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PurposeThis study aimed to develop novel non-contrast MR perfusion techniques for assessing micro-vascularity of the foot in human subjects.MethodsAll experiments were performed on a clinical 3 T scanner using arterial spin labeling (ASL). Seven healthy subjects (30-72 years old, 5 males and 2 females) were enrolled and bilateral feet were imaged with tag-on and tag-off alternating inversion recovery spin labeling for determining micro-vascularity. We compared an ASL technique with 1-tag against 4-tag pulses. For perfusion, we determined signal increase ratio (SIR) at varying inversion times (TI) from 0.5 to 2 s. SIR versus TI data were fit to determine perfusion metrics of peak height (PH), time to peak (TTP), full width at half maximum (FWHM), area under the curve (AUC), and apparent blood flow (aBF) in the distal foot and individual toes. Using analysis of variance (ANOVA), effects of tag pulse and region of interest (ROI) on the mean perfusion metrics were assessed. In addition, a 4-tag pulse perfusion experiment was performed on patients with peripheral artery disease (PAD) and Raynaud's disease.ResultsUsing our MR perfusion techniques, SIR versus TI data showed well-defined leading and trailing edges, with a peak near TI of 0.75-1.0 s and subsiding quickly to near zero by TI of 2 s, particularly when 4-tag pulses were used. When imaged with 4-tag pulse, we found significantly greater values in perfusion metrics, as compared to 1-tag pulse. The patients with PAD and Raynaud's disease showed a reduced or scattered perfusion curves compared to the healthy control.ConclusionMR perfusion imaging of the distal foot shows greater SIR and perfusion metrics with the 4-tag pulse compared to the 1-tag pulse technique. This will likely benefit those with low perfusion due to aging, PAD, diabetic foot, and other vascular diseases.

BackgroundThe endovascular repair of infrarenal abdominal aortic aneurysms (AAA) can be performed with a wide variety of devices. Many of these grafts elevate the aortic bifurcation which can limit future repairs if the graft material fails thereby creating a type III endoleak to aorto-uniliac (AUI) grafts. Many manufacturers have grafts susceptible to this, but we have seen this in the Medtronic AneuRx graft. Our goal is to provide technical details and outcomes regarding a novel technique to re-line these grafts while maintaining inline flow to the iliac arteries.MethodsThis was a single institution review of patients who had endoleaks requiring intervention after a previously placed graft with an elevated aortic bifurcation. Primary outcomes included technical success defined as placement of all planned devices, resolution of type III endoleak, aneurysm size at follow-up, and requirement of reintervention. Secondary outcomes included 30-day complications, aneurysm-related mortality (ARM), and all-cause mortality (ACM). Technical details of the operation include back table deployment of an Ovation device, modification of the deployment system tether and preemptive placement of an up and over 0.014" wire. The wire is placed up and over and hung outside the contralateral gate. Once the main body is introduced above the old graft, the 0.014" is snared from the contralateral side and externalized. The main body is then able to be seated at the bifurcation as the limb is not fully deployed and then device deployment is completed per IFU.ResultsOur study consists of four individuals, three of which had an AAA initially managed with an AneuRx EVAR and one with a combination of Gore and Cook grafts. All four patients were male with an average age of 84.5 years at time of re-line. All patients had at least 10 years between initial surgery and re-line at our institution. Primary outcomes revealed no type 1 or 3 endoleaks at follow-up, technical success was 100% and one patient required reintervention for aneurysm growth and type 2 endoleak. In terms of our secondary outcomes, there was one postoperative complication which was cardiac dysfunction secondary to demand ischemia, ARM was 0% and ACM was 25% at average follow up of 2.44 years.ConclusionAs individuals continue to age, there are more patients who would benefit from less invasive reinterventions following EVAR. Whether this is due to aortic degeneration, stent migration, or stent material damage is not always known. In this study we present an endovascular approach to treating type III endoleak patients with a previous graft and elevated aortic bifurcation using Ovation stent grafts and found no evidence of type 1 or 3 endoleaks on follow-up imaging. This approach may allow patients with type III endoleak the option of a minimally invasive, percutaneous approach where they previously would not have had one.

ObjectivePhysician modified endografts (PMEG) and custom manufactured devices (CMD) use branched and fenestrated techniques (F/BEVAR) to repair complex aneurysms. Traditionally many of these are deployed through a combination of upper and lower extremity access. However, with newer steerable sheaths, you can now simulate upper extremity access from a transfemoral approach. Single institution studies have demonstrated increased risks of access site complications and stroke when upper extremity access is used. This study compares outcomes after F/BEVAR in a national database between total transfemoral (TTF) access and mixed upper extremity (UEM) access.MethodsThis study is an analysis of the Vascular Quality Initiate for all patients who underwent F/BEVAR from 2014-2021. Patients were stratified based on a TTF delivery of all devices versus any UEM access for deployment of target vessel stents. Primary outcomes included stroke, myocardial infarction and perioperative death. Secondary outcomes included access site hematoma, occlusion, or embolization, operative time, fluoroscopy time, and technical success. Multivariable linear and logistic regression analyses were performed.Results3146 patients underwent a F/BEVAR; 2309 (73.4%) TTF and 837 (26.6%) UEM. Logistic regression analysis indicated a two-fold increased risk of death and MI and a three-fold increased risk of stroke in the UEM group. Furthermore, there is decreased operative time (221 versus 297 minutes, p

ObjectiveThe introduction of endovascular procedures has revolutionized the management of complex aortic aneurysms. Although repair has traditionally required longer operative times and increased radiation exposure compared with simple endovascular aneurysm repair, the recent introduction of three-dimensional technology has become an invaluable operative adjunct. Surgical augmented intelligence (AI) is a rapidly evolving tool initiated at our institution in June 2019. In our study, we sought to determine whether this technology improved patient and operator safety.MethodsA retrospective review of patients who had undergone endovascular repair of complex aortic aneurysms (pararenal, juxtarenal, or thoracoabdominal), type B dissection, or infrarenal (endoleak, coil placement, or renal angiography with or without intervention) at a tertiary care center from August 2015 to November 2021 was performed. Patients were stratified according to the findings from intelligent maps, which are patient-specific AI tools used in the operating room in conjunction with real-time fluoroscopic images. The primary outcomes included operative time, radiation exposure, fluoroscopy time, and contrast use. The secondary outcomes included 30-day postoperative complications and long-term follow-up. Linear regression models were used to evaluate the association between AI use and the main outcomes.ResultsDuring the 6-year period, 116 patients were included in the present study, with no significant differences in the baseline characteristics. Of the 116 patients, 76 (65.5%) had undergone procedures using AI and 40 (34.5%) had undergone procedures without AI software. The intraoperative outcomes revealed a significant decrease in radiation exposure (AI group, 1955 mGy; vs non-AI group, 3755 mGy; P = .004), a significant decrease in the fluoroscopy time (AI group, 55.6 minutes; vs non-AI group, 86.9 minutes; P = .007), a decrease in the operative time (AI group, 255 minutes; vs non-AI group, 284 minutes; P = .294), and a significant decrease in contrast use (AI group, 123 mL; vs non-AI group, 199 mL; P

Introduction: Rotator cuff tears are prevalent in the population above the age of 60. The disease progression leads to muscle atrophy, fibrosis, and fatty infiltration, which is not improved upon with surgical repair, highlighting the need to better understand the underlying biology impairing more favorable outcomes. Methods: In this study, we collected supraspinatus muscle tissue from 6 month old female rabbits who had undergone unilateral tenotomy for 8 weeks at 1, 2, 4, or 8 weeks post-repair (n = 4/group). RNA sequencing and enrichment analyses were performed to identify a transcriptional timeline of rotator cuff muscle adaptations and related morphological sequelae. Results: There were differentially expressed (DE) genes at 1 (819 up/210 down), 2 (776/120), and 4 (63/27) weeks post-repair, with none at 8 week post-repair. Of the time points with DE genes, there were 1092 unique DE genes and 442 shared genes, highlighting that there are changing processes in the muscle at each time point. Broadly, 1-week post-repair differentially expressed genes were significantly enriched in pathways of metabolism and energetic activity, binding, and regulation. Many were also significantly enriched at 2 weeks, with the addition of NIF/NF-kappaB signaling, transcription in response to hypoxia, and mRNA stability alongside many additional pathways. There was also a shift in transcriptional activity at 4 weeks post-repair with significantly enriched pathways for lipids, hormones, apoptosis, and cytokine activity, despite an overall decrease in the number of differentially expressed genes. At 8 weeks post-repair there were no DE genes when compared to control. These transcriptional profiles were correlated with the histological findings of increased fat, degeneration, and fibrosis. Specifically, correlated gene sets were enriched for fatty acid metabolism, TGF-B-related, and other pathways. Discussion: This study identifies the timeline of transcriptional changes in muscle after RC repair, which by itself, does not induce a growth/regenerative response as desired. Instead, it is predominately related to metabolism/energetics changes at 1 week post-repair, unclear or asynchronous transcriptional diversity at 2 weeks post-repair, increased adipogenesis at 4 weeks post-repair, and a low transcriptional steady state or a dysregulated stress response at 8 weeks post-repair.

BACKGROUND: Aortic aneurysms are normally treated by an endovascular approach. Due to the lack of devices and increasing experience, there is a growing number of complex aneurysms undergoing repair by physician modified endografts (PMEGs). Previously, our practice was to target visceral vessels exclusively through upper extremity access. We have since then shifted to an all transfemoral approach when possible. This study aims to show the operative benefits of transfemoral only approaches. METHODS: Patients who underwent a PMEG at a tertiary center between 2015 and 2020 were included. Patients were stratified into 2 groups based on branched vessel approach-transfemoral only versus axillary or composite (axillary and femoral). Forty-one patients had a pararenal or type IV thoracoabdominal aortic aneurysm (TAAA) and 15 patients had more complex TAAA. Primary outcomes were operative time, radiation exposure, fluoroscopy time, contrast, and blood loss. Secondary outcomes were 30-day mortality and major adverse events. Linear regression models were used to evaluate the association between approach type and the main outcomes. RESULTS: Fifty-six patients were included with 48% (n = 27) in the transfemoral group and 52% (n = 29) in the axillary/composite group. Baseline characteristics were similar between the groups. Intraoperative outcomes revealed significant increase in the average operative time (418 vs. 246 min, P

Based extensive fieldwork and interviews, this study explains teacher evaluation policy enactment as shaped by three conditions: (1) a principal's backgrounds, role perceptions, knowledge of instruction, and interactions with teachers; (2) teachers' perspectives; and (3) environmental demands. Notably, principals may lack the backgrounds, knowledge of teaching, role perceptions, and established interactional routines to engage teachers about their instruction in evaluative contexts. Furthermore, the teachers' press to earn high evaluation scores may inhibit instructional leadership, as teachers become focused on the accountability aspects of evaluation rather than on the affordances of evaluation reforms to help them improve.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

BackgroundMechanistic studies suggest that mitochondria DNA (mtDNA) dysfunction may be associated with increased risk of atrial fibrillation (AF). The association between mtDNA copy number (mtDNA-CN) and incident AF in the general population, however, remains unknown.MethodsWe conducted prospective analyses of 19,709 participants from the Atherosclerosis Risk in Communities Study (ARIC), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Cardiovascular Health Study (CHS). mtDNA-CN from the peripheral blood was calculated from probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms (SNP) Array 6.0 in ARIC and MESA and from multiplexed real-time quantitative polymerase chain reaction (qPCR) in CHS. Incident AF cases were identified through electrocardiograms, review of hospital discharge codes, Medicare claims, and death certificates.ResultsThe median follow-up time was 21.4 years in ARIC, 12.9 years in MESA, and 11.0 years in CHS, during which 4021 participants developed incident atrial fibrillation (1761 in ARIC, 790 in MESA, and 1470 in CHS). In fully adjusted models, participants with the lowest quintile of mitochondria DNA copy number had an overall 13% increased risk (95% CI 1 to 27%) of incident atrial fibrillation compared to those with the highest quintile. Dose-response spline analysis also showed an inverse association between mitochondria DNA copy number and hazard for atrial fibrillation for all three cohorts. These associations were consistent across subgroups.ConclusionsMitochondria DNA copy number was inversely associated with the risk of AF independent of traditional cardiovascular risk factors. These findings implicate mitochondria DNA copy number as a novel risk factor for atrial fibrillation. Further research is warranted to understand the underlying mechanisms and to evaluate the role of mitochondria DNA copy number in the management of atrial fibrillation risk.

BackgroundEndovascular aneurysm repair (EVAR) is the dominant treatment modality for abdominal aortic aneurysm (AAA). Periprocedural risks are low, and cardiovascular events are the principle determinants of long-term survival. Recently, the concept of endovascular aneurysm sealing (EVAS) has been introduced into clinical investigation. In previous cohort studies, EVAS has been associated with a lower all-cause mortality than expected despite device issues. We used a propensity weighted approach to investigate whether EVAS was associated with lower all-cause mortality after aneurysm repair.MethodsWe compared 333 patients in the Nellix United States Investigational Device Exemption trial to 15,431 controls from the Vascular Quality Initiative between 2014 and 2016 after applying the exclusion criteria from the investigational device exemption (hemodialysis, creatinine > 2.0 mg/dL, or rupture). We calculated propensity scores and applied inverse probability weighting to compare risk adjusted medium-term survival using Kaplan-Meier and Cox regression.ResultsAfter weighting, patients treated with the Nellix EVAS system experienced higher 3-year survival than controls from the Vascular Quality Initiative (93% vs. 88%, respectively). This corresponded to a 41% lower risk of mortality for EVAS compared with EVAR (HR 0.59 [0.38-0.92], P = 0.02). Subgroup analysis demonstrated that the association between EVAS and higher survival was strongest in the subgroup of patients with aneurysms over 5.5 cm (P for interaction

Mitochondrial DNA copy number (mtDNA-CN), a measure of the number of mitochondrial genomes per cell, is a minimally invasive proxy measure for mitochondrial function and has been associated with several aging-related diseases. Although quantitative real-time PCR (qPCR) is the current gold standard method for measuring mtDNA-CN, mtDNA-CN can also be measured from genotyping microarray probe intensities and DNA sequencing read counts. To conduct a comprehensive examination on the performance of these methods, we use known mtDNA-CN correlates (age, sex, white blood cell count, Duffy locus genotype, incident cardiovascular disease) to evaluate mtDNA-CN calculated from qPCR, two microarray platforms, as well as whole genome (WGS) and whole exome sequence (WES) data across 1,085 participants from the Atherosclerosis Risk in Communities (ARIC) study and 3,489 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). We observe mtDNA-CN derived from WGS data is significantly more associated with known correlates compared to all other methods (p < 0.001). Additionally, mtDNA-CN measured from WGS is on average more significantly associated with traits by 5.6 orders of magnitude and has effect size estimates 5.8 times more extreme than the current gold standard of qPCR. We further investigated the role of DNA extraction method on mtDNA-CN estimate reproducibility and found mtDNA-CN estimated from cell lysate is significantly less variable than traditional phenol-chloroform-isoamyl alcohol (p = 5.44x10-4) and silica-based column selection (p = 2.82x10-7). In conclusion, we recommend the field moves towards more accurate methods for mtDNA-CN, as well as re-analyze trait associations as more WGS data becomes available from larger initiatives such as TOPMed.

Context: The DICER1 syndrome is a multiple neoplasia disorder caused by germline mutations in the DICER1 gene. In DICER1 patients, aggressive congenital pituitary tumors lead to neonatal Cushings disease (CD). The role of DICER1 in other corticotropinomas, however, remains unknown. Objective: To perform a comprehensive screening for DICER1 variants in a large cohort of CD patients, and to analyze their possible contribution to the phenotype. Design, setting, patients, and interventions: We included 192 CD cases: ten young-onset (age