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African swine fever (ASF) is a severe hemorrhagic disease of suids caused by the African swine fever virus (ASFV). In 2023, the introduction of genotype II ASFV into Lombardy was a cause for serious concern; the region is home to approximately 50% of the national pig population and is of economic importance to the processing industry of the entire country. Since then, two ASF epidemics have resulted in a total of 30 outbreaks in domestic pigs in the same areas of Lombardy, where the disease is endemic in wild boars. The results of the control activities conducted in the affected areas seem to indicate the establishment of self-sustaining infection cycles in the wild boar population with spillover and spillback events occurring between wild boars and domestic pigs. This manuscript describes some epidemiological features of the ASF epidemics in Lombardy with the aim of providing useful information to combat the disease.

The management of unowned cats is an emerging problem, with public institutions and citizens’ concerns regarding their care and arrangement. Little is known regarding the outcome of traumatic orthopedic injuries in these patients. Indeed, complete functional recovery (CFR) should be the goal of treatment for return to their original location or adoption. The aim was to identify clinical factors influencing CFR in traumatized unowned cats with orthopedic lesions. This category of cats referred by the veterinary public service over three years was enrolled. Various clinical variables were retrospectively collected from the medical records and evaluated by nominal logistic analysis. Forty-eight unowned cats were enrolled, with a median estimated age of 24 (1–180) months and a body weight of 3 (0.7–5) kg. Thirty-four (71%) patients reached CFR. Estimated age, body weight, time from trauma to therapeutic intervention, spine involvement, presence of comorbidities, hospitalization time, and the radiographic score results were significantly associated with CFR. A longer time to therapeutic intervention seemed to be associated with a better outcome. Probably, cats severely traumatized did not live long enough to be evaluated and treated. Lighter cats experienced more severe consequences following blunt trauma. Younger and lighter cats bore a higher risk of panleukopenia-related death.

Ex-vivo gene therapy (GT) with hematopoietic stem and progenitor cells (HSPCs) engineered with integrating vectors is a promising treatment for monogenic diseases, but lack of centralized databases is hampering an overall outcomes assessment. Here we aim to provide a comprehensive assessment of the short and long term safety of HSPC-GT from trials using different vector platforms. We review systematically the literature on HSPC-GT to describe survival, genotoxicity and engraftment of gene corrected cells. From 1995 to 2020, 55 trials for 14 diseases met inclusion criteria and 406 patients with primary immunodeficiencies (55.2%), metabolic diseases (17.0%), haemoglobinopathies (24.4%) and bone marrow failures (3.4%) were treated with gammaretroviral vector (γRV) (29.1%), self-inactivating γRV (2.2%) or lentiviral vectors (LV) (68.7%). The pooled overall incidence rate of death is 0.9 per 100 person-years of observation (PYO) (95% CI = 0.37–2.17). There are 21 genotoxic events out of 1504.02 PYO, which occurred in γRV trials (0.99 events per 100 PYO, 95% CI = 0.18–5.43) for primary immunodeficiencies. Pooled rate of engraftment is 86.7% (95% CI = 67.1–95.5%) for γRV and 98.7% (95% CI = 94.5–99.7%) for LV HSPC-GT (p = 0.005). Our analyses show stable reconstitution of haematopoiesis in most recipients with superior engraftment and safer profile in patients receiving LV-transduced HSPCs. Ex-vivo gene therapy with hematopoietic stem and progenitor cells (HSPCs) is a promising treatment for monogenic diseases. Here the authors report a systematic review and meta-analysis of available evidence assessing clinical outcomes of HSPC gene therapy from clinical trials.

Few disciplines in contemporary clinical research have experienced the high expectations directed at the gene therapy field. However, gene therapy has been challenging to translate to the clinic, often because the therapeutic gene is expressed at insufficient levels in the patient or because the gene delivery vector integrates near protooncogenes, which can cause leukemia (see the Perspective by Verma ). Biffi et al. ( 1233158 , published online 11 July) and Aiuti et al. ( 1233151 ; published online 11 July) report progress on both fronts in gene therapy trials of three patients with metachromatic leukodystrophy (MLD), a neurodegenerative disorder, and three patients with Wiskott-Aldrich syndrome (WAS), an immunodeficiency disorder. Optimized lentiviral vectors were used to introduce functional MLD or WAS genes into the patients' hematopoietic stem cells (HSCs) ex vivo, and the transduced cells were then infused back into the patients, who were then monitored for up to 2 years. In both trials, the patients showed stable engraftment of the transduced HSC and high expression levels of functional MLD or WAS genes. Encouragingly, there was no evidence of lentiviral vector integration near proto-oncogenes, and the gene therapy treatment halted disease progression in most patients. A longer follow-up period will be needed to further validate efficacy and safety. Lentivirus-mediated gene therapy produces encouraging results in three children with a rare immunodeficiency disorder. [Also see Perspective by Verma ] Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was observed after 20 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.

Background Metabolomics opens novel avenues to study the basic biological mechanisms underlying complex traits, starting from characterization of metabolites. Metabolites and their levels in a biofluid represent simple molecular phenotypes (metabotypes) that are direct products of enzyme activities and relate to all metabolic pathways, including catabolism and anabolism of nutrients. In this study, we demonstrated the utility of merging metabolomics and genomics in pigs to uncover a large list of genetic factors that influence mammalian metabolism. Results We obtained targeted characterization of the plasma metabolome of more than 1300 pigs from two populations of Large White and Duroc pig breeds. The metabolomic profiles of these pigs were used to identify genetically influenced metabolites by estimating the heritability of the level of 188 metabolites. Then, combining breed-specific genome-wide association studies of single metabolites and their ratios and across breed meta-analyses, we identified a total of 97 metabolite quantitative trait loci (mQTL), associated with 126 metabolites. Using these results, we constructed a human-pig comparative catalog of genetic factors influencing the metabolomic profile. Whole genome resequencing data identified several putative causative mutations for these mQTL. Additionally, based on a major mQTL for kynurenine level, we designed a nutrigenetic study feeding piglets that carried different genotypes at the candidate gene kynurenine 3-monooxygenase ( KMO ) varying levels of tryptophan and demonstrated the effect of this genetic factor on the kynurenine pathway. Furthermore, we used metabolomic profiles of Large White and Duroc pigs to reconstruct metabolic pathways using Gaussian Graphical Models, which included perturbation of the identified mQTL. Conclusions This study has provided the first catalog of genetic factors affecting molecular phenotypes that describe the pig blood metabolome, with links to important metabolic pathways, opening novel avenues to merge genetics and nutrition in this livestock species. The obtained results are relevant for basic and applied biology and to evaluate the pig as a biomedical model. Genetically influenced metabolites can be further exploited in nutrigenetic approaches in pigs. The described molecular phenotypes can be useful to dissect complex traits and design novel feeding, breeding and selection programs in pigs.

Guidelines recommend lipid-lowering therapy (LLT) after an atherosclerotic cardiovascular disease (ASCVD) event. This study investigated real-world LLT initiation rate and its effect on total mortality in the Lombardy region. Individuals aged ≥40 with an ASCVD event between January and September 2022 were identified from Lombardy's administrative data. The prevalence of LLT initiation within 3 months was estimated, and factors influencing treatment initiation were evaluated using multivariate logistic regression (odds ratios [OR] and 95% confidence intervals [95% CI]). One-year post-event mortality was analyzed. Among 16,025 patients 41.14% did not receive a LLT after an ASCVD event. Treatment initiation was more likely in subjects hospitalized for a cardiovascular event (OR 2.22, 95%CI 2.07-2.38, vs. cerebrovascular event), in patients aged 51-60 years (OR 1.30, 95%CI 1.16-1.46), and in patients previously treated with antidiabetic (OR 1.42, 95%CI 1.25-1.62), antihypertensive (OR 1.96, 95%CI 1.80-2.13), and thyroid hormone replacement medications (OR 1.34, 95%CI 1.10-1.63). Conversely, older age (71-80 years: OR 0.79, 95%CI 0.71-0.87; >80 years: OR 0.47, 95%CI 0.42-0.52), female sex (OR 0.73, 95%CI 0.68-0.79), previous exposure to antithrombotic medications (OR 0.65, 95%CI 0.59-0.72), and polypharmacy (OR 0.90, 95%CI 0.81-0.99 for 5-9 medications, OR 0.61, 95%CI 0.52-0.72 for ≥10 medications) reduced the likelihood of treatment. Mortality at 1 year was 3.07% in treated versus 11.66% in untreated patients (p-value <0.001). This study underscores a suboptimal LLT initiation rate in post-ASCVD patients. Initiating LLT is associated with significantly reduced 1-year total mortality, highlighting the need to optimize secondary prevention strategies.

ß-thalassemia is caused by ß-globin gene mutations resulting in reduced (β + ) or absent (β 0 ) hemoglobin production. Patient life expectancy has recently increased, but the need for chronic transfusions in transfusion-dependent thalassemia (TDT) and iron chelation impairs quality of life 1 . Allogeneic hematopoietic stem cell (HSC) transplantation represents the curative treatment, with thalassemia-free survival exceeding 80%. However, it is available to a minority of patients and is associated with morbidity, rejection and graft-versus-host disease 2 . Gene therapy with autologous HSCs modified to express ß-globin represents a potential therapeutic option. We treated three adults and six children with ß 0 or severe ß + mutations in a phase 1/2 trial ( NCT02453477 ) with an intrabone administration of HSCs transduced with the lentiviral vector GLOBE. Rapid hematopoietic recovery with polyclonal multilineage engraftment of vector-marked cells was achieved, with a median of 37.5% (range 12.6–76.4%) in hematopoietic progenitors and a vector copy number per cell (VCN) of 0.58 (range 0.10–1.97) in erythroid precursors at 1 year, in absence of clonal dominance. Transfusion requirement was reduced in the adults. Three out of four evaluable pediatric participants discontinued transfusions after gene therapy and were transfusion independent at the last follow-up. Younger age and persistence of higher VCN in the repopulating hematopoietic cells are associated with better outcome. In a phase 1/2 clinical trial, gene therapy with autologous hematopoietic stem cells significantly reduced transfusion requirement in adults and children with transfusion dependent ß-thalassemia.

Background: Abdominal pain in hematological patients, particularly during chemotherapy-induced neutropenia, represents a significant diagnostic challenge due to the broad spectrum of potentially life-threatening conditions, including neutropenic enterocolitis (NEC). Computed tomography (CT) is considered the reference imaging modality; however, its use is limited by radiation exposure, and the need for patient transport. Bedside ultrasound (BS-US) may offer a rapid, non-invasive, and repeatable alternative. Methods: This prospective study compared BS-US and CT in 65 hematological patients presenting with acute abdominal pain. Concordance between the two modalities was evaluated in terms of intestinal site localization, bowel wall thickness (BWT), and final diagnosis. Diagnostic agreement was assessed using Cohen’s kappa coefficient, and additional diagnostic accuracy metrics—including sensitivity, specificity, positive predictive value, and negative predictive value—were calculated. BWT measurements were analyzed using Bland–Altman methods. Results: A high level of agreement was observed between BS-US and CT in both intestinal localization and final diagnosis. Agreement for intestinal site localization was good (Cohen’s κ = 0.964), as was diagnostic concordance (Cohen’s κ = 0.962), and using CT as the reference standard, BS-US showed uniformly good diagnostic performance across all evaluated conditions, with sensitivity, specificity, PPV, and NPV consistently reaching 1.00 and confirming strong agreement between BS-US and CT. These findings were consistent across different clinical settings (hematology unit and Intensive Care Unit) and independent of body mass index. In NEC cases, BWT measurements showed strong concordance between CT and BS-US, with only 4.6% of values outside the limits of agreement in Bland–Altman analysis. Conclusions: BS-US demonstrated a good agreement with CT and proved to be a reliable, safe diagnostic tool in hematological patients with acute abdominal pain. These findings indicate that bedside ultrasound represents a valuable and safe diagnostic tool in neutropenic hematological patients with acute abdominal pain, providing crucial information in a clinically fragile population that may not always be suitable for CT due to their unstable condition. While our study is hypothesis-generating, the role of BS-US in this setting emerges as a reasonable, evidence-supported hypothesis that warrants further prospective evaluation.

Purpose To evaluate the reliability of the Deauville score (DS) in therapy response assessment and to define the prognostic value of the metabolic response of end of induction (EOI) [ 18 F]FDG PET (PET) in follicular lymphoma patients. Methods Adult patients with untreated grade 1–3a FL/ stage II‐IV enrolled in the multicentre, prospective, phase III FOLL12 trial (NCT02063685) were randomized to receive standard immunochemotherapy followed by rituximab maintenance (standard arm) versus standard immunochemotherapy followed by response-adapted post‐induction management (experimental arm). Baseline and EOI PET were mandatory for the study. All PET scans were centralized on the WIDEN® platform and classified according to DS in a blind independent central review. DS1–3 was considered negative (CMR), whereas DS4‐5 was considered positive (not CMR). The primary endpoint was PFS. The main secondary endpoint was overall survival (OS). Results Overall, 807 follicular lymphoma patients—52% women, 89% stage III-IV disease, 40% with a high-risk FLIPI-2 score (3–5)—were enrolled in the study; 729 (90.4%) baseline and EOI PET were available for the analysis. EOI PET was positive (DS4–5) in 88/729 (12.1%) cases. Overall inter-reviewer agreement on PET pos/neg result was 0.92, while agreement on positive and negative cases was 0.77 and 0.94, respectively. The median follow-up was 69 months; 247 events were registered in the 5-yr follow-up, with a 5-yr PFS of 67% (95%CI: 63%–70%). The 5-yr PFS rate for PET neg (DS1–3) and PET pos (DS4–5) patients was 71% (95%CI: 67%–75%) and 36% (95%CI: 25%–46%), respectively, with HR 3.49 (95%CI: 2.57–4.72). Five-year PFS was worse as DS increased, with 74% (70%–78%), 58% (48%–67%; HR 1.71; p = 0.001)] and 36% (25%–46%; HR 3.88; p < 0.001) in DS1–2, DS3 and DS4–5, respectively. EOI PET maintained its prognostic value in both the standard and experimental arms. In the whole population, 5-yr OS was 94% (95%CI: 92%–96%), with 96% (95%CI: 94–97) and 82% (95%CI: 72%–89%) in EOI PET negative (DS1–3) and positive (DS4–5), respectively (HR 4.48; p < 0.001). When DS was associated with FLIPI-2, patients with DS3 or DS1–2 with high FLIPI-2 (3–5) experienced worse OS than patients with DS1–2 and low FLIPI-2 (1–2) (p = 0.003). Conclusion This study shows that DS is a reliable prognostic tool to evaluate EOI PET in follicular lymphoma patients, with prognostic value maintained both in the standard and experimental arms, making metabolic imaging a robust tool to assess response in FL. Moreover, although preliminary, this study provides further information on DS3 patients, who are considered as CMR but show a less favourable PFS than DS1–2 patients.

Background: EDU.RE.DRUG study is a prospective, multicentre, open-label, parallel-arm, controlled, pragmatic trial directed to general practitioners (GPs) and their patients. Methods: The study data were retrieved from health-related administrative databases of four local health units (LHUs) of Lombardy and four LHUs in Campania. According to the LHUs, the GPs/patients were assigned to (A) intervention on both GPs (feedback reports about appropriate prescribing among their patients and online courses) and patients (flyers and posters on proper drug use), (B) intervention on GPs, (C) intervention on patients, and (D) no intervention (control arm). A set of appropriate prescribing indicators (potential drug–drug interactions [pDDIs], potential and unnecessary therapeutic duplicates [pTDs], and inappropriate prescriptions in the elderly [ERD-list]) were measured at baseline and after the intervention phase. The effectiveness of the intervention was evaluated estimating the absolute difference in percentages of selected indicators carrying out linear random-intercept mixed-effect models. Results: A cohort of 3,586 GPs (2,567 in intervention groups and 1,019 in the control group) was evaluated. In Campania, the mean pre-intervention percentage of patients with at least one pDDI was always greater than 20% and always lower than 15% in Lombardy. The pre–post difference was quite heterogeneous among the LHUs, ranging from 1.9 to −1.4 percentage points. The mean pre-intervention percentage of patients with pTDs ranged from 0.59 to 2.1%, with slightly higher values characterizing Campania LHUs. The magnitude of the pre–post difference was very low, ranging from −0.11 to 0.20. In Campania, the mean pre-intervention percentage of patients with at least one ERD criterium was considerably higher than in Lombardy (approximately 30% in Lombardy and 50% in Campania). The pre–post difference was again quite heterogeneous. The results from the models accounting for GP geographical belonging suggested that none of the interventions resulted in a statistically significant effect, for all the three indicators considered. Conclusion: The proposed strategy was shown to be not effective in influencing the voluntary changes in GP prescription performance. However, the use of a set of explicit indicators proved to be useful in quantifying the inappropriateness. Further efforts are needed to find more efficient strategies and design more tailored interventions.