IRIS UniSR (’Università Vita-Salute San Raffaele)
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Disease Progression in Charcot-Marie-Tooth Disease Type 4B (CMT4B) Associated With Mutations in Myotubularin-Related Proteins 2 and 13
No full textBackground and Aims: In 2019, we conducted a cross-sectional study, collecting information on 50 patients with CMT4B, an ultrarare CMT subtype, to better define the clinical phenotype. We now aimed at investigating disease progression in 26 patients with CMT4B1/CMT4B2, recruited from the previous study and among the Inherited Neuropathy Consortium. Materials and Methods: We retrospectively analysed disease progression in patients with CMT4B1/CMT4B2, collecting MRC scores from nine muscle pairs, Charcot-Marie-Tooth Examination Score (CMTES), and a minimal dataset of clinical information (walking difficulties, aids dependency, upper limb impairment, cranial nerves involvement) at baseline and follow-up visits. Thirteen centres from four continents were involved. Results: Thirteen CMT4B1 and 13 CMT4B2 patients were followed up for 7.1 ± 4.9 and 7.9 ± 4.5 years, respectively. During follow-up, walking aid dependency increased: two CMT4B1 patients adopted AFOs (overall 11/12 at follow-up), and one started using wheelchair (6/12 at follow-up) at the age of 19; among CMT4B2 patients, two more required unilateral support in walking (4/11 at follow-up) by the age of 33 and 49 years, respectively. We found that disease progression, as measured by CMTES, was faster in CMT4B1 as compared to CMT4B2 patients (ΔCMTES/year 0.7 vs. 0.3, p = 0.037) but tended to slow down over time as burden of disease increased. At the end of follow-up, CMT4B1 was associated to higher disability. Conclusions: This international collective effort enabled collection of relevant data for characterizing natural history and estimating disease progression of CMT4B1/CMT4B2 ultrarare diseases, aiming at improving their management and paving the way for designing future clinical trials
The Last Mile in Beta-Cell Replacement Therapy for Type 1 Diabetes: Time to Grow Up
Get PDFBeta cell replacement therapy for type 1 diabetes (T1D) is undergoing a transformative shift, driven by advances in stem cell biology, gene editing, and tissue engineering. While islet transplantation has demonstrated proof-of-concept success in restoring endogenous insulin production, its clinical impact remains limited by donor scarcity, immune rejection, and procedural complexities. The emergence of stem cell-derived beta-like cells represents a paradigm shift, with initial clinical trials showing promising insulin secretion in vivo. However, translating these breakthroughs into scalable, widely accessible treatments poses significant challenges. Drawing parallels to space exploration, this paper argues that while scientific feasibility has been demonstrated, true accessibility remains elusive. Without a strategic shift, beta cell therapy risks becoming an elite intervention, restricted by cost and infrastructure. Lessons from gene and cell therapies for rare diseases highlight the dangers of unsustainable pricing and limited market viability. To bridge the "last mile" a Quality by Design approach is proposed, emphasizing scalability, ease of use, and economic feasibility from the outset. By emphasizing practical implementation over academic achievements, corporate interests, market economics, or patent constraints, beta cell therapy can progress from proof-of-concept to a viable, widely accessible treatment
Effects of early neuroanatomical variants on reading skills and brain function in typical adult Italian readers
No full textReading is a core feature of human communication that develops throughout intensive academic training. Recently, a group of studies examined whether neuroanatomical variants that predate literacy acquisition may influence reading abilities at later stages of life, yielding mixed results. To complement and expand previous knowledge, we used multimodal magnetic resonance imaging (MRI) to investigate whether distinct anatomical patterns of the left occipito-temporal sulcus (OTS), which hosts the so-called “visual word form area” (VWFA), are predictive of reading skills and brain activity in typical adult readers. Overall, our findings indicate that: (1) the pattern of the left OTS is not predictive of participants’ scores on reading fluency tests; (2) the pattern of the left OTS is not predictive of local brain activity during sentence-reading; (3) individual differences in the left OTS pattern are associated with the functional architecture of the left OTS as assessed by resting-state fMRI. In conclusion, while it is well-established that the acquisition of reading skills modifies brain structure and function, the predictive role of early neuroanatomical variants on reading skills and brain function in typical readers remains equivocal. Environmental and experience-related factors may have a greater and predominant role in accounting for ultimate reading abilities in healthy populations
Long-term follow-up of pancreatic islet transplantation in a patient with Wolfram syndrome: a case report
No full textA cross-talk established by tumor-targeted cytokines rescues CAR T cell activity and engages host T cells against glioblastoma in mice
No full textChimeric antigen receptor (CAR) T cells have shown limited efficacy against solid tumors because of poor tissue penetration, constrained activity, and early exhaustion due to the immunosuppressive tumor microenvironment (TME). Although stimulatory cytokines can counteract immune suppression, their systemic administration entails risk of toxicities and counter-regulatory responses. Here, we leveraged a population of tumor-associated TIE2-expressing macrophages (TEMs) to release interferon-α (IFN-α) and/or orthogonal interleukin-2 (oIL2) at the tumor site. Targeted cytokine delivery rescued CAR T cell functionality against the clinically relevant tumor antigen B7-homolog 3 (B7-H3) in an orthotopic, CAR T cell–refractory, immunocompetent mouse model of glioblastoma (GBM) named mGB2 that recapitulates pathological features of the human disease. Immunophenotypic and transcriptomic analyses revealed that inhibition of premature terminal exhaustion and induction of effector and memory states featuring activation of signaling pathways and transcriptional networks putatively boosted CAR T cell antitumor activity. Furthermore, IFN-α, especially when combined with private oIL2 signaling to CAR T cells, elicited potent endogenous T cell responses against multiple tumor-associated antigens, leading to delayed GBM growth and prolonged mouse survival even with tumors expressing B7-H3 in only a fraction of cells. These data suggest that the combination of TEM-based cytokine delivery and CAR T cells may have synergistic effects and support the further study of this approach for the treatment of patients with GBM
Improving Vaccine Coverage Among Older Adults and High-Risk Patients: A Systematic Review and Meta-Analysis of Hospital-Based Strategies
No full textBackground/Objectives: Adult vaccination remains suboptimal, particularly among older adults and individuals with chronic conditions. Hospitals represent a strategic setting for improving vaccination coverage among these high-risk populations. This systematic review and meta-analysis evaluated hospital-based interventions aimed at enhancing vaccine uptake in adults aged ≥60 years or 18–64 years with at-risk medical conditions. Methods: We conducted a systematic review and meta-analysis following PRISMA and MOOSE guidelines. Searches in PubMed, EMBASE, and Scopus identified studies published in the last 10 years evaluating hospital-based interventions reporting vaccination uptake. The risk of bias was assessed using validated tools (NOS, RoB 2, ROBINS-I, QI-MQCS). A meta-analysis was conducted for categories with ≥3 eligible studies reporting pre- and post-intervention vaccination coverage in the same population. Results: We included 44 studies. Multi-component strategies (n = 21) showed the most consistent results (e.g., pneumococcal uptake from 2.2% to 43.4%, p < 0.001). Reminder-based interventions (n = 4) achieved influenza coverage increases from 31.0% to 68.0% and a COVID-19 booster uptake boost of +38% after SMS reminders. Educational strategies (n = 11) varied in effectiveness, with one study reporting influenza coverage rising from 1.6% to 12.2% (+662.5%, OR 8.86, p < 0.01). Standing order protocols increased pneumococcal vaccination from 10% to 60% in high-risk adults. Hospital-based catch-up programs improved DTaP-IPV uptake from 56.2% to 80.8% (p < 0.001). For patient education, the pooled OR was 2.11 (95% CI: 1.96–2.27; p < 0.001, I2 = 97.2%) under a fixed-effects model, and 2.47 (95% CI: 1.53–3.98; p < 0.001) under a random-effects model. For multi-component strategies, the OR was 2.39 (95% CI: 2.33–2.44; p < 0.001, I2 = 98.0%) with fixed effects, and 3.12 (95% CI: 2.49–3.92; p < 0.001) with random effects. No publication bias was detected. Conclusions: Hospital-based interventions, particularly those using multi-component approaches, effectively improve vaccine coverage in older and high-risk adults. Embedding vaccination into routine hospital care offers a scalable opportunity to reduce disparities and enhance population-level protection. Future policies should prioritize the institutional integration of such strategies to support healthy aging and vaccine equity
The Spectrum of Macular Ischemia in West Nile Virus Chorioretinitis
No full textPurpose: This study reports a unique case of West Nile Virus (WNV)-associated multilevel macular ischemia, involving retinal capillary plexuses and choriocapillaris, confirmed through real-time polymerase chain reaction (RT-PCR) of aqueous humor and characterized using advanced multimodal imaging. Methods: A 35-year-old immunocompromised male presented with bilateral, acute, and painless visual loss persisting for 14 days. Ophthalmic evaluation included ultra-widefield fundus photography, spectral-domain optical coherence tomography (SD-OCT), OCT angiography (OCT-A), fluorescein angiography (FA), and indocyanine green angiography (ICGA). Laboratory testing included serology and RT-PCR analysis of aqueous humor. Results: Presenting visual acuity was hand motion in both eyes. Fundus examination revealed bilateral pale optic discs, attenuated arteries, and deep creamy chorioretinal lesions in the posterior pole and mid-periphery. SD-OCT demonstrated nerve fiber layer ischemia and hyperreflective bands in the inner and outer nuclear layers. OCT-A showed flow deficits in the deep capillary plexus and choriocapillaris. FA and ICGA revealed active lesions with late-phase leakage and hyperfluorescence, alongside target-like patterns suggesting chronic atrophy. RT-PCR analysis of aqueous humor confirmed WNV infection with a viral load of 1,335 copies/mL. Serial imaging demonstrated the progression to inner retinal and RPE atrophy over 8 weeks. Conclusions: This case represents the first documented use of RT-PCR analysis of aqueous humor to confirm WNV infection, providing a novel diagnostic approach for atypical presentations. Multimodal imaging, including SD-OCT and OCT-A, revealed multilevel ischemic retinal damage and highlighted the acute and chronic lesions. These findings underscore the importance of advanced imaging and molecular diagnostics in identifying and managing ocular manifestations of WNV
