Mutations in the Transketolase-like Gene TKTL1: Clinical Implications for Neurodegenerative Diseases, Diabetes and Cancer

SUMMARY KEY WORDS Pentose phosphate pathway, transketolase, neurodegenerative disease, aging, advanced glycation endproduct (AGE), diabetes, cancer, aerobic glycolysis, Warburg effect, glucose metabolism, positron emission tomography (PET

Mutations in the Transketolase-like Gene TKTL1: Clinical Implications for Neurodegenerative Diseases, Diabetes and Cancer

SUMMARY KEY WORDS Pentose phosphate pathway, transketolase, neurodegenerative disease, aging, advanced glycation endproduct (AGE), diabetes, cancer, aerobic glycolysis, Warburg effect, glucose metabolism, positron emission tomography (PET

Safety and performance of a novel cerebral embolic protection device for transcatheter aortic valve implantation: the PROTEMBO C Trial

Background: Stroke remains a feared complication associated with transcatheter aortic valve implantation (TAVI). Embolic cerebral injury occurs in the majority of TAVI cases and can lead to cognitive dysfunction. Aims: The PROTEMBO C Trial evaluated the safety and performance of the ProtEmbo Cerebral Protection System in TAVI patients. Methods: Forty-one patients were enrolled in this single-arm study conducted at 8 European centres. The primary safety endpoint was the rate of VARC 2-defined major adverse cardiac and cerebrovascular events (MACCE) at 30 days; the primary performance endpoint was the composite rate of technical success versus performance goals (PG). Secondary endpoints included brain diffusion-weighted magnetic resonance imaging (DW-MRI), new lesion volume, and the rate of death or all strokes compared to historical data. Results: Thirty-seven of 41 enrolled patients underwent TAVI with the ProtEmbo device (intention-to-treat [ITT] population). Both primary endpoints were met. MACCE at 30 days was 8.1% (upper limit of the 95% confidence interval [CI]: 21.3% vs PG 25%; p=0.009), and technical success was 94.6% (lower limit of the 95% CI: 82.3% vs PG 75%; p=0.003). New DW-MRI lesion volumes with ProtEmbo were smaller than in historical data, and 87% of patients completing MRI follow-up had no single lesion >150 mm(3). There was 1 stroke in a patient in whom the device was removed prematurely before TAVI completion. Conclusions: The PROTEMBO C Trial met its primary safety and performance endpoints compared to prespecified historical PGs. Patients had smaller brain lesion volumes on DW-MRI compared to prior series and no larger single lesions. These results warrant further evaluation of the ProtEmbo in a larger randomised controlled trial (RCT)

Rationale and design of the PRAETORIAN-DFT trial: A prospective randomized CompArative trial of SubcutanEous ImplanTable CardiOverter-DefibrillatoR ImplANtation with and without DeFibrillation testing

In transvenous implantable cardioverter-defibrillator (TV-ICD) implants, routine defibrillation testing (DFT) does not improve shock efficacy or reduce arrhythmic death but patients are exposed to the risk of complications related to DFT. The conversion rate of DFT in subcutaneous ICD (S-ICD) is high and first shock efficacy is similar to TV-ICD efficacy rates. Study Design: The PRAETORIAN-DFT trial is an investigator-initiated, randomized, controlled, multicenter, prospective two-arm trial designed to demonstrate non-inferiority of omitting DFT in patients undergoing S-ICD implantation in which the S-ICD system components are optimally positioned. Positioning of the S-ICD will be assessed with the PRAETORIAN score. The PRAETORIAN score is developed to systematically evaluate implant position of the S-ICD system components which determine the defibrillation threshold on post-operative chest X-ray. A total of 965 patients, scheduled to undergo a de novo S-ICD implantation without contra-indications for either DFT strategy, will be randomized to either standard of care S-ICD implantation with DFT, or S-ICD implantation without DFT but with evaluation of the implant position using the PRAETORIAN score. The study is powered to claim non-inferiority of S-ICD implantation without DFT in de novo S-ICD patients in respect to the primary endpoint of first shock efficacy in spontaneous arrhythmia episodes. Patients with a high PRAETORIAN score (≥90) in the interventional arm of this study will undergo DFT according to the same DFT protocol as in the control arm. Conclusion: The PRAETORIAN-DFT trial is a randomized trial that aims to gain scientific evidence to safely omit a routine DFT after S-ICD implantation in patients with correct device positioning