Search Results (782)

Introduction: Immune evasion through inhibition of effector T cells is a key survival mechanism of lymphoma cells. We hypothesized that reinstating effector T cell activity through concurrent inhibition of the PD1/PD-L1 axis and of Treg activity will result in a synergistic anti-tumor effect with an acceptable toxicity profile. Methods: Phase I multi-institutional NCI-ETCTN trial aimed to evaluate the safety and tolerability of the combination of mogamulizumab and pembrolizumab in relapsed or refractory non-Hodgkin lymphoma. The study used a 3 + 3 design. Treatment consisted of mogamulizumab 1 mg/kg on days 1, 8, and 15 of cycle 1, followed by 1.5 mg/kg on day 1 of each subsequent 21-day cycle in combination with pembrolizumab 200 mg on day 1 of each cycle. A de-escalation level was defined as a 50% reduction in the dose of mogamulizumab (registered in clinicaltrials.gov NCT03309878). Results: The study was discontinued early, after treating seven patients (two angioimmunoblastic T cell lymphoma, four transformed follicular lymphoma, and one diffuse large B cell lymphoma of germinal center subtype) for concerns of futility and non-tolerability. Only two patients completed the first two cycles of treatment. Three patients presented with an early progression and three withdrew consent in the setting of general deterioration with clinically suspected progression. All six patients expired shortly after withdrawal from the study. The remaining patient experienced stress cardiomyopathy during the third cycle and was taken off the study. Discussion: In striking difference to the observation in solid malignancies, the combination of mogamulizumab with pembrolizumab was associated with low tolerability and suspected hyper-progression in patients with lymphoma. Full article

Antibiotic feeding in shrimp farming is an optional practice conducted with the aim of preventing and controlling bacterial diseases. However, the administration of antibiotics can disrupt the microbiota of both shrimp and surrounding environment, potentially compromising host health. Given the limited effective antibiotic options in aquaculture, it is crucial to evaluate the effects of florfenicol (FF) on the intestinal health of shrimp and the associated microbial communities. This study first investigated the impact of FF on the intestinal structure of Penaeus vannamei over two feeding durations (5 and 10 days), each followed by a 10-day basal diet recovery period. Simultaneously, variations in microbial communities and antibiotic resistance genes (ARGs) in both the intestine and rearing water were explored. The results showed that intestinal damage was aggravated with the extension of FF duration and gradually recovered after FF withdrawal. Significant changes in microbial composition and β-diversity were observed in both the rearing water and intestine following FF feeding. Extending the FF treatment to 10 days led to a reduced abundance of Rhodobacteraceae and an increased abundance of Flavobacteriaceae and Vibrionaceae in the intestine after 10 days of feeding the basic diet, which may pose a potential risk to shrimp health. Based on correlation analysis of ARGs, microbial communities and pathogenic bacteria, we speculated that rearing water may serve as a reservoir for ARGs dissemination compared to the shrimp intestine. These findings are of great importance for assessing the impact of administration duration under the FF therapeutic dose and highlight the potential risks associated with its overuse in shrimp farming. Full article

Background/Objectives. Chronic benzodiazepine (BDZ) use is frequently maintained beyond recommended durations due to neuroadaptation, psychological dependence, and withdrawal-related issues. Passiflora incarnata L., herba (P. incarnata) has shown anxiolytic and GABAergic activity that may mitigate withdrawal symptoms, while cognitive-behavioural therapy (CBT) targets maladaptive beliefs and behaviours sustaining BDZ misuse. This study investigates the independent and interactive effects of P. incarnata and CBT on BDZ dose reduction during a three-month tapering program. Methods. This retrospective observational study included 186 outpatients with anxiety or depressive disorders in clinical remission undergoing BDZ tapering, of whom 93 received a dry extract of P. incarnata as adjunctive treatment and 93, matched for diagnosis, age and sex, followed a standard tapering protocol. BDZ doses were assessed at baseline and three months. CBT was recorded as a binary variable based on the information documented in the medical records. An ANCOVA was performed to assess the impact of CBT and P. incarnata on BDZ reduction (change in mg diazepam equivalents), adjusting for sex, age, education, baseline anxiety and depression scores, initial BDZ and antidepressant dosage. A subgroup analysis was conducted to investigate the role of P. incarnata dosage in BDZ reduction. Results. Both CBT and P. incarnata were associated with significantly greater reductions in BDZ dosage at three months (CBT: p = 0.005, effect size: 0.032; P. incarnata: p < 0.001, effect size: 0.128). A significant interaction between CBT and P. incarnata was also observed (p = 0.037, effect size: 0.018), indicating a synergistic effect when both interventions were combined. Baseline sociodemographic characteristics, BDZ and antidepressant dosage and symptom severity did not differ significantly between groups. Patients taking 400–600 mg of P. incarnata dry extract showed a higher BDZ reduction compared to those taking 200 mg. Conclusions. These findings suggest that P. incarnata and CBT exert independent yet complementary effects in supporting BDZ tapering. Their combination appears to enhance dose reduction beyond either intervention alone, supporting a multimodal approach that addresses both neurobiological and psychological components of BDZ addiction. Prospective controlled studies are needed to confirm these results and to clarify their impact on long-term discontinuation outcomes. Full article

Background: Patients with dental phobia frequently require intravenous sedation (IVS) to undergo dental treatment; however, some can gradually discontinue IVS through repeated clinical experiences. The physiological and psychological factors influencing successful IVS withdrawal remain unclear. This study aimed to compare physiological (sAA, HR) and subjective (VAS) measures between patients who discontinued IVS and those who remained dependent on IVS. Methods: This prospective cohort study included 51 patients with dental phobia treated under IVS. Participants were classified into a Non-Sedation Group (NSG; n = 25) and a Sedation-Dependent Group (SDG; n = 26) based on their ability to discontinue IVS during the course of treatment. Salivary alpha-amylase (sAA), heart rate (HR), and visual analog scale (VAS) scores for fear, tension, and anxiety were assessed at predefined time points from the waiting room to venous cannulation. Treatment satisfaction and expectations for future treatment were also evaluated. Results: sAA activity was significantly higher in the SDG than in the NSG at T0 and T1 (p < 0.05), indicating higher levels of selected physiological measures during anticipatory phases; however, the difference at T2 was not significant. HR differed significantly only in the waiting room, whereas no between-group differences were observed in self-reported VAS scores for fear, tension, or anxiety at any time point, indicating a dissociation between physiological and subjective stress measures. Treatment satisfaction and expectations for future treatment were significantly higher in the SDG. Conclusions: Patients who remained dependent on IVS showed higher levels in selected physiological measures at the group level during anticipatory stages, whereas no corresponding differences were observed in self-reported subjective measures. These findings are exploratory and descriptive in nature and do not imply predictive or causal relationships. Full article

Background/Objectives: Neonatal Intensive Care Units (NICUs) constitute a highly complex clinical environment characterized by patient fragility and frequent ethically sensitive decisions. To date, systematic studies investigating how Italian NICUs address these challenges and what forms of ethics support are effectively available are lacking. The aim of this study is therefore to assess how ethical issues are managed in Italian NICUs, with particular attention to the availability, use, and perceived usefulness of clinical ethics support in everyday practice. Methods: A 25-item questionnaire was developed by adapting an existing tool for investigating clinical ethics activities to the neonatal context. Following expert review by the GIBCE (Gruppo Interdisciplinare di Bioetica Clinica e Consulenza Etica in ambito sanitario), the final instrument covered four areas (general data, experience with ethical dilemmas, tools and procedures, opinions and training needs). A manual web search identified all Italian NICUs and their clinical directors, who were asked to disseminate the survey among staff. Participation was voluntary and anonymous. Data collection was conducted via Google Forms and analyzed through qualitative thematic analysis. Results: A total of 217 questionnaires were collected. The most frequent ethical dilemmas concern quality of life with anticipated multiple or severe disabilities (72.4%) and decisions to withdraw or withhold life-sustaining treatments (64.5%). Major challenges include fear of medico-legal repercussions (57.6%) and communication divergences between physicians and nurses (49.8%). More than half of respondents (52.1%) reported no formal training in clinical ethics, and 68.7% had never developed a Shared Care Plan (Shared Document for healthcare ethics planning) as defined by the Italian Law 219/2017. Conclusions: Findings highlight marked fragmentation in ethical practices across Italian NICUs. On this basis, establishing structured and accessible CEC services could help promote consistency, reinforce shared ethical standards, and support transparent and equitable decision-making in critical neonatal care. Full article

NF2-related Schwannomatosis (NF2-SWN) remains a disorder with few effective treatment options. Patients develop vestibular schwannomas (VSs) on both auditory nerves, which gradually impair hearing and often result in significant communication difficulties, social withdrawal, and higher rates of depression. Progress in understanding NF2-SWN biology and translating discoveries into therapies has been slowed by the absence of robust animal models that faithfully reproduce both tumor behavior and the associated neurological deficits. In this review, we summarized the development of animal models that not only reproduce tumor growth in the peripheral nerve microenvironment but also reproduce tumor-induced neurological symptoms, such as hearing loss and ataxia. We further highlight the currently available organotypic models for NF2-SWN. Together, these systems provide an essential foundation for advancing mechanistic studies and accelerating the development of effective therapies for this devastating disorder. Full article

Background: Tumor necrosis factor-α (TNFα) inhibitors have significantly improved outcomes in children with non-systemic juvenile idiopathic arthritis (JIA), achieving long-term clinical remission for many patients. However, the optimal strategy for TNF-α inhibitor withdrawal remains unknown, whether through abrupt discontinuation, gradual dose reduction, or interval extension. Objective: We aim to identify patient-, disease-, and treatment-related predictors of successful TNF-α inhibitor withdrawal in children with non-systemic JIA. Methods: In this prospective, randomized, open-label, single-center study, 76 children with non-systemic JIA in stable remission for ≥24 months on etanercept or adalimumab were enrolled. At the time of TNF-α inhibitor discontinuation, all patients underwent a comprehensive evaluation, including a clinical examination, laboratory tests (serum calprotectin [S100 proteins] and high-sensitivity C-reactive protein [hsCRP]), and advanced joint imaging (musculoskeletal ultrasound and magnetic resonance imaging [MRI]) to assess subclinical disease activity. Patients were randomized (1:1:1, sealed-envelope allocation) to one of three predefined tapering strategies: (I) abrupt discontinuation; (II) extension of dosing intervals (etanercept 0.8 mg/kg every 2 weeks; adalimumab 24 mg/m² every 4 weeks); or (III) gradual dose reduction (etanercept 0.4 mg/kg weekly; adalimumab 12 mg/m² every 2 weeks). Follow-up visits were scheduled at 3, 6, 9, 12, and 18 months to monitor for disease relapse. Results: Higher baseline Childhood Health Assessment Questionnaire (CHAQ) scores (≥2), elevated serum calprotectin [S100 proteins] and hsCRP levels at withdrawal, imaging evidence of subclinical synovitis, and a history of uveitis were all significantly associated with increased risk of flare. No significant associations were found for other clinical or demographic characteristics. Conclusions: Early significant clinical response, absence of subclinical disease activity, and concomitant low-dose methotrexate therapy were key predictors of sustained drug-free remission. These findings may inform personalized strategies for biologic tapering in pediatric JIA. Full article

Osteoporosis is a prevalent skeletal disorder characterized by reduced bone mass and microarchitectural deterioration, leading to increased fracture risk, particularly in aging populations. Postmenopausal osteoporosis (PMOP) remains the most common primary form and results from abrupt estrogen deficiency after menopause, which disrupts bone remodeling by accelerating the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis, suppressing Wnt/β-catenin signaling, and promoting inflammatory cytokine production. In contrast, drug-induced osteoporosis (DIOP) encompasses a heterogeneous group of secondary bone disorders arising from pharmacologic exposures. Glucocorticoids suppress osteoblastogenesis, enhance osteoclast activity, and increase reactive oxygen species; long-term bisphosphonate therapy may oversuppress bone turnover, resulting in microdamage accumulation; denosumab withdrawal triggers a unique rebound surge in RANKL activity, often leading to rapid bone loss and multiple vertebral fractures. Medications including aromatase inhibitors, SSRIs, proton pump inhibitors, heparin, and antiepileptic drugs impair bone quality through diverse mechanisms. Standard antiresorptive agents remain first-line therapies, while anabolic agents such as teriparatide, abaloparatide, and romosozumab provide enhanced benefits in high-risk or drug-suppressed bone states. Transitional bisphosphonate therapy is essential when discontinuing denosumab, and individualized treatment plans—including drug holidays, lifestyle interventions, and monitoring vulnerable patients—are critical for optimizing outcomes. Emerging approaches such as small interfering RNA (siRNA)-based therapeutics, anti-sclerostin agents, digital monitoring technologies, and regenerative strategies show promise for future precision medicine management. Understanding the distinct and overlapping molecular mechanisms of osteoporosis is essential for improving fracture prevention and long-term skeletal health. Full article

Background/Objectives: Patients with moderate-to-severe psoriasis who experience inadequate response or loss of efficacy to multiple biologic agents (“multi-failure patients”) represent a particularly challenging subgroup in clinical practice. Evidence regarding the efficacy of bimekizumab in this setting is still limited. This multicentre, real-life study aimed to evaluate the effectiveness, safety, and treatment persistence of bimekizumab in patients with moderate-to-severe psoriasis who had failed at least two previous biologic therapies. Methods: This multicentre, retrospective, real-life study across Italian referral centers retrospectively collected clinical data from 33 adult patients with plaque psoriasis treated with bimekizumab across Italian referral centers. Efficacy was assessed through changes in Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores at weeks 4 and 16. Logistic regression was performed to identify predictors of treatment response, and Kaplan–Meier analysis evaluated drug survival up to 12 months. Results: The mean baseline PASI was 14.5 ± 7.1, decreasing to 1.5 ± 4.0 at week 16 (p < 0.001). PASI90 and PASI100 responses were achieved by 57.6% and 42.4% of patients at this timepoint, respectively, while mean DLQI improved by 84.2%. In this small cohort, no significant differences in efficacy were observed according to the number or class of prior biologic failures. Genital psoriasis was associated with a lower likelihood of achieving PASI100. Adverse events were generally mild to moderate in severity and manageable in routine clinical practice. No discontinuations occurred due to lack of efficacy; all withdrawals were related to mild adverse events or personal reasons. Twelve-month drug survival reached 85.4% (95% CI 63.8–100). Conclusions: Bimekizumab demonstrated rapid, marked, and sustained clinical improvements with a favorable safety profile in multi-failure psoriasis patients. These findings support its role as an effective and well-tolerated therapeutic option for individuals with highly refractory disease in real-life practice. Full article

Early-life development of immune functions is crucial for calf health, growth, and future productivity. Galacto-oligosaccharides (GOSs) have been reported to facilitate ruminal microbial establishment and improve growth in Holstein dairy calves, but their prolonged influence on immunoglobulin levels, hindgut microbiota, and metabolic regulation remains insufficiently understood. This study evaluated the effects of early-life GOS supplementation on immune-related indicators, intestinal microbial ecology, and metabolic profiles in Holstein calves. Twenty-four newborn Holstein female dairy calves were randomly assigned to a control group (CON, n = 12) or a GOS group (GOS, n = 12; 10 g/day from birth to day 28). After supplementation ceased on day 28, calves previously receiving GOS were referred to as the GOSS group (n = 6). Immunoglobulin levels, gut microbiota, and fecal and serum metabolomes were evaluated during supplementation and six weeks after withdrawal. GOS supplementation significantly increased serum IgA and IgG levels during the treatment, with IgG levels remaining elevated for six weeks after discontinued supplementation. Although overall microbial diversity was not markedly altered, GOS selectively enriched bacterial taxa and function pathways linked to amino acid synthesis, unsaturated fatty acid production, and coenzyme-related metabolism. On day 70, GOSS group displayed distinct fecal and serum metabolomic profiles, with altered metabolites primarily associated with vitamin B6, folate, cobalamin metabolism, branched-chain amino acid biosynthesis, and purine and arginine pathways. These results demonstrate that early-life GOS supplementation promotes sustained immune and metabolic alterations following supplementation cessation, potentially mediated by modulation of gut microbial functions. These findings suggest that early dietary GOS supplementation may support physiological maturation in calves and could be useful as a nutritional strategy in calf-rearing systems. Full article

Patients with respiratory tract malignancies who undergo tracheostomy often experience profound psychosocial challenges related to visible anatomical changes and altered communication. The aim of this study was to evaluate psychosocial barriers and perceived social acceptance in patients living with a tracheostomy, compared with patients treated for similar cancers without requiring a tracheostomy. A matched case–control study with frequency matching at the group level was conducted including 150 patients with permanent tracheostomies and 150 matched controls treated with organ-preserving approaches. Groups were frequency-matched at the group level based on age, sex, primary tumor site, and disease stage at diagnosis. Participants completed a study-specific questionnaire assessing social withdrawal, self-consciousness, and perceived reactions of others using a five-point Likert scale. A composite Psychosocial Barrier Score was calculated, and subgroup analyses examined differences according to gender and age. Patients with tracheostomies demonstrated significantly higher psychosocial burden than controls, with markedly elevated composite scores and higher endorsement of stigma-related items. Female and younger patients within the tracheostomy group reported the greatest psychosocial difficulties, including increased social avoidance and reduced confidence in public settings. In contrast, gender- and age-related differences were minimal in the control group. These findings indicate that tracheostomy is strongly associated with heightened psychosocial barriers and perceived social stigma, particularly among younger and female patients. Integrating targeted psychosocial support into routine post-treatment care may be essential to improve social reintegration and quality of life in this population. Full article

Background/Objectives: Anti-calcitonin gene-related peptide monoclonal antibodies (CGRP-mAbs) are effective injectable medications for the treatment of migraine. This study aimed to evaluate continuation, resumption, and withdrawal rates of CGRP-mAb treatment under real-world clinical conditions. Methods: Treatment-naïve patients with at least 3 months of follow-up after starting CGRP-mAb treatment were included. The decision to continue, discontinue, or resume CGRP-mAb treatment was made freely by the patients. Headache Impact Test-6 (HIT-6) and the Migraine-Specific Quality of Life Questionnaire (MSQ) were administered before starting treatment and one month after each CGRP-mAb injection. The endpoints were as follows: continuation rates of CGRP-mAb treatment after treatment initiation; resumption rate; withdrawal rate; changes in HIT-6 and MSQ scores; and differences in background factors between the resumption and withdrawal groups. Results: Of the 1162 migraine patients, 146 were included in the analysis. Continuation rates of CGRP-mAb treatment at 3, 6, 9, 12, 18, and 24 months were 93.2%, 80.2%, 68.9%, 58.8%, 55.4%, and 51.7%, respectively. For the patients who discontinued, the resumption rate was 76.8%, and the withdrawal rate was 20.7%. HIT-6 and MSQ scores were significantly decreased at all assessment points compared with before CGRP-mAb treatment. There were no significant differences in factors between the resumption and withdrawal groups. Conclusions: Under real-world clinical conditions in which patients were free to choose their own treatment, the continuation rate of CGRP-mAb treatment 12 months after treatment initiation was 58.8%, and more than half of patients remained on treatment after 24 months. The resumption rate was 76.8% and the withdrawal rate was 20.7%. Full article

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder linked to impaired cognition and altered dopamine neurotransmission. Emerging evidence suggests that women with ADHD experience pronounced hormone-related difficulties, with menstrual cycle-related changes in mood and cognition interfering with daily functioning and diminishing treatment efficacy. This review examines the influence of hormonal fluctuations during the menstrual cycle on cognitive functioning and ADHD symptomatology in women. A comprehensive literature search of Ovid EmBase identified studies published between 2015 and 2025 examining cognitive performance, including attention, executive functioning, working memory, and inhibitory control, across menstrual cycle phases in women with or without ADHD. Twenty-nine studies met inclusion criteria. Neurobiological measurements included hormonal assays, neuroimaging, and neurotransmitter models. Seven studies in non-clinical populations suggested that attentional processing was enhanced during the mid-luteal phase, which may be linked to higher progesterone levels. By contrast, four studies in women with ADHD and six studies in women with mood-related disorders, such as PMS or PMDD, consistently observed impairments in attention, executive function, and impulsivity during the mid-luteal and pre-menstrual phases. These objective findings parallel subjective reports of worsened cognition, heightened mood symptoms, and diminished medication efficacy during the luteal phase. Current evidence indicates that ADHD-related cognitive functioning fluctuates with the menstrual cycle, with impairments particularly evident in women with ADHD and/or comorbid mood disorders. These changes may reflect increased sensitivity to allopregnanolone, peri-menstrual oestrogen withdrawal, and the absence of compensatory neural adaptations observed in non-clinical populations. However, findings remain preliminary and sometimes contradictory due to methodological heterogeneity and small sample sizes. Further research is needed to clarify these mechanisms and, importantly, to translate theoretical insights into clinical application through female-specific diagnostic procedures and treatment strategies. Full article

Background: Acute coronary syndromes (ACSs) remain a leading cause of death and disability. Since the publication of the 2023 ESC ACS guidelines, multiple studies and an ESC/EAS dyslipidaemia update have refined how clinicians diagnose, revascularize, and treat ACS across the care continuum. Content: This state-of-the-art review synthesizes advances from 2023 to 2025 across five domains. Diagnosis: High-sensitivity troponin-based accelerated pathways remain foundational; GRACE 3.0 improves calibration for early vs. delayed angiography, while selective use of CCTA and routine use of intracoronary imaging/physiology help define the mechanism and optimize PCI. Revascularization: complete revascularization continues to underpin care in multivessel disease, with recent data favouring culprit-only PCI acutely and staged non-culprit treatment during the index stay in most STEMI presentations, particularly with heart-failure physiology. Antithrombotic therapy: Aspirin remains critical early after ACS-PCI; emerging evidence supports shorter DAPT and aspirin withdrawal after 1 month in carefully selected, low-ischaemic-risk patients, whereas day-0 aspirin-free strategies in unselected ACS are not non-inferior. Secondary prevention: A “strike early and strong” approach to LDL-cholesterol—often with combination therapy in hospital—is emphasized, alongside nuanced roles for SGLT2 inhibitors and GLP-1 receptor agonists. Special populations and implementation: Sex- and age-aware tailoring (including MINOCA/SCAD evaluation), pragmatic bleeding-risk mitigation, digitally enabled cardiac rehabilitation, and registry-driven quality improvement translate evidence into practice. Summary: Contemporary ACS care is moving from uniform protocols toward risk-stratified, mechanism-informed pathways. We offer practical algorithms and checklists to align interventional timing, antithrombotic intensity/duration, and secondary prevention with individual patient risk—bridging new evidence to bedside decisions. Full article

Background: Informed consent and assent are fundamental ethical and legal requirements in paediatric healthcare, yet their application in paediatric dentistry is complex and underexplored in clinical practice. Objective: This study aimed to analyse the implementation of informed consent and assent processes in paediatric dental care within a Spanish population, identifying key characteristics and factors that influence communication, understanding, and decision-making. Methods: An observational, descriptive, cross-sectional study was conducted in Spanish Paediatric Dentistry Clinics (January–June 2023). Participants included 520 child-caregiver pairs and 52 dental students. Data were collected via a semi-structured observational protocol and interviews, assessing information provided, decision-making conditions, and influencing factors. Statistical analysis was performed using SPSS v23.0, employing Chi-square, Cochran’s Q, and Kendall’s W tests. Results: The information most frequently provided was the nature of the dental problem (92%), treatment details (88%), and benefits (85%). Information on risks (64%), alternatives (37%), and the right to withdraw consent (41%) was less consistently communicated. After multivariable adjustment, child schooling remained independently associated with the disclosure of risks and alternatives (p < 0.01), whereas caregiver education showed no independent effect. Kendall’s concordance coefficient showed moderate agreement (W = 0.62, 95% CI: 0.54–0.69, p < 0.01) among operators, caregivers, and patients, which decreased in adolescents aged 16–18 years (W = 0.41, 95% CI: 0.28–0.55, p = 0.07). Conclusions: The processes of informed consent and assent in paediatric dentistry are more strongly linked to the child’s cognitive maturity and schooling than to parental education. While communication of treatment benefits is adequate, critical aspects like risks and alternatives are often overlooked. The findings underscore the need for standardized protocols and enhanced bioethical training to ensure consistent, ethical, and participatory practices that respect the progressive autonomy of minors. Full article