Antonio Toscano

Dentin-derived biomaterials are hierarchical collagen–mineral composites increasingly used as bio-based scaffolds for bone regeneration. However, the effect of prolonged storage of extracted teeth on their physicochemical integrity remains unclear. This study evaluated the stability of dentin-derived biomaterials following long-term refrigerated storage (up to six years) using Raman spectroscopy. Extracted human teeth were processed using three preparation systems (BonMaker, Tooth Transformer, and Smart Dentin Grinder), and Raman-derived indices describing mineral and collagen structure were compared with freshly extracted controls. No time-dependent changes were observed in mineral crystallinity, carbonate substitution, or collagen-related parameters, indicating preservation of the collagen–mineral interface during storage. In contrast, the observed differences were primarily associated with processing pathways. Tooth Transformer and Smart Dentin Grinder exhibited Raman profiles closely resembling native dentin, whereas BonMaker showed reduced mineral content and altered mineral–matrix balance consistent with its demineralization protocol. These findings demonstrate that dentin behaves as a structurally stable hierarchical composite, reflecting intrinsic structural organization that limits physicochemical degradation over time. Long-term storage does not compromise dentin integrity, supporting its use as a reliable source of biomaterial for regenerative applications and future tooth banking strategies.

BACKGROUND: Collateral blood flow is a critical determinant of successful recanalization in acute ischemic stroke caused by large vessel occlusion. Head down tilt −15° (HDT15), similar to Trendelenburg positioning, is a simple, low-cost positional therapy that may augment cerebral collateral blood flow and penumbral survival. The aim of the study is to assess the safety, feasibility, and efficacy of HDT15 in improving cerebral collateral circulation and clinical outcomes in patients with large vessel occlusion–acute ischemic stroke treated with mechanical thrombectomy (MT). METHODS: The DOWN-SUITE trial (Head Down Tilt 15° to Increase Collateral Flow in Acute Ischemic Stroke) is a multicenter, randomized, open-label, phase 2a/b clinical trial with blinded outcome assessment, conducted across 7 Italian stroke centers. A total of 118 patients with acute ischemic stroke due to M1 segment middle cerebral artery occlusion will be randomized 1:1 in the emergency department to receive HDT15 or standard positioning (head-of-bed 0° to +30°) before and during MT. RESULTS: The primary end point is good collateral status (American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology grade 3–4), assessed on the first angiographic sequence during MT by a blinded imaging core laboratory. Secondary end points include feasibility (proportion maintaining HDT15, admission-to-MT time), safety (symptomatic intracranial hemorrhage, pneumonia, vomiting, neurological deterioration, vital signs), and efficacy (neurological improvement before MT, at 24 hours, and at 7 days or discharge, modified Rankin Scale score at 90 days). CONCLUSIONS: The DOWN-SUITE trial will provide evidence on the acute cerebrovascular effect of HDT15 in large vessel occlusion–acute ischemic stroke, potentially establishing a cost-effective, practice-changing intervention to improve collaterals for global stroke care. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06297863.

The management of anterior circulation tandem lesion stroke remains controversial, given its under-representation in randomized thrombectomy trials and uncertainty regarding optimal extracranial carotid intervention. We aimed to determine whether emergent carotid stenting (eCAS) during endovascular thrombectomy (EVT) for anterior circulation tandem lesions improves 90-day functional outcomes compared with a no-stenting strategy. We conducted an international multicenter longitudinal retrospective cohort study (CERES-TANDEM, NCT06965036) of consecutive adults treated at 49 comprehensive stroke centers in Europe, North America, and Singapore for anterior circulation acute ischemic stroke due to tandem lesions from January 1, 2018, to December 31, 2024. Exclusion criteria were primary hemorrhagic stroke, absence of intracranial occlusion, presentation >24 hours from symptom onset, and age younger than 18 years. We compared 90-day modified Rankin Scale (mRS) scores between participants receiving eCAS and those receiving no stenting during EVT. The primary estimand was mRS shift, analyzed by stabilized inverse probability of treatment weighting (IPTW)-weighted ordinal regression. Additional estimands were direct-effect estimand adjusting for successful recanalization (defined as Thrombolysis in Cerebral Infarction grade 2b or higher) and symptomatic intracranial hemorrhage (sICH) (estimand 2) and stratum estimand restricting to never-crossers (estimand 3). Of 4,053 patients (mean age 70 years, 65.5% female), 2,522 underwent eCAS and 1,531 received no stenting. After IPTW, eCAS was associated with an improved 90-day functional outcome (common odds ratio (OR) 1.31; 95% CI 1.17-1.47;p < 0.001) and higher odds of mRS score 0-1 (OR 1.27; 95% CI 1.08-1.50; p = 0.005) and mRS score 0-2 (OR 1.30; 95% CI 1.13-1.51; p < 0.001), without a significant increase in sICH (OR 1.21; 95% CI 0.93-1.56; p = 0.15). Findings were consistent in direct-effect (common OR 1.17; 95% CI 1.04-1.31; p = 0.008) and stratum (common OR 1.37; 95% CI 1.21-1.55; p < 0.001) estimands. There was no interaction for intracranial occlusion site, IV thrombolysis, sedation technique, EVT approach, or access site. Sensitivity analysis including recanalization in IPTW-weighted estimand 1 framework confirmed the association of eCAS with improved 90-day functional outcomes (common OR 1.14, 95% CI1.02-1.27, p = 0.008). In this large real-world cohort, eCAS during EVT for anterior circulation tandem lesions was associated with superior 90-day functional recovery without increased hemorrhagic risk. These findings support consideration of eCAS in clinical practice and warrant confirmation in randomized trials. Registered in clinicaltrials.gov, NCT06965036. This study provides Class II evidence that in patients with stroke due to anterior circulation tandem lesions, eCAS during EVT improves 90-day functional outcomes compared with EVT alone.

Background: Pompe disease and Mucopolysaccharidoses Type I (MPS-I) are lysosomal disorders caused by a deficiency of α-glucosidase and alpha-L-iduronidase, respectively. The mainstay of treatment is enzyme replacement therapy (ERT), a life-long treatment that requires regular I.V. infusions. Hospital-based therapy can, however, negatively impact quality of life over time. The purpose of the HomERT study (Home infusions of ERT) was to evaluate the safety, treatment compliance, and treatment satisfaction related to home therapy of Pompe disease patients with Myozyme ^® (alglucosidase alfa) and MPS-I patients with Aldurazyme ^® (laronidase). The final results are presented in this paper. Results: The HomERT study was a multicenter, non-interventional, minimum 12-month prospective observational, double-cohort study that analyzed 56 patients from 14 sites in Italy from October 2021 to February 2024: cohort A (Pompe disease − 47 patients) and cohort B (MPS-I − 9 patients: 6 Hurler/Scheie, 3 Scheie). During the observation period, the mean (SD) number of missed infusions was 5.8 (3.92) in cohort A and 3.0 (3.52) in cohort B, corresponding to a mean (SD) of missed infusions of 19.8 (32.7)% and 4.1 (4.2)%, respectively, versus the number of planned infusions. Only 2 patients in cohort A returned to the hospital setting due to “adverse event” and “other” reasons. A total of 13 Adverse Drug Reactions (ADR) were reported during the home-care setting before and after enrollment. The average number of ADRs per patient was 0.2 (1.46) in cohort A and 0.2 (0.67) in group B, and the rate of ADRs/year was 0.15 (95% CI: 0.06; 0.34) in cohort A and 0.06 (95% CI: 0.01; 0.38) in cohort B. The majority of patients preferred home-based infusions (cohort A: 93.6%; cohort B: 88.9%), and the main reason was attributed to treatment convenience (cohort A: 93.6%; cohort B: 100%). Despite the underlying conditions, most patients self-evaluated their health as “Fair” in cohort A (36.2%) and “Good” in cohort B (44.5%). Conclusion: The use of ERT with α-glucosidase and alpha-L-iduronidase alfa remains a strong candidate for home therapy, with favorable safety profile, improved treatment ERT compliance, and patient satisfaction. NCT05073783.

The management of anticoagulation after ischemic stroke while on direct oral anticoagulants (DOACs) is controversial. We performed an aggregate-data meta-analysis to compare anticoagulation strategies against each other to define the effect of switch to warfarin, switch to another DOAC, change in dosage, and add-on antiplatelet for the prevention of recurrent stroke, intracranial hemorrhage (ICH), any stroke, and mortality. The study protocol was deposited with PROSPERO (CRD42025639057). We systematically searched MEDLINE, Scopus, and the Cochrane Library-all studies reporting on anticoagulation strategies after a stroke while on DOAC up to January 31, 2025. We included randomized controlled clinical studies and cohort studies with sample size ≥50 that (1) enrolled adult patients who experienced ischemic stroke while on DOACs, (2) assessed modifications to anticoagulation therapy, and (3) reported on at least one of the outcomes. Main outcome was recurrent ischemic stroke; secondary outcomes were ICH, all-cause mortality, and any stroke. We pooled estimates by random-effects modelling, reporting risk ratio (RR) with 95% CIs comparing anticoagulation strategies against each other. We retrieved 2,171 results, with 8 observational studies reaching quantitative synthesis (n = 14,307 patients, mean age = 75 years, 48% female). Switching to warfarin was associated with a higher risk of ischemic stroke compared with keeping the same DOAC (RR 1.80, 95% CI 1.42-2.29, I² = 0%, n_studies = 5) or changing DOAC dosage (RR 1.72, 95% CI 1.20-2.45, I² = 0%, n_studies = 4). Switching to warfarin was also associated with higher ICH rates compared with keeping the same DOAC (RR 2.90, 95% CI 2.01-4.18, I² = 0%, n_studies = 5) and DOAC-to-DOAC switch (RR 3.25, 95% CI 2.13-4.96, I² = 0%; n_studies = 5). Keeping the same DOAC and switching to another DOAC, independently from mechanism, had similar rates of primary and secondary outcomes. Our meta-analysis indicates that switching to warfarin after a stroke while on DOAC seems less effective and safe in stroke recurrence prevention, ICH, and mortality compared with DOAC-based strategies.

Background: Serum creatine kinase (CK) has been used as a diagnostic marker for neuromuscular disorders since 1959. As manufacturer‐provided normative data indicate, CK levels can be elevated in normal individuals. Recent evidence suggests these data often underestimate true CK values, which are influenced by age, race, gender, and other physiological factors. Therefore, establishing a reliable normal range for CK is crucial before further investigation, particularly in oligo/asymptomatic patients.Objective: This systematic review aims to determine the normal CK levels across various populations.Methods: We systematically reviewed observational studies with a cross‐sectional, descriptive design. We included studies focusing on healthy adults (> 18 years) of any race who aimed to establish normal CK values, including at least 100 participants. We utilized the following databases: PubMed, Embase, and Cochrane.Results: CK values typically exhibit a non‐Gaussian distribution. Black individuals demonstrate significantly higher CK values compared to Caucasians and Asians. The upper reference limits for CK in Caucasian and Asian males range from 227–440 U/L, while for Black males, it is between 520–810 U/L. The upper reference limits for females range from 135–248 U/L and up to 354 U/L, respectively.Conclusions: Normal CK values might be higher than previously suggested, especially among specific racial groups. Each laboratory should ideally determine its reference values for CK that reflect its local population.

The risk of recurrent ischemic stroke, intracranial hemorrhage, and mortality in people with atrial fibrillation detected after stroke (AFDAS) is still unclear compared with people with known atrial fibrillation (KAF). We systematically reviewed the literature to provide updated estimates for the risk of recurrent stroke, intracerebral hemorrhage, and mortality in AFDAS compared with KAF. Our protocol was registered in PROSPERO (CRD42024583064). Presentation followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. We searched MEDLINE, EMBASE, Cochrane CENTRAL, and MedRxiv up to August 28, 2024, for studies comparing AFDAS and KAF for the following outcomes of interest: recurrent ischemic stroke (primary), intracerebral hemorrhage, mortality, and any stroke recurrence. We included cohort, observational studies (either prospective or retrospective) and randomized controlled trials and excluded studies with less than 15 patients per group. Eligible studies were assessed for bias using the Risk of Bias in Non-Randomized Studies tool. We pooled study-level results through random-effect meta-analysis of risk ratios (RRs). We also performed prespecified sensitivity analysis for study quality, timing of search for AF, propensity score matching, and study data source (administrative vs local data), and we planned meta-regression analysis to test for the interaction of sex, comorbid cardiovascular risk factors, and anticoagulation status on the difference between AFDAS and KAF. Seventeen studies were retrieved (n = 113,365; n_KAF = 80,339; n_AFDAS = 33,026; female in KAF, 49.0%; female in AFDAS, 45.1%), eight of which had low risk of bias. Ischemic stroke recurrence was significantly lower in AFDAS compared with the KAF group (RR = 0.79, 95% CI = 0.66-0.95, I² = 70%; n_studies = 10). Meta-regression analysis revealed no interaction of anticoagulation, CHA₂DS₂-VASc score, or sex on the difference in risk of recurrent ischemic stroke between groups. Mortality was lower in the AFDAS group compared with KAF (RR = 0.84, 95% CI = 0.74-0.95, I² = 74%; n_studies = 14). The rates of any intracerebral bleeding (RR = 0.97, 95% CI = 0.68-1.39, I² = 58%; n_studies = 5) and any stroke recurrence (RR = 0.99, 95% CI = 0.75-1.30; I² = 60; n_studies = 3) were similar in AFDAS and KAF. AFDAS may carry a lower risk of ischemic stroke recurrence and mortality compared with KAF, with similar risk of intracerebral hemorrhage. Stratification through implementation of AF burden measures may support more personalized management for people with AFDAS.

Background and purpose: The European Academy of Neurology (EAN) has adhered to the global plan for reducing the burden of neurological disorders and promoting brain health launched by the World Health Organisation (WHO), the WHO Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders. This study reports the results of an EAN survey among national neurological societies (NNSs) on their awareness of brain health policies.Methods: The EAN survey on the current state of national brain health policies was conducted among the 47 presidents of the NNSs affiliated with the EAN, with the aim of developing the best strategy for close collaboration among stakeholders.Results: From June 2023 to February 2024, 36/47 responses (77%) were collected. Among respondents, 67% were in contact with their Ministry of Health and 78% were aware of and in contact with one or more national neurological patient organisation, while 17% had no contacts with any association. Ninety‐two percent declared a high to medium degree of awareness of the need to support brain health and of brain health plans and strategies in their country.Conclusions: Our findings suggest good awareness of the importance of brain health and of the strategies implemented at the national level among the EAN‐affiliated NNSs and representatives. Efforts towards improvement may be directed towards cooperation between NNSs and political institutions, as well as patient organisations, to optimise brain and global public health and neurological care in each country.

Background: The Italian Medicines Agency (AIFA) demands precise information on benefit/risk profile of home-based enzyme replacement therapy (ERT) for the treatment of patients with Pompe disease and Mucopolysaccharidosis type I (MPS I). This passage is necessary to obtain the authorization for ERT home therapy, even after the coronavirus disease-19 (COVID-19) pandemic period. This research intends to evaluate the safety, treatment satisfaction, and compliance of MPS I patients treated with laronidase (Aldurazyme®) and Pompe Disease patients treated with alglucosidase alfa (Myozyme®) in a homecare setting.Results: We report herein an early interim analysis of the HomERT (Home infusions of ERT) study, a multicenter, non-interventional, double-cohort study that retrospectively analyzed 38 patients from 14 sites in Italy: cohort A (Pompe disease − 32 patients) and cohort B (MPS I − 6 patients). Among the selected patients who started home therapy before enrollment, the average number of missed home-based infusions was 0.7 (1.3) in cohort A and 3.8 (6.4) in cohort B with no return to the hospital setting. Irrespective of the treatment location, 3 prior ADRs per cohort were reported. The majority of patients preferred home-based infusions (cohort A: 96.9%; cohort B: 100%): the main reason was attributed to treatment convenience (cohort A: 81.3%; cohort B: 83.3%). Despite the underlying conditions, most patients self-evaluated their health as “good” (cohort A: 50%; cohort B: 83.3%).Conclusions: Evidence of favorable safety profile, improved treatment compliance and personal satisfaction validates the use of ERT with laronidase and alglucosidase alfa as a strong candidate for home therapy.