Citations

Abstract Background Intracranial aneurysm (IA) has been associated with bicuspid aortic valve (BAV) with prevalence of 6–10% which has led some to recommend routine surveillance for IA in BAV patients. Higher incidence of IA in BAV could signal towards systemic arteriopathy beyond the thoracic aorta. With CoA as an independent risk factor for IA formation, it is currently uncertain if the association between IA and BAV reflects the association of BAV and CoA, or the result of BAV-related systemic arterial changes. Purpose Despite this association, 2 small studies suggest no increased risk of the most important patient outcome: aneurysmal sub-arachnoid hemorrhage (aSAH). Our primary aim was identifying the prevalence of BAV in aSAH patients and compare it with that of a control group without aSAH. Secondary aims included neurologic outcomes of aSAH and anatomical characteristics of IA in BAV, and final disposition and outcome. Methods Patients (>18 years age) with an accurate diagnosis of aSAH and at least one echocardiogram in the system between January 2000-December 2019 were identified from a prospectively maintained registry of aSAH admissions. Controls, without a diagnosis of SAH ever, were age- and gender-matched (1:2 cases:controls). BAV prevalence was echocardiographically-confirmed in all patients. Severity of aSAH was categorized using the modified Fisher (mFisher) and the World Federation of Neurological Scale (WFNS). Results A total of 488 aSAH cases and 990 controls were included in the final analysis with confirmed aortic valve status. The prevalence of BAV in aSAH patients was 1.2% (6/488) vs 3.5% (35/990) in controls, p=0.01. None of the aSAH cases were noted to have CoA, whereas 3 (0.3%; p=0.12) control patients had presence of both BAV and CoA. Within aSAH patients, BAV+aSAH were noted to be younger than tricuspid aortic valve (TAV)+aSAH (56±11 vs 68±14; p=0.03). Aneurysm size was smaller in the BAV+aSAH group (5±2 vs 7±4 in TAV+aSAH; p=0.31). The severity of the bleed was lesser in BAV+aSAH than TAV+aSAH (mFisher grade >2 50% vs 74%; p=0.19, WFNS grade >3 17% vs 36%; p=0.43) which is clinically significant. The BAV+aSAH group had higher disposition rate to home (67% vs 39%; p=0.21) with no difference in in-hospital mortality rates (17% vs 18%; p=0.93). BAV had lower odds on univariate and multivariate analyses adjusted for age/sex/body mass index (OR 0.33 [CI 0.14–0.81]; p=0.01, OR 0.23 [CI 0.08–0.65]; p=0.01) of presenting with aSAH. Conclusion Within a large prospective registry with accurate aSAH diagnoses, we found 3-times lower prevalence of echocardiographically-confirmed BAV as compared to non-aSAH controls. We observed 3-times higher prevalence of BAV in controls than among aSAH cases. In addition, size of intracranial aneurysms was clinically smaller in BAV patients, and the severity of SAH was significantly lesser in BAV from a clinical standpoint. Our findings argue against routine surveillance for IA in BAV patients without CoA. Funding Acknowledgement Type of funding sources: None.

Abstract Background Wild type transthyretin cardiac amyloidosis (wtATTR-CA) is increasingly recognized as a cause of heart failure with preserved ejection fraction (HFpEF) but prognosis is often limited due to late or misdiagnosis.Longitudinal left ventricular strain and biomarkers are established as markers of disease severity, but the role of RV free wall strain, reflecting RV contractility, is less well understood. Purpose We sought to determine whether RV free wall strain might add incremental prognostic value in wtATTR-CA. Methods Consecutive patients diagnosed with wtATTR-CA with tissue confirmation at Mayo clinic between 2013 and 2015 were included. Patients with TTR gene mutations were excluded. Baseline characteristics and transthoracic echocardiography measurements were obtained from the medical records. Speckle tracking RV free wall longitudinal 2D strain and peak LA longitudinal 2D strain were measured using Tom Tec Imaging System. Survival was determined using Kaplan Meier estimates and using the cox proportional hazard ratio, univariate and multivariable analysis were performed to identify predictors of mortality in patients with wtATTR. Results The study group comprised 139 patients (mean age 74.9±8.6, 92.8% male), of which 102 had adequate image quality for RV strain, and 99 for LA strain. Amongst these, 102 (73.3%) had AF and 118 patients (84.8%) had HF. During 3.23±2.0 years of follow up, 66 patients died. Both mean RV and LA strain were impaired at baseline: RV free wall strain was −14.7±4.9, and peak atrial longitudinal strain (PALS) was 13.2±8.8%. Using ROC analysis, RV strain of −16.8% was an independent predictor of all-cause mortality. In univariate modeling, higher levels of NT-proBNP (HR: 1.1 per 1000 pg.ml; 95%, CI 1.05–1.15, p<0.001) and Troponin T (HR: 2.0 per 0.1ng/ml; 95% CI 1.49–2.61, p<0.001) were associated with increased all-cause mortality. In addition, LV GLS (HR: 1.13 per 1%; 95% CI1.04–1.24, p=0.003), RV free wall LS (HR: 2.16 per 5%; 95%, CI 1.57–3.03, p<0.0001), and PALS (HR: 0.91 per1%; 95% CI 0.85–0.96, p<0.0001) were univariate predictors of all-cause mortality. In multivariate analysis using a stepwise regression model, RV free wall longitudinal strain (HR: 1.81; 95% CI 1.29–2.62, p<0.001) and Troponin T (HR: 1.7; 95% CI 1.25–2.26, p=0.001) remained independent predictors. Kaplan-Meier survival analysis demonstrated a higher mortality rate above −16.8 RV strain cut-off (Wilcoxon <0.0001). All stages were divided into two groups by −16.8% RV strain, and survival in individual stages analyzed. Stage 1 and 2 with <−16.8 RV free wall strain value had higher mortality than ≤-16.8% RV strain (Stage 1: Wilcoxon = 0.0041 and Stage 2: Wilcoxon = 0.023). However, there was not a survival difference between two RV strain groups in stage3 (Wilcoxon = 0.34) Conclusion RV free wall strain is an independent predictor of survival in wtATTR patients and may add incremental prognostic value to NT-proBNP and Troponin. Funding Acknowledgement Type of funding sources: None. Kaplan-Meier curve of all patientsKaplan-Meier curve of stages

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Background: Rigorous study of ventricular fibrillation (VF) is not feasible in humans. The spatiotemporal characteristics of prolonged VF remain undefined, limiting our understanding of this lethal rhythm. Methods: VF was mapped in 4 canines. The endocardial and epicardial left ventricle (LV) and right ventricle (RV) were sequentially mapped at 0 to 15, 15 to 30, 30 to 45, and 45 to 60 minutes post-induction. Ten consecutive beats were used to determine the average cycle length and regularity index of ventricular and His-Purkinje system signals in discrete regions during each time interval. Results: Average VF time was 58±12 minutes. The shortest ventricular cycle length was present in the RV apical region (70±10 msec) at 0 to 15 minutes and at 15 to 30 minutes (89±31 msec) and LV apical region at 45 to 60 minutes (242±163 msec). The His-Purkinje system cycle length was the shortest at the RV outflow tract (75±3 msec) at 0 to 15 minutes, RV inflow and free wall (89±12 msec) at 15 to 30 minutes, LV apical region (83±14 msec) at 30 to 45 minutes, and inferior and inferolateral LV (145±23 msec) at 45 to 60 minutes. Regularity index was the highest in the RV inflow and free wall (78%) at 0 to 15 minutes, RV apical region (86%) at 15 to 30 minutes, LV septum and epicardial anterior RV (80%) at 30 to 45 minutes, and anterior and anterolateral LV (75%) at 45 to 60 minutes. Conclusions: These data suggest significant regional changes in electrical activity throughout VF in canines. A transition of fastest electrical activity from RV to LV apical regions across VF was observed. These novel insights of the temporal and spatial changes of VF merit further evaluation in diseased hearts to assess for reproducibility of findings.

Abstract Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.

Abstract We studied the performance of an algorithm combining multiplex polymerase chain reaction with phenotypic detection of extended-spectrum β-lactamases and carbapenemases directly from positive blood culture bottles in patients with gram-negative bacteremia and found good concordance with routine cultures. Such an algorithm may be a tool to improve time to optimal therapy in patients with gram-negative bacteremia.

AbstractBackgroundRecent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.Methods483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.ResultsPRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.ConclusionsPopulation-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

Targeting the main protease of SARS-CoV-2 Inside host cells, the RNA genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is translated into two polyproteins that are cleaved to give the individual viral proteins. The main viral protease, known as Mpro or 3CLpro, plays a key role in these cleavages, making it an important drug target. Drayman et al . identified eight drugs that target 3CLpro from a library of 1900 clinically safe drugs. Because of the challenge of working with SARS-CoV-2, they started by screening for drugs that inhibit the replication of a human coronavirus that causes the common cold. They then evaluated the top hits for inhibiting SARS-CoV-2 replication and for inhibiting 3CLpro. Masitinib, a broad antiviral, inhibited the main proteases of coronaviruses and picornaviruses and was effective in reducing SARS-CoV-2 replication in mice. —VV