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Contemporary risk models in chronic myelomonocytic leukemia (CMML) focus on the prognostic relevance of individual rather than concurrent mutations. In the current study of 605 Mayo Clinic patients with CMML, we applied machine-learning algorithms in order to examine the influence of cooperative mutational interactions on blast transformation (BT). A hierarchical clustering algorithm was developed and tailored for patient stratification using survival outcomes and co-occurrence of genomic alterations. Five molecular clusters were identified with 3-year blast BT rates ranging from 0% to 100% (AUC at 3 years 0.78). A subsequent Cox regression analysis confirmed independent detrimental impact of specific mutations or their combinations including NPM1 (HR 26.7; p  < 0.01), “ NRAS  +  SETBP1 ” (HR 12.6; p  < 0.01), “ ASXL1  +  BCOR” (HR 8.4; p  < 0.01), “ ASXL1  +  RUNX1 ” (HR 2.2, p  < 0.01), JAK2 (HR 2.1; p  < 0.01), and “ ASXL1  +  TET2 ” (HR 1.7; p  = 0.02) while “ PHF6 +wild-type ASXL1” (HR 5.61e−10; p  < 0.01) had a favorable impact. Furthermore, compared to NPM1 wild-type cases , NPM1 -mutated patients were less likely to have co-occurring mutations involving ASXL1 (0% vs. 43%, p  < 0.01), RUNX1 (0% vs. 17%, p  = 0.02), and SRSF2 (7% vs. 39%, p  < 0.01) and were more likely DNMT3A (71% vs. 7%, p  < 0.01). The prognostic relevance of “ NRAS  +  SETBP1 ”, “ ASXL1  +  RUNX1 ”, NPM1 and BCOR was validated in an external cohort from Italy ( N  = 501). Taken together, these observations highlight i) the possibility of prognostic interaction of mutations in CMML that should be considered in the development of future risk models and ii) the distinct genotypic and prognostic characteristics of NPM1 -mutated CMML.

Background Psychopathological disorders are often comorbid diagnosis in eating disorders (EDs). We aimed to assess the presence of psychopathological traits and symptoms associated with EDs in an Italian high school adolescent population. Methods A sample of high school adolescents was enrolled, and demographic and clinical data were collected. Two self-report questionnaires, the Eating Disorder Inventory-3 (EDI-3) and the Questionnaire for the Assessment of Psychopathology in Adolescence (Q-PAD), were administered. Results 548 adolescents (333 F/215 M; 16.89 ± 0.85 years) were included. Symptoms associated with EDs of clinical or high clinical concern were prevalent in a range of individuals, with percentages varying from 26.82% for body dissatisfaction to 51.83% for Interoceptive Deficits. The findings from the Q-PAD assessment indicated the presence of psychological distress, leading to discomfort or challenging situations requiring potential intervention in a percentage of adolescents ranging from 2.93% for psychosocial risks to 23.77% for anxiety. These percentages showed differences between genders (F > M, p  < 0.001). Our study also highlighted an association between symptoms of EDs and lifestyle factors within families. We observed correlations between Q-PAD measures and EDI-3 scores, including a positive correlation between Q-PAD and EDI-3 body dissatisfaction ( r  = 0.7), Q-PAD interpersonal conflicts and EDI-3 interpersonal problems ( r  = 0.6) and a negative correlation between Q-PAD self-esteem and well-being and EDI-3 ineffectiveness Composite ( r =-0.7). Conclusions a substantial prevalence of ED symptoms and psychological distress among high school adolescents were recorded. These conditions are interrelated, suggesting the importance of addressing them comprehensively. Early detection is essential to improve treatment outcomes and to implement preventive strategies.

We explored the impact of luspatercept therapy on overall survival (OS) and possible predictors of response in low‐risk (LR) myelodysplastic syndrome (MDS) patients. We evaluated 331 anemic patients treated with luspatercept. Hematological response (HI) was defined as (i) hemoglobin (Hb) increase of ≥1.5 g/dL in nontransfusion‐dependent (NTD) patients, and (ii) red blood cell (RBC) transfusion independence (TI) with a concomitant Hb increase of ≥1.5 g/dL, or RBC‐TI without an Hb increase of 1.5 g/dL, or >50% reduction in RBC transfusion burden (TB) for TD patients. Response was observed in 166 patients (50.2%), with significantly higher response in NTD and low TB versus high TB patients (p < 0.001). A significant correlation between lower Molecular International Prognostic Scoring System (IPSS‐M) risk scores and response was observed. No statistically significant difference in HI was found in SF3B1‐mutated versus wild‐type MDS patients (53.8% vs. 40.1%, respectively). SF3B1mut hotspots (K700E vs. others) and variant allele frequencies (VAFs; <38% VAF vs. ≥38% VAF) did not impact on HI. SF3B1‐mutated MDS with del5q showed inferior HI compared to other LR‐MDS (p = 0.046). The median treatment duration overall was 35 weeks (20.86–90.29), the median time to response was 11 weeks (8.71–21.86), and the median duration of response was 65 weeks (26.5–114). After a median follow‐up of 13 months, median OS was not reached (NR) for responders and 24 months for nonresponders (hazard ratio [HR] 0.25, 95% confidence interval 0.14–0.44, p < 0.001). This analysis of 331 luspatercept real‐life‐treated LR‐MDS patients demonstrated a significant OS benefit upon luspatercept response. Low baseline RBC‐TB and lower risk IPSS‐M scores correlated with higher HI and could constitute predictive markers of response.

Myelodysplastic syndromes (MDS) are clinically and biologically diverse disorders, emphasizing the need for personalized treatment approaches. The International Working Group for Prognostication of MDS (IWG_(P)M) recently introduced a molecular classification, referred to as the MDS taxonomy, that categorizes patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at TP53 and TET2 loci. This study sought to validate and enhance the clinical relevance of the MDS taxonomy by analyzing a large retrospective cohort (n = 5136) and transcriptomic data from a prospective cohort (n = 477). The taxonomy successfully identified subgroups with distinct clinical characteristics and disease progression patterns. However, incorporating gene interactions from taxonomy subgroups did not improve the prognostic performance of the Molecular International Prognostic Scoring System (IPSS‐M). We further assessed whether the taxonomy could guide management in patients receiving disease‐modifying therapies. Except for the “TP53‐complex” subgroup, taxonomy classifications were not predictive of hypomethylating agent response or transplant outcomes. Nonetheless, they correlated with overall survival, suggesting that while both IPSS‐M and the taxonomy capture disease biology, other non‐genetic factors may influence treatment response. RNA sequencing confirmed the biological distinctiveness of the taxonomy groups. Transcriptomic profiling of CD34+ bone marrow cells revealed unique, homogeneous gene expression patterns, particularly within the AML‐like, biTET2, SF3B1, and TP53‐complex subgroups. Further integration of multi‐omics data may refine MDS classification, improving clinical decision‐making and guiding the development of targeted therapies.

Background Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. Acute complications may impact on disease progression but their prevalence is unclear and prognostic outcomes of complicated patients have been poorly studied. The aim of the study was to estimate the prevalence of acute complications of TB at the time of diagnosis. Short-term outcomes were also evaluated. Methods A cross-sectional study was carried out in Milan (Italy), from January 2018 to December 2023. Results 201 patients with TB were recruited. 88 complications were recorded in 65 (32.3%) patients. Disseminated TB was the most frequent complication (30, 34.1%) followed by acute respiratory failure (23, 26.1%) and pleural empyema (6, 6.8%). In-hospital and 30-days mortality in complicated patients were 9/65 (13.8%) and 10/65 (15.4%), respectively. In-hospital mortality was significantly higher in patients with > 1 versus (VS) 1 complication (6, 31.6% VS 3, 6.5%, p  = 0.02) without any difference in 1-month mortality (6, 31.6% VS 4, 9.8%, p  = 0.06) between subgroups. Acute respiratory failure was the most lethal complication. Conclusions The study shows a substantial rate of complications in patients with a new diagnosis of TB associated to a significant short-term mortality. A prompt screen of complications at diagnosis is needed to improve short-term outcomes of these patients.

Administrative data were used to investigate changes in hospitalizations for atrial fibrillation (AF), AF-related stroke, and treatment patterns between 2012 and 2016. From the ‘Ricerca e Salute’ database, a population- and patient-based repository involving >12 million inhabitants and linking demographics, prescriptions, and hospital discharge records, all patients discharged alive with a diagnosis of AF between 2012 and 2015 were followed for 1 year. A total of 194,030 AF patients were included. The number of AF cases increased ~10% over time, from 4.0 per 1,000 inhabitants in 2012 to 4.4 per 1,000 in 2015. At 1 year, hospitalizations for ischemic stroke decreased from 21.3 per 1,000 patients with AF in 2012-2013 to 14.7 per 1,000 in 2015-2016 (−31%, 95% CI −18 to −41). Over the same period, oral anticoagulant (OAC) use increased from 56.7% to 64.4% (+14%, 95% CI +8 to +26), vitamin K antagonist use decreased (from 55.9 to 36.7%; −34%, 95% CI −21 to −44), whereas direct OACs (DOACs) increased (from <1% in 2012 to 27.7% in 2015). Antiplatelet prescriptions fell from 42.6% in 2012 to 28.1% in 2015. Hospitalizations for major bleeds, mainly gastrointestinal, increased from 1.5‰ in 2012-2013 to 2.3‰ in 2015-2016, whereas hemorrhagic stroke admissions decreased from 6.5‰ to 4.1‰. There was a slight increase in the prevalence of AF between 2012 and 2015, whereas the overall use of antiplatelet agents decreased and that of OAC, particularly DOACs, increased. Over the same period, 1-year hospitalizations for ischemic stroke declined substantially, with a declining rate of hemorrhagic strokes.

Fatty liver disease (FLD) caused by metabolic dysfunction is the leading cause of liver disease and the prevalence is rising, especially in women. Although during reproductive age women are protected against FLD, for still unknown and understudied reasons some develop rapidly progressive disease at the menopause. The patatin-like phospholipase domain-containing 3 ( PNPLA3 ) p.I148M variant accounts for the largest fraction of inherited FLD variability. In the present study, we show that there is a specific multiplicative interaction between female sex and PNPLA3 p.I148M in determining FLD in at-risk individuals (steatosis and fibrosis, P  < 10 −10 ; advanced fibrosis/hepatocellular carcinoma, P  = 0.034) and in the general population ( P  < 10 −7 for alanine transaminase levels). In individuals with obesity, hepatic PNPLA3 expression was higher in women than in men ( P  = 0.007) and in mice correlated with estrogen levels. In human hepatocytes and liver organoids, PNPLA3 was induced by estrogen receptor-α (ER-α) agonists. By chromatin immunoprecipitation and luciferase assays, we identified and characterized an ER-α-binding site within a PNPLA3 enhancer and demonstrated via CRISPR–Cas9 genome editing that this sequence drives PNPLA3 p.I148M upregulation, leading to lipid droplet accumulation and fibrogenesis in three-dimensional multilineage spheroids with stellate cells. These data suggest that a functional interaction between ER-α and PNPLA3 p.I148M variant contributes to FLD in women. Analysis using a combination of molecular and genetic epidemiological approaches reveals an interaction between female sex and the genetic variant PNPLA3 p.I148M that might explain why some women have increased susceptibility to fatty liver disease after onset of menopause.