IRIS UniSR (’Università Vita-Salute San Raffaele)
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Metabolic, genetic and immunological features of relatives of type 1 diabetes patients with elevated insulin resistance
No full textPurposeInsulin resistance plays a pivotal role in the preclinical stages of type 1 diabetes (T1D).ObjectiveThis study aims at exploring the genetic, metabolic, and immunological features associated with insulin resistance among individuals at risk of developing T1D.MethodsWe retrospectively selected relatives of individuals with T1D from participants in the TrialNet Pathway to Prevention study. They were categorized into two groups: high-H (n = 27) and low-H (n = 30), based on the upper and lower quartiles of insulin resistance assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Genetic predisposition was determined using the T1D Genetic Risk Score 1 (GRS1). Additionally, glucose control was evaluated through an oral glucose tolerance test and levels of metabolic hormones and inflammatory cytokines were measured in the serum. Flow cytometry analysis was employed to assess frequency and phenotype of islet-specific CD8 T cells.ResultsWhile GRS1 were similar between the low-H and high-H groups, high-H individuals displayed a distinct metabolic profile, characterized by compensatory hyperinsulinemia, even while maintaining normoglycemia. Circulating cytokine levels were similar between the two groups. However, immune profiling revealed a central memory and activated profile of GAD65-specific CD8 T cells, along with an increased frequency of insulin-specific CD8 T cells in high-H individuals. The enrichment in insulin-specific CD8 T cells was independent of body mass.ConclusionThese findings highlight the intricate interplay between insulin resistance, genetic factors, and immune activation in the context of T1D susceptibility, indicating potential connections between insulin resistance and immune responses specific to islet cells
Optimizing Tildrakizumab Dosing in Psoriasis: A 52-Week Multicenter Retrospective Study Comparing 100 mg and 200 mg—IL PSO (Italian Landscape Psoriasis)
No full textIntroduction: Tildrakizumab is a monoclonal antibody targeting interleukin (IL)-23 approved for the treatment of moderate-to-severe plaque psoriasis across two different dosages (100 mg and 200 mg). The higher dosage is recommended for patients with a body weight ≥ 90 kg or a high disease burden (Psoriasis Area and Severity Index [PASI] ≥ 16 or the involvement of difficult-to-treat areas). We conducted a 52-week multicenter retrospective study to compare the effectiveness and safety of both dosages and assess their impact on specific patient subgroups. Methods: We enrolled a total of 540 patients with high disease burden or body weight ≥ 90 kg; 177 and 363 were treated with tildrakizumab 200 mg and 100 mg, respectively. The effectiveness was evaluated in terms of PASI 90, PASI 100, and PASI ≤ 2 at weeks 16, 28, and 52. We also performed subanalyses according to the body weight (≥ 90 kg), PASI ≥ 16, prior biologic exposure, involvement of difficult-to-treat areas, and the presence of at least one cardiometabolic comorbidity. Results: After 16 weeks of treatment, a higher proportion of patients in the 200-mg group achieved PASI 90 and PASI 100 compared to those in the 100-mg group (43.5% vs. 34.3% and 36.4% vs. 24.2%, respectively). These results were sustained at 1 year, with PASI 90 and PASI 100 reached by 68.6% and 52.9% of patients in the 200-mg group, respectively, versus 57.3% and 35% in the 100-mg group. All subgroup analyses consistently indicated a trend toward greater effectiveness with tildrakizumab 200 mg, particularly in terms of PASI 90 and PASI 100 achievement at weeks 16 and 52. No differences in the safety profile were observed throughout the study period. Conclusion: Our findings confirm the superior effectiveness of tildrakizumab 200 mg over 100 mg in specific subgroups of patients with a comparable safety profile across the study period
How to Do Echocardiography in Heart Failure Patients with Long-term Left Ventricular Assist Devices: A Consensus Statement of the Italian Society of Echocardiography and Cardiovascular Imaging
No full text1. LVADs have emerged as destination therapy for advanced heart failure, however, these are still limited by many potential complications after implant, such as right heart failure, aortic regurgitation, thrombosis, infections 2. A seriate and accurate echocardiographic evaluation is needed in LVAD carriers but may sometimes be challenging, due to artifacts or poor acoustic windows due to the device 3. Left ventricular unloading is the main feature to consider to evaluate and adjust device function and requires many echocardiographic parameters to be assessed 4. Ramp test during echocardiography may be of additional value to optimize device speed and to early identify pump dysfunctio
Tracking remyelination in a model of multiple sclerosis: Visual evoked potentials reveal therapeutic effect from brain stimulation and exercise
No full text: Visual evoked potentials (VEPs) represent an accurate, fast, and cost-effective diagnostic tool to evaluate visual function in multiple sclerosis (MS), and its use in preclinical research can support longitudinal monitoring of treatments effects with implications for translational purposes. Anodal transcranial direct current stimulation (tDCS) and physical exercise (PE) are known to exert neuromodulatory effects on the central nervous system, increasing brain activity, promoting plasticity and remyelination. To improve our understanding of the effects of tDCS and PE on demyelination/remyelination processes and refine its therapeutic use in MS, VEPs were employed to monitor the mouse visual pathway during cuprizone (CPZ) demyelination including before and after therapeutic interventions. In CPZ-fed mice, VEP latency delays were associated with MBP loss in the dorsolateral geniculate nucleus (dLGN) confirming VEP as a biomarker of demyelination in the subcortical visual pathway. Combination of anodal tDCS and PE showed a strong beneficial effect on VEP latency during CPZ demyelination. Both VEP latency and behavioural motor function improvements were stronger after combined protocols, highlighting the potential of this multimodal approach in demyelinating conditions. Differential and synergistic contribution by anodal tDCS and PE was associated with reduced microglia/macrophage levels whilst effects on myelin by the first, and reduced cell death and BDNF protein were driven by the second. VEPs efficiency to detect modulation of visual function by brain stimulation and physical activity, strongly correlated with myelin changes in the visual pathway, providing a potent platform for the translatability of preclinical findings to the clinic
Radioembolization for Hepatocellular Carcinoma: a Comparison on Dual-phase Cone-beam CT, Contrast-enhanced CT (CECT) and 99mTc-macroaggregated albumin-SPECT/CT in predicting final distribution volumes and dosimetry of the post-embolization 90Y PET/CT
No full textPurpose: Personalized treatment schemes are being systematically applied to ensure best treatment outcome in oncologic patients. This is true also for personalized dosimetry in transarterial radioembolization (TARE) in hepatocellular carcinoma (HCC) patients. Precise and detailed volumetric and functional data derived from radiological and nuclear imaging methods are essential for personalized dosimetry. We sought to evaluate accuracy of dual-phase cone-beam CT (CBCT) in comparison to pre-treatment contrast-enhanced CT (CECT), and 99mTc-macroaggregated albumin-SPECT/CT ([99mTc]MAA SPECT/CT) to predict and assess the efficacy of TARE based on post-treatment 90Y PET/CT. Material and methods: Thirty consecutive patients with HCC treated with TARE were included. Intraprocedural dual-phase CBCT acquisition protocol was developed to distinguish tumor volume in the early arterial phase and perfused volume of non-affected liver in the late arterial phase. Volumetric data obtained from pre-treatment CECT, dual-phase CBCT and [99mTc]MAA SPECT/CT were compared to post-treatment 90Y PET/CT considered the standard reference. Treatment simulations for final calculated dose from the different imaging derived volumes were then compared to post-treatment 90Y PET/CT. Results: CBCT resulted as the most accurate method in predicting tumor- (R2 0.88) and perfused volumes (R2 0.82). Dosimetry prediction planning performed on derived volumes from the different methods did not show significant difference (p < 0.05), yet highest concordance with 90Y PET/CT data was observed with dual-phase CBCT. Conclusion: Our study shows that dual-phase CBCT acquisition is a novel alternative method for correctly and safely administering more accurate and defined doses during TARE. clinicaltrials.gov ID: NCT03981497
Resistance to targeted therapies in chronic lymphocytic leukemia: Current status and perspectives for clinical and diagnostic practice
No full textThe integration of BTK and BCL2 inhibitors into the treatment of patients with chronic lymphocytic leukemia (CLL) represents a paradigm shift and has led to significant improvements in clinical outcomes, including prolonged survival and enhanced quality of life. However, despite the efficacy of these agents, resistance to targeted therapy remains a major challenge, ultimately resulting in treatment failure and disease progression for a significant proportion of patients. Related to this, diagnostic testing for genetic variants associated with resistance, such as mutations in BTK, PLCG2 and BCL2, may become an increasingly common part of clinical routine practice. Addressing the need for placing the current knowledge in context, here we summarize the evidence from clinical studies and examine the underlying biology of both genetic and non-genetic resistance. Furthermore, we outline methodological approaches for the detection of gene alterations associated with targeted therapy resistance, discuss how to interpret these findings and highlight interpretation challenges. Finally, we offer insights into the clinical relevance of identifying genetic resistance to inform personalized treatment strategies and improve patient outcomes
Changing clinical and laboratory characteristics of Progressive Multifocal Leukoencephalopathy: a retrospective national cohort study
No full textBackground: Progressive Multifocal Leukoencephalopathy (PML) is a severe demyelinating disease caused by JC polyomavirus (JCV), affecting immunocompromised individuals. We describe PML demographic, clinical, radiological and laboratory characteristics and survival over time and according to underlying condition in a large retrospective patient cohort. Methods: This is a retrospective cohort including Italian PML patients observed between 1987 and 2024, with known year of diagnosis and underlying disease. Results: We included 456 cases with either a definite (n=376, 82.4%) or clinico-radiological (n=80, 17.6%) PML diagnosis. The relative frequency of HIV-associated cases decreased through four time periods (1987-1996; 1997-2004; 2005-2012; 2013-2024) from 99% to 43%, in parallel with increasing age (p<0.0001), proportion of women (p<0.001) and CD4+ counts (p<0.001), but not cerebrospinal fluid (CSF) or plasma JCV-DNA levels at diagnosis. One-year survival probability increased from 23.8% in 1987-1996 to 59.2% in 2013-2024, with highest values in natalizumab-treated multiple sclerosis (93.8%), followed by combination antiretroviral treatment (cART)-treated HIV infection (55%), hematological malignancies (50.8%), primary immunodeficiencies (41.3%) and cART-untreated HIV infection (11.9%). At multivariate analysis excluding cART-untreated people with HIV, JCV-DNA levels in both CSF and plasma were independently associated with an increased mortality risk of 2.9% and 7.2%, respectively, for each Log increase in JCV-DNA. Conclusions: This observational study showed a changing epidemiological context over 37 years. Although survival improved over time, it remained poor even in the last decade, with a one-year survival probability of 59.2%
Extracorporeal membrane oxygenation for prevention of barotrauma in patients with respiratory failure: A scoping review
Get PDFBackground: Barotrauma is a frequent complication in patients with severe respiratory failure and is associated with poor outcomes. Extracorporeal membrane oxygenation (ECMO) implantation allows to introduce lung-protective ventilation strategies that limit barotrauma development or progression, but available data are scarce. We performed a scoping review to summarize current knowledge on this therapeutic approach. Methods: We systematically searched PubMed/MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for studies investigating ECMO as a strategy to prevent/limit barotrauma progression in patients with respiratory failure. Pediatric studies, studies on perioperative implantation of ECMO, and studies not reporting original data were excluded. The primary outcome was the rate of barotrauma development/progression. Results: We identified 21 manuscripts presenting data on a total of 45 ECMO patients. All patients underwent veno-venous ECMO. Of these, 21 (46.7%) received ECMO before invasive mechanical ventilation. In most cases, ECMO implantation allowed to modify the respiratory support strategy (e.g., introduction of ultraprotective/low pressure ventilation in 12 patients, extubation while on ECMO in one case, and avoidance of invasive ventilation in 15 cases). Barotrauma development/progression occurred in <10% of patients. Overall mortality was 8/45 (17.8%). Conclusion: ECMO implantation to prevent barotrauma development/progression is a feasible strategy and may be a promising support option.Background: Barotrauma is a frequent complication in patients with severe respiratory failure and is associated with poor outcomes. Extracorporeal membrane oxygenation (ECMO) implantation allows to introduce lung-protective ventilation strategies that limit barotrauma development or progression, but available data are scarce. We performed a scoping review to summarize current knowledge on this therapeutic approach. Methods: We systematically searched PubMed/MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for studies investigating ECMO as a strategy to prevent/limit barotrauma progression in patients with respiratory failure. Pediatric studies, studies on perioperative implantation of ECMO, and studies not reporting original data were excluded. The primary outcome was the rate of barotrauma development/progression. Results: We identified 21 manuscripts presenting data on a total of 45 ECMO patients. All patients underwent veno-venous ECMO. Of these, 21 (46.7%) received ECMO before invasive mechanical ventilation. In most cases, ECMO implantation allowed to modify the respiratory support strategy (e.g., introduction of ultraprotective/low pressure ventilation in 12 patients, extubation while on ECMO in one case, and avoidance of invasive ventilation in 15 cases). Barotrauma development/progression occurred in <10% of patients. Overall mortality was 8/45 (17.8%). Conclusion: ECMO implantation to prevent barotrauma development/progression is a feasible strategy and may be a promising support option
Anatomy at the threshold: Teaching the human body in a hybrid age
No full textAs emerging technologies reshape both the body and how we represent it, anatomical education stands at a threshold. Virtual dissection tools, AI-generated images, and immersive platforms are redefining how students learn anatomy, while real-world bodies are becoming hybridized through implants, neural interfaces, and bioengineered components. This Viewpoint explores what it means to teach human anatomy when the body is no longer entirely natural, and the image is no longer entirely real. Based on recent evidence and educational reflections, it suggests that anatomy can serve as a critical human science, one that goes beyond structural knowledge, encouraging students to develop visual literacy, structural reasoning, and ethical awareness. As experiences with donated bodies are replaced with digital models, students risk losing contact with the lived, variable, and vulnerable aspects of the human form. Yet, rather than resisting change, anatomists can respond by integrating new tools within a pedagogical model grounded in presence and meaning. In an age where biology and technology are converging with unexpected speed, anatomy offers a powerful lens to question not only how bodies work, but what bodies mean. The role of the anatomist is therefore both conservative and visionary: to hold the line of deep biological knowledge, while opening the door to critical engagement with the hybrid human condition