PAX5-altered acute lymphoblastic leukemia (PAX5-alt ALL) is a recently recognized molecular subtype of B-ALL characterized by a distinct transcriptional signature and frequent PAX5 fusions (PAX5-r). While PAX5-alt ALL has been associated with intermediate outcomes, clinical data specifically investigating pediatric PAX5-r ALL remain limited. We collected and analyzed 159 pediatric cases of PAX5-r ALL treated between 2001-2024 within AIEOP-BFM ALL studies across Italy, Germany and Austria, revealing high-risk clinical features. Comparative analyses of patients consecutively enrolled in the AIEOP-BFM ALL 2017 study (PAX5-r, n=96 vs. non-PAX5-r, n=1948) confirmed higher rates of hyperleukocytosis at diagnosis (22.9% vs. 8%, p<0.001) and enrichment of IKZF1plus profile (14.7% vs. 7.8%, p=0.0015) in PAX5-r patients. No relevant differences in terms of minimal/measurable residual disease (MRD)-based treatment response and risk-group stratification were observed. PAX5-r patients had a 4-year EFS and OS of 72.6±5.7% and 95.4±2.3%, respectively. Four-year EFS were 100%, 63.4±9.7% and 63.3±10% for standard-risk, medium-risk (MR) and high-risk (HR) groups, respectively, indicating that the poor prognostic impact of PAX5-r applies only when end-of-induction MRD is positive (MR/HR). Whole transcriptome sequencing revealed high FLT3 median expression in PAX5-r ALL and high-throughput drug screening of patient-derived xenografts (PDXs) showed marked sensitivity to several FLT3 inhibitors. Gilteritinib showed potent ex vivo cytotoxicity and synergism with dexamethasone in PAX5-r PDX models. Collectively, this study investigated clinical and biological features of pediatric PAX5-r ALL highlighting its MRD-dependent unfavorable prognosis and identifying FLT3 overexpression as a novel, potential therapeutic target.

Background Postacute sequelae of SARS-CoV-2 infection (PASC), including persistent symptoms and acute and chronic diagnoses, have become a major research focus. Diabetes mellitus, beyond its established link to COVID-19 severity, is increasingly recognized as a potential long-term outcome. This study investigated the association between SARS-CoV-2 infection and incident diabetes using population-level health administrative data (HAD) from the Agency for Health Protection of Milan, where the epicenter of the pandemic in Italy took place.Methods This retrospective cohort study included adult residents without a history of diabetes who underwent SARS-CoV-2 testing between 1 March and 31 December 2020. Test-positive individuals were matched 1:1 to test-negative individuals based on sex, age, and testing week. The cohort was followed through 31 December 2021. The incidence of diabetes, identified using an HAD-based case-detection algorithm, was compared between the two groups, and in stratified analyses by sex and age, using weighted Cox models adjusted for chronic comorbidities, area-level deprivation, influenza and pneumococcal vaccinations. Weights were calculated via the inverse probability weighting approach. Effect estimates are presented as hazard ratios (HRs).Results Our final cohort included 248,176 residents (124,026 test-negative, 124,150 test-positive). Over a median follow-up time of 415 days, 739 positive (0.60%) and 657 negative (0.53%) individuals were newly identified with diabetes. The incidence among positive individuals was 572.82 per 100,000 person-years (CI 531.52-614.12), and that among negative individuals was 509.50 per 100,000 person-years (CI 470.54-548.46). The overall HR was 1.13 (CI 1.02-1.25). In stratified analyses, this effect was prominent in women aged 41-60 years (HR 1.31; CI 1.02-1.68).Conclusions This study provides population-based evidence supporting an association between SARS-CoV-2 infection and newly detected diabetes. These findings contribute to understanding the long-term health impact of COVID-19 and may inform public health strategies for PASC prevention and management.

Heart failure (HF) remains a major cause of morbidity and mortality, highlighting the need for reliable prognostic models. This study provides a systematic review and meta-analysis of prognostic models focused on mortality, hospitalization, and their composite event. We screened 2271 papers and reviewed 58 prognostic models from 44 studies involving 362,759 HF patients. The predictive performance of these models was assessed, and a meta-analysis was performed for the Seattle Heart Failure Model (SHFM), which focuses on mortality outcomes at 1 year. The models were evaluated via the PROBAST tool for risk of bias and applicability. Of the 58 models, 86

Objectives Post-COVID-19 condition (PCC) has emerged as a major public health concern. We aimed to estimate the 1-year incidence of PCC in adults with confirmed SARS-CoV-2 infection in Lombardy, Italy, comparing community-managed and hospitalised patients and to assess the prognostic value of the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) score to support estimation of long-term PCC prevalence.Design Retrospective-prospective observational cohort study enrolling patients infected between 1 March 2020 and 31 December 2022. The study visit was conducted between 16 January and 23 December 2024.Setting Multicentre study involving seven public hospitals and general practitioners across Lombardy.Participants Randomly sampled adults aged 18–70 years with confirmed SARS-CoV-2 infection. Hospitalised patients (HP) were admitted for COVID-19; general practitioner patients (GPP) were managed in the community. The total sample comprised: 1162 (546 HP, 616 GPP).Intervention This is an observational study with no active intervention.Primary and secondary outcome measures Primary outcome: 1-year incidence of PCC retrospectively assessed at the study visit.Secondary outcomes: symptom profiles, long-term PCC prevalence at the study visit and predictive value of the NIH RECOVER score.Results Median age was 57.1 years in HP and 42.9 years in GPP; 66.1% of HP and 47.7% of GPP were male. PCC developed in 280 patients (223 HP, 57 GPP). The 1-year cumulative incidence was 39.9% in HP (95% CI 35.9% to 44.1%) and 9.1% in GPP (95% CI 7.1% to 11.7%). The NIH RECOVER score was associated with PCC at 1 year (OR 1.18, 95% CI 1.14 to 1.21). Model-based long-term PCC prevalence was 31.8% in HP and 6.3% in GPP.Conclusions PCC remained frequent and heterogeneous, particularly among previously HP. In this cohort, the NIH RECOVER score showed prognostic value for estimating longer-term PCC burden. These findings underscore the need for structured long-term follow-up across both hospital and primary care settings.

INTRODUCTION:Acute myocarditis can lead to chronic inflammatory cardiomyopathy (Infl-CMP), a condition characterized by increased risk of ventricular arrhythmias (VA), left ventricular (LV) systolic dysfunction (LVSD), and heart failure (HF). Immunosuppressive therapy is generally not recommended for Infl-CMP when diagnosed non-invasively by cardiac magnetic resonance imaging (CMRI) or fluorodeoxyglucose-positron emission tomography (FDG-PET). We are assessing, in the CMP-MYTHiC trial, whether colchicine (0.5 mg in patients <70 kg or 1 mg in patients ≥70 kg), an immunomodulatory drug with a good safety profile, can reduce myocardial inflammation in patients with Infl-CMP. STUDY DESIGN:The CMP-MYTHiC, a multicenter investigator-initiated single-blinded randomized controlled trial, screens adult patients diagnosed with Infl-CMP by CMRI or FDG-PET within the prior 3 months at 12 Italian centres. Eligibility is further defined by the presence of VA or LVSD/HF phenotype. VA phenotype is determined by a high burden of premature ventricular complexes (PVCs) on baseline 24-h ECG ambulatory monitoring, non-sustained ventricular tachycardia (NSVT), or sustained ventricular tachycardia (SVT). The LVSD/HF phenotype is characterized by reduced LV ejection fraction (LVEF <50% on echocardiogram or <60% on CMRI) or elevated natriuretic peptide levels. Key exclusion criteria include a history of myocardial infarction, cardiomyopathy attributed to other specific causes, and systemic autoimmune disorders.The efficacy of colchicine compared with placebo will be assessed when CMRI or FDG-PET scans and 24-h ambulatory ECG monitoring are repeated at 6 months after randomization. The primary endpoint of the trial analysed according to the intention-to-treat population is the proportion of patients who are alive and free from any clinical (cardiac death or hospitalization due to HF or VA episodes), arrhythmic (PVC burden increase ≥50%, NSVT increase ≥30%, or any SVT), or imaging (LVEF reduction >10% or new areas of oedema plus increased inflammation) worsening, and who demonstrate improvement in either imaging (reduction in oedema on CMRI or FDG uptake) or arrhythmic (PVC burden reduction ≥70% with no NSVT/SVT) outcomes at 6 months. Assuming 80% power with an overall type I error of 0.025 using one-sided Fisher's Exact test, 40 patients per group are required to demonstrate that the primary endpoint will be reached in 66% of patients in the colchicine group compared with 33% in the placebo. Twenty-nine patients were randomized since December 2023, and the conclusion is expected in 2029. DISCUSSION:The results can define the role of colchicine in treating patients with Infl-CMP non-invasively diagnosed by CMRI or FDG-PET. CLINICALTRIALS.GOV IDENTIFIER:NCT06158698.

PURPOSE:Modern ALL therapy aims to reduce toxicity, while maintaining and improving the current high cure rates. Acute and late sequelae of anthracyclines are of major concern. The AIEOP-BFM ALL 2009 trial aimed to clarify the need for anthracyclines in low-risk patients. PATIENTS AND METHODS:After 2 weeks of induction therapy, which included two daunorubicin (DNR) doses once weekly (30 mg/m2 each) as part of a 4-drug therapy, patients age 1-17 years with newly diagnosed non-high-risk B-ALL either positive for ETV6::RUNX1 or with rapid treatment response, as assessed by induction day-15 evaluation, were randomly assigned to receive either two additional doses of DNR (control arm [CA]) or no further DNR during induction (experimental arm [EA]). Patients treated as randomly assigned were included in the primary analysis on noninferiority in event-free survival (EFS). Adverse reactions of special interest (ARSI) were analyzed in the as-treated population. RESULTS:Of 6,136 patients enrolled in AIEOP-BFM ALL 2009, 2,514 patients (41.0%) were eligible for this random assignment, with 82.7% actually randomly assigned (EA: n = 1,040 and CA: n = 1,039). The 5-year EFS was 92.5% (SE 0.8%) in CA and 92.2% (SE 0.9%) in EA. Accordingly, cumulative incidence of relapse was 5.8% (SE 0.7%) and 5.7% (SE 0.7%), and overall survival was 97.6% (SE 0.5%) and 97.4% (SE 0.5%) in CA and EA, respectively. Life-threatening and fatal ARSI were similar in the two arms, but there was a three times lower incidence of invasive fungal infections in the EA (0.5% v 1.5%, P = .02). CONCLUSION:A reduced DNR dose during induction did not compromise the outcome of patients with favorable prognostic factors but did diminish infectious toxicity indicated by the lower rate of invasive fungal infections.

Many applications in health research involve the analysis of multivariate distributions of random variables. In this paper, we review the basic theory of copulas to illustrate their advantages in deriving a joint distribution from given marginal distributions, with a specific focus on bivariate cases. Particular attention is given to the Archimedean family of copulas, which includes widely used functions such as Clayton and Gumbel–Hougaard, characterized by a single association parameter and a relatively simple structure. This work differs from previous reviews by providing a focused overview of applied studies in biomedical research that have employed Archimedean copulas, due to their flexibility in modeling a wide range of dependence structures. Their ease of use and ability to accommodate rotated forms make them suitable for various biomedical applications, including those involving survival data. We briefly present the most commonly used methods for estimation and model selection of copula’s functions, with the purpose of introducing these tools within the broader framework. Several recent examples in the health literature, and an original example of a pediatric study, demonstrate the applicability of Archimedean copulas and suggest that this approach, although still not widely adopted, can be useful in many biomedical research settings.

To improve the outcome of pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients, the AIEOP-BFM ALL 2009 trial modified T-ALL stratification and treatment based on AIEOP-BFM ALL 2000 and other pediatric ALL groups' results. This report aims to describe the outcome of T-ALL patients in trial AIEOP-BFM ALL 2009 and evaluate prognostic features defined within the end of induction (EOI) therapy, for future protocols stratification and interventions. From 06/2010 to 02/2017, 872 T-ALL patients, aged 1-17, were enrolled. High risk (HR) criteria were prednisone poor response (PPR), Day 15 flow cytometry minimal residual disease (MRD) ≥ 10%, no complete remission at EOI, or polymerase chain reaction (PCR)-MRD ≥ 5 × 10-4 at end of consolidation (EOC). Three Cox regression models on event-free survival (EFS) evaluated prognostic factors. Overall, 5-year EFS and survival were 79.9% ± 1.4% and 84.9% ± 1.2% with cumulative incidence of relapse (CIR) and death of 13.0% ± 1.2% and 5.9% ± 0.8%. Five-year EFS and CIR were 86.8% ± 1.6% and 8.7% ± 1.3% in non-HR patients (n = 470); 71.9% ± 2.3% and 18.0% ± 1.9% in HR patients (n = 402). High PCR-MRD levels at EOI and EOC were prognostic in all models, with EOC-MRD ≥ 5 × 10-3 related to a hazard ratio of 6.22 (P < 0.001). When a model considered factors identified at EOI only, central nervous system (CNS)3 (hazard ratio = 2.3, P < 0.001), PPR (hazard ratio = 1.74, P = 0.02), and high EOI-MRD (hazard ratio 4.71 for ≥5 × 10-2 vs. negative, P < 0.001) significantly impacted EFS. Results of T-ALL patients in AIEOP-BFM ALL 2009 were favorable. While EOC-MRD remained the strongest prognostic predictor, PPR, CNS3 disease, and EOI-MRD showed relevant prognostic value, with CNS3 and EOI-MRD ≥ 5 × 10-2 being candidate criteria for early stratification and intervention modifications.

Introduction:Post-acute sequelae of COVID-19 (PASC) encompass several clinical outcomes, from new-onset symptoms to both acute and chronic diagnoses, including pulmonary and extrapulmonary manifestations. Health administrative data (HAD) from health information systems allow population-level analyses of such outcomes. Our primary aim was to identify clinical conditions potentially attributable to SARS-CoV-2 infection, and the types of HAD and "diagnostic criteria" used for their detection. Methods:We performed a literature review to identify HAD-based cohort studies assessing the association between SARS-CoV-2 infection and medium-/long-term outcomes in the general population. From each included study, we extracted data on design, algorithms used for outcome identification (sources, coding systems, codes, time criteria/thresholds), and whether significant associations with SARS-CoV-2 infection were reported. Results:We identified six studies investigating acute and chronic conditions grouped by clinical domain (cardiovascular, respiratory, neurologic, mental health, endocrine/metabolic, pediatric, miscellaneous). Two studies also addressed the onset of specific symptoms. Cardio/cerebrovascular conditions were most studied, with significant associations reported for deep vein thrombosis, heart failure, atrial fibrillation, and coronary artery disease. Conditions in other domains were less investigated, with inconsistent findings. Only three studies were designed as test-positive vs. test-negative comparisons. Discussion:Heterogeneity in data sources, study design, and outcome definitions hinder the comparability of studies and explain the inconsistencies in findings about associations with SARS-CoV-2 infection. Rigorously designed studies on large populations with wide availability of data from health information systems are needed for population-level analyses on PASC, and especially on its impact on chronic diseases and their future burden on healthcare systems.

The simplest multistate model is named “illness-death” because subjects can move from the initial state to the final state (death) possibly transiting to an intermediate state (illness). This framework applies also when the intermediate state is a therapeutic intervention (treatment), administered after waiting some time since the initial event. Within such context, it could be of interest to compare the hazards of mortality without vs after treatment administration. In the Mantel-Byar test, an extension of the log-rank test accounting for the time-dependent nature of treatment indicator, all patients initially belong to the “untreated” group but some are shifted to the “treated” group at the time of treatment administration. Using this approach, the hazard of death is always defined as function of time since origin, also after treatment (“clock-forward” time scale). Using theoretical arguments and simulations, we show that this method is valid only under the Markov assumption but it is not suitable when the process is not markovian. This happens when the hazard of death after treatment depends: (i) on time since treatment (semi-Markov process) or (ii) on time since treatment and also on the waiting time to treatment (extended semi-Markov process). We propose two modifications of the Mantel-Byar test suitable for semi-Markov and extended semi- Markov scenarios, respectively. These procedures are both based on the adoption of the “clock-reset” scale that allows the hazard of death for treated patients to depend on time since treatment administration.

BACKGROUND AND AIMS:Sarcopenia has a negative impact on clinical outcome in adult patients with Crohn's Disease (CD), but data on children are scarce. The aim of this study is to evaluate the prevalence of sarcopenia in children with CD using magnetic resonance enterography (MRE) and describe its relationship with baseline values and clinical outcome. METHODS:We included children with a new diagnosis of CD from 2 tertiary referral pediatric Inflammatory Bowel Disease (IBD) centres, who underwent MRE at diagnosis between 2013 and 2023. Muscle mass was assessed by measuring the total area of the total psoas muscle (tPMA) at the level of the fourth and fifth lumbar vertebrae (L4/L5). Data were compared with pediatric reference values of tPMA, and sarcopenia was defined as a tPMA below the 3rd percentile. Demographic and anthropometric data, laboratory results, clinical disease activity and endoscopic index were collected at diagnosis and during follow-up. Clinical outcomes included relapse frequency, treatment changes, surgery, and IBD-related complications. RESULTS:A total of 74 children (25 females, mean age 13.2 years) with CD were enrolled in the study. Sarcopenia was present in 34/74 patients (46 %) at diagnosis. Patients with sarcopenia had a lower Body Mass Index z-score and hemoglobin levels. Clinical disease activity (assessed using the Pediatric CD Activity Index) and endoscopic activity (assessed using the Simple Endoscopic Score for CD) were significantly higher in sarcopenic compared to non-sarcopenic children (median and quartiles scores: 25 [20, 40] vs. 21 [13, 35] and 10 [5, 13] vs. 6 [3, 13], respectively). During the follow-up period (median: 35 months; range: 1-99 months), no significant differences were observed between the sarcopenic and non-sarcopenic groups in terms of the composite outcome (defined as the occurrence of at least one unfavorable event). However, the rate of flares (number per person-year) was also higher in sarcopenic children compared to non-sarcopenic ones (27 % vs. 15 %; p = 0.0679). CONCLUSIONS:Sarcopenia is highly prevalent among children with CD at diagnosis. MRE-based muscle mass measurement correlates with traditional anthropometric measurements and can be valuable for comprehensive nutritional screening in pediatric CD patients. Patients with sarcopenia presented with more severe clinical, laboratory, and endoscopic findings at diagnosis; although sarcopenic children experienced more clinical relapses we were not able to show a significant association between sarcopenia and outcomes. Larger series need to be studied.

High-dose methotrexate (HD-MTX) infusions are commonly used to consolidate remission in children with acute lymphoblastic leukemia (ALL). We investigate the potential role of candidate polymorphisms in SLCO1B1 (rs4149056 and rs2306283), ABCB1 (rs1045642), ABCC2 (rs717620), ABCC3 (rs9895420), and ABCC4 (rs7317112) drug transporters genes on HD-MTX pharmacokinetics and patients' outcome (meant both as relapse and drug-related toxicities) in an Italian cohort of 204 ALL pediatric patients treated according to the AIEOP-BFM ALL 2009 protocol. TaqMan SNP genotyping assays determined patient's genotypes. Measurements of HD-MTX plasma concentration were available for 814 HD-MTX courses in 204 patients; MTX clearance was estimated by a two-compartmental linear pharmacokinetic model with first-order elimination and a Bayesian approach, via ADAPT. Independent contributions of age and ABCC4 SNP rs7317112 (A>G, intronic) on MTX clearance were detected in a multivariate analysis (p = 1.57 × 10-8 and p = 2.06 × 10-5, respectively), suggesting a delayed elimination of the drug in older patients and an accelerated one in carriers of the variant GG genotype. After multiple corrections, the association between ABCC2 SNP rs717620 (-24 C>T) and severe hematological toxicity was found (p < 0.005). Moreover, SLCO1B1 SNP rs4149056 (c.521T>C, p.V174A) affected patients' outcomes: carriers of the variant C allele presented a reduced risk of relapse compared to wild-type TT (hazard risk: 0.27, 95% confidence interval [CI]: 0.08-0.90, p = 0.037). Taken together, these data highlighted the importance of variants in drug transporters genes on HD-MTX disposition in the AIEOP-BFM ALL 2009 protocol consolidation phase, and their putative role as predictive markers of outcome.

Background: Asparaginase (ASPase) plays an important role in the therapy of acute lymphoblastic leukemia (ALL). Serum ASPase activity (SAA) can be modified and even abolished by host immune responses; therefore, current treatment guidelines recommend to monitor SAA during treatment administration. The SAA monitoring schedule needs to be carefully planned to reduce the number of samples without hampering the possibility of measuring pharmacokinetics (PK) parameters in individual patients. Complex modelling approaches, not easily applicable in common practice, have been applied in previous studies to estimate ASPase PK parameters. This study aimed to estimate PK parameters by using a simplified approach suitable for real-world settings with limited sampling. Methods: Our study was based on 434 patients treated in Italy within the AIEOP-BFM ALL 2009 trial. During the induction phase, patients received two doses of pegylated ASPase and were monitored with blood sampling at five time points, including time 0. PK parameters were estimated by using the individually available SAA measurements with simple modifications of the classical non-compartmental PK analysis. We also took the opportunity to develop and validate a series of limited sampling models to predict ASPase exposure. Results: During the induction phase, average ASPase activity at day 7 was 1380 IU/L after the first dose and 1948 IU/L after the second dose; therapeutic SAA levels (>100 IU/L) were maintained until day 33 in 90.1% of patients. The average AUC and clearance were 46,937 IU/L × day and 0.114 L/day/m2, respectively. The database was analyzed for possible associations of PK parameters with biological characteristics of the patients, finding only a limited dependence on sex, age and risk score; however, these differences were not sufficient to allow any dose or schedule adjustments. Thereafter the possibility of further sampling reduction by using simple linear models to estimate the AUC was also explored. The most simple model required only two samplings 7 days after each ASPase dose, with the AUC being proportional to the sum of the two measured activities A(7) and A(21), calculated by the formula AUC = 14.1 × [A(7) + A(21)]. This model predicts the AUC with 6% average error and 35% maximum error compared to the AUC estimated with all available measures. Conclusions: Our study demonstrates the feasibility of a direct estimation of PK parameters in a real-life situation with limited and variable blood sampling schedules and also offers a simplified method and formulae easily applicable in clinical practice while maintaining a reliable pharmacokinetic monitoring.

Objective:The aim of this study was to comparatively assess the risk of cardiovascular events (CVEs) in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis) or tumor necrosis factor inhibitors (TNFis) and to explore the interactions with patient profiles [including age, baseline cardiovascular (CV) risk, and frailty, which is a state of decreased physiological reserve, assessed using a validated frailty index (FI) for healthcare administrative databases (AHDs)]. Methods:This retrospective study was based on AHDs of the Lombardy region, Italy (from 1st January 2020 to 31st December 2023). Cox regression models, both crude and adjusted, were applied to estimate the association between treatments and outcomes [CVEs, major adverse cardiovascular events (MACEs), and thromboembolic events (TEs)]. We tested the interaction between the drug treatment and the regulatory agency prescription rule changes [before or after 06th July 2021, the date of the first European Medicine Association (EMA) pronouncement on tofacitinib safety] or patient profiles. Results:We identified 7,541 therapeutic courses in 5,563 patients: 2,343 started as TNFi users, 1,443 as JAKi users, and 1,777 started with other drugs (1,459 days of follow-up). The crude incidence rates (IRs) for new CVEs were 16.6 [95% confidence intervals (95% CI): 12.8-21.2] and 18.6 (95% CI: 14.2-23.9) per 1,000 person-years (PYs) for TNFi and JAKi users, respectively. Exposure to JAKis was not associated with a significantly increased risk of CVEs [adjusted hazard ratio (HR): 0.92; 95% CI: 0.64-1.32], MACEs (adjusted HR: 0.71; 95% CI: 0.37-1.33), or TEs (adjusted HR: 1.53; 95% CI: 0.65-3.65) compared to TNFis. Each 0.1-point increment of the FI significantly increased the HR for new CVEs (HR: 1.80; 95% CI: 1.48-2.19), MACEs (HR: 1.66; 95% CI: 1.10-2.51), and TEs (HR: 1.69; 95% CI: 1.03-2.78). When assessing the interaction between the period of drug delivery and the treatment with JAKis on the risk of new CVEs, no significant interaction was observed (p = 0.838), while the interaction was statistically significant for baseline CV risk (p = 0.007). Conclusion:RA patients treated with JAKis in real-world settings have a risk of developing CVEs no higher than those of TNFi users, but potential signals remain for TEs, even if the sample was not sufficiently powered. Patient profiles, particularly the frailty, have a more substantial impact on the risk of CVEs than the specific disease-modifying anti-rheumatic drug (DMARD) choice.

Introduction:Coeliac disease (CD) manifests more frequently in individuals with Down syndrome (DS) and its prevalence varies across different studies. This study aims to assess the prevalence of CD in children with DS and to describe their clinical, serological, and histological features. A secondary aim was to analyze the time needed for the normalization of anti-transglutaminase IgA (TGA-IgA) and anti-endomysium IgA (EMA-IgA) levels in DS compared to non-syndromic (NS) children. Materials and methods:This retrospective monocentric cohort study included patients with DS under 18 years of age, diagnosed with CD between 2005 and 2022. Each DS patient was matched for year of birth and sex with two NS celiac children. Follow-up was 6-, 12- and 24-months post-diagnosis. Results:The prevalence of CD in 770 children with DS was 7.5% (95% CI: 5.8%-9.6%). 57 children with CD and DS were compared with 114 CD NS matched controls (total sample size = 171). DS demonstrated less symptoms than 114 NS CD children (26% vs. 79%, P < 0.001). In the CD DS group 81% had anti-TGA levels 10 times higher the upper limit of normal, compared to 72% in the control group. Among patients with CD and DS, 93% had histological damage equal to 3rd grade of Marsh-Oberhuber classification at diagnosis. The velocity of normalization of anti-TGA was higher in patients without DS (P = 0.005). Discussion:This study reinforces the higher prevalence of CD in DS, emphasizing the necessity for routine screening, even in asymptomatic individuals. Despite less symptomatic presentation, patients with DS exhibited elevated antibody levels and severe histological damage. Clinicians should expect a prolonged time for antibody normalization following gluten-free diet in DS, mirroring potential challenges in diet adherence and altered immune responses.

Frailty indices derived from electronic health records offer an efficient approach to identify vulnerable individuals in the general population. We aimed to validate the electronic-regional healthcare database frailty index (e-RHD-FI) in the general adult population, describe its distribution by sex and age, evaluate its predictive validity for mortality, hospitalization and fragility fractures, and assess the performance of frailty cut-off points. We conducted a population-based study of 8,404,004 adult beneficiaries of the Lombardy Regional Health System. The e-RHD-FI was calculated from 40 health deficits using electronic health records from 2008 to 2018. We assessed its distribution, predictive validity for 1-year mortality, hospitalizations and fragility fractures through multi-state analysis and multivariable models evaluating performance across subgroups. The e-RHD-FI distribution was highly asymmetrical (median 0.0125, first-third quartiles 0-0.0375), with 45.8% of adults having no deficits. The index was higher in older adults. Each 0.1-point increment in e-RHD-FI was associated with doubled 1-year mortality risk (HR 2.12, 99% CI 2.11-2.14), 2.5-fold increased hospitalization rate (IRR 2.51, 99% CI 2.49-2.53), and a 55% higher risk of fragility fracture (HR 1.55, 99% CI 1.53-1.57). The AUC for 1-year mortality was 0.883 (99% CI 0.881-0.884). The e-RHD-FI demonstrates strong predictive validity for adverse outcomes in the general population and can effectively identify at-risk individuals for targeted interventions.

Introduction:Maximal resection has a pivotal role in the treatment of glioblastoma (GB), prolonging both progression free survival (PFS) and overall survival (OS). Only few studies analyze the delicate equilibrium between maximal resection, clinical outcome and prognosis. Research question:the aim of this work is to determine the impact of neurological impairment on PFS, OS and access to adjuvant therapies on patients with GB operated with perilesional resection technique.Material and Methods: this retrospective study encompassed patients operated for GB at Fondazione IRCCS San Gerardo dei Tintori Monza (IT), from 2015 to 2023. Histological diagnosis was performed according to the WHO 2021 classification. Patients were more than 18 years old, with pre- and postoperative MRI, who underwent surgery and adjuvant treatments at our Institution. Results:A total of 209 patients fulfilled the criteria. Patients with improvement or complete regression of preoperative deficit had a higher rate of access to adjuvant therapies (p = 0.015). Patients with hemiparesis at discharge had the worst PFS (median 4.60 months) followed by patients with aphasia (6.60 months), and patients with normal neurological examination (9.67 months; p < 0.0001). The median OS was 17.93 months for patients with hemianopia, 6.40 for patients with hemiparesis and 15.7 months for those with aphasia (p < 0.0001). Discussion and conclusion:Hemianopia has no impact on the patient's prognosis, while hemiparesis and aphasia at discharge worsen both PFS and OS prolonging time-to-treatment. When resecting GB, it is mandatory to avoid major neurological deficits that concur which reduce OS and PFS.