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Background: Distal myopathies (MPDs) are heterogeneous diseases of complex diagnosis whose prevalence and distribution in specific populations are unknown., Methods: Demographic, clinical, genetic, neurophysiological, histopathological and muscle imaging characteristics of a MPDs cohort from a neuromuscular reference center were analyzed to study their epidemiology, features, genetic distribution and factors related to diagnosis., Results: The series included 219 patients (61% were men, 94% Spanish and 41% sporadic cases). Mean age at onset and years of follow-up were 29 and 12.4, respectively. Patients commonly presented with gait disturbances in adulthood and did not usually exhibit a purely distal involvement, but disto-proximal involvement. HyperCKemia was detected in 56.6%, leading to consultation in 11.7%. Myopathic electromyography patterns and spontaneous activity were common; however, neurogenic features were also observed. Muscle imaging was useful for diagnosis as were certain histological features. Suspected pathogenic variants were identified in 68.7% of patients across 19 genes, but 85% concentrated in 8: MYH7, ANO5, DYSF, TTN, MYOT, HSPB1, GNE and HNRNPDL. Founder/cluster variants were found as well as overlap between myopathic and neurogenic processes. Onset before 60 years old, familial cases, very high CK levels and myopathic histopathological features were associated with a higher probability of molecular diagnosis. We found a minimum prevalence of MPDs of 3.9 per 100,000 individuals in the Valencian Community., Conclusions: This series being the largest cohort of patients with MPDs presents their frequency and behavior. This study identifies new genes presenting as MPDs, provides data to guide diagnosis and lays the groundwork for cooperative studies., Competing Interests: Declarations. Conflicts of interest: All authors reviewed and approved the manuscript prior to its submission. The authors have no conflicts of interest to declare., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Recent studies have demonstrated the association between constitutional ring chromosome 21 (r(21)c) and the development of B-cell acute lymphoblastic leukemia (B-ALL) with intrachromosomal amplification of chromosome 21 (iAMP21). iAMP21 acts as a driver which is often accompanied by secondary alterations that influence disease progression. Here, we report an atypical case of iAMP21 B-ALL with a unique molecular profile in the context of r(21)c. The onset of B-ALL occurred significantly earlier than previously reported in iAMP21-ALL, likely due to the presence of r(21)c. Only scarce cases of iAMP21 with concomitant PAX5 fusions have been reported. Through an extensive genomic characterization, the novel WWOX::PAX5 as well as 13q12.2 deletion involving FLT3 overexpression was found. These findings suggest that r(21)c may induce chromosomal instability on chromosome 21, triggering chromothripsis and leading to iAMP21-ALL. This case provides valuable insights to unravel the complex interplay between germline and somatic genetic alterations in leukemia. Moreover, it underscores the need for thorough genetic evaluation and multidisciplinary management in patients with syndromic presentation, particularly when rare genetic events may contribute to hematologic malignancies.

Background: Patients with secondary acute myeloid leukemia who previously received hypomethylating agents for prior myeloid neoplasms (HMA-sAML) face a dismal prognosis., Methods: The authors analyze the characteristics, therapeutic approaches, and outcomes of patients with HMA-sAML from the Programa Español para el Tratamiento de Hemopatías Malignas (PETHEMA) registry., Results: A total of 479 patients were included, mostly from prior myelodysplastic syndrome (84%). Frontline therapy consisted of intensive chemotherapy (IC) in 31%, low-dose cytarabine-based in 19%, supportive care and clinical trial 17% each, and HMA-based therapy in 12% and 4% in venetoclax-based regimen. Complete remission was achieved in 95 patients (27%), with higher rate among IC and venetoclax-based groups (44% and 41%, respectively). The median overall survival (OS) was 4.93 months, with 7.68 months for IC patients, 7.82 months after HMA monotherapy, and 4.66 months after venetoclax-based regimens. Patients who underwent allogeneic hematopoietic stem cell transplantation in first remission (n = 33, 9%) had a better survival outcome (median OS not reached). Multivariate analyses identified age (≥65 years), Eastern Cooperative Oncology Group >2, higher white blood cell count, and adverse risk cytogenetic as adverse prognostic factors, whereas NPM1 mutation was a favorable factor., Conclusions: Patients with HMA-sAML have a poor prognosis and suboptimal outcomes with conventional treatments, including BCL2 inhibitors, highlighting the need for clinical trials targeting this population., (© 2025 American Cancer Society.)

Study Question: What is the transcriptomic response of human blastocysts following internalization of extracellular vesicles (EVs) secreted by the human endometrium?, Summary Answer: EVs secreted by the maternal endometrium induce a transcriptomic response in human embryos that modulates molecular mechanisms related to embryo development and implantation., What Is Known Already: EVs mediate intercellular communication by transporting various molecules, and endometrial EVs have been postulated to be involved in the molecular regulation of embryo implantation. Our previous studies showed that endometrial EVs carry miRNAs and proteins associated with implantation events that can be taken up by human blastocysts; however, no studies have yet investigated the transcriptomic response of human embryos to this EV uptake, which is crucial to demonstrate the functional significance of this communication system., Study Design, Size, Duration: A prospective descriptive study was performed. Primary human endometrial epithelial cells (pHEECs), derived from endometrial biopsies collected from fertile oocyte donors (n = 20), were cultured in vitro to isolate secreted EVs. Following EV characterization, Day 5 human blastocysts (n = 24) were cultured in the presence or absence of the EVs for 24 h and evaluated by RNA-sequencing., Participants/materials, Setting, Methods: EVs were isolated from the conditioned culture media using ultracentrifugation, and characterization was performed using western blot, nanoparticle tracking analysis, and transmission electron microscopy. Human blastocysts were devitrified, divided into two groups (n = 12/group), and cultured in vitro for 24 h with or without previously isolated EVs. RNA-sequencing analysis was performed, and DESeq2 was used to identify differentially expressed genes (DEGs) (FDR < 0.05). QIAGEN Ingenuity Pathway Analysis was used to perform the functional enrichment analysis and integration with our recently published data from the pHEECs' EV-miRNA cargo., Main Results and the Role of Chance: Characterization confirmed the isolation of EVs from pHEECs' conditioned culture media. Among the DEGs in blastocysts co-cultured with EVs, we found 519 were significantly upregulated and 395 were significantly downregulated. These DEGs were significantly enriched in upregulated functions related to embryonic development, cellular invasion and migration, cell cycle, cellular organization and assembly, gene expression, and cell viability; and downregulated functions related to cell death and DNA fragmentation. Further, the intracellular signaling pathways regulated by the internalization of endometrial EVs were previously related to early embryo development and implantation potential, for their role in pluripotency, cellular homeostasis, early embryogenesis, and implantation-related processes. Finally, integrating data from miRNA cargo of EVs, we found that the miRNAs carried by endometrial EVs targeted nearly 80% of the DEGs in human blastocysts., Limitations, Reasons for Caution: This is an in vitro study in which conditions of endometrial cell culture could not mimic the intrauterine environment., Wider Implications of the Findings: This study provides novel insights into the functional relevance of EVs secreted by the human endometrium, and particularly the role of EV-miRNA regulation on global transcriptome behavior of human blastocysts during early embryogenesis and embryo implantation. It provides potential biomarkers that could become useful diagnostic targets for predicting implantation success., Study Funding/competing Interest(s): This study was supported by the Spanish Ministry of Education through FPU awarded to M.S.-B. (FPU18/03735), Generalitat Valenciana through VALi+d Programme awarded to M.C.C.-G. (ACIF/2019/139), and Instituto de Salud Carlos III and cofounded by the European Social Fund (ESF) "Investing in your future" through the Miguel Servet Program (CP20/00120 [H.F.]; CP19/00149 [I.C.]). The authors have no conflicts of interest to disclose., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Gadolinium-based contrast agents (GBCAs) are widely and routinely used to enhance the diagnostic performance of magnetic resonance imaging and magnetic resonance angiography examinations. T1 relaxivity (r 1 ) is the measure of their ability to increase signal intensity in tissues and blood on T1-weighted images at a given dose. Pharmaceutical companies have invested in the design and development of GBCAs with higher and higher T1 relaxivity values, and "high relaxivity" is a claim frequently used to promote GBCAs, with no clear definition of what "high relaxivity" means, or general concurrence about its clinical benefit. To understand whether higher relaxivity values translate into a material clinical benefit, well-designed, and properly powered clinical studies are necessary, while mere in vitro measurements may be misleading. This systematic review of relevant peer-reviewed literature provides high-quality clinical evidence showing that a difference in relaxivity of at least 40% between two GBCAs results in superior diagnostic efficacy for the higher-relaxivity agent when this is used at the same equimolar gadolinium dose as the lower-relaxivity agent, or similar imaging performance when used at a lower dose. Either outcome clearly implies a relevant clinical benefit. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3., (© 2024 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Introduction and Objectives: Limited information is available on the safety of pregnancy in patients with genetic dilated cardiomyopathy (DCM) and in carriers of DCM-causing genetic variants without the DCM phenotype. We assessed cardiac, obstetric, and fetal or neonatal outcomes in this group of patients., Methods: We studied 48 women carrying pathogenic or likely pathogenic DCM-associated variants (30 with DCM and 18 without DCM) who had 83 pregnancies. Adverse cardiac events were defined as heart failure (HF), sustained ventricular tachycardia, ventricular assist device implantation, heart transplant, and/or maternal cardiac death during pregnancy, or labor and delivery, and up to the sixth postpartum month., Results: A total of 15 patients, all with DCM (31% of the total cohort and 50% of women with DCM) experienced adverse cardiac events. Obstetric and fetal or neonatal complications were observed in 14% of pregnancies (10 in DCM patients and 2 in genetic carriers). We analyzed the 30 women who had been evaluated before their first pregnancy (12 with overt DCM and 18 without the phenotype). Five of the 12 (42%) women with DCM had adverse cardiac events despite showing NYHA class I or II before pregnancy. Most of these women had a history of cardiac events before pregnancy (80%). Among the 18 women without phenotype, 3 (17%) developed DCM toward the end of pregnancy., Conclusions: Cardiac complications during pregnancy and postpartum were common in patients with genetic DCM and were primarily related to HF. Despite apparently good tolerance of pregnancy in unaffected genetic carriers, pregnancy may act as a trigger for DCM onset in a subset of these women., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)