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Summary: Background: Dysfunctional allostatic-interoception, altered processing of bodily signals in response to environmental demands, occurs in behavioural-variant frontotemporal dementia (bvFTD) patients. Previous research has not investigated the dynamic nature of interoception using methods like intrinsic neural timescales. We hypothesised that longer intrinsic neural timescales of interoception would occur in bvFTD patients, evidencing dysfunctional allostatic-interoception. Methods: One-hundred and twelve participants (31 bvFTD patients, 35 Alzheimer's disease patients, AD and 46 healthy controls) completed a well-validated task measuring cardiac-interoception and exteroception. Simultaneous EEG and ECG were recorded. Intrinsic neural timescales were measured via the autocorrelation window (ACW) of broadband EEG signals from each heartbeat and a time-lagged version of itself. Spatiotemporal clustering analyses identified clusters with significant between-group differences in each condition. Voxel-based morphometry was used to target the allostatic-interoceptive network. Neuropsychological tests of cognition and social cognition were assessed. Findings: In bvFTD patients, longer interoceptive-ACWs than controls were observed in the bilateral fronto-temporal and parietal regions. In AD patients, longer interoceptive-ACWs than controls were observed in central and occipitoparietal brain regions. No differences were observed during exteroception. In bvFTD patients only, longer interoceptive-ACW was linked to worse sociocognitive performance. Structural neural correlates of interoceptive-ACW in bvFTD involved the anterior cingulate, insula, orbitofrontal cortex, hippocampus, and angular gyrus. Interpretation: Our findings suggest a core allostatic-interoceptive deficit occurs in people with bvFTD. Further, altered interoceptive intrinsic neural timescales may provide a neurobiological mechanism underpinning the complex behaviours observed in bvFTD patients. Our findings support synergistic models of brain disease and can inform clinical practice. Funding: All funding sources are reported in the Acknowledgements.

Background: The Child Amputee Prosthetics Project—Prosthesis Satisfaction Inventory (CAPP-PSI) is a comprehensive instrument designed to measure satisfaction across functionality, aesthetic, and service domains. This study aimed to translate, culturally adapt, and evaluate the psychometric properties of the CAPP-PSI in an Italian pediatric population. Methods: Following international guidelines, the CAPP-PSI was translated and culturally adapted. Internal consistency was evaluated using Cronbach’s alpha, while test–retest reliability was assessed with intraclass correlation coefficients (ICCs). Construct validity was measured by analyzing correlations among subscales. Results: A total of 113 children with congenital or acquired upper limb amputation, accompanied by their parents, were recruited from the Bambino Gesù Children’s Hospital in Rome. The Italian CAPP-PSI demonstrated excellent internal consistency (Cronbach’s alpha = 0.913) and strong test–retest reliability (ICC = 0.966). Subscale correlations showed strong relationships between child and parent satisfaction (r = 0.724, p < 0.01) and parent satisfaction with service (r = 0.612, p < 0.01), while moderate correlations were observed between child satisfaction and service (r = 0.434, p < 0.01). Conclusions: The Italian version of the CAPP-PSI is a reliable and valid tool for assessing prosthetic satisfaction in pediatric populations. It provides valuable insights for clinicians and researchers, supporting patient-centered care and targeted improvements in prosthetic design and services. Future studies should explore longitudinal outcomes and the role of psychosocial factors in prosthetic acceptance.

Venous thromboembolism (VTE) and arterial thrombosis (AT) are distinct yet closely related pathological processes. While traditionally considered separate entities, accumulating evidence suggests that they share common risk factors, such as inflammation and endothelial dysfunction (ED). This review explores the parallels and differences between venous and arterial thrombosis, with particular attention to the role of unprovoked VTE and its potential links to atherosclerosis and systemic inflammation. A key focus is the role of ED, which is emerging as a critical factor in thrombogenesis across both the venous and arterial systems. We examine the current methods for clinically detecting ED, including the use of biomarkers and advanced imaging techniques. Additionally, we discuss novel research avenues, such as the potential of endothelial colony-forming cells and other innovative methodologies, to further unravel the complex mechanisms of thrombosis. Finally, we propose future clinical scenarios where targeting endothelial health could pave the way for more effective prevention and treatment strategies in thrombosis management.

Summary: Study of disease-relevant immune cells, namely monocytes and macrophages, is limited based on availability of primary tissue, a limitation that can be remedied using human induced pluripotent stem cell (hiPSC) technology. Here, we present a protocol for differentiation of monocytes and macrophages from hiPSCs. We describe steps for hiPSC maintenance, mesoderm lineage induction, hematopoietic progenitor cells (HPCs) commitment and expansion, and myeloid lineage induction. We then detail procedures for monocyte formation and functional macrophage formation and polarization.For complete details on the use and execution of this protocol, please refer to Chen et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

A growing number of Congenital Heart Disease (CHD) patients will achieve adulthood. We aim to assess the characteristics, clinical course, and outcomes of Adult CHD (ACHD) patients attending the Emergency Department (ED) of a referral center. Seventy-five patients, 35 females (47%) were included. The mean age was 40 (±15) years. 35 patients (47%) had complex defects, and 29 patients (39%) were in NYHA class III-IV. Main symptoms were: dyspnea 22 (29 %), palpitations 20 (27%), fever 8 (11%), syncope 6 (8%), neurologic symptoms 7 (9.3%), chest pain 5 (7%). Heart failure and arrhythmias accounted for 23 (31%) and 20 (27%) of ED diagnoses. Twenty-eight patients (37%) were discharged, one patient died during observation, 32 patients (69 %) were admitted to a cardiology ward, 6 (13%) to the intensive care unit, and 8 (17%) to a non-cardiological ward. At a follow-up of 701 (554-984) days, 10 patients (13%) died, 2 (2.6%) were transplanted, 3 (4%) were listed for a heart transplant, and 30 (41 %) were re-admitted. In multivariate analysis, complex anatomy was weakly associated with readmissions. These preliminary data indicate that attendance of ACHD patients is epidemiologically relevant.

Objective: To evaluate neurogenic bladder and bowel dysfunction (NBBD) in children with cerebral palsy (CP) and acquired brain injury (ABI), a condition considered less frequent in those patients than in children with spinal cord injury (SCI), and to study the relationship between NBBD and disability grade in this population. Study Design: We retrospectively reviewed the clinical data of all patients (aged 3–18 years old) admitted during a three-month observation in our neurorehabilitation department. Data collected were as follows: demographic parameters; disability status (Wee-FIM Scale, Gross Motor Function Classification System (GMFCS) and the Communication Function Classification System); and gastrointestinal and urological symptoms (diaries, Bristol scale, Pad Test and International Consultation on Incontinence Modular Questionnaire). Results: Sixty patients were enrolled (31 females, 29 males): 30 CP, 17 ABI, 3 SCI, and 10 others with neurological diseases. All presented urinary incontinence without gender differences. CP and ABI had major incidences of bowel dysfunction (50% and 64.7%, respectively) and SCI of urinary tract infections (66.6%) and enuresis (100%). A major incidence of symptoms was recorded in patients with higher GMFCS levels (level 3-4-5). Conclusions: NBBD has a high frequency in children with CP and ABI, as in SCI. More attention is needed from pediatricians and pediatric urologists for this clinical entity. Further studies are needed to better understand clinical relevance and, therefore, to establish specific management.

Titanium and titanium alloys are the prevailing dental implant materials owing to their favorable mechanical properties and biocompatibility, but how roughness dictates the biological response is still a matter of debate. In this study, laser texturing was used to generate eight paradigmatic roughened surfaces, with the aim of studying the early biological response elicited on MC3T3-E1 pre-osteoblasts. Prior to cell tests, the samples underwent SEM analysis, optical profilometry, protein adsorption assay, and optical contact angle measurement with water and diiodomethane to determine surface free energy. While all the specimens proved to be biocompatible, supporting similar cell viability at 1, 2, and 3 days, surface roughness could impact significantly on cell adhesion. Factorial analysis and linear regression showed, in a robust and unprecedented way, that an isotropic distribution of deep and closely spaced valleys provides the best condition for cell adhesion, to which both protein adsorption and surface free energy were highly correlated. Overall, here the authors provide, for the first time, a thorough investigation of the relationship between roughness parameters and osteoblast adhesion that may be applied to design and produce new tailored interfaces for implant materials.

Spatial cell organization and biofabrication of microcapillary networks in vitro has a great potential in tissue engineering and regenerative medicine. This study explores the impact of local cell density enhancement achieved through an innovative sound-based patterning on microcapillary networks formation and their proteomic profile. Human umbilical vein endothelial cells (HUVEC) and human pericytes from placenta (hPC-PL) were mixed in a fibrin suspension. The mild effect of sound-induced hydrodynamic forces condensed cells into architected geometries showing good fidelity to the numerical simulation of the physical process. Local cell density increased significantly within the patterned areas and the capillary-like structures formed following the cell density gradient. Over five days, these patterns were well-maintained, resulting in concentric circles and honeycomb-like structures.Proteomic analysis of the pre-condensed cells cultured for 5 days, revealed over 900 differentially expressed proteins when cells were preassembled through mild-hydrodynamic forces. Gene ontology (GO) enrichment analysis identified cellular components, molecular functions, and biological processes that were up- and down-regulated, providing insights regarding molecular processes influenced by the local density enhancement. Furthermore, we employed Ingenuity Pathway Analysis (IPA) to identify altered pathways and predict upstream regulators. Notably, VEGF-A emerged as one of the most prominent upstream regulators.Accordingly, this study initiates the unraveling of the changes in microcapillary networks at both molecular and proteins level induced by cell condensation obtained through sound patterning. The findings provide valuable insights for further investigation into sound patterning as a biofabrication technique for creating more complex microcapillary networks and advancing in vitro models.

Thymic epithelial tumors (TETs) are rare mediastinal cancers originating from the thymus, classified in two main histotypes: thymoma and thymic carcinoma (TC). TETs affect a primary lymphoid organ playing a critical role in keeping T-cell homeostasis and ensuring an adequate immunological tolerance against “self”. In particular, thymomas and not TC are frequently associated with autoimmune diseases (ADs), with Myasthenia Gravis being the most common AD present in 30% of patients with thymoma. This comorbidity, in addition to negatively affecting the quality and duration of patients’ life, reduces the spectrum of the available therapeutic options. Indeed, the presence of autoimmunity represents an exclusion criteria for the administration of the newest immunotherapeutic treatments with checkpoint inhibitors. The pathophysiological correlation between TETs and autoimmunity remains a mystery. Several studies have demonstrated the presence of a residual and active thymopoiesis in adult patients affected by thymomas, especially in mixed and lymphocytic-rich thymomas, currently known as type AB and B thymomas. The aim of this review is to provide the state of art in regard to the histological features of the different TET histotype, to the role of the different immune cells infiltrating tumor microenvironments and their impact in the break of central immunologic thymic tolerance in thymomas. We discuss here both cellular and molecular immunologic mechanisms inducing the onset of autoimmunity in TETs, limiting the portfolio of therapeutic strategies against TETs and greatly impacting the prognosis of associated autoimmune diseases.

This study investigated the impact of early prosthetic intervention on children with upper limb agenesis or amputation. The aim was to assess both how early prosthetics improve a child’s movement and coordination skills, as well as how satisfied both the child and their parents are with the prosthesis. Twenty-nine children were evaluated using the Unilateral Below Elbow Test (UBET) and Child Amputee Prosthetics Project—Prothesis Satisfaction Inventory (CAPP-PSI). Results suggest that while children performed tasks faster and more fluidly without a prosthesis, they were satisfied with the prostheses and the service provided. This may be due to ongoing adaptation to the new device. The single child re-evaluated at 12 months showed improvement in prosthesis use, highlighting the potential benefits of early intervention coupled with motor re-education. Further research is needed to optimize prosthetic features and address initial challenges associated with prosthesis use.

Congenital or acquired hand differences, including unilateral below-elbow deficiencies, present complex challenges in pediatric rehabilitation. Surgical management and prosthetic provision represent a big challenge to find a good balance for guaranteeing optimal hand function. There is no specific assessment tool for measuring these aspects in the Italian context. The present study investigates the psychometric properties of the ABILHAND-Kids in children with congenital unilateral below-elbow deficiencies and acquired amputation of the upper limb. We measure internal consistency using Cronbach coefficient alpha and the intraclass correlation coefficient (ICC) for measuring test-retest reliability. Differences in hand function in both children with acquired or congenital diseases were also investigated. Participants to the study were 107 (49 F and 58 M) children, with a mean (SD) age of 8.88 (4.25). For test retest reliability, conducted on a sub-sample of 58 children, the ICC was 0.92, while for internal consistency, the Cronbach coefficient alpha was 0.90. We did not find statistically significant differences in scoring (p = 0.33) in the use (mean 29.25 SD 6.58) or non-use of a prosthetic device (mean 30.74 SD 7.43), while statistically significant differences were found in hand function (p < 0.01) for children who had a congenital impairment (mean 31.87 SD 6.49) and children who had an acquired amputation (mean 27.77 SD 6.60). In conclusion, the ABILHAND-Kids showed good internal consistency and reliability and can capture differences in hand function in children with both congenital and acquired hand disorders.

Background: Children with Down syndrome (DS) experience more difficulties with oral motor skills, including chewing, drinking, and swallowing. The present study attempts to measure the preliminary effectiveness of Global Intensive Feeding Therapy (GIFT) in DS. GIFT is a new rehabilitation program addressing the specific difficulties and needs of each child, focusing on sensory and motor oral abilities. It follows an intensive schedule comprising 15 sessions over 5 consecutive days, with 3 sessions per day. The principles of GIFT are applied with specific objectives for DS. Methods: GIFT was preliminarily implemented among 20 children diagnosed with DS. To measure the efficacy of GIFT, the Karaduman Chewing Performance Scale (KCPS), the International Dysphagia Diet Standardization Initiative (IDDSI), and the Pediatric Screening–Priority Evaluation Dysphagia (PS–PED) were used. Data were analyzed using the Wilcoxon signed-rank test before (T0) and after intervention (T1) and at one-month follow-up (T2). The effect size was also measured for specific outcomes, using Kendall’s W. Results: Our findings revealed that children with DS showed no risk of dysphagia according to the PS–PED (mean score 2.80). Furthermore, statistically significant improvements in chewing performance were observed, as measured by the KCPS (p < 0.01), as well as in texture acceptance and modification, as measured by the IDDSI post-intervention (p < 0.01). For both the KCPS and IDDSI, a large effect size was found (Kendall’s W value > 0.8). Parents/caregivers continued using GIFT at home, and this allowed for a positive outcome at the one-month follow-up. Conclusions: GIFT proved to be effective in the rehabilitation of feeding and swallowing disorders in children with DS, as well as for food acceptance.

Onabotulinum Toxin-A (BTX-A) is a second-line treatment for neurogenic bladder (NB). It requires repeated injections over time, which is a possible limit for long-term adherence, especially in children, as general anesthesia is required. Almost 50% of adults discontinue therapy; few data on pediatric patients are present. The aim of this study is to share our long-term experience of BTX-A adherence in children. This study is a retrospective review of 230 refractory NB patients treated with BTX-A. The inclusion criteria were ≥3 treatments and the first injection performed ≥10 years before the study endpoint. Fifty-four patients were included. Mean follow-up was 10.2 years; mean treatment number was 6.4 for each patient. During follow-up, 7% did not need BTX-A anymore; 76% discontinued therapy, with a prevalence of acquired NB (64% acquired vs. 34% congenital; p = 0.03); sex-based and urodynamic findings did not influence the discontinuation rate (p = 0.6, p = 0.2, respectively). Considering those who withdrew from the therapy, 43% were lost to follow-up/died after a mean of 7.5 years (although 33% still experienced clinical efficacy); 33% changed therapy after a mean of 5.8 years (with reduced efficacy in 22%, persistent efficacy in 11%). BTX-A is a safe and effective therapy for pediatric patients. The treatment abandonment rate is higher for children than for adults; no specific reasons were highlighted. It is necessary to evaluate any age-specific factors to explain these data.

Peripartum Cardiomyopathy (PPCM) is a polymorphic myocardial disease occurring late during pregnancy or early after delivery. While reduced systolic function and heart failure (HF) symptoms have been widely described, there is still a lack of reports about the arrhythmic manifestations of the disease. Most importantly, a broad range of unidentified pre-existing conditions, which may be missed by general practitioners and gynecologists, must be considered in differential diagnosis. The issue is relevant since some arrhythmias are associated to sudden cardiac death occurring in young patients, and the overall risk does not cease during the early postpartum period. This is why multimodality diagnostic workup and multidisciplinary management are highly suggested for these patients. We reported a series of 16 patients diagnosed with PPCM following arrhythmic clinical presentation. Both inpatients and outpatients were identified retrospectively. We performed several tests to identify the arrhythmic phenomena, inflammation and fibrosis presence. Cardiomyopathies phenotypes were reclassified in compliance with the updated ESC guidelines recommendations. Arrhythmias were documented in all the patients during the first cardiological assessment. PVC were the most common recorder arrhythmias, followed by VF, NSVT, AF, CSD.

Fracture non-unions affect many patients worldwide, however, known risk factors alone do not predict individual risk. The identification of novel biomarkers is crucial for early diagnosis and timely patient treatment. This study focused on the identification of microRNA (miRNA) related to the process of fracture healing. Serum of fracture patients and healthy volunteers was screened by RNA sequencing to identify differentially expressed miRNA at various times after injury. The results were correlated to miRNA in the conditioned medium of human bone marrow mesenchymal stromal cells (BMSCs) during in vitro osteogenic differentiation. hsa-miR-1246, hsa-miR-335-5p, and miR-193a-5p were identified both in vitro and in fracture patients and their functional role in direct BMSC osteogenic differentiation was assessed. The results showed no influence of the downregulation of the three miRNAs during in vitro osteogenesis. However, miR-1246 may be involved in cell proliferation and recruitment of progenitor cells. Further studies should be performed to assess the role of these miRNA in other processes relevant to fracture healing.

Abstract Background The role of left atrial appendage occlusion (LAAO) for atrial fibrillation patients that during oral anticoagulant therapy (OAC) suffer from ischemic events or present LAA sludge, and the best postinterventional anticoagulant regimen, need to be defined. We present our experience with a hybrid approach of LAAO+ lifelong OAC therapy in this cohort of patients. Methods Out of 425 patients treated with LAAO, 102 underwent LAAO because, despite OAC, suffered from ischemic events or presented with LAA sludge. Patients without high bleeding risk were discharged with the aim of maintaining lifelong OAC. This cohort was then matched to a population who underwent LAAO in primary ischemic events prevention. The primary endpoint was the composite of all‐cause death and major adverse cardiovascular events consisting of ischemic stroke, systemic embolism (SE), and major bleeding. Results Procedural success was 98%, and 70% of patients were discharged with anticoagulant therapy. After a median follow‐up of 47.2 months, the primary endpoint occurred in 27 patients (26%). At multivariate analyses, coronary artery disease (OR 5.1, CI 1.89–14.27, p = .003) and OAC at discharge (OR 0.29, CI 0.11–0.80, p = .017) were associated with the primary endpoint. After propensity score matching, no significant difference was found in the survival free from the primary endpoint according to the indication for LAAO (p = .19). Conclusions In this high‐ischemic risk cohort, LAAO + OAC seem a long‐term safe and effective therapeutical approach, with no difference in the survival free from the primary endpoint according to the indication for LAAO in a matched cohort.

In the early stages of carcinogenesis, the transformed cells become “invisible” to the immune system. From this moment on, the evolution of the tumor depends essentially on the genotype of the primitive cancer cells and their subsequent genetic drift. The role of the immune system in blocking tumor progression from the earliest stages is largely underestimated because by the time tumors are clinically detectable, the immune system has already completely failed its task. Therefore, a clinical treatment capable of restoring the natural anti-tumor role of the immune system could prove to be the “ultimate weapon” against cancer. Herein, we propose a novel therapeutic approach for the treatment of solid cancer that exploits the capability of activated monocytes to transfer major histocompatibility complex I (MHC-I) molecules bound to antigenic peptides to cancer cells using microvesicles as cargo, making tumor cells target of a “natural” CD8+ T lymphocyte cytotoxic response.

Background: Multiple sclerosis (MS) is increasing in the pediatric population and, as in adults, symptoms vary among patients. In children the first manifestations can sometimes overlap with acute neurological symptoms. Urological symptoms have not been much studied in childhood. We shared our experience with MS urological manifestation in children. Methods: This article is a retrospective evaluation of all children with MS, according to the Krupp criteria, who also present with urological symptoms. We collected demographic and clinical history, the MR localization of demyelinating lesions, urological symptoms, and exams. Results: We report on six MS pediatric cases with urological manifestation. Urinary symptoms, characterized by urinary incontinence in five patients and urinary retention in one patient, appeared in a different time frame from MS diagnosis. Urodynamic exams showed both overactive and underactive bladder patterns. Treatment was defined according to lower urinary tract dysfunction, using clean intermittent catheterization, oxybutynin, and intradetrusor Onabotulinum Toxin-A injection. A low acceptance rate of invasive evaluation and urological management was observed. Conclusions: The MS diagnosis was traumatic for all our patients. We believe it is important to address urological care in young people from the time of diagnosis for prompt management; it could be useful to include a pediatric urologist in multidisciplinary teams.

These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.