Explore the vast range of titles available.

Duchenne muscular dystrophy (DMD) is a devastating genetic disorder, whose management is still a major challenge, despite progress in genetic and pharmacological disease-modifying treatments have been made. Mitochondrial dysfunctions contribute to DMD, however, there are no effective mitochondrial therapies for DMD. SIRT1 is a NAD + -dependent deacetylase that controls several key processes and whose impairment is involved in determining mitochondrial dysfunction in DMD. In addition to well-known resveratrol, other potent selective activators of SIRT1 exist, with better pharmacokinetics properties and a safer profile. Among these, SRT2104 is the most promising and advanced in clinical studies. Here we unveil the beneficial effects of SRT2104 in flies, mice, and patient-derived myoblasts as different models of DMD, demonstrating an anti-inflammatory, anti-fibrotic, and pro-regenerative action of the drug. We elucidate, by molecular dynamics simulations, that a conformational selection mechanism is responsible for the activation of SIRT1. Further, the impact of SRT2104 in reshaping muscle proteome and acetylome profiles has been investigated, highlighting effects that mimic those induced by exercise. Overall, our data suggest SRT2104 as a possible therapeutic candidate to successfully counteract DMD progression.

The activity of acid sphingomyelinase (ASMase), a key enzyme in sphingolipid metabolism, has been found to be increased in a variety of human diseases. Studies conducted on animal and cellular models showed that sphingolipids and ASMase play a central role in the pathogenesis of type 1 diabetes (T1D) and T1D-related vascular damage. Currently, no studies have investigated the role of ASMase activity in pediatric patients with T1D. Therefore, we conducted a cross-sectional study to evaluate the activity of the secretory form of ASMase (S-ASMase) in the serum of patients with T1D aged 2-16 years in comparison with a control group (healthy subjects matched for age, gender, and pubertal stage). We recruited children and adolescents affected by T1D (including patients with new-onset and established T1D) aged 2-16 years and healthy normal-weight subjects with normal timing of puberty (matched for age, gender, and pubertal stage), who were consecutively admitted-as outpatients-to our institution for screening purposes. Serum lipid profile, glycated hemoglobin (HbA1c), and urine albumin-creatinine ratio (uACR) were assessed in all T1D patients. S-ASMase activity was measured in all study participants through a colorimetric assay. In total, 68 T1D patients and 51 healthy controls were recruited in this study. None of the T1D patients had T1D-related complications. No difference in S-ASMase activity was observed between subjects with T1D and healthy controls. However, when T1D patients were stratified according to the duration of diabetes, we found a significantly higher activity of S-ASMase in patients with new-onset T1D (recruited within 1 week after the disease diagnosis) as compared to that observed in patients with established T1D. In all patients with T1D, S-ASMase activity correlated positively with HbA1c and triglyceride levels, while it correlated negatively with total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels. However, there were no significant differences in S-ASMase activity between T1D patients with new-onset disease who presented with diabetic ketoacidosis (DKA; n = 12) and T1D patients with new-onset disease who did not present with DKA (n = 13). Our study evaluated, for the first time, the in vivo activity of S-ASMase in a pediatric cohort of patients with T1D. In pediatric patients with new-onset T1D, we found a significantly higher S-ASMase activity as compared to that observed in patients with established T1D. In all T1D patients, the positive correlation between S-ASMase activity, HbA1c, and triglyceride levels, as well as the negative correlation between S-ASMase activity and HDL-C levels, suggests a potential role played by sphingolipids in T1D pathophysiology. Further mechanistic studies are needed to better elucidate the role of S-ASMase in patients with T1D at different stages of the disease.

This study aimed to explore the potential role of artificial intelligence in optimizing botulinum toxin type A treatment for spasticity and to evaluate its alignment with expert clinical decisions. A comparative analysis was conducted using thirty hypothetical clinical cases involving individuals with spasticity resulting from various neurological conditions. Five rehabilitation physicians, each with more than five years of experience, participated in the study. An artificial intelligence model trained on scientific literature and clinical guidelines generated treatment recommendations, including target muscles and dosages, which were compared with those proposed independently by the physicians. The primary outcome was the level of agreement in muscle selection and dosage. The model demonstrated consistency and adherence to guidelines but showed limited adaptability in complex presentations, such as an adducted thigh and equinovarus foot. It generally recommended lower dosages and differed significantly from physicians in both muscle selection and treatment strategies. Artificial intelligence shows promise as a clinical support tool in spasticity management, offering standardized and reproducible recommendations. However, its limited capacity to interpret clinical subtleties currently restricts its practical application. Future models should integrate multimodal clinical data and real-time clinician feedback to better emulate expert decision-making processes.

Abstract A 68-year-old man had recurrent bacteremia by Klebsiella pneumoniae carbapenemase (KPC)–producing K. pneumoniae resistant to ceftazidime-avibactam and cefiderocol. The sequencing of a target region showed that it harbored a KPC-3 variant enzyme (D179Y; KPC-31), which confers resistance to ceftazidime-avibactam and restores meropenem susceptibility. The patient was successfully treated with meropenem-vaborbactam.

Background: The impact of prolonged digital device exposure on physical and mental health in children has been widely investigated by the scientific community. Additionally, the lockdown periods due to the COVID-19 pandemic further exposed children to screen time for e-learning activities. The aim of this systematic review (PROSPERO Registration: CRD42022315596) was to evaluate the effect of digital device exposure on children’s health. The impact of the COVID-19 pandemic was additionally explored to verify the further exposure of children due to the e-learning environment. Methods: Available online databases (PubMed, Google Scholar, Semantic Scholar, BASE, Scopus, Web of Science, and SPORTDiscus) were searched for study selection. The PICO model was followed by including a target population of children aged 2 to 12 years, exposed or not to any type of digital devices, while evaluating changes in both physical and mental health outcomes. The quality assessment was conducted by using the Joanna Briggs Institute (JBI) Critical Appraisal Tool. Synthesis without meta-analysis (SWiM) guidelines were followed to provide data synthesis. Results: Forty studies with a total sample of 75,540 children were included in this systematic review. The study design was mainly cross-sectional (n = 28) and of moderate quality (n = 33). Overall, the quality score was reduced due to recall, selection, and detection biases; blinding procedures influenced the quality score of controlled trials, and outcome validity reduced the quality score of cohort studies. Digital device exposure affected physical activity engagement and adiposity parameters; sleep and behavioral problems emerged in children overexposed to digital devices. Ocular conditions were also reported and associated with higher screen exposure. Home confinement during COVID-19 further increased digital device exposure with additional negative effects. Conclusions: The prolonged use of digital devices has a significant negative impact on children aged 2 to 12, leading to decreased physical activity, sleep disturbances, behavioral issues, lower academic performance, socioemotional challenges, and eye strain, particularly following extended online learning during lockdowns.

Background: Mantle Cell Lymphoma (MCL) is an aggressive malignancy with variable clinical behavior, largely reflecting the underlying molecular heterogeneity. The genomic landscape of MCL encompasses gene mutations with strong prognostic implications and secondary genetic events, which are also implicated in the pathogenesis and prognosis of the disease. Methods: We evaluated the diagnostic samples of 73 patients with relapsed/refractory MCL that were enrolled in the Fondazione Italiana Linfomi Mantle First-BIO study. All patients had available data for correlating CNVs with the presence of TP53 mutation. Time to first relapse or progression of disease (POD) was used as the primary outcome measure. Results: We identified CNVs associated with MCL, with Del 9p21.3 (CDKN2A) being the strongest predictor of shorter time to POD (p = 0.01), independently of TP53 mutation in multivariable analysis. Unsupervised clustering identified molecularly defined clusters that were associated with significantly different times to POD (p = 0.01). Pairwise log-rank tests confirmed TP53 mutated vs. wild-type (WT) as the strongest prognostic factor, with cluster assessment improving the prognostic predictivity among patients: clusters TP53-mut vs. TP53-WT, p = 0.001, HR = 3.92; and p = 0.014, HR = 2.23, respectively. In conclusion, CNV-based molecular clusters might represent a novel approach to identify patients at higher risk of treatment failure, further contributing to the prognostic predictivity of TP53 mutation.

The standard treatment for young patients with untreated PTCLs is based on anthracycline containing-regimens followed by high-dose-chemotherapy and stem-cell-transplantation (HDT + SCT), but only 40% of them can be cured. Romidepsin, a histone-deacetylase inhibitor, showed promising activity in relapsed PTCLs; in first line, Romidepsin was added with CHOP. We designed a study combining romidepsin and CHOEP as induction before HDT + auto-SCT in untreated PTCLs (PTCL-NOS, AITL/THF, ALK-ALCL), aged 18–65 years. A phase Ib/II trial was conducted to define the maximum tolerated dose (MTD) of Ro-CHOEP, and to assess efficacy and safety of 6 Ro-CHOEP as induction before HDT. The study hypothesis was to achieve a 18-month PFS of 70%. Twenty-one patients were enrolled into phase Ib; 7 dose-limiting toxicities were observed, that led to define the MTD at 14 mg/ms. Eighty-six patients were included in the phase II. At a median follow-up of 28 months, the 18-month PFS was 46.2% (95%CI:35.0–56.7), and the 18-month overall survival was 73.1% (95%CI:61.6–81.7). The overall response after induction was 71%, with 62% CRs. No unexpected toxicities were reported. The primary endpoint was not met; therefore, the enrollment was stopped at a planned interim analysis. The addition of romidepsin to CHOEP did not improve the PFS of untreated PTCL patients.

Takotsubo syndrome (TTS) is characterized by a transient left ventricular systolic dysfunction, burdened by significant acute and long-term mortality and morbidity. The prognosis of TTS, especially in the long-term, is influenced by both non-cardiovascular (non-CV) and CV comorbidities, among which cancer is one of the most common. The presence of a malignancy is proven to be associated with higher mortality in TTS. Moreover, a number of anticancer treatments has been reported to possibly cause TTS as a form of cardiotoxicity, even though clearcut associations are lacking. The aim of this narrative review is to sum up contemporary knowledge on the association of cancer and TTS, addressing unmet needs and practical implications. The importance of a close collaboration between cardiologists and oncologists is herein highlighted, both to allow an adequate management of the acute TTS phase, and to actively and safely return to the oncologic management once the acute setting is resolved.

Myocardial bridging (MB) and a long recurrent wraparound left anterior descending artery (wrap-LAD) are coronary anatomic variants that have been recently suggested to be associated with takotsubo syndrome (TS). Until now, coronary artery tortuosity (CAT) has never been investigated in this setting. Our study sought to evaluate the prevalence of the aforementioned anatomic variants in a large population with TS. In this retrospective angiographic study, 109 patients with TS were compared with 109 age- and gender-matched subjects without coronary artery disease, valve heart disease, or cardiomyopathy. CAT was identified by ≥3 consecutive curvatures ≥90° (criteria 1) or by ≥2 consecutive curvatures ≥180° (criteria 2). Wrap-LAD was defined if any part of the vessel outreached the apex of the left ventricle and MB as the presence of a milking effect or a step-up and step-down phenomenon. An anatomic variant was found in 79 patients with TS (72%) and in 48 controls (44%) (p <0.001). CAT in at least 1 vessel (criteria 1: 49% vs 20%, p <0.001; criteria 2: 38% vs 13%, p <0.001), ≥2 vessels (criteria 2: 14% vs 3%, p = 0.005), and wrap-LAD (41% vs 27%, p = 0.02) were significantly more frequent in patients with TS than in controls. The prevalence of MB (9% vs 5%, p = 0.18) did not differ between groups. In conclusion, CAT and wrap-LAD have higher prevalence in patients with TS than in matched controls. These findings could support the hypothesis that anatomic variants might act as potential pathogenic substrates in TS.