Ripple AT Plus - isthmus-guided vs conventional ablation in the treatment of scar-related atrial tachycardia: study protocol for a randomised controlled trial.

BACKGROUND: Catheter ablation is routinely used to treat scar-related atrial tachycardia (s-AT). Conventional ablation often involves creating anatomical "lines" that transect myocardial tissue supporting reentry. This can be extensive, creating iatrogenic scar as a nidus for future reentry, and may account for arrhythmia recurrence. High-density mapping may identify "narrower isthmuses" requiring less ablation, with ripple mapping proven to be an effective approach in identifying. This trial explores whether ablation of narrower isthmuses in s-AT, defined using ripple mapping, results in greater freedom from arrhythmia recurrence compared to conventional ablation. METHODS: The Ripple-AT-Plus trial (registration ClinicalTrials.gov , NCT03915691) is a prospective, multicentre, single-blinded, randomised controlled trial with 12-month follow-up. Two hundred s-AT patients will be randomised in a 1:1 fashion to either "ripple mapping-guided isthmus ablation" vs conventional ablation on the CARTO3 ConfiDENSE system (Biosense Webster). The primary outcome will compare recurrence of any atrial arrhythmia. Multicentre data will be analysed over a secure web-based cloud-storage and analysis software (CARTONETTM). CONCLUSION: This is the first trial that considers long-term patient outcomes post s-AT ablation, and whether targeting narrower isthmuses in the era of high density is optimal.

An affinity-directed phosphatase, AdPhosphatase, system for targeted protein dephosphorylation.

Reversible protein phosphorylation, catalyzed by protein kinases and phosphatases, is a fundamental process that controls protein function and intracellular signaling. Failure of phospho-control accounts for many human diseases. While a kinase phosphorylates multiple substrates, a substrate is often phosphorylated by multiple kinases. This renders phospho-control at the substrate level challenging, as it requires inhibition of multiple kinases, which would thus affect other kinase substrates. Here, we describe the development and application of the affinity-directed phosphatase (AdPhosphatase) system for targeted dephosphorylation of specific phospho-substrates. By deploying the Protein Phosphatase 1 or 2A catalytic subunits conjugated to an antigen-stabilized anti-GFP nanobody, we can promote the dephosphorylation of two independent phospho-proteins, FAM83D or ULK1, knocked in with GFP-tags using CRISPR-Cas9, with exquisite specificity. By redirecting protein phosphatases to neo-substrates through nanobody-mediated proximity, AdPhosphatase can alter the phospho-status and function of target proteins and thus, offers a new modality for potential drug discovery approaches.

Target protein localization and its impact on PROTAC-mediated degradation.

Proteolysis-targeting chimeras (PROTACs) bring a protein of interest (POI) into spatial proximity of an E3 ubiquitin ligase, promoting POI ubiquitylation and proteasomal degradation. PROTACs rely on endogenous cellular machinery to mediate POI degradation, therefore the subcellular location of the POI and access to the E3 ligase being recruited potentially impacts PROTAC efficacy. To interrogate whether the subcellular context of the POI influences PROTAC-mediated degradation, we expressed either Halo or FKBP12F36V (dTAG) constructs consisting of varying localization signals and tested the efficacy of their degradation by von Hippel-Lindau (VHL)- or cereblon (CRBN)-recruiting PROTACs targeting either Halo or dTAG. POIs were localized to the nucleus, cytoplasm, outer mitochondrial membrane, endoplasmic reticulum, Golgi, peroxisome or lysosome. Differentially localized Halo or FKBP12F36V proteins displayed varying levels of degradation using the same respective PROTACs, suggesting therefore that the subcellular context of the POI can influence the efficacy of PROTAC-mediated POI degradation.

Improving urinary catheterisation practices in a rural hospital in Ontario.

INTRODUCTION: A urinary catheter constitutes a one-point patient restraint, can induce deconditioning and may lead to patient mortality. An audit performed at Winchester District Memorial Hospital revealed that 20% of patients had a urinary catheter, of whom 31% did not meet the criteria for catheterisation. The main objective of this study was to use the Influencer Change Model and the Choosing Wisely Canada toolkit to create a bundle of interventions that would reduce the unnecessary use of urinary catheters in hospitalised patients. METHODS: In a rural teaching hospital, a time-series quasi-experiment was employed to decrease inappropriate use of urinary catheters. Both the Choosing Wisely Canada toolkit for appropriate use of urinary catheters and the Influencer change management approach were used to create effective interventions. RESULTS: This study revealed that there was no improvement in appropriate urinary catheter use during Plan-Do-Study-Act (PDSA) cycle 1. There was gradual improvement during PDSA cycle 2, with the percentage of inappropriate urinary catheter use dropping from an initial 31% before any interventions to less than 5% by the end of this study. DISCUSSION/CONCLUSION: This study aimed to reduce the inappropriate use of urinary catheters in a rural hospital with limited resources. The findings indicate that by using a change model, such as the Influencer Change Model, it is possible to promote better patient care through empowering healthcare staff to implement accepted protocols more stringently and thereby to decrease the inappropriate use of urinary catheters to 0%.

Discriminant analysis of Beck Depression Inventory and Hamilton Rating Scale for Depression in Huntington's disease.

Depression is common in Huntington's disease, but standard rating scales have doubtful validity in this population. Using data from the European Huntington's Disease REGISTRY study, the authors examined the discriminant value of items on the Beck Depression Inventory (N=843) and the Hamilton Rating Scale for Depression (N=768). Good discriminators of depression, apart from "depressed mood," were "guilt," "loss of interest," and "suicidality." Items that discriminated poorly were "weight loss," "sleep disturbance," "loss of appetite," "psychomotor retardation," "agitation," and "irritability." These findings highlight the limited usefulness of these scales within the area of Huntington's disease.

Distinct expression of neuronal apoptosis inhibitory protein (NAIP) during murine development.

The childhood spinal muscular atrophies (SMAs) are autosomal recessive neurodegenerative conditions characterized by progressive degeneration of lower motor neurons. The gene encoding NAIP (neuronal apoptosis inhibitory protein) has been proposed to be a modulator of the severity of SMA and is frequently deleted in type I SMA. In this study we have assessed NAIP (murine homologue of NAIP) transcript levels during mouse embryogenesis. NAIP mRNA is present in the developing brain and spinal cord of E9.5-E14.5 mouse embryos as detected by various in situ hybridization techniques. It is also found in the embryonic branchial arches, the nasal epithelium and in the future digits. At E16.5, NAIP mRNA transcripts were found in the marginal zone of the lateral ventricle, the follicles of the vibrissae, in the retina and in the intestinal villi. These results are the first report of NAIP gene transcript levels in embryogenesis. If motor neuron attrition occurs in the second and third trimester of gestation in SMA, the observation of NAIP transcription in the mouse spinal cord between E9.5 and E14.5 is consistent with a role for NAIP in modifying this disorder.