Citations

AbstractBackgroundLeft atrial (LA) appendage closure (LAAC) is effective in patients with atrial fibrillation who are not candidates for long‐term anticoagulation. However, the impact of LAAC on LA function is unknown. The aim of this study is to evaluate the impact of LAAC on atrial function.MethodsThis meta‐analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. A search strategy was designed to utilize PubMed/Medline, EMBASE, and Google scholar for studies showing the effect of LAAC on the LA function from inception to November 20, 2021. The standardized mean difference (SMD) was calculated from the means and standard deviations.ResultsOf 247 studies initially identified, 8 studies comprising 260 patients were included in the final analysis. There was a significant increase in LA emptying fraction following LAAC compared with preoperative function (SMD: 0.53; 95% confidence interval [CI]: 0.04–1.01; p = .03; I2 = 75%). In contrast, there were no significant differences in LA volume (SMD: −0.07; 95% CI: −0.82–0.69; p = .86; I2 = 92%) peak atrial longitudinal strain (SMD: 0.50; 95% CI: −0.08–1.08; p = .09; I2 = 89%), peak atrial contraction strain (SMD: 0.38; 95% CI: −0.22–0.99; p = .21; I2 = 81%), strain during atrial contraction (SMD: −0.24; 95% CI: −0.61–0.13; p = .20; I2 = 0%), strain during ventricular systole (SMD: 0.47; 95% CI: −0.32–1.27; p = .24; I2 = 89%), strain during ventricular diastole (SMD: 0.09; 95% CI: −0.32–0.51; p = .66; I2 = 65%).ConclusionLAAC is associated with improvement in the left atrial emptying fraction, but did not significantly influence other parameters.

Background: A composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data. Methods: We assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low–glucose and low-glucose hypoglycemia; very high–glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation. Results: The analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals. Conclusion: The GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments.

Open reading frame 8 (ORF8) shows one of the highest levels of variability among accessory proteins in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19). It was previously reported that the ORF8 protein inhibits the presentation of viral antigens by the major histocompatibility complex class I (MHC-I), which interacts with host factors involved in pulmonary inflammation. The ORF8 protein assists SARS-CoV-2 in evading immunity and plays a role in SARS-CoV-2 replication. Among many contributing mutations, Q27STOP, a mutation in the ORF8 protein, defines the B.1.1.7 lineage of SARS-CoV-2, engendering the second wave of COVID-19. In the present study, 47 unique truncated ORF8 proteins (T-ORF8) with the Q27STOP mutations were identified among 49,055 available B.1.1.7 SARS-CoV-2 sequences. The results show that only one of the 47 T-ORF8 variants spread to over 57 geo-locations in North America, and other continents, which include Africa, Asia, Europe and South America. Based on various quantitative features, such as amino acid homology, polar/non-polar sequence homology, Shannon entropy conservation, and other physicochemical properties of all specific 47 T-ORF8 protein variants, nine possible T-ORF8 unique variants were defined. The question as to whether T-ORF8 variants function similarly to the wild type ORF8 is yet to be investigated. A positive response to the question could exacerbate future COVID-19 waves, necessitating severe containment measures.

Introduction: Increasing stenosis has been questioned as a factor increasing risk of carotid endarterectomy (CEA) or carotid stenting (CAS) in patients with severe asymptomatic carotid stenosis. Hypothesis: Greater severity of carotid stenosis is associated with higher rates of periprocedural stroke and death following revascularization for asymptomatic patients. Methods: Asymptomatic patients with carotid stenosis ≥ 70% by ultrasound or ≥ 60% by angiogram were eligible for the Carotid Revascularization Endarterectomy vs Stenting Trial (CREST). Patients who had a catheter-angiogram were divided into tertiles based on the degree of stenosis. Outcomes were the occurrence of any stroke or death at 30 days. Proportional hazards models adjusting for age and treatment were used to assess risk of 30 day stroke or death by tertile of stenosis. Results: Among 1181 asymptomatic patients, qualifying angiograms were done for 662 patients who had assigned procedure performed within 30 days of randomization. Median % stenosis was 62.6, 73.4, and 83.0 for the tertiles that otherwise differed only for female sex (40% female in tertile 1, 36% in tertile 2, 29% in tertile 3, p=0.01). The 30-day stroke and death rates did not differ significantly by severity of stenosis (Table), but the number of stroke and deaths was only 14 across the tertiles (Table). Similarly meaningful comparison of CEA vs CAS was not possible. Conclusion: This is the largest contemporary study of carotid angiograms performed in patients with severe asymptomatic carotid stenosis. No relationship was detected between severity of stenosis and 30-day stroke and death. The safety of CEA and CAS in asymptomatic patients limits detection of other factors that may increase risk because so few events complicate these procedures.

Objective: To compare the perioperative risk of any stroke, death and MI and the long-term risk of re-stenosis and stroke following CEA with patching (a prosthetic or vein patch sutured to the arterial opening to widen the closure) versus CEA with primary closure in CREST. Methods: We included patients who were randomized and underwent CEA in CREST. We compared peri-procedural and 4-year event rates and 2-year restenosis rates, in addition to rates of reoperation between the two groups. Re-stenosis was defined as elevated peak systolic velocity ≥3.0 m/s on carotid duplex US. Treatment differences were assessed using proportional hazard models adjusting for age, sex, and symptomatic status. Results: There were 1,148 patients who underwent CEA (755 {66%} patch; 328 {29%} primary closure). We excluded 43 patients who underwent eversion CEA and 24 patients missing CEA data (5%). There was no significant difference between the two groups with respect to age, sex, race and comorbidities (Table 1). There were significant reductions in the risk of any periprocedural stroke and death (HR 0.35, 95% CI 0.15-0.82, P<0.02), in re-operation (OR 0.33, 95% CI 0.14-0.80, P<0.01), in the 4-year risk of stroke (HR 0.52, 95% CI 0.28-0.97, P<0.04) and in the 2-year risk of re-stenosis (HR 0.26, 95% CI 0.14-0.45, P<0.0001) in the patch compared to the primary closure group (Table 2). Conclusion: Patch closure should be considered for all CEAs because of the association of patch closure with reductions in risk of periprocedural stroke and death, re-operation, and long-term clinical and anatomic durability.

Background: We have previously reported that carotid artery stenting (CAS) carries a higher stroke risk than carotid endarterectomy (CEA) in patients over the age of 70. The question arises if advanced age is a surrogate for other factors? If so, can those factors be separately identified such that advanced chronological age alone would not be considered a contra-indication for CAS? Here we consider whether the CAS/CEA choice could be guided by other factors known in the clinical center at the time of patient evaluation, independent of age, in order to provide optimal 4-year outcomes. Methods: Demographic factors (age, sex and race), symptomatic status, patient risk factors (hypertension, diabetes, dyslipidemia, smoking), and arterial characteristics (percent stenosis) were available on 2,502 patients. Additional detailed arterial characteristics (ulcerated plaque, distal tortuosity, sequential lesions, circumferential calcification) were available on 1141 CAS and 438 CEA patients. Potential differential treatment efficacy was assessed by the addition of factor-by-treatment interaction terms to a proportional hazard model containing established predictors of outcome (treatment, symptomatic status, sex, age and age-by-treatment interaction). Results: No other factor was found to mitigate advanced age with evidence of additional treatment effect modification of 4-year outcome (p > 0.10). Discussion: Beyond the previously described differential treatment efficacy by age, there were no other patient or arterial characteristic detected to identify patient subgroups that would differentially benefit from the choice of CAS versus CEA. Our inability to identify factors to guide treatment choices could be due to the low number of stroke and death events, incomplete information regarding arterial characteristics in the CEA population, or the potential exclusion of “high risk” groups (such as those with severe arterial tortuosity) from the study.

Background The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) enrolled 2502 patients between December of 2000 and mid-July of 2008. We analyzed temporal changes in outcomes for both CEA and CAS over the course of this study. Methods Enrollment was divided into 3 consecutive epochs (5 years, 14 months, and 16 months), each with approximately 834 patients ( Table ). Rates for the primary outcome of death, stroke, and myocardial infarction (DSMI) and for death and stroke (DS) during the periprocedural period were calculated. Poisson regression was used to adjust rates for age, sex, dyslipidemia, and symptomatic status, all of which were found to influence outcomes. Results For CAS, there was a 26% decline in DSMI (6.2% → 4.6%) and a 35% decline in DS (5.5% → 3.6%). For both composite endpoints in CEA there was no consistent pattern ( Table ). As CREST progressed, it enrolled younger patients, more men, patients more likely to be dyslipidemic and enrolled more asymptomatic patients (all p < 0.05). Adjustment for these changes mediated the improvement in event rates for the CAS patients, and had no consistent effect on CEA event rates ( Table ). Conclusion Periprocedural safety for CAS improved over time in CREST. Changes were inconsistent for CEA. Improvements for CAS in part appear to reflect changes in patient selection related to age, sex, and risk factors, as adjustment for those variables attenuated the decline in rates. Linking rates to operator experience was not feasible because of the large number of new interventionalists and surgeons entering CREST over time.

Abstract A small population of self-renewing stem cells initiate tumors and maintain therapeutic resistance in glioblastoma (GBM). Given the limited treatment options and dismal prognosis for this disease, there is urgent need to identify drivers of stem cells that could be druggable targets. Previous work showed that the endosomal pH regulator NHE9 is upregulated in GBM and correlates with worse survival prognosis. Here, we probed for aberrant signaling pathways in patient-derived GBM cells and found that NHE9 increases cell surface expression and phosphorylation of multiple receptor tyrosine kinases (RTKs) by promoting their escape from lysosomal degradation. Downstream of NHE9-mediated receptor activation, oncogenic signaling pathways converged on the JAK2-STAT3 transduction axis to induce pluripotency genes Oct4 and Nanog and suppress markers of glial differentiation. We used both genetic and chemical approaches to query the role of endosomal pH in GBM phenotypes. Loss-of-function mutations in NHE9 that failed to alkalinize endosomal lumen did not increase self-renewal capacity of gliomaspheres in vitro. However, monensin, a chemical mimetic of Na+/H+ exchanger activity, and the H+ pump inhibitor bafilomycin bypassed NHE9 to directly alkalinize the endosomal lumen resulting in stabilization of RTKs and induction of Oct4 and Nanog. Using orthotopic models of primary GBM cells we found that NHE9 increased tumor initiation in vivo. We propose that NHE9 initiates inside-out signaling from the endosomal lumen, distinct from the established effects of cytosolic and extracellular pH on tumorigenesis. Endosomal pH may be an attractive therapeutic target that diminishes stemness in GBM, agnostic of specific receptor subtype.