Citations

Abstract We identified the lowest composition necessary to generate a vaccination adjuvant that promotes a Treg response following immunization in mice and named it “complete tolerogenic adjuvant.” This novel adjuvant may allow us to utilize the well-established “antigen plus adjuvant” method of vaccination to induce Treg cell-mediated antigen-specific immunosuppression. The minimal composition is dexamethasone, rapamycin, and monophosphoryl lipid A with the following mass ratios: 8:20:3. We have demonstrated why immunosuppressive and immunogenic substances are both required for the formation of genuine adjuvants for Treg cells by dissecting the roles of each of these components during vaccination. Currently, research is ongoing in our group to begin to assess the usefulness of this adjuvant for antigen immunization in murine models of human autoimmune/inflammatory diseases. Specifically, we are evaluating the tolerogenic efficacy of this adjuvant for vaccination regimen targeting the apolipoprotein B antigen, using the ApoE−/− mouse model of atherosclerosis. These studies are expected to help drive the development of further, perhaps more effective, complete tolerogenic adjuvants that could be used to create a plethora of new, novel vaccines for treating immunological illnesses. Master program and NIH grant

BACKGROUND: Common genetic variants are associated with risk for hypertrophic cardiomyopathy and dilated cardiomyopathy and with left ventricular (LV) traits. Whether these variants are associated with myocardial fibrosis, an important pathophysiological mediator of cardiomyopathy, is unknown. METHODS: Multi-Ethnic Study of Atherosclerosis participants with T1-mapping cardiac magnetic resonance imaging in-whom extracellular volume was assessed, and genotyping information was available were included (N=1255). Log extracellular volume (%) was regressed on 50 candidate single nucleotide polymorphisms (previously identified to be associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and LV traits) adjusting for age, sex, diabetes, blood pressure, and principal components of ancestry. Ancestry-specific results were pooled by fixed-effect meta-analyses. Gene knockdown experiments were performed in human cardiac fibroblasts. RESULTS: The SMARCB1 rs2186370 intronic variant (minor allele frequency: 0.18 in White and 0.50 in Black participants), previously identified as a risk variant for dilated cardiomyopathy and hypertrophic cardiomyopathy, was significantly associated with increased extracellular volume ( P= 0.0002) after adjusting for confounding clinical variables. The SMARCB1 rs2070458 locus previously associated with increased LV wall thickness and mass was similarly significantly associated with increased extracellular volume ( P= 0.0002). The direction of effect was similar in all 4 ancestry groups, but the effect was strongest in Black participants. The variants are strong expression quantitative loci in human LV tissue and associated with genotype-dependent decreased expression of SMARCB1 ( P= 7.3×10 -22 ). SMARCB1 knockdown in human cardiac fibroblasts resulted in increased TGF (transforming growth factor)-β1–mediated α-smooth muscle actin and collagen expression. CONCLUSIONS: Common genetic variation in SMARCB1 previously associated with risk for cardiomyopathies and increased LV wall thickness is associated with increased cardiac magnetic resonance imaging–based myocardial fibrosis and increased TGF-β1 mediated myocardial fibrosis in vitro. Whether these findings suggest a pathophysiologic link between myocardial fibrosis and cardiomyopathy risk remains to be proven.

AbstractBackgroundReal‐world clinical data on the adverse events related to the use of cryoballoon catheter for pulmonary vein isolation remains limited.ObjectiveTo report and describe the adverse events related to the use of Artic Front cryoballoon catheters (Arctic Front, Arctic Front Advance, and Arctic Front Advance Pro) reported in the Food and Drug Administration's (FDA) Manufacturers and User Defined Experience (MAUDE) database.MethodsWe reviewed all the adverse events reported to the FDA MAUDE database over a 10.7‐year study period from January 01, 2011 to September 31, 2021. All events were independently reviewed by two physicians.ResultsDuring the study period, a total of 320 procedural‐related adverse events reported in the MAUDE database were identified. The most common adverse event was transient or persistent phrenic nerve palsy (PNP), accounting for 48% of all events. This was followed by cardiac perforation (15%), pulmonary vein stenosis (8%), transient ischemic attack or stroke (6%), vascular injury (4%), transient or persistent ST‐elevation myocardial infarction (3%), hemoptysis (2%), pericarditis (2%), and esophageal ulcer or fistula (1%). There were six reported intra‐procedural death events as a result of cardiac perforation.ConclusionThe two most common procedural adverse events associated with cryoballoon ablation were PNP and cardiac perforation. All cases of procedural mortality were due to cardiac perforation.

AbstractBackgroundEvidence on the impact of obesity on catheter ablation for ventricular tachycardia (VT) is scarce.Method and ResultsWe queried the Nationwide Readmissions Database to determine the hospital outcomes and procedural complications of VT ablation among the obese and nonobese populations. Obesity was associated with a more prolonged length of stay (p < .01), higher cost of hospitalization (p < .01), and higher rates of pericardial effusion or hemopericardium (p = .05) and vascular complications (p = .05). There was no significant difference in early mortality, 30‐day readmissions, and other procedural complications.ConclusionVT ablation could be performed relatively safely among patients with obesity.

AbstractObjectivesAlthough hemispheric surgeries are among the most effective procedures for drug‐resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1‐, 2‐, and 5‐years post‐hemispherectomy.MethodsRetrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time‐to‐seizure recurrence. A multivariate Cox proportional‐hazards regression model was developed to predict the likelihood of post‐hemispheric surgery seizure freedom at three time points (1‐, 2‐ and 5‐ years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops‐calculator.com/).ResultsThe selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non‐hemispheric resective surgery, and contralateral fluorodeoxyglucose–positron emission tomography [FDG‐PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time‐to‐seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG‐PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non‐lesional MRI, non‐stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%.SignificanceOnline calculators are useful, cost‐free tools that can assist physicians in risk estimation and inform joint decision‐making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Abstract Background: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. Methods: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. Results: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88–1.22; MR-Egger OR, 0.89; 95% CI, 0.65–1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90–1.27; MR-Egger OR, 0.93; 95% CI, 0.67–1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. Conclusions: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. Impact: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.

AbstractBackgroundWomen have higher rates of hypertension at the time of menopausal transition than men. Although elevated systolic and diastolic blood pressures (SBP and DBP) are risk factors for white matter (WM) injury both in women and men, WM hyperintensities (WMH), a marker of WM injury, are more common in women than in men after the age of 60. Thus, women may be vulnerable to the effects of elevated BP on WM integrity during menopausal transition. We investigated the association of BP in recently postmenopausal women with good cardiovascular health with WMH volume assessed 13 years later.MethodWomen (n = 212; median age = 67; range 58‐72), who were previously enrolled in a multi‐site randomized menopausal hormone therapy trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59). Participants who were on antihypertensive medications at KEEPS baseline were excluded from the analysis (n = 34). Approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions, WM integrity was assessed with automated WMH volume measurements from 3D‐FLAIR MRI. Associations of baseline SBP and DBP with logWMH volume measured 13 years later were tested by linear regression analyses. Model 1 was adjusted for age, study site, and total intracranial volume. Model 2 was adjusted for covariates of model 1, triglycerides, low density lipoproteins, and waist/hip ratio.ResultThe median SBP was 116 (range 83‐158) and DBP was 74 (range 56‐98). Higher SBP was associated with greater WMH volume (model 1:p = 0.005; model 2:p = 0.005). Similarly, higher DBP was associated with greater WMH volume (model 1:p = 0.008; model 2:p = 0.006) (Figure 1). Neither menopausal hormone therapies versus placebo, nor having high/low SBP (≥120/<120) modified these associations. Voxel‐based analyses demonstrate the association of BPs with the spatial distribution of WMHs (Figure 2).ConclusionHigher BPs in recently menopausal women were associated with greater WM injury more than a decade later after adjusting for CVD risk factors. Early postmenopausal stage is a critical time for BP control in women, which may reduce the risk of WM injury later in life.

Background: Long-term outcomes of lead management strategies of lead abandonment (LA) or transvenous lead extraction (TLE) during cardiac implantable electronic devices (CIED) procedures requiring lead addition or replacement remain unclear. Hypothesis: We hypothesized that there is no difference in long-term (10-year) outcomes of LA versus TLE during CIED procedures requiring lead addition. Methods: We performed a retrospective cohort study of a population residing in seven adjacent counties of southeastern Minnesota with follow-up at the Mayo Clinic and its health systems. Patients who underwent LA or TLE for sterile leads from January 1, 2000, to January 1, 2011, and had follow-up for at least 10-years or until their death were included. Outcomes were identified through a detailed chart review of the electronic health record from within the Mayo Clinic system. Results: A total of 172 patients were included in the study with 153 patients who underwent LA and 19 who underwent TLE for sterile leads. In long-term follow-up, indications for subsequent lead extraction arose in 9.1% (n=14) of patients with initial LA and 5.3% (n=1) in patients with initial TLE, after an average of 7-years. Moreover, out of 14 patients, who required secondary extraction in the LA cohort, 28.6% did not proceed with the extraction. Of the remaining 10 patients, 60% had clinical success and 40% had a clinical failure with the extraction. Subsequent device upgrades or revisions were performed in 18.3% of patients in the LA group and 31.6% in the TLE group, with no significant differences in procedural challenges such as requiring balloon venoplasty or serial dilation (5.2% vs. 5.3%, P=1.0). There was no difference in 10-year survival probability among LA group and TLE group (P=0.64). Conclusion: Indications for subsequent extraction arose in 9.1% of patients with the initial LA approach for sterile leads after an average of 7.3 years and 28.6% did not proceed with the extraction. Of the patients who underwent the subsequent extraction, 60% had clinical success and 40% had a clinical failure. There was no difference in 10-year survival probability between patients with the initial LA approach or TLE approach.