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Introduction: In recent years, multiple myeloma (MM) research has increasingly focused on unraveling the complex interactions between malignant plasma cells and their surrounding bone marrow microenvironment (BMME). To further elucidate these interactions, we developed a comprehensive single-cell atlas of the MM BMME, integrating both coding and noncoding (ncRNA) transcriptional profiles. By correlating these profiles with specific cytogenetic abnormalities in myeloma cells, we aim to uncover how ncRNAs regulate the phenotypic and functional states of myeloma cells and, consequently, shape the cellular landscape of the BMME. A detailed understanding of how the noncoding transcriptome affects the cellular components and immune landscape of the BMME is essential for advancing our knowledge of MM pathogenesis and identifying novel biomarkers and therapeutic targets. Methods: Our atlas was constructed using single-cell RNA sequencing data from 481 samples of CD138neg cells sorted from bone marrow aspirates of MM patients enrolled in the MMRF CoMMpass study. This dataset includes accompanying whole-genome sequencing and survival data, enabling correlative analysis between transcriptional profiles, cytogenetic abnormalities, and patient outcomes. To generate a combined coding and non-coding transcriptome, we developed an expanded human reference genome by systematically merging mRNA and ncRNA transcripts from the LncBook2.0 and GENECODEv42 reference genomes. The sequencing data was aligned to this expanded genome, followed by quality control processing, batch correction, clustering, and supervised analysis. Results: The resulting coding and non-coding atlas comprises over 1.9 million cells, spanning immune, plasma, and stromal compartments. Remarkably, ncRNAs constituted 46% of the associated genes, including 22,102 long ncRNAs (lncRNAs) and 3,112 small ncRNAs. Subclustering analysis of the major immune compartments (B lymphoid, myeloid, and NK and T lymphoid) yielded 70 subclusters, with ncRNAs representing 24-38% of the top 100 differentially expressed genes within each compartment. This underscores the significant role of ncRNAs in distinguishing immune subpopulations. Moreover, examining the association between specific cytogenetic abnormalities and the immune composition of the BMME, 30 subclusters were found to be differentially abundant (P < 0.05) between cytogenetic abnormalities, supporting our hypothesis that myeloma cell genotypes significantly shape the immune microenvironment. For instance, patients with CCND1 amplification displayed an increase CD4+ central memory T cells with a decrease in CD8+ cytotoxic T cells. Similarly, patients with 1q21 gain exhibited an increase in TGFβ-stimulated monocytes, while a decrease in cytotoxic CD8+ T and CD56dim NK cells was observed in patients with 17p13 deletion. Next, examining which ncRNAs are associated with specific cytogenetic abnormalities, we identified 14 ncRNAs significantly differentially expressed across cytogenetic abnormalities. Increased expression of six of these ncRNAs were associated with poor overall survival both independently and in combination (P < 0.05, HR = 3.7). Notably, three of these ncRNAs have documented roles in cancer progression but have not been previously studied in the context of MM. Subsequently stratifying patients based on their enrichment of these outcome-associated ncRNAs revealed even stronger associations with immune composition, including an increase in CD4+ regulatory T cells (P < 0.05). This further supports our hypothesis that myeloma cell genotypes shape the BMME. Lastly, by constructing a gene regulatory network to predict the interactions between coding and noncoding RNAs, we illustrate the regulatory networks of ncRNAs modulating the phenotypes of myeloma and immune cell subpopulations. Conclusion: In summary, we present the first high-resolution transcriptomic atlas of the MM BMME, integrating both coding and noncoding RNAs. This study reveals distinct immune subpopulations associated with specific myeloma cell genotypes and highlights the central role of ncRNAs in modulating the phenotypic and functional states of both malignant and non-malignant cells in the MM BMME. Our findings emphasize the potential of ncRNAs as therapeutic targets and prognostic markers for MM, offering new avenues for research and clinical intervention.

INTRODUCTION: There is a significant shortage of specialized Adult Congenital Heart Disease (ACHD) cardiologists despite a rising prevalence of adults with this condition. AIM: Our study explores the specific motivations and deterrents that influence adult and pediatric cardiologists’ ACHD career decisions, which could serve as the basis for future solutions to overcome this shortage in each specific region. METHODS: An anonymous global survey was distributed to adult and pediatric cardiologists and trainees via email, social media, and medical society newsletters. The survey included demographics, ACHD exposure, career considerations, Likert scale ratings, and open-ended inquiries on ACHD career recommendations. Respondents included non-ACHD and ACHD cardiologists (defined as those caring for ACHD with or without formal training). The analysis covered regional variations across continents. Responses with less than 75% completion were excluded. RESULTS: A total of 811 valid responses were collected (53.5% female, 48.3% aged 31-40, and 43.3% White). ACHD cardiologists were 21%, mostly practicing in North America (44.1%) and Europe (32.9%). Almost all ACHD cardiologists (94.7%) recommended it as a career. Among the 641 non-ACHD cardiologists, 85.7% had been exposed to ACHD, however, only 35.1% considered pursuing it themselves. For ACHD cardiologists the top global motivators for pursuing an ACHD career were awareness of the field and its significance, mentor's influence, and sufficient clinical exposure during residency (Figure 1A). Factors that deterred non-ACHD cardiologists included a lack of compensation compared to other cardiology subspecialties, limited job opportunities, and the longer duration of training (Figure 1B). Absence of specialized training and educational programs emerged as a major deterrent in all continents except North America. The lack of mentorship or role models in ACHD was particularly pronounced in Africa and Central and South America. Limited exposure to ACHD during training was a significant issue in Europe and Africa. CONCLUSION: Most ACHD cardiologists recommend a career in ACHD. However, only a few non-ACHD cardiologists recommend it. Influential mentors, clinical exposure motivate; low compensation, lengthy training deter. Regional disparities require targeted interventions for better ACHD cardiologist recruitment.

Abstract Most TERT promoter (TERTp) clinically relevant sequence variants in CNS tumors are the canonical C228T and C250T mutations. Non-canonical TERTp mutations have been reported mainly in non-CNS tumors. We describe 12 CNS tumors with non-canonical TERTp variants interpreted as clinically relevant. Using clinical targeted NGS panels (2020-2024), we detected c.-100_-79dup (n=2), c.-92_-91insGGCGGCCCCGCCCCTTCCTTTC (n=1), c.-118_-117insTCCCCGGCCCAGCCCCTTCCGGG (n=1), c.-123_-76dup (n=1), c.-110_-89dup (n=2), and c.-57A>C (n=5). Most cases had chromosomal microarray (n=11) and/or methylation array data analyzed using the NCI/Bethesda v.2 classifier (n=9). All non-canonical TERTp variants occurred at a variant allele frequency suggestive of somatic clonal origin (mean, 34%; range, 18-46), and in adults (mean age, 60 years; range, 36-88). Except for the c.-57A>C variant, all non-canonical TERTp variants occurred in tumors with histological and/or molecular diagnostic features of glioblastoma, IDH-wildtype (GBM), often epigenetically aligning to this tumor type. All five tested cases matched to superfamily glioblastoma (score ≥ 0.9), with three to class GBM_RTK_I (>0.9 in 2, 0.86 in 1) and two to GBM_RTK_II (>0.9). The size and sequence of such variants suggest that these may be functionally equivalent to canonical mutations or generate favorable TERTp activation motif conformations like previously reported activating duplications. The c.-57A>C variant is a well-established oncogenic mutation observed in other cancer types but has not been reported in CNS tumors. We describe five cases with the c.-57A>C variant: one GBM matching to methylation class GBM_MES_TYP (0.99); two oligodendroglioma, IDH-mutant and 1p/19q-codeleted, one of which had methylation data matching to class O_IDH (0.99); one diffuse glioma, IDH-mutant, which was partially 1p/19q-codeleted and matched to class O_IDH (0.99); and one anaplastic meningioma, aligning to superfamily meningioma (0.99)/MNG_MAL (0.79). Our findings show that non-canonical TERTp variants typically occur in tumor types that often harbor TERTp canonical mutations, expanding the spectrum of TERTp clinically relevant variants that are molecular biomarkers in CNS tumors.

BACKGROUND AND OBJECTIVES: We aimed to develop and validate a prediction score for futile recanalization (FR) for large vessel occlusion (LVO) presenting low Alberta Stroke Program Early Computed Tomography Score (ASPECTS) for patients who underwent endovascular thrombectomy (EVT). METHODS: Patients with anterior circulation LVO with low ASPECTS (<6) who underwent successful EVT (modified treatment in cerebral ischemia score ≥2b) from Stroke Thrombectomy and Aneurysm Registry were retrospectively analyzed. FR was defined as 90-day modified Rankin Scale (mRS) scores ≥4 despite successful EVT. Multivariable logistic regression was used to identify independent predictors of FR, and they were used to create a clinical score. The performance of the score was assessed by receiver operating characteristic curve analyses. RESULTS: Of 219 patients, 170 and 49 patients were randomly assigned to the training and validation cohort, respectively. Independent predictors of FR identified in the training cohort were used to construct the SNAP score: site of occlusion (middle cerebral artery = 0, internal carotid artery = 1), National Institutes of Health Stroke Scale score at admission (≤10 = 0, 10 to 19 = 1, ≥20 = 2), age (<75 = 0, ≥75 = 2), and prestroke mRS score (0-3). Receiver operating characteristic curve analyses of the SNAP score in the training and validation cohorts showed areas under the curve of 0.79 (95% CI 0.72-0.86) and 0.79 (95% CI 0.65-0.92) for predicting FR, respectively. A SNAP score ≥5 had a positive predictive value of 92.1% [95% CI 78.8%-97.3%] for FR. CONCLUSION: The SNAP score may be useful in predicting FR after EVT in low-ASPECTS patients with LVO. It can provide patients, family members, and physicians with reliable outcome expectations among patients with acute ischemic stroke with large infarcts.

BACKGROUND AND OBJECTIVES: First-line therapy for most intracranial dural arteriovenous fistulas (dAVFs) is endovascular embolization, but some require microsurgical ligation due to limited endovascular accessibility, anticipated lower cure rates, or unacceptable risk profiles. We investigated the most common surgically treated dAVF locations and the approaches and outcomes of each. METHODS: The Consortium for Dural Arteriovenous Fistula Outcomes Research database was retrospectively reviewed. Patients who underwent dAVF microsurgical ligation were included. Patient demographics, angiographic information, surgical details, and postoperative outcomes were collected. The 5 most common surgically treated dAVF locations were analyzed about used surgical approaches and postoperative outcomes. Univariate analyses were performed with statistical significance set at a threshold of P < .05. RESULTS: In total, 248 patients in the Consortium for Dural Arteriovenous Fistula Outcomes Research database met inclusion criteria. The 5 most common surgically treated dAVF locations were tentorial, anterior cranial fossa (ACF), transverse-sigmoid sinus (TSS), convexity/superior sagittal sinus (SSS), and torcular. Most tentorial dAVFs were approached using a suboccipital, lateral supracerebellar infratentorial approach (39.3%); extended retrosigmoid approach (ERS) (25%); or posterior subtemporal approach (19.6%). All ACF dAVFs used a subfrontal approach; 5.3% also included an anterior interhemispheric approach. Most TSS dAVFs were ligated via ERS (31.3%) or subtemporal (31.3%) approaches. All convexity/SSS dAVFs used an interhemispheric approach. All torcular dAVFs used the suboccipital, lateral supracerebellar infratentorial approach, with 10.5% undergoing simultaneous ERS craniotomy. Angiographic occlusion rates after microsurgery were 85.5%, 100%, 75.8%, 79.2%, and 73.7% for tentorial, ACF, TSS, convexity/SSS, and torcular dAVFs, respectively ( P = .02); the permanent neurological complication rates were 1.8%, 2.6%, 9.1%, 0%, and 0% ( P = .31). There were no statistically significant differences in development of complications ( P = .08) or Modified Rankin Scale at the last follow-up ( P = .11) by fistula location. CONCLUSION: Although endovascular embolization is the first-line treatment for most intracranial dAVFs, surgical ligation is an important alternative. ACF and tentorial fistulas particularly demonstrate high rates of postoperative obliteration.

Importance In 2022, the US House of Representatives passed a bipartisan resolution (House of Representatives Resolution 1118 at the 117th Congress [2021-2022]) calling for meaningful nutrition education for medical trainees. This was prompted by increasing health care spending attributed to the growing prevalence of nutrition-related diseases and the substantial federal funding via Medicare that supports graduate medical education. In March 2023, medical education professional organizations agreed to identify nutrition competencies for medical education. Objective To recommend nutrition competencies for inclusion in medical education to improve patient and population health. Evidence Review The research team conducted a rapid literature review to identify existing nutrition-related competencies published between July 2013 and July 2023. Additional competencies were identified from learning objectives in selected nutrition, culinary medicine, and teaching kitchen curricula; dietetic core competencies; and research team–generated de novo competencies. An expert panel of 22 nutrition subject matter experts and 15 residency program directors participated in a modified Delphi process and completed 4 rounds of voting to reach consensus on recommended nutrition competencies, the level of medical education at which they should be included, and recommendations for monitoring implementation and evaluation of these competencies. Findings A total of 15 articles met inclusion criteria for competency extraction and yielded 187 competencies. Through review of gray literature and other sources, researchers identified 167 additional competencies for a total of 354 competencies. These competencies were compiled and refined prior to voting. After 4 rounds of voting, 36 competencies were identified for recommendation: 30 at both undergraduate and graduate levels, 2 at the undergraduate level only, and 4 at the graduate level only. Competencies fell into the following nutrition-related themes: foundational nutrition knowledge, assessment and diagnosis, communication skills, public health, collaborative support and treatment for specific conditions, and indications for referral. A total of 36 panelists (97%) recommended nutrition competencies be assessed as part of licensing and board certification examinations. Conclusions and Relevance These competencies represent a US-based effort to use a modified Delphi process to establish consensus on nutrition competencies for medical students and physician trainees. These competencies will require an iterative process of institutional prioritization, refinement, and inclusion in current and future educational curricula as well as licensure and certification examinations.

Abstract Objective The presence of comorbidities can substantially affect patients’ quality of life, but data regarding their impact on idiopathic inflammatory myopathies (IIMs) are limited. Methods We examined the prevalence of comorbidities in IIM patients, other autoimmune rheumatic diseases (oAIRDs) and healthy controls (HCs), using data from the self-reported COVAD-2 survey. We defined basic multimorbidity (BM) as the presence of ≥2 non-rheumatic chronic conditions and complex multimorbidity (CM) as the presence of ≥3 non-rheumatic chronic conditions affecting ≥3 organ systems. Hierarchical clustering on principal components was performed for grouping. Results Among the COVAD respondents, 1558 IIMs, 4591 oAIRDs and 3652 HCs were analysed. IIMs exhibited a high burden of comorbidities (odds ratio [OR]: 1.62 vs oAIRDs and 2.95 vs HCs, P &lt; 0.01), BM (OR: 1.66 vs oAIRDs and 3.52 vs HCs, P &lt; 0.01), CM (OR: 1.69 vs AIRDs and 6.23 vs HCs, P &lt; 0.01) and mental health disorders (MHDs) (OR: 1.33 vs oAIRDs and 2.63 vs HCs, P &lt; 0.01). Among the IIM patients, those with comorbidities or MHDs had lower PROMIS Global Physical (PGP), PROMIS Global Mental (PGM), and PROMIS Physical Function (SF10) scores, and higher fatigue (F4a) scores (all P &lt; 0.001). PGP, PGM, SF10a and F4a were influenced by age, active disease, BM and MHDs. Four distinct clusters were identified among the IIMs according to comorbidities and PROMIS scores. Conclusion Patients with IIMs have a higher burden of comorbidities that influence physical and mental health, identifiable as clinical clusters for optimized and holistic management approaches.