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Rescue Bare-Metal Device Placement to Treat Iatrogenic Acute Type A Aortic Dissection During Transcatheter Aortic Valve Replacement
No full textTotal Aortic Arch Replacement Using the Thoraflex Hybrid Device: Evolution From Investigational to Federally Approved Use in the United States
No full textBackground: After the US Food and Drug Administration (FDA) approved the Thoraflex Hybrid device in April 2022, hybrid devices to facilitate total arch replacement (TAR) became commercially available in the United States. However, little is known about how the Thoraflex device has been used since then. We present our experience (2016-2025) with this device.
Methods: At our practice, 62 patients [median age, 65 (54-73) years] underwent frozen elephant trunk (FET) TAR with the Thoraflex device: 14 under an investigational device exemption (IDE) (2016-2018) and 48 after FDA approval (2022-2025). Both Ante-Flo (straight) and Plexus (branched) models were used.
Results: Patients with aortic dissection were common (n=38; 61%). Many patients had prior open or endovascular aortic repair (n=28; 45%). Initial cannulation was commonly done via the innominate artery (n=30; 48%) or the right axillary artery (n=22; 36%). Both branched and island strategies were used to reattach the brachiocephalic arteries. Selectively, left subclavian artery (LSCA) bypass was performed before TAR in 18 patients (29%). The distal anastomosis was performed proximal to the LSCA in 27 repairs (43%). A short (10-cm) endograft extension was used in most cases (n=49; 79%). Eight (13%) patients underwent concomitant aortic root replacement. Overall, four patients (7%) had operative deaths, and three (5%) were discharged with stroke or persistent need for renal dialysis. Two patients had spinal cord deficits that resolved before discharge. Twenty-five downstream extensions (12 open, 13 endovascular) were needed in 22 patients; two patients underwent more than one repair. After discharge, seven additional patients died within one year of surgery.
Conclusions: TAR is a complex procedure. Patients requiring such repair tend to have substantial disease that often eventually necessitates subsequent downstream aortic repair, especially when dissection is present. Using the Thoraflex Hybrid device in TAR results in good early outcomes and provides a reliable base for extension
Gene Expression in Tumor and Adjacent Normal Tissues in Lung Adenocarcinoma Subtypes
No full textBackground: Lung adenocarcinoma (LUAD) has several histologically distinct subtypes that differ by a number of clinical features including patient survival. Molecular mechanisms underlying histological and clinical differences between subtypes remain poorly understood.
Methods: We conducted a comparative analyses of gene expression in acinar, lepidic, papillary and solid subtypes, as well as mucinous adenocarcinoma. We used a novel, more efficient approach to identify subtype-specific genes. We compared the mean gene expression level separately for tumors and adjacent normal tissue with pure or a highly represented (≥ 75%) subtype of interest to the mean expression in tumors where the subtype of interest was not present. We also performed tumor to adjacent normal tissue comparisons and identified genes differentially expressed between tumor and adjacent normal tissues for each subtype.
Results: The number of subtype-specific genes varied from 1 for the acinar to 482 for the papillary subtype. Comparative analysis of gene expression in adjacent normal tissues also identified subtype-specific genes, 38 in total. Gene set enrichment analysis identified oxidative phosphorylation as a biological function associated with papillary, and immune response - with solid subtype. Using data on differential expression between tumor and adjacent normal tissue among the subtype-specific genes and existing evidence for association with lung carcinogenesis, we have identified several candidate subtype-specific driver genes.
Conclusio: n We identified subtype-specific genes, biological functions, and potential drivers of subtype-specific carcinogenesis for LUAD subtypes. The study showed importance of gene expression in adjacent normal tissue for subtype-specific tumorigenesis
Targeted Analysis of Dyslexia-Associated Regions on Chromosomes 6, 12 and 15 in Large Multigenerational Cohorts
No full textDyslexia is a common learning impairment with a genetic basis that affects word reading and spelling. An increasing list of loci and genes have been implicated, but analyses to-date have investigated only limited genomic variation within each locus with no confirmed pathogenic variants identified. Our study is the first to comprehensively sequence both coding and cis-acting regulatory regions of such genes in a large study sample. In a collection of \u3e2000 participants in families from three independent sites, we performed targeted capture and comprehensive sequencing of all exons and some regulatory elements of five candidate risk genes (DNAAF4, CYP19A1, DCDC2, KIAA0319 and GRIN2B) for which prior evidence for a role in dyslexia exists from more than one sample. We evaluated evidence for association in each of six dyslexia-related quantitative phenotypes (traits) using both individual common single nucleotide polymorphisms and aggregated rare variants. We detected no promoter alterations and few deleterious variants in the coding exons, none of which showed evidence of association with any trait. Single variant and aggregate testing of DNAAF4 failed to detect significant evidence of association with any of the traits. The other four genes provided evidence of association with one or more traits. A common variant downstream of CYP19A1 showed significant evidence of association with multiple traits with or without verbal IQ (VIQ) adjustment. A haplotype that stretches from the downstream region of KIAA0319 to the second intron of DCDC2 was associated with reduced performance on timed real word reading. Finally, rare exonic variants in GRIN2B were associated with performance on spelling, with or without adjustment for VIQ. Our findings from this large-scale sequencing study complement those from genome-wide association studies, argue against the causative involvement of large-effect coding variants in these five candidate genes, support a multigenic etiology, and suggest a role of transcriptional regulation
GraphAge: Unleashing the Power of Graph Neural Network to Decode Epigenetic Aging
No full textDNA methylation is a crucial epigenetic marker used in various clocks to predict epigenetic age. However, many existing clocks fail to account for crucial information about CpG sites and their interrelationships, such as co-methylation patterns. We present a novel approach to represent methylation data as a graph, using methylation values and relevant information about CpG sites as nodes, and relationships like co-methylation, same gene, and same chromosome as edges. We then use a graph neural network (GNN) to predict age. Thus our model, GraphAge leverages both the structural and positional information for prediction as well as better interpretation. Although, we had to train in a constrained compute setting, GraphAge still showed competitive performance with a mean absolute error of 3.207 and a mean squared error of 25.277, substantially outperforming the existing models. Perhaps more importantly, we utilized GNN explainer for interpretation purposes and were able to unearth interesting insights (e.g. key CpG sites, pathways and their relationships through methylation regulated networks in the context of aging), which were not possible to decode without leveraging the unique capability of GraphAge to encode various structural relationships. GraphAge has the potential to consume and utilize all relevant information (if available) about an individual that relates to the complex process of aging. So, in that sense it is one of its kind and can be seen as the first benchmark for a multimodal model which can incorporate all these information in order to close the gap in our understanding of the true nature of aging
Deciphering the Mycn-Driven Metabolic Microenvironment of Neuroblastoma
No full textOncogenic MYCN drives aggressive disease in many cancers including neuroblastoma (NB). Metabolic reprogramming is essential to support cancer cell homeostasis and survival under nutrient- and oxygen-deprived conditions. MYCN directly reprograms many nodes of tumor-intrinsic metabolism, which have significant repercussions on the cells of the tumor microenvironment (TME), resulting in complex intercellular metabolic circuits that contribute to the immunosuppressive microenvironment of NB. These metabolic circuits are also regulated by the organismal and cellular circadian clock and host diet to further impact the TME and NB oncogenesis. This review discusses the mechanisms by which MYCN regulates the metabolic crosstalk between tumor, TME, and host, and provides evidence that therapeutic targeting of MYCN-reprogrammed metabolism can improve patient outcomes
Rare Epigenetic Alterations Are Conserved Across Hematopoietic Differentiation Stages After Mycobacterial Infection
No full textInfection leads to durable cell-autonomous changes in hematopoietic stem and progenitor cells (HSPCs), resulting in production of innate immune cells with heightened immunity. The mechanisms underlying this phenomenon, termed central trained immunity, remain poorly understood. We hypothesized that infection induces histone modifications leading to changes in chromatin accessibility that are conserved during differentiation from HSPCs to myeloid progenitors and monocytes. We conducted genome-wide surveillance of histone marks H3K27ac and H3K4me3 and chromatin accessibility in hematopoietic stem cells, multipotent progenitor 3, granulocyte-monocyte progenitors, monocytes and macrophages of naïve and Mycobacterium avium infected mice. Interferon signaling pathways and related transcription factor binding motifs including IRFs, NF-κB, and CEBP showed increased activating histone marks and chromatin accessibility across cell types. However, histone marks and increased chromatin accessibility were conserved at only a few loci, notably Irf1 and Gbp6. Knock out of IRF1 disrupted enhanced mitochondrial respiration and bacterial killing in human monocyte cell lines, while GBP6 KO monocyte cell lines showed dysregulated mitochondrial respiration. In summary, this study identifies IRF1 and GBP6 as two key loci at which infection-induced systemic inflammation leads to epigenetic changes that are conserved from HSPCs to downstream monocytes, providing a mechanistic avenue for central trained immunity
Destructive and Protective Effects and Therapeutic Targets of Il-36 Family Cytokines in Dry Eye Disease
No full textPurpose: To explore the destructive and protective effects and therapeutic targets of IL-36 cytokines in dry eye disease using a murine dry eye model.
Methods: A dry eye model was established in C57BL/6 mice exposed to desiccating stress (DS) with untreated mice as controls. A topical challenge model was performed in normal mice with exogenous rmIL-36α, rhIL-38 and 2 % ectoine, or PBS vehicle. IL-36 cytokine expression was assessed by RT-qPCR and immunofluorescent (IF) staining. Corneal epithelial damage was evaluated by corneal smoothness score, Oregon Green Dextran (OGD) fluorescent staining, and tight junction barrier.
Results: All members of the IL-36 family were expressed by murine ocular surface epithelium. The expression of IL-36α and IL-36γ was upregulated while IL-38 and IL-36RN were down regulated in ocular surface of dry eye mice. A topical challenge of rmIL-36α directly destructed corneal surface with distorted smoothness, increased OGD uptake and IF intensity, and disrupted tight junction proteins ZO-1 and occludin. Co-application with rhIL-38 prevented all these corneal damages by rmIL-36α. Ectoine treatment reversed the pathological expression pattern of IL-36 cytokines, protected corneal epithelium from defects, and restored the tight junction barrier in DS mice, and even prevented corneal damage by rmIL-36α.
Conclusions: Our findings demonstrate the upregulated pro-inflammatory agonists IL-36α and IL-36γ with downregulated antagonists IL-38 and IL-36RA in dry eye model, which provides a previously unknown mechanism and therapeutic targets in dry eye disease. The therapeutic efficacy of ectoine may be through reversing the pathological alteration of IL-36 cytokines in dry eye mice
The Influence of the American Association for Thoracic Surgery on Clinical Trial Development by Cardiothoracic Surgeons
No full textObjective: Clinical trials play a critical role in the rapidly evolving field of cardiothoracic surgery and the American Association for Thoracic Surgery Clinical Trials Methods Course has provided a biannual symposium led by preeminent surgeons with vast experience in planning, conducting, and analyzing surgical clinical trials. This study hypothesizes that participation in the course is associated with future success in clinical trial leadership.
Methods: A list of course attendees (2014-2022) was queried in ClinicalTrials.gov, a database of clinical trials funded by the US Department of Health and Human Services and the National Institutes of Health. The type of clinical trial and publications from the trial were collected. Demographic information about the participants was collected from faculty pages.
Results: A total of 107 participants from various professional backgrounds attended the American Association for Thoracic Surgery Clinical Trials Methods course and led 91 clinical trials. The average time to starting a clinical trial after attending the workshop was 3.04 years for participants who had not already been involved with a trial. Of the 107 participants, 36 (33.6%) were either the principal investigator or a subinvestigator for 91 clinical trials.
Conclusions: The American Association for Thoracic Surgery Clinical Trials Methods course provides participants the tools for successfully leading surgical clinical trials. Although participation has been limited, those who attend the course and lead a clinical trial do so within approximately 3 years. The Clinical Trials Methods Course provides an excellent return on investment and the American Association for Thoracic Surgery should continue sponsorship of this program because it supports the develop of future leaders in cardiothoracic surgery
Microbial Associations and Viruses on the Risk of Celiac Disease (MAVRiC): A Longitudinal Post-hoc Case-Cohort Study
No full textCeliac disease etiopathogenesis requires genetic predisposition and exposure to gluten, yet these factors alone are not sufficient. Larger longitudinal studies are needed to determine the role of time-varying infections and gut microorganisms. The aim was to design a celiac disease case-cohort longitudinal study using The Environmental Determinants of Diabetes in the Young (TEDDY) study. By age 3-years, persistent tissue transglutaminase autoantibodies (tTGA), i.e., celiac disease autoimmunity (CDA), was confirmed in 704 of the 6132 genetically at-risk TEDDY children. Celiac disease onset (CD-onset) was defined as the age CDA developed when followed by a biopsy-proven diagnosis. A competing risk analysis on CD-onset and CDA children with no diagnosis (CDA-only) revealed female-sex, HLA and non-HLA genes and higher gluten-consumption correlate with an increased risk of both outcomes. However, reports of virus-related respiratory infections from August to October correlate consistently with an increased risk of CD-onset and not CDA-only. A sub-cohort of 561 children (9% sampling fraction) has been randomly selected to represent the TEDDY cohort. All incident CD-onset cases (N = 306) were included. The case-cohort will be utilized to analyze virus antibodies and bacteriome from longitudinal plasma and stool samples (the Microbial Associations and Viruses on the Risk of Celiac disease study, MAVRiC)