Randomized controlled trial of liberal vs. standard fasting instructions in percutaneous cardiac procedures.

BACKGROUND: Pre-procedural fasting to reduce aspiration risk is usual care prior to surgery requiring anesthesia. Prolonged fasting, however, can result in dehydration and may adversely affect patient experience and outcomes. Previous studies suggest that providing a supplemental beverage to patients undergoing cardiac and a variety of other surgical procedures improves patients' subjective assessment of thirst and hunger and potentially decreases the need for inotrope and vasopressor therapy. Less is known, however, about the effects of ad libitum clear liquids up to 2 h prior to surgery. METHODS: Adult patients undergoing transcatheter aortic valve replacement (TAVR) or arrhythmia ablation were randomized (1:1) to ad libitum clear liquids up to 2 h prior to their procedure vs. nil per os (NPO) after midnight (control group, usual care). The primary endpoint was a composite satisfaction score that included patient-reported thirst, hunger, headache, nausea, lightheadedness, and anxiousness prior to surgery. The incidence of case-delay was recorded. Intraoperative vasopressor administration, changes in creatinine, anti-emetic use, and hospital length of stay (LOS) were recorded. Safety endpoints including aspiration were assessed. RESULTS: A total of 200 patients were randomized and 181 patients were included in the final analysis. Overall, 92% of patients were ASA class III or IV and 23% of patients had NYHA class III or IV symptoms. Groups were well balanced with no significant differences in age, sex or baseline cardiac or renal disease. The composite satisfaction score (primary endpoint) was not significantly different between groups (Ad libitum median = 12, IQR = [6, 17], vs Standard NPO median = 10, IQR = [5, 15], [95% CI = [-1, 4]). No significant differences between the two groups were observed in any of the individual survey questions (thirst, hunger, headache, nausea, lightheadedness, anxiousness). No significant differences between groups were observed for intra-operative vasopressor use, changes in creatinine, rescue anti-emetic use or hospital LOS. There were no case delays attributed to the intervention. There were no cases of suspected aspiration. CONCLUSION: No adverse events or case delays were observed in the ad libitum clears group. No significant benefit, however, was observed in patient satisfaction or any of the pre-specified secondary endpoints in patients randomized to ad libitum clear liquids up to 2 h prior to their procedure. TRIAL REGISTRATION: NCT04079543.

Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling.

Dominant mutations in tyrosyl-tRNA synthetase (YARS1) and six other tRNA ligases cause Charcot-Marie-Tooth peripheral neuropathy (CMT). Loss of aminoacylation is not required for their pathogenicity, suggesting a gain-of-function disease mechanism. By an unbiased genetic screen in Drosophila, we link YARS1 dysfunction to actin cytoskeleton organization. Biochemical studies uncover yet unknown actin-bundling property of YARS1 to be enhanced by a CMT mutation, leading to actin disorganization in the Drosophila nervous system, human SH-SY5Y neuroblastoma cells, and patient-derived fibroblasts. Genetic modulation of F-actin organization improves hallmark electrophysiological and morphological features in neurons of flies expressing CMT-causing YARS1 mutations. Similar beneficial effects are observed in flies expressing a neuropathy-causing glycyl-tRNA synthetase. Hence, in this work, we show that YARS1 is an evolutionary-conserved F-actin organizer which links the actin cytoskeleton to tRNA-synthetase-induced neurodegeneration.

Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family.

Charcot-Marie-Tooth (CMT) disease is a form of inherited peripheral neuropathy that affects motor and sensory neurons. To identify the causative gene in a consanguineous family with autosomal recessive CMT (AR-CMT), we employed a combination of linkage analysis and whole exome sequencing. After excluding known AR-CMT genes, genome-wide linkage analysis mapped the disease locus to a 7.48-Mb interval on chromosome 14q32.11-q32.33, flanked by the markers rs2124843 and rs4983409. Whole exome sequencing identified two non-synonymous variants (p.T40P and p.H915Y) in the AHNAK2 gene that segregated with the disease in the family. Pathogenic predictions indicated that p.T40P is the likely causative allele. Analysis of AHNAK2 expression in the AR-CMT patient fibroblasts showed significantly reduced mRNA and protein levels. AHNAK2 binds directly to periaxin which is encoded by the PRX gene, and PRX mutations are associated with another form of AR-CMT (CMT4F). The altered expression of mutant AHNAK2 may disrupt the AHNAK2-PRX interaction in which one of its known functions is to regulate myelination.

Human Rab7 mutation mimics features of Charcot-Marie-Tooth neuropathy type 2B in Drosophila.

Charcot-Marie-Tooth disease type 2B (CMT2B) is an inherited axonal peripheral neuropathy. It is characterised by prominent sensory loss, often complicated by severe ulcero-mutilations of toes or feet, and variable motor involvement. Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity. Rab7 is ubiquitously expressed and is involved in degradation through the lysosomal pathway. In the neurons, Rab7 plays a role in the long-range retrograde transport of signalling endosomes in the axons. Here we developed the first animal model of CMT2B, modelling one of the mutations (L129F) in Drosophila melanogaster. Behavioural assays show that this model recapitulates several hallmarks of the human disease. Upon expression of mutant Rab7 in the sensory neurons, larvae present with a reduction of temperature and pain perception. Furthermore, the larvae exhibit a crawling defect when the mutant protein is expressed in the motor neurons. Analysis of axonal transport of Rab7 positive vesicles in sensory neurons of Drosophila larvae and in neurites of mammalian neuroblastoma cells demonstrates that mutant vesicles pause less than their wild-type counterparts. This latter finding indicates that alterations in vesicle transport might contribute to the pathomechanism of CMT2B.