Fondazione FADOI

Artificial intelligence (AI) undoubtedly represents one of the most significant innovations in modern medicine. From early diagnosis to personalized treatment, from decision support to management of continuity of care, its applications extend to all phases of the clinical journey. However, in the context of Internal Medicine, reflection on the adoption of AI cannot ignore a critical and multidimensional assessment, encompassing not only technological and operational aspects, but also, and above all, ethical, relational, and educational aspects.

The prognostic impact of intracerebral hemorrhage (ICH) volume varies according to location, with smaller volume tolerance in deep ICH, and hematoma expansion (HE) contributes to final ICH volume. We tested the hypothesis that HE influences outcome only when the final ICH volume achieves a critical threshold that differs according to ICH location. Retrospective analysis of patients with supratentorial ICH admitted at 10 centers in North America and China (development cohort) and Europe (replication cohort). HE was defined as growth >33% and/or >6 mL. Location-specific (lobar versus deep) volume cutoffs for the prediction of poor outcomes were derived using receiver operating characteristic curves and the Youden index. The prognostic impact of HE stratified by location and final volume was explored with logistic regression (poor outcome: 90-day modified Rankin Scale score of 4-6), accounting for age, Glasgow Coma Scale, baseline volume, intraventricular hemorrhage, and admission center. We identified 1774 patients with ICH in the development cohort and 1746 in the replication cohort. A total of 1058 (mean age, 68 years; 47.8% men) and 1423 (mean age, 71 years; 44.7% men) subjects met the inclusion criteria, respectively. The optimal final ICH volume cutoff for poor outcome differed by location: ≥36 mL for lobar and ≥17 mL for deep ICH. HE with final volume below the cutoff was not associated with higher odds of poor outcome compared with patients without HE (adjusted odds ratio, 1.85 [95% CI, 0.78-4.38]; P=0.163 in lobar ICH; adjusted odds ratio, 0.85 [95% CI, 0.38-1.89]; P=0.685 in deep ICH). The combination of HE and final volume over the critical threshold was, however, significantly associated with poor prognosis, and the magnitude of this effect was substantial (adjusted odds ratio, 8.55 [95% CI, 2.87-25.48]; P<0.001 in lobar ICH; adjusted odds ratio, 10.34 [95% CI, 2.86-37.44]; P<0.001 in deep ICH). These findings were confirmed in the replication cohort. HE significantly impacts severe outcomes only when the final ICH volume exceeds a critical target threshold, and this threshold is lower in deep versus lobar ICH. These findings might inform clinical practice and future trials.

ADVANCE-CIDP IVIG evaluated the efficacy and safety of immune globulin infusion (human) 10% solution (IVIG 10%; GAMMAGARD LIQUID, also known as Kiovig) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as a rescue treatment for patients relapsing during the ADVANCE-CIDP 1 trial. Open-label ADVANCE-CIDP IVIG included adult patients with confirmed CIDP relapse (≥ 1-point increase in adjusted Inflammatory Neuropathy Cause and Treatment [INCAT] disability scores from pre-treatment baseline) during ADVANCE-CIDP 1, which assessed the efficacy and safety of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10%. Patients received an induction IVIG 10% dose (2 g/kg) followed by maintenance infusions at the same monthly equivalent dose of pre-randomization IVIG, 3-weekly for 6 months. The primary outcome was the responder rate (≥ 1-point decrease in adjusted INCAT scores at treatment cessation vs. pre-IVIG 10% baseline, in patients receiving placebo in ADVANCE-CIDP 1). Other outcomes included the responder rate across all patients relapsing on fSCIG 10% or placebo in ADVANCE-CIDP 1, time to functional improvement (≥ 1-point decrease in adjusted INCAT score), and change in adjusted INCAT scores and Rasch-built Overall Disability Scale (R-ODS) centile scores from pre-IVIG 10% baseline. Overall, 20 patients received IVIG 10% (n = 4 [fSCIG 10%-relapse group]; n = 16 [placebo-relapse group]). Responder rate (95% confidence interval) was 100.0% (80.6%-100.0%) in the placebo-relapse group and 95.0% (76.4%-99.1%) in the overall-relapse population. Across all patients, median time to functional improvement was 25 days. At treatment cessation, mean changes from pre-IVIG 10% baseline in adjusted INCAT and R-ODS centile scores were -1.9 and 12.9, respectively. IVIG 10% effectively treated CIDP relapse and improved functional abilities.

Autism Spectrum disorders (ASD) are diagnosed more often in males than in females, by a ratio of about 3:1; this is likely to be due to a difference in risk burden between the sexes and/or to "compensatory skills" in females, that may delay the diagnosis of ASD. Identifying specific risk factors for ASD in females may be important in facilitating early diagnosis. We investigated whether HLA- class I: -A, -B, -C and class II -DRB1 alleles, which have been suggested to play a role in the development of ASD, can be considered as sex-related risk/protective markers towards the ASD. We performed HLA allele genotyping in 178 Italian children with ASD, 94 healthy siblings, and their parents. HLA allele distribution was compared between children with ASD, sex-matched healthy siblings, and a cohort of healthy controls (HC) enrolled in the Italian bone marrow donor registry. Allele transmission from parents to children with ASD and their siblings was also assessed. Our findings suggest that HLA-A*02, B*38, and C*12 alleles are more frequently carried by females with ASD compared to both HC and healthy female siblings, indicating these alleles as potential risk factors for ASD in females. Conversely, the HLA-A*03 allele was more commonly transmitted to healthy female siblings, suggesting it might have a protective effect. Additionally, the HLA-B*44 allele was found to be more prevalent in boys with ASD, indicating it is a potential risk factor for male patients. This is the first Italian study of sex-related HLA association with ASD. If confirmed, these results could facilitate early ASD diagnosis in female patients, allowing earlier interventions, which are crucial in the management of neurodevelopmental disorders.

In wild brown bears, likely factors triggering hibernation response to harsh environmental conditions are temperature, photoperiod, and food resources availability. In fact, constantly fed captive brown bears are described as skipping hibernation being active all year-round. Is the hibernation response so flexible and subordinate to contingencies, or else is an adaptation that, if dismissed, may negatively impact on bear well-being? This study investigates the potential hibernation response in captive brown bears under unvaried management conditions using an integrative approach simultaneously analyzing multiple animal-based variables together with environmental covariates. Data from a mid-latitude zoo revealed distinct behavioral, fecal glucocorticoids, and body condition score seasonal fluctuations, resembling natural hibernation cycles, despite constant food access. Environmental variables like photoperiod and visitor numbers significantly influenced activity levels. Bears exhibited behaviors indicative of hyperphagia and fall transition, such as appetitive feeding and denning behaviors. Hormonal analyses revealed high fecal cortisol metabolites levels during hyperphagia, suggesting physiological responses to seasonal changes. Findings underscore the importance of environmental cues and food availability in shaping zoo bear behavior and physiology. Considering that the hibernating vs. non-hibernating description might represent an oversimplification, management strategies should deal with captive bear potential need to freely express their adaptive predispositions by accommodating their natural behaviors, such as providing denning spots and adjusting diet composition as soon as typical hyperphagic and predenning behaviors emerge, ultimately enhancing their well-being.

Background: The availability of high-efficacy disease-modifying therapy (DMT), including natalizumab, improved treatment efficacy in adults with highly-active relapsing-remitting multiple sclerosis (RRMS). Natalizumab patent protection has expired, and the natalizumab biosimilar (Tyruko®) has been recently reimbursed by AIFA. As the price of natalizumab biosimilar is expected to be lower as compared with natalizumab originator’s price, a budget impact analysis was conducted to assess the economic impact associated to the introduction of natalizumab biosimilar for patients with highly-active RRMS. Methods: A budget impact model was developed, considering the INHS perspective and a 5-years time horizon. The number of patients treated with natalizumab was estimated based on historical natalizumab consumption data, disease prevalence rates and natalizumab market share. The budget impact population was divided into prevalent and incident patients. The model assumes that some patients in treatment with natalizumab originator will switch to natalizumab biosimilar and that some naïve patients will directly start treatment with natalizumab biosimilar. The ex-factory price of natalizumab originator (intravenous and subcutaneous) and biosimilar (intravenous) and the corresponding administration costs were included. All assumptions were validated by expert opinion. Results: Eligible population was estimated at 7,552, 7,779, 8,090, 8,494 and 8,834 in years 1, 2, 3, 4 and 5 respectively. The introduction of natalizumab biosimilar, considering a progressive increase in market share from 9.6% (year 1) to 40.5% (year 5), would provide an overall savings (5-years time horizon) over € 47 million to the INHS. The scenario analysis highlights that the lower treatment cost of biosimilar natalizumab compared to originator natalizumab would offset the higher cost associated with intravenous versus subcutaneous administration. Conclusion: Considering the results of this budget impact analysis, it is realistic to expect that the presence of biosimilar natalizumab will contribute to the sustainability of public pharmaceutical expenditure.

Principi generali di antimicrobial stewardshipS. Tedeschi L’interpretazione dell’antibiogrammaE. Carretto La terapia antibiotica empirica della sepsiP. Bocchi, P.G. Giuri, M. Gianfreda, S. Detrenis Il trattamento delle infezioni delle vie urinarieB. Laface, C. Moressa, E. Palaghita, G. Palamà, B. Marchisio, P. Colagrande, M. Giusti Approccio clinico alle polmoniti battericheM. Galassi, S. Fiorino, F. Lari Le infezioni di cute e tessuti molliS. Spiezia, C. Santini Infezioni fungine in Medicina InternaA. Milia, L. Corbo, F. Pieralli

The objective of this study was to assess the performance of the first publicly available automated 3D segmentation for spontaneous intracerebral hemorrhage (ICH) based on a 3D neural network before and after retraining. We performed an independent validation of this model using a multicenter retrospective cohort. Performance metrics were evaluated using the dice score (DSC), sensitivity, and positive predictive values (PPV). We retrained the original model (OM) and assessed the performance via an external validation design. A multivariate linear regression model was used to identify independent variables associated with the model's performance. Agreements in volumetric measurements and segmentation were evaluated using Pearson's correlation coefficients (r) and intraclass correlation coefficients (ICC), respectively. With 1040 patients, the OM had a median DSC, sensitivity, and PPV of 0.84, 0.79, and 0.93, compared to thoseo f 0.83, 0.80, and 0.91 in the retrained model (RM). However, the median DSC for infratentorial ICH was relatively low and improved significantly after retraining, at p < 0.001. ICH volume and location were significantly associated with the DSC, at p < 0.05. The agreement between volumetric measurements (r > 0.90, p > 0.05) and segmentations (ICC ≥ 0.9, p < 0.001) was excellent. The model demonstrated good generalization in an external validation cohort. Location-specific variances improved significantly after retraining. External validation and retraining are important steps to consider before applying deep learning models in new clinical settings.

The presence of anaemia in patients with chronic kidney disease (CKD) is associated with decreased quality of life, along with increased morbidity, mortality, and hospitalization rates. This, in turn, affects healthcare costs and the utilization of medical resources. The mechanisms involved in anaemia of CKD are diverse and complex. They include reduced production of endogenous erythropoietin (EPO), absolute and/or functional iron deficiency (due to inflammation leading to elevated levels of hepcidin), the diminished response of the bone marrow to EPO due to uraemic toxins, the shortened lifespan of red blood cells (RBC), and deficiencies in vitamin B12 or folic acid. [...]