Perioperative variable rate intravenous insulin infusion: a quality improvement project on a vascular surgery ward.

AIMS: Variable rate intravenous insulin infusion (VRIII) is used perioperatively to maintain normoglycaemia in patients with diabetes who are undergoing surgery. The aims of this project were as follows: (1) to audit the extent to which perioperative prescribing of VRIII for diabetic vascular surgery inpatients at our hospital meets established standards and (2) to use the results of the audit to guide improvement in the quality and safety of prescribing practices and reduce VRIII overuse. METHODS: Vascular surgery inpatients who had perioperative VRIII were included in the audit. Baseline data were collected consecutively from September to November 2021. There were three main interventions: a VRIII Prescribing Checklist, education of junior doctors and ward staff, and electronic prescribing system updates. Postintervention and reaudit data were collected consecutively from March to June 2022. RESULTS: The number of VRIII prescriptions totalled 27 in preintervention, 18 in postintervention and 26 in reaudit periods. Prescribers used the 'refer to paper chart' safety check more frequently postintervention (67%) and on reaudit (77%) compared with preintervention (33%) (p=0.046). Rescue medication was prescribed in 50% of postintervention and 65% of reaudit cases compared with 0% preintervention (p<0.001). Intermediate/long-acting insulin was appropriately amended more often in the postintervention versus preintervention period (75% vs 45%, p=0.041). Overall, VRIII was appropriate for the situation in 85% of cases. CONCLUSIONS: The quality of perioperative VRIII prescribing practices improved following the proposed interventions, with prescribers more frequently using recommended safety measures such as 'refer to paper chart' and rescue medication. There was a marked sustained improvement in prescriber-initiated adjustment of oral diabetes medications and insulins. VRIII is occasionally administered unnecessarily in a subset of patients with type 2 diabetes and may be an area for further study.

Glutathione peroxidase activity is neuroprotective in models of Huntington's disease.

Huntington's disease is a fatal neurodegenerative disorder caused by a CAG repeat expansion encoding a polyglutamine tract in the huntingtin (Htt) protein. Here we report a genome-wide overexpression suppressor screen in which we identified 317 ORFs that ameliorate the toxicity of a mutant Htt fragment in yeast and that have roles in diverse cellular processes, including mitochondrial import and copper metabolism. Two of these suppressors encode glutathione peroxidases (GPxs), which are conserved antioxidant enzymes that catalyze the reduction of hydrogen peroxide and lipid hydroperoxides. Using genetic and pharmacological approaches in yeast, mammalian cells and Drosophila, we found that GPx activity robustly ameliorates Huntington's disease-relevant metrics and is more protective than other antioxidant approaches tested here. Notably, we found that GPx activity, unlike many antioxidant treatments, does not inhibit autophagy, which is an important mechanism for clearing mutant Htt. Because previous clinical trials have indicated that GPx mimetics are well tolerated in humans, this study may have important implications for treating Huntington's disease.

Variants of the protein PRDM9 differentially regulate a set of human meiotic recombination hotspots highly active in African populations.

PRDM9 is a major specifier of human meiotic recombination hotspots, probably via binding of its zinc-finger repeat array to a DNA sequence motif associated with hotspots. However, our view of PRDM9 regulation, in terms of motifs defined and hotspots studied, has a strong bias toward the PRDM9 A variant particularly common in Europeans. We show that population diversity can reveal a second class of hotspots specifically activated by PRDM9 variants common in Africans but rare in Europeans. These African-enhanced hotspots nevertheless share very similar properties with their counterparts activated by the A variant. The specificity of hotspot activation is such that individuals with differing PRDM9 genotypes, even within the same population, can use substantially if not completely different sets of hotspots. Each African-enhanced hotspot is activated by a distinct spectrum of PRDM9 variants, despite the fact that all are predicted to bind the same sequence motif. This differential activation points to complex interactions between the zinc-finger array and hotspots and identifies features of the array that might be important in controlling hotspot activity.

Functional gene expression profiling in yeast implicates translational dysfunction in mutant huntingtin toxicity.

Huntington disease (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine tract in the huntingtin (htt) protein. To uncover candidate therapeutic targets and networks involved in pathogenesis, we integrated gene expression profiling and functional genetic screening to identify genes critical for mutant htt toxicity in yeast. Using mRNA profiling, we have identified genes differentially expressed in wild-type yeast in response to mutant htt toxicity as well as in three toxicity suppressor strains: bna4Δ, mbf1Δ, and ume1Δ. BNA4 encodes the yeast homolog of kynurenine 3-monooxygenase, a promising drug target for HD. Intriguingly, despite playing diverse cellular roles, these three suppressors share common differentially expressed genes involved in stress response, translation elongation, and mitochondrial transport. We then systematically tested the ability of the differentially expressed genes to suppress mutant htt toxicity when overexpressed and have thereby identified 12 novel suppressors, including genes that play a role in stress response, Golgi to endosome transport, and rRNA processing. Integrating the mRNA profiling data and the genetic screening data, we have generated a robust network that shows enrichment in genes involved in rRNA processing and ribosome biogenesis. Strikingly, these observations implicate dysfunction of translation in the pathology of HD. Recent work has shown that regulation of translation is critical for life span extension in Drosophila and that manipulation of this process is protective in Parkinson disease models. In total, these observations suggest that pharmacological manipulation of translation may have therapeutic value in HD.