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Background: Treatment-Resistant Depression (TRD) affects almost 30 % of patients with Major Depressive Disorder (MDD). Esketamine Nasal Spray (ESK-NS) has recently been approved for TRD in combination with a Serotonin Specific Reuptake Inhibitor/SSRI or a Serotonin-Norepinephrine Reuptake Inhibitor/SNRI. There is a lack of studies investigating the effectiveness and safety of ESK-NS in combination with other oral antidepressants., Aim: To assess the efficacy of Vortioxetine plus ESK-NS in mitigating depressive symptoms and emotional blunting, as well as its tolerability in TRD subjects, compared to the standard-of-care of SSRI/SNRI plus ESK-NS., Methods: We conducted a post-hoc analysis of the REAL-ESK study. The study included twenty TRD patients, ten subjects taking Vortioxetine as the main oral antidepressant with ESK-NS, and ten subjects taking SSRI or SNRI with ESK-NS. Psychometric assessments (Montgomery-Åsberg Depression Rating Scale/MADRS, Brief Psychiatric Rating Scale/BPRS) were conducted at baseline(T0), one month(T1), and three months after the treatment initiation(T2)., Results: The combination of Vortioxetine and ESK-NS was as effective as the standard-of-care in reducing depressive symptoms, with a higher effect size in reducing emotional blunting at T2. The safety and tolerability profile of the Vortioxetine+ESK-NS combination appeared to be better, with a lower rate of treatment-emergent adverse events., Conclusion: The combination of Vortioxetine and ESK-NS may be a valuable alternative to the standard-of-care SSRI/SNRI plus ESK-NS in TRD patients, particularly regarding the reduction of emotional blunting and potentially a better safety and tolerability profile. Further randomized controlled trials with larger sample sizes and prospective designs are needed to confirm these findings., Competing Interests: Declaration of competing interest Dr. Ileana Andriola was a speaker at Janssen sponsored conference. Dr. Antonio Vita received grant/research support and speaker/consultant fees for Angelini, Boheringer Ingelheim, Innovapharma, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Recordati, Roche, Rovi Pharma, Takeda. Dr. Bernardo Maria Dell'Osso has received lecture honoraria from Angelini, Lundbeck, Janssen, Pfizer, Neuraxpharm, Arcapharma, and Livanova. Dr. Giorgio Di Lorenzo has been a speaker and/or a consultant for Angelini, FB-Health, Janssen-Cilag, Livanova, Lundbeck, Neuraxpharm, Otsuka, and Recordati. Dr. Giovanni Martinotti has been a consultant and/or a speaker and/or has received research grants from Angelini, Doc Generici, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Recordati. The remaining authors declare that the research was conducted without any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Vascular surgical training is evolving towards simulation-based methods to enhance skill development, ensure patient safety, and adapt to changing regulations. This study aims to investigate the utilization of simulation training among vascular surgeons in France, amidst ongoing shifts in teaching approaches and educational reforms., Methods: A national survey assessed the experiences and perceptions of vascular surgery professionals regarding simulation training. Participation was open to self-reported health professionals specialized (or specializing) in vascular surgery, including interns or fellows. Participants were recruited through various channels, and data were collected via a questionnaire covering participant characteristics, simulation experiences, and perceptions., Results: Seventy-six participants, predominantly male (74%) took part in the survey. While 58% reported access to simulation laboratories, only 17% had organized simulation sessions 1-3 times a year, and 5% had sessions more than 10 times annually. High fidelity simulators were available in 57% of institutions, while low fidelity simulators were available in 50%. Regarding funding, 20% received financial assistance for training, predominantly from industry (18%). One-third of the participants experienced 9 or more sessions (34%), lasting between 1 and 2 hours (34%), 30% expressed satisfaction with access to simulation, while 33% were dissatisfied with communication of simulation training opportunities., Conclusions: Despite recognizing the benefits of simulation training, its integration into vascular surgery education in France remains incomplete. Challenges such as limited access and communication barriers hinder widespread adoption. Collaborative efforts are needed to ensure uniformity and enhance the effectiveness of simulation training in vascular surgery education., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Prostate cancer and its treatment, particularly androgen deprivation therapy (ADT), can profoundly impact patients' quality of life. The aim of the prospective observational study reported here was to evaluate the effects of ADT on various aspects of quality of life in men with prostate cancer at a community-based hospital in Southern Italy., Methods: Eligible men initiating hormonal therapy were recruited between December 2021 and December 2023. Data were collected at baseline (T 0 ) and after 3 months (T 1 ) and 6 months (T 2 ) of ADT using standardized questionnaires (European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30, EORTC QLQ-PR25) and semi-structured interviews., Results: Of the 52 participants, 43 completed all three assessments. The EORTC QLQ-C30 showed a statistically significant worsening in physical functioning (mean score decrease from 83.8 at T 0 to 76.7 at T 2 ; p < 0.001), increased fatigue (from 23.7 to 35.2; p < 0.001), and insomnia (from 23.7 to 31.8; p = 0.048) following ADT initiation. The QLQ-PR25 revealed a significant decline in sexual functioning (from 59 to 26.9; p < 0.001) and sexual activity (from 27.3 to 12; p = 0.001). Interviews revealed a significant rise in the number of patients reporting depressed mood. Interviews also highlighted a worsening in body image perception and sexuality, increased feelings of dependence, and challenges in the social and relational spheres., Conclusions: ADT significantly impacts various aspects of quality of life in men with prostate cancer, particularly physical functioning, fatigue, sexual function, body image, and emotional well-being. These results underscore the critical importance of a comprehensive, patient-centered approach that addresses both the physical and psychosocial aspects of care., Competing Interests: Declarations Conflict of Interest Francesca Cappuccio, Carlo Buonerba, Luca Scafuri, Rossella Di Trolio, Pasquale Dolce, Serena Orsola Trabucco, Filomena Erbetta, Elvira Tulimieri, Antonella Sciscio, Concetta Ingenito and Antonio Verde have nothing to disclose. Giuseppe Di Lorenzo is an Editorial Board member of Oncology and Therapy. He was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ethical Approval The study was approved by the Ethics Committee (“Comitato Etico Campania Centro”; approval/ protocol number 1945). The research was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent. Permission was received by the EORTC Quality of Life Group to use the questionnaires., (© 2024. The Author(s).)

Early detection of recurrences in gynecological cancers is crucial for women's health. Circulating tumor DNA (ctDNA) analysis through liquid biopsy offers a promising approach for monitoring disease progression and identifying relapses. This study investigated the utility of digital Polymerase Chain Reaction (dPCR) for ctDNA detection in three gynecological cancer patients with clinically confirmed relapses during a two-year post-surgical follow-up. Patient-specific tumor mutations were identified through whole-exome sequencing (WES) and confirmed via Sanger sequencing. dPCR probes targeting these mutations were used to quantify the ctDNA levels in plasma samples collected throughout the follow-up period, and the findings were compared with standard serum biochemical markers. In two patients, persistent positive dPCR signals for the selected mutations were detected after tumor removal, with ctDNA levels progressively increasing even after post-surgical chemotherapy. Notably, dPCR identified elevated ctDNA levels before an increase in the cancer antigen 125 (CA125) biochemical marker was observed. In the third patient, no ctDNA signals from the two selected mutations were detected despite clinical evidence of recurrence, suggesting the emergence of new mutations. While this study highlights the promise of dPCR for early recurrence detection in gynecological cancers, it also underscores the critical need for comprehensive mutation panels to overcome the inherent challenges posed by tumor heterogeneity and the emergence of new mutations during disease progression.

Chronic kidney disease (CKD) represents a significant global health challenge, affecting millions of individuals and leading to substantial morbidity and mortality. This review aims to explore the epidemiology, cardiovascular complications, and management strategies associated with CKD, emphasizing the importance of preventing cardiovascular disease and early intervention. CKD is primarily driven by conditions such as diabetes mellitus, hypertension, and cardiovascular diseases, which often coexist and exacerbate renal impairment. Effective management requires a multifaceted approach, including lifestyle modifications, pharmacological interventions, and regular monitoring. Dietary changes, such as sodium restriction and a controlled intake of phosphorus and potassium, play a vital role in preserving renal function. Pharmacological therapies, particularly angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and emerging agents like SGLT2 inhibitors, have shown efficacy in slowing disease progression and improving patient outcomes. Furthermore, patients undergoing dialysis face increased cardiovascular risk, necessitating comprehensive management strategies to address both renal and cardiac health. As the landscape of CKD treatment evolves, ongoing research into novel therapeutic options and personalized medical approaches are essential. This review underscores the urgent need for awareness, education, and effective preventive measures to mitigate the burden of CKD and enhance the quality of life for affected individuals., Competing Interests: The authors declare no conflicts of interest.

Bladder cancer, which has a rising incidence, is the 10th most common cancer. The transitional cell carcinoma histotype is aggressive and often current therapies are ineffective. We investigated the anti-proliferative effect of quercetin, a natural flavonoid, in combination with the alkylating agent mafosfamide (MFA) on two human bladder cancer cell lines, namely RT112 and J82, representing the progression from low-grade to high-grade tumors, respectively. In both cell types, the combined treatment led to a synergic reduction in cell viability confirmed by a combination index of less than one, though different biological responses were noted. In J82 cells, MFA alone and, to a lesser extent, with quercetin caused cell cycle arrest in the G2/M phase, but only the combined treatment triggered apoptotic cell death. In contrast, in RT112 cells, quercetin induced autophagy, evidenced by the autophagosome formation and the increase in LC-3 lipidation. Interestingly, the synergistic effect was observed only when cells were pre-treated with MFA for 24 h before adding quercetin, not in the reverse order. This suggests that quercetin may help overcome MFA resistance to apoptosis. Although further studies are needed, investigating the combined effects of quercetin and MFA could help elucidate the mechanisms of drug resistance in bladder cancer treatment.

Background/Objectives : Parkinson's disease (PD) is a progressive neurodegenerative disorder that requires comprehensive and personalized rehabilitation. This retrospective study focused primarily on the usability and patient acceptability of the innovative pathway. In addition, the secondary objective was to evaluate the effectiveness of a personalized and multidisciplinary rehabilitation pathway on cognitive function, especially executive functions. Methods: We conducted a retrospective study on 80 patients with PD (Hoehn and Yahr scores 1-3). Patients were divided into an experimental group (EG), which received the innovative pathway, and a control group (CG), which received traditional therapy. The rehabilitation program included three phases: initial outpatient assessment, a two-month inpatient program, and a telerehabilitation phase in a day hospital (DH) or home environment. Interventions combined traditional therapies with treatments based on robotic and virtual reality. Cognitive assessments (Mini Mental State Examination-MMSE-and frontal assessment battery-FAB), mood (Hamilton Rating Scale-Depression-HRS-D), anxiety (HRS-Anxiety-HRS-A), and goals achievement (GAS) were the primary outcome measures. Results : At baseline, there were no significant differences between the groups in terms of age, gender, education, or test scores. After rehabilitation, EG showed significant improvements in all measures ( p < 0.001), particularly in cognitive tests and goal achievement. CG improved in GAS ( p < 0.001) and mood (HRS-D, p = 0.0012), but less than EG. No significant changes were observed in the MMSE of CG ( p = 0.23) or FAB ( p = 0.003). Conclusions : This study highlights the high usability and acceptability of VR and robotics in PD rehabilitation, contributing to improved adherence and patient engagement. The experimental group showed greater cognitive benefits, particularly in executive functions. These results are in line with the existing literature on personalized technology-based rehabilitation strategies for PD.

Background: Oxidative stress has emerged as a key contributor to numerous NCDs (non-communicable diseases), including cardiovascular diseases, cancer, and diabetes. This study aims to explore the potential of targeted interventions to mitigate oxidative stress as part of a primary prevention strategy., Methods: The study included 32 healthy participants (11 men, 21 women) aged 45-65 who completed both the initial and follow-up assessments of the Healthy Days Initiative, a community-based wellness program organized by the non-profit Associazione O.R.A. ETS. Through blood analysis, vital sign assessment, lifestyle questionnaires, and individualized recommendations, participants received guidance on improving their health and reducing disease risk. The initiative also offered the opportunity for participants to consume a flavonoid supplement containing quercitrin, rutin, and hesperidin, with the goal of reducing oxidative stress. Participants who opted for supplementation were instructed to take 1-2 tablets daily for two weeks. Data collected included demographic information, anthropometric measurements, vital signs, dietary and lifestyle habits, medical history, WHO-5 Well-Being Index scores, and blood parameters., Results: Significant reductions were observed in glucose levels (from 82 to 74.5 mg/dL), reactive oxygen metabolites (d-ROMs) (from 394.5 to 365.5 U.CARR), and systolic blood pressure (from 133 to 122 mmHg) after the two-week flavonoid intervention. Most participants (26/31) reported no side effects, and the majority (30/31) expressed a willingness to continue using a product combination of quercitrin, rutin, and hesperidin or a similar product long-term., Conclusions: While limited in scope and duration, the PREVES-FLAVON study contributes valuable insights to the growing body of evidence suggesting that flavonoid supplementation may play a significant role in reducing risk factors associated with NCDs in primary prevention settings. By targeting novel risk factors such as oxidative stress, this intervention holds promise for mitigating the global burden of NCDs and promoting healthy aging.

Type 2 diabetes mellitus (T2DM) is a prevalent chronic metabolic disorder characterized by insulin resistance and progressive beta cell dysfunction, presenting substantial global health and economic challenges. This review explores recent advancements in diabetes management, emphasizing novel pharmacological therapies and their physiological mechanisms. We highlight the transformative impact of Sodium-Glucose Cotransporter 2 inhibitor (SGLT2i) and Glucagon-Like Peptide 1 Receptor Agonist (GLP-1RA), which target specific physiological pathways to enhance glucose regulation and metabolic health. A key focus of this review is tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors. Tirzepatide illustrates how integrating innovative mechanisms with established physiological pathways can significantly improve glycemic control and support weight management. Additionally, we explore emerging treatments such as glimins and glucokinase activators (GKAs), which offer novel strategies for enhancing insulin secretion and reducing glucose production. We also address future perspectives in diabetes management, including the potential of retatrutide as a triple receptor agonist and evolving guidelines advocating for a comprehensive, multifactorial approach to care. This approach integrates pharmacological advancements with essential lifestyle modifications-such as dietary changes, physical activity, and smoking cessation-to optimize patient outcomes. By focusing on the physiological mechanisms of these new therapies, this review underscores their role in enhancing T2DM management and highlights the importance of personalized care plans to address the complexities of the disease. This holistic perspective aims to improve patient quality of life and long-term health outcomes.

Alexithymia, characterized by difficulty in recognizing and verbalizing emotions, is reported to be more prevalent in subjects with Parkinson's disease (PD) than in the general population. Although it is one of the nonmotor symptoms of PD, alexithymia is often overlooked in clinical practice. The aim of this systematic review is to investigate the prevalence of alexithymia in PD, assess its impact on quality of life, and explore the rehabilitation approaches for alexithymia. Research articles, selected from PubMed, Scopus, and Web of Science, were limited to those published in English from 2013 to 2023. The search terms combined were "Alexithymia," "Parkinson's disease,", and "Quality of life." Current literature review indicates that alexithymia is commonly assessed using the Toronto Alexithymia Scale (TAS-20), and it is associated with deficits in visuospatial and executive functions. Presently, rehabilitation interventions for alexithymia are scarce, and their effectiveness remains controversial. Future research should focus on developing comprehensive assessments and rehabilitation strategies for emotional processing, considering its significant impact on the quality of life of both patients and caregivers., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Laura Culicetto et al.)

Allergic respiratory diseases such as asthma might be considered multifactorial diseases, having a complex pathogenesis that involves environmental factors and the activation of a large set of immune response pathways and mechanisms. In addition, variations in genetic background seem to play a central role. The method developed for the analysis of the complexities, as association rule mining, nowadays may be applied to different research areas including genetic and biological complexities such as atopic airway diseases to identify complex genetic or biological markers and enlighten new diagnostic and therapeutic targets. A total of 308 allergic patients and 205 controls were typed for 13 single nucleotide polymorphisms (SNPs) of cytokine and receptors genes involved in type 1 and type 2 inflammatory response (IL-4 rs2243250 C/T, IL-4R rs1801275A/G, IL-6 rs1800795 G/C, IL-10 rs1800872 A/C and rs1800896 A/G, IL-10RB rs2834167A/G, IL-13 rs1800925 C/T, IL-18 rs187238G/C, IFNγ rs 24030561A/T and IFNγR2 rs2834213G/A), the rs2228137C/T of CD23 receptor gene and rs577912C/T and rs564481C/T of Klotho genes, using KASPar SNP genotyping method. Clinical and laboratory data of patients were analyzed by formal statistic tools and by a data-mining technique-market basket analysis-selecting a minimum threshold of 90% of rule confidence. Formal statistical analyses show that IL-6 rs1800795GG, IL-10RB rs2834167G positive genotypes, IL-13 rs1800925CC, CD23 rs2228137TT Klotho rs564481TT, might be risk factors for allergy. Applying the association rule methodology, we identify 10 genotype combination patterns associated with susceptibility to allergies. Together these data necessitate being confirmed in further studies, indicating that the heuristic approach might be a straightforward and useful tool to find predictive and diagnostic molecular patterns that might be also considered potential therapeutic targets in allergy.

Background/Objectives : Assertiveness, defined as the positive affirmation of oneself, encompasses the ability to refuse requests, express anger, disagree or oppose others, show affection, and uphold personal beliefs without causing conflict. Deficits in assertive behavior are often linked to pathological changes in the basal ganglia and prefrontal dopaminergic systems, commonly observed in Parkinson's disease (PD), and are predictive of poor clinical outcomes. Psychological factors such as mood alterations and cognitive dysfunction may also impact assertiveness. This study investigated the psychological factors influencing assertiveness in individuals with PD. Methods : A cross-sectional study was conducted, involving 160 patients with PD attending a movement disorders outpatient clinic. The participants underwent assessment using a battery of standardized neuropsychological tests to evaluate cognitive function, assertiveness, mood, dysarthria, and quality of life (QoL). Results: All dimensions of assertiveness correlated with depression and anxiety. Individuals experiencing mood disturbances may struggle to express themselves assertively. Similarly, some dimensions of assertiveness correlated also with the QoL, indicating that, overall, well-being affects assertive behavior. Gender emerged as a significant influencer of assertiveness across all dimensions. Specifically, in subjects with PD, the male gender was associated with lower scores in assertiveness compared to women. No significant correlations were found between assertiveness and dysarthria. Conclusions : The findings highlight the importance of adopting a holistic approach to PD management, addressing not only motor symptoms but also psychological challenges which patients may encounter in their daily lives.

Introduction: Magnetic resonance-guided focused ultrasound (MRgFUS) is a contemporary non-invasive ablative procedure that utilizes high- or low-intensity ultrasound, guided and monitored by magnetic resonance imaging (MRI). While MRgFUS has been established as an effective treatment for conditions like essential tremor and tremor-dominant Parkinson's disease, it has recently emerged as a safe and promising ablative minimally invasive procedure for the management of treatment-resistant psychiatric disorders. Indeed, despite the availability of various pharmacological and behavioral therapies, a subset of psychiatric patients remains refractory to conventional treatments., Evidence Acquisition: To assess the feasibility and safety of MRgFUS in psychiatric disorders, a comprehensive literature search in PubMed and Scopus databases was conducted, resulting in the inclusion of five relevant articles in this review., Evidence Synthesis: While data on this innovative procedure are still limited, MRgFUS demonstrates potential as a safer and less invasive surgical technique for treating these disorders., Conclusions: Continued research efforts and data validation are imperative to establish MRgFUS as an additional, minimally invasive procedure for treatment-resistant psychiatric patients in the near future.

Endoplasmic reticulum (ER) remodeling is vital for cellular organization. ER-phagy, a selective autophagy targeting ER, plays an important role in maintaining ER morphology and function. The FAM134 protein family, including FAM134A, FAM134B, and FAM134C, mediates ER-phagy. While FAM134B mutations are linked to hereditary sensory and autonomic neuropathy in humans, the physiological role of the other FAM134 proteins remains unknown. To address this, we investigate the roles of FAM134 proteins using single and combined knockouts (KOs) in mice. Single KOs in young mice show no major phenotypes; however, combined Fam134b and Fam134c deletion (Fam134b/c dKO ), but not the combination including Fam134a deletion, leads to rapid neuromuscular and somatosensory degeneration, resulting in premature death. Fam134b/c dKO mice show rapid loss of motor and sensory axons in the peripheral nervous system. Long axons from Fam134b/c dKO mice exhibit expanded tubular ER with a transverse ladder-like appearance, whereas no obvious abnormalities are present in cortical ER. Our study unveils the critical roles of FAM134C and FAM134B in the formation of tubular ER network in axons of both motor and sensory neurons., (© 2024. The Author(s).)

Introduction: Income inequality, a pivotal determinant of general and mental health, operates through intricate mechanisms at various geographical scales. While established at country or region levels, the impact of lower-level (municipal or neighborhood) inequality remains inconsistent. This study explores the influence of regional- and municipal-level income inequality on individual psychological distress during the COVID-19 pandemic in Italy, employing a multilevel data analysis., Materials and Methods: In a post hoc analysis of data from the first wave of the pandemic (March to April 2020), three hierarchical levels were considered: individual participants, municipalities, and regions. Depressive and anxiety symptoms were measured using the PHQ-9 and GAD-7 scales, while the Gini coefficient gauged income inequality at municipal and regional levels. The analysis incorporated demographic variables as potential confounders., Results: The study encompassed 21 regions, 3,900 municipalities, and 21,477 subjects. Income inequality at both regional and municipal levels exhibited associations with distress scores, suggesting independent effects. Notably, higher distress scores were identified in southern regions with elevated inequality, despite a more substantial COVID-19 impact in the north., Discussion: Findings contribute to existing literature by emphasizing the independent impact of lower-level (municipal) and higher-level (regional) income inequality on population psychopathology. The study supports theories suggesting diverse pathways through which inequality at different levels influences health, such as potential associations with healthcare system dysfunction at the regional level and welfare dysfunction at the municipal level. The observed north-south gradient in distress scores highlights the need for psychosocial interventions to alleviate income inequality, especially in historically disadvantaged southern regions. Future research should explore the nuanced interplay between income inequality and various ecological variables to provide a comprehensive understanding of its health impact.