SRX), in contrast to the less inhibited Disordered Relaxed State (DRX). The SRX is typically measured using the mantATP chasing technique, where the decay of a fluorescent ATP analogue is fitted using a multiexponential function. Recently, significant concerns have been raised regarding the use of this technique, particularly when applied to soluble myosin preparations. While skinned fibers offer the advantage of preserving the native thick filament structure and myosin cooperativity, limited diffusion and nonspecific mantATP binding pose challenges. In this study, we combine experimental data and in-silico modeling to dissect the contributions of different components in the mantATP chasing signal. We analyze control skinned fibers and fibers subjected to myosin extraction. Our analysis shows that the nonspecific component partially overlaps with the DRX timescale. In contrast, the slow component linked to myosin SRX nucleotide release is characterized by a time constant that significantly differs from those of the nonspecific signal and DRX, enabling its reliable estimation using this technique. Our findings indicate that evaluating nonspecific mantATP components is necessary to obtain a reliable estimation of both SRX and DRX. We validated our analysis by comparing populations and time constants obtained from chasing with mantATP to mantATPase rates in control conditions and upon piperine-induced SRX destabilization.

Introduction Digital ulcers (DU) are one of the most frequent manifestations in systemic sclerosis (SSc). The presence of DU seems to be a sentinel sign of internal organ involvement and is related to a poor prognosis of the disease. The aim of this study was to evaluate the prevalence and the relationship of DU with clinical manifestations/variants in a large SSc cohort from the SPRING registry. Methods SSc patients fulfilling the ACR/EULAR 2013 classification criteria without missing data on digital ulcers were enrolled in a cross-sectional study. Logistic regression models were built to test the association between the presence of DU and SSc-related features. Results Among 1873 eligible SSc patients, the presence of DU was significantly associated with gastrointestinal involvement (OR 1.88, 2.04 and 1.74; p < 0.001) and serum ATA positivity (OR 2.15; p < 0.001), as well as with telangiectasias, sclerodactyly, digital pitting scar, and calcinosis (OR 1.40, p = 0.005; OR 3.43, p < 0.001, OR 9.12, p < 0.001 and OR 2.77, p < 0.001; respectively). In the multivariable regression models, even after adjustment for covariates, ATA positivity (OR 1.76, p = 0.039), puffy fingers (OR 2.82, p < 0.001), and a higher revEUSTAR-AI (OR 6.63, p < 0.001) emerged as risk factors for the presence of DU. Moreover, a low presence of DU was recorded in SSc patients with a history of previous immunosuppressive treatments (OR 0.53, p = 0.032). Conclusion In our Italian SSc cohort, DUs were significantly associated with the presence of puffy fingers, high revEUSTR-AI, and ATA seropositivity. Noteworthy, immunosuppressive treatments were associated with a low rate of DU, suggesting that they might contribute to the prevention of these harmful manifestations. Key Points • Digital ulcers were significantly associated with the presence of puffy fingers, high disease activity, and anti-Scl70 seropositivity. • Immunosuppressive treatments were associated with a low rate of digital ulcers, suggesting that they might contribute to the prevention of these harmful manifestations.

Obscurin is a large muscle protein whose multiple functions include providing mechanical strength to the M-band and linking the sarcomere to the sarcoplasmic reticulum. Mutations in obscurin are linked to various forms of muscle diseases. This study compares cardiac function in a murine model of obscurin deletion (KO) with wild-type (WT) in vivo and ex vivo. Echocardiography showed that KO hearts had larger (+20%) end-diastolic and end-systolic volumes, reduced fractional shortening, and impaired ejection fraction, consistent with dilated cardiomyopathy. However, stroke volume and cardiac output were preserved due to increased end-diastolic volume. Morphological analyses revealed reduced sarcoplasmic reticulum volume, with preserved T-tubule network. While myofilament function was preserved in isolated myofibrils and skinned trabeculae, experiments in intact trabeculae revealed that Obscn KO hearts compared with WT displayed (1) reduced active tension at high frequencies and during resting-state contractions, (2) impaired positive inotropic and lusitropic response to β-adrenergic stimulation (isoproterenol 0.1 μM), and (3) faster mechanical restitution, suggesting reduced sarcoplasmic reticulum refractoriness. Intracellular [Ca²⁺]i measurements showed reduced peak systolic and increased diastolic levels in KO versus WT cardiomyocytes. Western blot experiments revealed lower SERCA and phospholamban (PLB) expression and reduced PLB phosphorylation in KO mice. While action potential parameters and conduction velocity were unchanged, β-adrenergic stimulation induced more frequent spontaneous Ca²⁺ waves and increased arrhythmia susceptibility in KO compared with WT. Taken together, these findings suggest that obscurin deletion, in adult mice, is linked to compensated dilated cardiomyopathy, altered E-C coupling, impaired response to inotropic agents, and increased propensity to arrhythmias.

Background Regional anesthesia techniques have become integral to modern perioperative care, offering enhanced pain management and recovery outcomes. However, their application in patients with specific conditions, such as anticoagulation therapy or preexisting comorbidities, raises concerns regarding safety and efficacy. Current guidelines addressing these issues are fragmented, necessitating comprehensive, evidence-based recommendations. Methods A multidisciplinary panel of experts in anesthesiology and pain management was convened under the auspices of the Italian Society of Anesthesia, Analgesia, Resuscitation, and Intensive Care (SIAARTI). The guidelines presented herein were developed according to the GRADE system (Grading of Recommendations of Assessment Development and Evaluations), in compliance with the methodological manual for the production of clinical practice guidelines published by the National Center for Clinical Excellence, Quality, and Safety of Care, Italian National Institute of Health. Results The guidelines encompass recommendations on neuraxial blocks in anticoagulated patients, the dual guidance use in peripheral nerve blocks, the role of sterile field preparation, and post-procedural monitoring. Evidence from meta-analyses and large-scale observational studies supported most recommendations, though limitations in study heterogeneity were noted. Conclusions These guidelines provide a structured framework for clinicians to enhance patient safety and procedural efficacy in regional anesthesia. Further research is encouraged to address identified gaps, particularly regarding specific patient subgroups and novel regional anesthesia techniques.

Objective Surgery involving the skull base has recently gained significant prominence in treatment of head and neck cancer. “En bloc temporal‐parotid resection,” as applied in primary malignancies of the external ear, should be considered as a shift in the surgical landscape of “extended total parotidectomies” to achieve negative surgical margins and decrease the risk of tumor spillage during the procedure. The purpose of this systematic review is to evaluate survival outcomes and margin status in patients with parotid malignancies involving the temporal bone and treated with temporal‐parotid resection (TPR). Data Sources PubMed, Scopus, and Embase databases were systematically searched until 11 February 2025. Review Methods The protocol of this investigation was registered on PROSPERO in February 2024 and the systematic review was performed according to the PRISMA method. Results The study included 336 patients from 13 articles published between 1993 and 2019. Negative surgical margins were achieved in 74.5% of cases. After a median follow‐up of 32 months, 64.0% of patients achieved local disease control. Most patients (51.4%) experienced distant metastases during follow‐up. Three‐year overall survival (OS) and disease‐specific survival (DSS) ranged between 72.4%–57.1% and 79.0%–66.7%, respectively. Conclusion TPR represents a viable strategy to achieve safe oncological margins and adequate local disease control in patients with parotid gland malignancies infiltrating or abutting the temporal bone. Our findings support the growing interest in TPR, highlighting the need for further studies to refine patient selection criteria, surgical techniques, and postoperative management strategies. Trial Registration: PROSPERO: CRD42024512013 Level of Evidence NA.

Objective To examine rates of overweight or obese (OvOb) body condition score, including the association between OvOb and gonadectomy, in 15 dog breeds. Methods The analysis considered the 5 most recorded large breeds (26,369 dogs) and 10 most recorded toy/small breeds (90,002 dogs) in Banfield Pet Hospital’s database from 2013 to 2019. Cox proportional hazards models evaluated associations between OvOb and gonadectomy status, gonadectomy age, sex, and primary breed. Models estimated OvOb rates in gonadectomized versus intact dogs of each breed and, separately, OvOb rates according to gonadectomy age. Results There was substantial breed variation in underlying (intact dog) OvOb rates among the 15 breeds. Pugs, Golden Retrievers, and Labrador Retrievers had highest underlying susceptibility to OvOb outcomes. There was some variation in relative OvOb rates among breeds, but breeds differing substantially from size group peers were limited. Among all toy/small breeds, gonadectomy at 3 or 6 months had hazard ratios (relative risks) lower than, or not statistically different from, gonadectomy at 1 year or older. For large dogs, OvOb outcomes associated with prepubertal gonadectomy varied by breed. Conclusions Underlying susceptibility to OvOb varies by breed. Gonadectomy offers significant benefits at individual and population levels. As with many veterinary care decisions, however, there is complexity, and associated OvOb risks are not uniform across breeds. Clinical Relevance Results may facilitate more individualized recommendations for gonadectomy timing and proactive strategies (specifically diet and exercise) to mitigate risk of OvOb outcomes, while accounting for the broader context of individual dog and population-level benefits of gonadectomy.

Background: Osteoporosis is a chronic condition characterized by increased fracture risk. Fragility fractures, especially hip fractures, represent a significant health and economic burden due to population aging. Despite the efficacy of approved treatments in lowering fracture recurrence, post-fracture treatment rates remain suboptimal. To address these issues, various post-fracture care programs, including Fracture Liaison Services (FLS), have been implemented worldwide. While FLS models effectively reduce refracture risk and maintain cost-effectiveness, it is unclear if these benefits apply equally to all patients, especially those with higher comorbidities and reduced functional capacity, who may face worse prognoses. This study aimed to identify the primary factors influencing anti-fracture therapy decisions in older patients with fragility fractures, using a multidimensional geriatric assessment approach integrated into our FLS program. Methods: A retrospective analysis was conducted on patients aged 65 and above with hip fractures admitted to Azienda Ospedale-Università Padova. Patients were categorized based on anti-fracture treatment (bisphosphonates, Denosumab, anabolic agents) or calcium/vitamin D supplements only. Clinical data, including the Multidimensional Prognostic Index (MPI) and its components, were collected. Statistical comparisons between treated and untreated groups were made, and a CHAID decision tree was used to explore decision-influencing factors. Results: The study included 493 patients (average age 84.7 years, 71.8% female). Patients receiving anti-fracture treatment were notably younger, with only 11.2% classified as MPI class 3 (severe prognosis) compared to 60.8% of untreated patients (p < 0.001). Among treated patients (n = 427), 75.3% received bisphosphonates, 7.3% Denosumab, and 2.2% anabolic agents. The CHAID decision tree highlighted MPI class as the primary determinant of treatment, with functional autonomy (Instrumental Activity of Daily Living or IADL) and cognitive status as subsequent factors, leading to an overall prediction accuracy of 70%. Conclusion: The integration of the MPI into multidisciplinary taking care of old patients with hip fractures may provide a structured approach for individualizing treatment decisions, considering aspects such as prognosis, functional autonomy, and cognitive status. Further studies are needed to validate the long-term outcomes of this approach.