Factors associated with cognitive decline and delirium after transcatheter aortic valve implantation: Preliminary evidence

Background: Transcatheter aortic valve implantation (TAVI) has become the standard for treating severe symptomatic aortic stenosis in those with prohibitive surgical risk. Cognitive complications, including delirium and cognitive decline are common following TAVI, yet an understanding of pre-procedural factors associated with these outcomes is lacking. This prospective observational study set out to identify geriatric pre-procedural factors associated with post-procedural delirium and cognitive decline in patients undergoing TAVI. / Methods: Cognitive outcomes of TAVI patients aged ≥60 years (N=32) were measured over one-year post-TAVI. Pre-procedural measures included frailty, gait, visual symptoms, voice pitch, dysphagia, blink rate, mood, and sleep. Primary outcomes were post-procedural delirium and cognitive decline. / Results: Delirium was present in 25% of patients over two days following TAVI and 26% experienced cognitive decline in the year post-TAVI. Daily physical activity was a protective factor against cognitive decline, and worse baseline visual memory was associated with delirium. While non-significant and with very large confidence intervals, moderate to large effect sizes were found for associations between slowed gait speed, pre-existing atrial fibrillation, and dysphagia for delirium, and slower gait speed, higher blink rate, pre-existing atrial fibrillation for cognitive decline. / Conclusion: Though underpowered, measures of considerable effect size were identified (although non-significant and with large variability). In larger studies, these novel geriatric factors could further be explored for predicting cognitive complications following TAVI. Improvement of risk prediction for cognitive decline and delirium following TAVI could assist with early identification of those at risk, informing clinical decision-making and allowing for targeted intervention to reduce post-procedural incidence of these complications

The Rad9–Hus1–Rad1 (9–1–1) clamp activates checkpoint signaling via TopBP1

DNA replication stress triggers the activation of Checkpoint Kinase 1 (Chk1) in a pathway that requires the independent chromatin loading of the ATRIP–ATR (ATR-interacting protein/ATM [ataxia-telangiectasia mutated]–Rad3-related kinase) complex and the Rad9–Hus1–Rad1 (9–1–1) clamp. We show that Rad9’s role in Chk1 activation is to bind TopBP1, which stimulates ATR-mediated Chk1 phosphorylation via TopBP1’s activation domain (AD), a domain that binds and activates ATR. Notably, fusion of the AD to proliferating cell nuclear antigen (PCNA) or histone H2B bypasses the requirement for the 9–1–1 clamp, indicating that the 9–1–1 clamp’s primary role in activating Chk1 is to localize the AD to a stalled replication fork

Sex Differences in Baseline Characteristics Do Not Predict Early Outcomes after Percutaneous Coronary Intervention: Results from the Australian GenesisCare Cardiovascular Outcomes Registry (GCOR)

Objective: The effect of baseline differences between men and women on early outcomes after percutaneous coronary intervention (PCI). Design, setting, participants: This is an observational study of all participants in the GenesisCare Cardiovascular Outcomes Registry, undergoing PCI. The registry holds data for both emergency and elective procedures. Data was collected on 10,989 consecutive patients from 12 Australian Private Hospitals, including baseline demographics, co-morbidities, risk factors, PCI procedures, and lesion characteristics. Main outcome measures: Outcome was measured for complications (in-hospital death, peri-procedural myocardial infarctions, and bleeding events), at discharge and at 30-days for death, myocardial infarction, target lesion revascularisation (TLR), major adverse cardiac events (MACE), and unplanned readmissions. Results: Women represented 23% of the study population, were significantly older, with a higher rate of hypertension and hyperlipidaemia. Heart failure was more common in women and was associated with a significantly higher average ejection fraction than in men. Women had a lower rate of pre-existing coronary artery disease (CAD), had less complex CAD, and needed fewer stents. Periprocedural complications were similar, but major bleeding was more common in women. The 30-day outcome was similar between men and women for death, myocardial infarction, target lesion revascularisation (TLR), major adverse cardiovascular events (MACE), and unplanned readmissions. Conclusions: Although significant differences were observed between women and men in both clinical presentation and complexity of disease, the 30-day outcome was similar for death and MACE. Women had a higher rate of major bleeding events, and lower adherence to statins and dual antiplatelet therapy (DAPT)

Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis

The antithrombotic surface of endothelium is regulated in a coordinated manner. Tissue factor pathway inhibitor (TFPI) localized at the endothelial cell surface regulates the production of FXa by inhibiting the TF/VIIa complex. Systemic homozygotic deletion of the first Kunitz (K1) domain of TFPI results in intrauterine lethality in mice. Here we define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis using TFPI conditional knockout mice. We used a Cre-lox strategy and generated mice with a floxed exon 4 (TFPIFlox) which encodes for the TFPI-K1 domain. Mice bred into Tie2-Cre and LysM-Cre lines to delete TFPI-K1 in endothelial (TFPITie2) and myelomonocytic (TFPILysM) cells resulted in viable and fertile offspring. Plasma TFPI activity was reduced in the TFPITie2 (71% ± 0.9%, P < .001) and TFPILysM (19% ± 0.6%, P < .001) compared with TFPIFlox littermate controls. Tail and cuticle bleeding were unaffected. However, TFPITie2 mice but not TFPILysM mice had increased ferric chloride–induced arterial thrombosis. Taken together, the data reveal distinct roles for endothelial- and myelomonocytic-derived TFPI