Citations

Myelodysplastic syndromes with isolated deletion of chromosome 5q [MDS-del(5q)] constitute a distinct biological entity traditionally associated with favorable outcomes, although up to one quarter of patients progress to acute myeloid leukemia (AML). Existing prognostic models, developed in heterogeneous MDS populations, may not adequately capture risk within this subgroup. We assembled an international cohort of 682 patients with MDS-del(5q) to evaluate the performance of the IPSS-R and IPSS-M, identify prognostic variables, and develop a disease-specific prognostic tool, the IPSS-del(5q). Most patients were classified as lower-risk by IPSS-R (94.4%) and IPSS-M (85.5%), yet both systems showed limited discriminatory ability (C-indices ≈0.5). Independent adverse prognostic factors included age ≥70 years, male sex, anemia (hemoglobin ≤10 g/dL), thrombocytopenia (platelets ≤100×10⁹/L), the presence of one additional chromosomal abnormality, ≥2 gene mutations, SF3B1 mutations, and high-risk TP53 status. Six variables were included in the IPSS-del(5q), stratifying patients into standard-risk (74.3%) and high-risk (25.7%) groups with significantly different LFS (69.2 vs. 32.0 months; p<0.01). Moreover, this model reclassified 19.1% of lower-risk IPSS-R and 14.6% of lower-risk IPSS-M patients into the high-risk IPSS-del(5q) group. However, its discriminative power remained modest, with a C-index of 0.60. Overall, this study provides the most comprehensive prognostic evaluation of MDS-del(5q) to date, demonstrates the limited discriminatory capacity of existing MDS scores in this entity, and underscores the need to develop refined disease-specific prognostic approaches for this MDS subtype.

Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) predominantly affects children and young adults (CAYA) and presents as localized disease with excellent prognosis. Although most tumors harbor IRF4 rearrangements (IRF4-R), the existence of cryptic rearrangements has been suggested. Whether IRF4-R LBCL in adults represents the same biological entity remains unclear. To address this question, 35 CAYA patients diagnosed with LBCL-IRF4 and 7 adult (>40-year-old) LBCL with IRF4-R were investigated by an integrative molecular approach. Targeted sequencing structural variant analysis (SV-NGS) confirmed the IRF4-R in 84% of investigated cases. In CAYA, an enrichment (55% vs 29% in adults) of translocations involving IGH, with a breakpoint cluster 3' to IRF4 (EXOC2) was observed, including a cryptic insertion of IGHM-IGHJ5 into IRF4 locus. Novel translocations, IRF4::MIR142 in two CAYA (7%) and IRF4::BATF in one adult, were discovered. Whole-exome sequencing analysis identified unreported mutations in LBCL-IRF4 as YY1 and ZC3H12A (11% each). The high incidence of mutations affecting the B-cell receptor/NF-KB pathways in LBCL-IRF4 was confirmed in cases with diffuse component only. None of the CAYA tumors were classified by LymphGen tool. Adult IRF4-R LBCL showed higher levels of genetic complexity and a distinct mutational profile with mutations on KMT2D and DTX1 (43% each), and MYD88-L265P (29%), and were predicted as EZB or MCD (29% each). These differential genetic features were in line with different clinical presentations (extranodal involvement and advanced stage). In conclusion, IRF4-R architecture and mutational profile differ according to age, supporting that not all cases should be classified as LBCL-IRF4.

Abstract Background: Endocrine therapies remain central to estrogen receptor alpha-positive (ERα+) breast cancer treatment, yet their predominantly cytostatic effects highlight the need for combinatorial approaches that promote tumor cell death. We therefore tested BH3 mimetics as single agents and in combination with (Z)-endoxifen (ENDX) across endocrine sensitive and endocrine resistant ERα+ breast cancer models. Methods: Six BH3 mimetics were tested in MCF7 and T47D cells and matched ENDX-resistant and fulvestrant-resistant derivatives. ENDX combinations were assessed using 2D proliferation and synergy assays, 3D RASTRUM® bioprinted cultures, migration assays, and in vivo MCF7 xenograft studies. Results: BH3 mimetics showed broad anti-proliferative activity as single agents in endocrine sensitive and resistant models. ENDX combinations were predominantly additive in 2D assays, with limited synergy confined to specific dose windows. In 3D culture, selected combinations of an MCL1 inhibitor (MCL1i) or navitoclax with ENDX produced greater suppression than single agents and, in several conditions, reduced growth below baseline, consistent with loss of viability. Combination treatment also enhanced suppression of migration under select concentrations. In MCF7 xenograft studies, ENDX robustly suppressed tumor growth; however, adding MCL1i or navitoclax did not provide additional antitumor benefit at the doses, schedules, and timeframes tested. Conclusion: BH3 mimetics show activity in ERα+ breast cancer models in vitro , including endocrine resistant models. Although ENDX combination benefit did not translate in vivo under the conditions tested, these data support further study of optimized BH3 mimetic combinations, including evaluation of dose, ratio, schedule, tumor target engagement, and other clinically advanced agents.

Abstract Background Adults with congenital heart disease (ACHD) represent a rapidly expanding population with complex lifelong clinical and psychosocial needs. Nurses play a pivotal role within multidisciplinary ACHD care, yet internationally their education, scope of practice and professional preparation remain highly variable, with no globally agreed curriculum. This gap has limited role clarity, workforce development and international harmonisation of standards. The aim of this project was to develop the first dedicated, competency-based curriculum for ACHD nursing to support consistent, high-quality, patient-centred care worldwide. Methods An international, multidisciplinary working group led by the Association of Cardiovascular Nurses and Allied Professions of the European Society of Cardiology, in collaboration with the Working Group on Adult Congenital Heart Disease and the International Society for Adult Congenital Heart Disease, developed the curriculum through expert consensus. The development group included nurses, physicians, educators and individuals with lived experience of ACHD, ensuring patient perspectives were embedded throughout the process. Existing international guidance, professional frameworks and evidence on ACHD nursing practice were synthesised. The curriculum was structured around Entrustable Professional Activities (EPAs), mapped to the CanMEDS professional roles and designed to accommodate international variation in regulation, resources and scope of practice. Results The resulting curriculum defines core and specialist competencies across the ACHD lifespan, encompassing clinical care, transition, reproductive health, psychosocial support, prevention, advanced therapies, care coordination and research. EPAs specify required knowledge, skills, attitudes, assessment strategies and levels of entrustment, with a minimum standard for practice. The framework supports career progression from specialist to advanced practice roles and is adaptable for academic, workplace-based and continuing professional development contexts. Conclusions This curriculum represents the first internationally applicable, competency-based framework for ACHD nursing. By standardising expectations while allowing contextual flexibility, it strengthens role clarity, supports workforce development and promotes harmonised, high-quality ACHD care globally.

BACKGROUND: Surgeons and ostomy nurses receive a high volume of stoma photos from patients. OBJECTIVE: This study aimed to develop and validate an automated and scalable artificial intelligence pipeline for identification and triage of patient-submitted intestinal ostomy photos. DESIGN: Retrospective derivation and validation study with stakeholder engagement to guide model design. Clinical teams reviewed photos in duplicate and categorized them into: (a) obstructed view, (b) healthy stoma, (c) suitable for conservative management, or (d) requiring in-person review. Pre-trained neural networks including MobileNetV4, ResNet50, ViT and CLIP-ViT were fine-tuned with 5-fold cross-validation. SETTINGS: Nine Mayo Clinic hospitals (2019–2022). PATIENTS: Adult patients (≥18 years) undergoing surgery who submitted images within 30 days after surgery. MAIN OUTCOME MEASURES: Model performance was evaluated with area under the receiver operator curve, precision, recall, and F1-scores. RESULTS: In this study, 538 photos of abdominal ostomies were sent in by 191 patients (median age 52 years, IQR 40–63; 60.4% female). Expert consensus triaged 236 (43.9%) photos as having an obstructed view, 30 (5.6%) as healthy, 177 (32.9%) for conservative management, and 95 (17.7%) for in-person review. All models achieved area under the receiver operator curve >0.97 for identifying stomas. The CLIP-ViT model performed best at triage (macro- area under the receiver operator curve 0.94 ± 0.06; F1 0.77 ± 0.10). End-to-end detection and triage using CLIP-ViT achieved area under the receiver operator curve of 0.99 ± 0.01, precision of 0.87 ± 0.08, recall of 0.93 ± 0.04, and F1 of 0.89 ± 0.07. Attention maps showed that models focused on stomas to determine classification. LIMITATIONS: Low sample size and lack of prospective validation. CONCLUSIONS: A vision language model pipeline accurately detected and triaged patient-submitted ostomy photos. Prospective evaluation is now needed to support integration into multidisciplinary digital workflows. See Video Abstract .

ABSTRACT Pulmonary hypertension (PH) comprises a heterogeneous group of disorders characterized by elevated pressure in the pulmonary arteries. Despite advances in awareness, utilization of non‐invasive screening with echocardiography, increasing number of targeted therapies, and evolving clinical guidelines emphasizing referral to PH specialty centers, barriers to timely diagnosis and treatment persist. Key challenges span patient‐related and system‐level domains that hinder the effective diagnosis, management, and treatment of PH, particularly pulmonary arterial hypertension (PAH). In this article, the obstacles to PH care are examined and actionable recommendations are proposed. By integrating patient‐related and system‐level perspectives, this review provides a framework to bridge persistent gaps in PH care delivery in the United States.

Background Cardiac rehabilitation (CR) leads to increased exercise capacity (VO 2 peak) and risk reduction of major adverse cardiovascular events (MACEs). Women exhibit blunted VO 2 peak improvements following CR. The purpose was to examine sex differences in the clinical predictors of VO 2 peak improvement and odds of MACEs following CR. Methods From 1999 to 2017, all consecutive patients undergoing cardiopulmonary exercise testing before and after CR were included. Sex differences in peak exercise metrics in response to CR were compared. Multiple logistic regression models were fit to assess clinical predictors of VO 2 peak improvement (defined as >0% from pre‐CR) and MACEs following CR for men and women. Results A total of 513 men and 158 women were included. Men had greater increases in VO 2 peak than women following CR ( P =0.001). For men, independent predictors of VO 2 peak improvement following CR included higher CR session attendance (odds ratio [OR], 1.04 [95% CI, 1.02–1.06]), peripheral artery disease (OR, 0.47 [95% CI, 0.25–0.86]), and pre‐CR VO 2 peak (OR, 0.98 [95% CI, 0.97–0.99]) (all, P <0.02). Independent predictors of lower odds of MACEs following CR in men included higher number of CR sessions (OR, 0.97 [95% CI, 0.95–0.99]), pre‐CR VO 2 peak (OR, 0.98 [95% CI, 0.97–0.99]), surgical CR indication (OR, 0.34 [95% CI, 0.18–0.68]), and no history of peripheral artery disease (OR, 2.94 [95% CI, 1.60–5.38]) (all, P <0.02). For women, the selected clinical characteristics were not statistically significant independent predictors of VO 2 peak improvement or odds of MACEs (except for diabetes) following CR. Conclusions These findings suggest that clinical predictors of VO 2 peak improvement and odds of MACEs following CR are sex specific.

Background Hypertensive disorders of pregnancy (HDP) are a leading global cause of maternal and fetal morbidity/mortality. Most estimates of HDP occurrence are reported for composite exposures of HDP or preeclampsia alone, with limited disaggregation by obstetrical subgroup (eg, multi‐fetal deliveries). Consequently, our understanding of HDP prevalence and temporal trends remains limited, and methods for identifying specific diagnoses in administrative data remain underexamined. This population‐based descriptive study assessed how enhanced administrative case‐finding definitions influence prevalence estimates of HDP in pregnancy and postpartum. Methods Included were individuals aged ≥18 years discharged from an Ontario hospital following their first obstetrical delivery between April 1, 2002, and December 31, 2017. We calculated overall and annual prevalence estimates and assessed temporal trends for any HDP and major subtypes by case‐finding definitions, stratified by plurality (singleton versus multi‐fetal deliveries). Results Most subjects had a singleton first delivery (n=781 258; 98%); however, HDP was 2.2 to 2.4 times more prevalent in multi‐fetal deliveries. When pre‐pregnancy hypertension was considered during case‐finding, HDP prevalence increased from 193.6 to 207.6 per 1000 multi‐fetal deliveries and from 79.9 to 92.6 per 1000 singleton deliveries. Gestational hypertension was the most common diagnosis in both populations but was nearly twice as common in those who delivered a multiple gestation (94.4–100.0 versus 49.7–53.4 per 1000 deliveries). Prevalence trends differed by coding strategy and plurality. Conclusions Although informative, data from discharge abstracts alone are insufficient for HDP surveillance, particularly for chronic hypertension in pregnancy. Validation studies should assess the accuracy of our case‐finding definitions against suitable reference standards.

Background The current classification of pulmonary hypertension (PH), based largely on expert opinion, has limitations in prognostication and guiding therapies. We hypothesize that novel PH clusters that predict survival will reveal mechanistic phenotypes associated with biomarkers of vascular health across all PH groups. Methods We first identify novel PH clinical clusters by performing unsupervised clustering analysis on the CC‐PH (Cleveland Clinic PH) registry (N=1529). We develop classification models to predict the new PH clusters and then apply them to the multicenter PVDOMICS (Pulmonary Vascular Diseases Phenomics) cohort (N=853) for validation. We compare transplantation‐free survival across the new PH clusters. We quantify metabolites of the arginine‐nitric oxide pathway and D‐dimer levels and calculate global arginine bioavailability (arginine/[ornithine+citrulline]) to assess endothelial function and activation in the new clusters and link these biomarkers to clinical outcomes. Results Clustering analysis identify 3 clear clusters in CC ‐ PH that are validated in PVDOMICS and outperform conventional classifications in predicting transplantation‐free survival. The phenotype associated with the worst survival is characterized by reduced lung diffusion capacity, decreased arginine bioavailability and nitrate levels, and elevated D‐dimer levels, consistent with loss of pulmonary microcirculation and endothelial dysfunction. Conclusions We identify new informative PH phenotypes associated with mortality and defined by biomarkers of endothelial function and activation. Loss of endothelial health and pronounced pulmonary vascular rarefication contribute more substantially to mortality across the spectrum of PH than right heart function. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.

Background: We had a large-scale measles exposure event affecting 626 patients. Management of exposed patients was urgent, involving quarantine, post-exposure prophylaxis (PEP), and symptom monitoring on a case-by-case basis. Cases were initially tracked and managed using a combination of multiple spreadsheets amongst stakeholders as well as lists within the electronic health record (EHR). Using shared spreadsheets and lists created significant challenges with maintaining and editing multiple copies and updating workbooks simultaneously. Methods: Infection Prevention and Control (IPAC) worked with primary care personnel and EHR developers to create a shared registry that would prioritize communication and follow-up for exposed patients based on age and immunity. Patients are initially added to the shared registry within the EHR by reviewing non-registry reports and tagging patients, identified using exposure timeframes that overlapped with the index measles cases, in a manner that transferred them to the shared registry. From this registry, measles, mumps, and rubella vaccine status can be confirmed, immune status can be identified, and criteria for PEP assigned. High-risk patients are then contacted with recommendations from IPAC and primary care. Communication and follow-up are tracked directly within the shared registry to ensure appropriate patient management. The exposure management registry is further leveraged throughout the measles outbreak timeframe by allowing real-time monitoring of patients that require additional precautions or guidance related to their exposure. Result: The shared registry enhanced documentation accuracy and transparency between stakeholders. It led to availability of real-time status of exposed patients for the duration of the measles outbreak timeframe. Overall, the registry enabled time-sensitive patient communication to all exposed patients and rapid identification of those who needed PEP. Communication could happen rapidly and seamlessly between care teams within the organization, and the necessary information could be shared quickly with public health authorities as required. Conclusion: Large scale exposures are a challenge to manage and ensure appropriate action and communication occurs. Errors can be prevented by having a single shared exposure management registry. A registry enables care teams to quickly identify and prioritize patients for measles follow-up, communication, PEP, and ongoing management across outbreak timeframes. This process reduces both time and operational burdens of exposure follow-up tracking outside of the EHR.