Citations

Key Points Renovascular disease impairs the capacity of human adipose tissue–derived mesenchymal stem/stromal cells to repair ischemic murine kidneys. miR-378h modulated the capacity of renovascular disease adipose tissue–derived mesenchymal stem/stromal cells to repair ischemic kidneys in vivo . Background Renovascular disease leads to renal ischemia, hypertension, and eventual kidney failure. Autologous transplantation of adipose tissue–derived mesenchymal stem/stromal cells (MSCs) improves perfusion and oxygenation in stenotic human kidneys, but associated atherosclerosis and hypertension might blunt their effectiveness. We hypothesized that renovascular disease alters the human MSC transcriptome and impairs their reparative potency. Methods MSCs were harvested from subcutaneous abdominal fat of patients with renovascular disease and healthy volunteers ( n =3 each), characterized and subsequently injected (5×10 5 /200 μ l) into mice 2 weeks after renal artery stenosis or sham surgery ( n =6/group). Two weeks later, mice underwent imaging and tissue studies. MSCs from healthy volunteers and in those with renovascular disease were also characterized by mRNA/microRNA (miRNA) sequencing. Based on these, MSC proliferation and mitochondrial damage were assessed in vitro before and after miRNA modulation and in vivo in additional renal artery stenosis mice administered with MSCs from renovascular disease pretreated with miR-378h mimic ( n =5) or inhibitor ( n =4). Results MSCs engrafted in stenotic mouse kidneys. Healthy volunteer MSCs (but not renovascular disease MSCs) decreased BP, improved serum creatinine levels and stenotic-kidney cortical perfusion and oxygenation, and attenuated peritubular capillary loss, tubular injury, and fibrosis. Genes upregulated in renovascular disease MSCs versus healthy volunteer MSCs were mostly implicated in transcription and cell proliferation, whereas those downregulated encoded mainly mitochondrial proteins. Upregulated miRNAs, including miR-378h, primarily target nuclear-encoded mitochondrial genes, whereas downregulated miRNAs mainly target genes implicated in transcription and cell proliferation. MSC proliferation was similar, but their mitochondrial structure and reparative function both in vivo and in vitro improved after miR-378h inhibition. Conclusions Renovascular disease impaired the reparative capacity of human MSCs, possibly by dysregulating miR-378h that targets mitochondrial genes. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_08_21_ASN0000000000000440.mp3

Background Multiple randomized trials could not establish the noninferiority of endovascular thrombectomy (EVT) alone without preceding intravenous thrombolysis (IVT) or superiority of IVT followed by EVT in anterior circulation large‐vessel occlusion stroke. The role of prior IVT in posterior circulation large‐vessel occlusion remains controversial. Methods In this multicenter, retrospective study, patients with stroke with large‐vessel occlusion in the posterior circulation who received EVT alone or with IVT were selected from the stroke thrombectomy and aneurysm registry between 2013 and 2022. Effects of IVT followed by thrombectomy on favorable functional outcome (defined as modified Rankin scale≤3 at 90 days) and safety were investigated using multivariable logistic and linear regression models. Results Of the 588 included patients, 67% (n = 394) were treated with EVT alone and 29% (n = 170) with EVT after IVT, and 4% (n = 24) have missing values on this variable. Controlling for multiple confounding factors, IVT was not associated with a higher likelihood of favorable functional outcome at 90 days (odds ratio, 1.04 [95% CI, 0.52–2.09; P = 0.901). Thrombectomy alone did not show any safety advantages compared with those receiving IVT. Conclusion Similar functional outcomes and complication rates were seen in patients with posterior circulation large‐vessel occlusion treated with EVT alone versus EVT after IVT. Further prospective studies are required to determine the utility of IVT in posterior circulation stroke, especially in patients being directly admitted to thrombectomy centers.

Abstract Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 patients with CCUS investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count of <100 × 109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the clonal cytopenia risk score (CCRS), which stratified patients into low- (score of <2.5 points), intermediate- (score of 2.5 to <5), and high-risk (score of ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high-risk (37.2%) groups, respectively, by the Gray test (P < .0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P = .005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

Abstract Currently, the role of DNA methylation in the immunoglobulin M (IgM) monoclonal gammopathy disease spectrum remains poorly understood. In the present study, a multiomics prospective analysis was conducted integrating DNA methylation, RNA sequencing (RNA-seq), and whole-exome sequencing data in 34 subjects (23 with Waldenström macroglobulinemia [WM], 6 with IgM monoclonal gammopathy of undetermined significance [MGUS], and 5 normal controls). Analysis was focused on defining differences between IgM gammopathies (WM/IgM-MGUS) compared with controls, and specifically between WM and IgM-MGUS. Between groups, genome-wide DNA methylation analysis demonstrated a significant number of differentially methylated regions that were annotated according to genomic region. Next, integration of RNA-seq data was performed to identify potentially epigenetically deregulated pathways. We found that pathways involved in cell cycle, metabolism, cytokine/immune signaling, cytoskeleton, tumor microenvironment, and intracellular signaling were differentially activated and potentially epigenetically regulated. Importantly, there was a positive enrichment of the CXCR4 signaling pathway along with several interleukin (interleukin 6 [IL-6], IL-8, and IL-15) signaling pathways in WM compared with IgM-MGUS. Further assessment of known tumor suppressor genes and oncogenes uncovered differential promoter methylation of several targets with concordant change in gene expression, including CCND1 and CD79B. Overall, this report defines how aberrant DNA methylation in IgM gammopathies may play a critical role in the epigenetic control of oncogenesis and key cellular functions.

BACKGROUND AND OBJECTIVES: The coexistence of complete carotico-clinoid bridge (CCB), an ossification between the anterior (ACP) and the middle clinoid (MCP), and an interclinoidal osseous bridge (ICB), between the ACP and the posterior clinoid (PCP), represents an uncommonly reported anatomic variant. If not adequately recognized, osseous bridges may complicate open or endoscopic surgery, along with the pneumatization of the ACP, especially when performing anterior or middle clinoidectomies. METHODS: According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines, a systematic scoping review was conducted up to June 5, 2023. PubMed, Scopus, Web of Science databases, and additional citations were searched. Two hundred high-resolution noncontrast computed tomography (CT) scans (400 sides) and 41 dry skulls (82 sides) were analyzed to identify the different morphology of sellar bridges, focusing on the coexistence of complete CCF and ICB. Two embalmed latex-injected heads with coexisting CCF and ICB were dissected step-by-step to show the anatomic relationship with the surrounding structures from an endoscopic and microscopic perspective. RESULTS: A total of 19 articles were included. The review identified a complete CCF and ICB rate ranging from 4.92% to 6.3%. The analysis of 200 CT scans revealed a rate of coexistence in 4% of the cases, all encountered in White women. Two different types of interclinoid bridges were identified based on the degree of bone mineralization. Both endoscopic and macroscopic step-by-step dissections highlighted variability in morphology and consistency of the sellar bridges and the close relationship with the cavernous sinus neurovascular structures. CONCLUSION: The coexistence of CCF and ICB is an anatomic variation found in 4% of cases. Preoperative knowledge of the degree of mineralization and its relationship with surrounding structures is essential to performing safe surgery and minimizing cranial nerve and vascular injuries. Preoperative high-resolution CT scans can adequately identify these anatomic variations.

Abstract Activation of β-catenin in CD4+CD8+ double-positive (DP) thymocytes halts development before the thymic selection stage and predisposes to transformation. Leukemogenesis, but not the developmental block, depends on TCF-1, β-catenin’s DNA-binding partner. In this study, we show that β-catenin activation directs the DNA-binding protein HEB to block DP thymocyte development. Conditional loss of HEB in DP thymocytes with stabilized β-catenin restores the frequencies of postselection TCRβhi/CCR7+ and TCRβhi/CD69+ DPs and their cell-cycle profile. This recovery is associated with significant reversal of β-catenin-induced expression changes, particularly those related to the CD69+ DP cell signature and to cell-cycle pathways. Stabilizing β-catenin in DP thymocytes directs HEB binding to ≈11,000 novel DNA sites throughout the genome. Novel HEB sites mark most CD69+ DP cell signature genes that change expression upon activation of β-catenin and then revert after loss of HEB. Moreover, many of the novel HEB sites occupy promoter regions of genes enriched in mitotic cell cycle pathways. HEB binding to those regions correlates with downregulation of the associated genes, and HEB inactivation restores expression to physiologic levels. These findings highlight a molecular interplay between HEB and β-catenin that can impair thymic development.

Abstract Generative artificial intelligence (AI) holds immense potential for medical applications, but the lack of a comprehensive evaluation framework and methodological deficiencies in existing studies hinder its effective implementation. Standardized assessment guidelines are crucial for ensuring reliable and consistent evaluation of generative AI in healthcare. Our objective is to develop robust, standardized guidelines tailored for evaluating generative AI performance in medical contexts. Through a rigorous literature review utilizing the Web of Sciences, Cochrane Library, PubMed, and Google Scholar, we focused on research testing generative AI capabilities in medicine. Our multidisciplinary team of experts conducted discussion sessions to develop a comprehensive 32‐item checklist. This checklist encompasses critical evaluation aspects of generative AI in medical applications, addressing key dimensions such as question collection, querying methodologies, and assessment techniques. The checklist and its broader assessment framework provide a holistic evaluation of AI systems, delineating a clear pathway from question gathering to result assessment. It guides researchers through potential challenges and pitfalls, enhancing research quality and reporting and aiding the evolution of generative AI in medicine and life sciences. Our framework furnishes a standardized, systematic approach for testing generative AI's applicability in medicine. For a concise checklist, please refer to Table S or visit GenAIMed.org .

Abstract Introduction: Historically, children undergoing cardiac catheterization have been managed with general endotracheal anesthesia (GETA). However, recent practice has favored general anesthesia with total intravenous anesthesia (TIVA). This study compares procedural outcomes in the pediatric cardiac catheterization laboratory (PCCL) for children undergoing low-risk cardiac catheterization with GETA vs. TIVA. Methods: We reviewed all patients aged 1–12 years, who underwent outpatient diagnostic or simple interventional catheterization from January 2016 – September 2023. Patients were divided into cohorts by type of anesthesia (GETA vs. TIVA). The primary outcome measure was total patient time in the PCCL (“door-to-door” time). Secondary outcomes were procedure duration (“sheath time”), length of hospital stay, and the major adverse event (MAE) rate. Results: A total of 401 patients were included. Of these patients, 226 underwent GETA and 175 underwent TIVA. There were 148 interventional procedures and 72 patients had single-ventricle physiology. There was no significant difference between the two cohorts in terms of demographic factors such as age, weight, procedure indication and physiological complexity as well as outcomes such as sheath time, hospital stay and MAE. However, the average door-to-door time of the TIVA cohort was 25 minutes shorter than the GETA cohort (p < 0.001). Conclusions: In this single center, retrospective study of anesthesia management for children undergoing low-risk cardiac catheterization, TIVA is associated with significantly shorter door-to-door time in the PCCL without an increase in procedure duration, hospital stay, or rate of complications. These findings have potential clinical significance supporting increased use of TIVA during pediatric cardiac catheterization.

AbstractObjectiveWe performed a pilot stroke incidence study, focused on feasibility and inclusion of the CONSIDER reporting guidelines, to model the design of a future population‐based study aiming to definitively determine stroke incidence, antecedents, treatment, and outcomes.Study designProspective stroke incidence study (pilot study).Setting, participantsAll people aged 15 years or older who lived in postcode‐defined areas of South Australia and Northern Territory (885 472 people, including 45 127 Aboriginal people [5.1%]) diagnosed with stroke for the first time during 1 October – 31 December 2015 and admitted to public hospitals or stroke and transient ischaemic attack clinics.Main outcome measuresFeasibility of a prospective population‐based stroke incidence study.ResultsOf the 123 participants with first strokes, ten were Aboriginal (8%); the median age of Aboriginal people was 45 years (interquartile range [IQR], 33–55 years), of non‐Indigenous people 73 years (IQR, 62–84 years). For Aboriginal people, the age‐standardised incidence of stroke was 104 (95% confidence interval [CI], 84–124) per 100 000 person‐years, for non‐Indigenous people 33 (95% CI, 22–44) per 100 000 person‐years. We found that a prospective population‐based stroke incidence study in Aboriginal people was feasible, including with respect to establishing an adequate sample size, diagnostic confirmation, identification of incident stroke, confirming stroke subtypes, establishing a stable statistical population, standardising data reporting for comparison with other stroke incidence studies, and ethical research reporting that conforms to CONSIDER guidelines.ConclusionsA larger, population‐based study of the incidence of stroke in Aboriginal people is both feasible and needed to provide robust estimates of stroke incidence, antecedents, treatments and outcomes to help guide strategies for reducing the risk of and outcomes of stroke in Aboriginal people.