Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington's disease

: Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing ("early treatment") or reversing ("late treatment") HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally. We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic ("early treatment") or symptomatic ("late treatment") stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments ("2 cycle treatment") lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates. These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients. DATA AVAILABILITY: This study does not include data deposited in public repositories. Data are available on request to the corresponding authors

Towards a taxonomy of influencing factors for human reliability analysis (HRA) applications in surgery

AbstractDespite the growing interest in HRA applications in healthcare and in particular in surgery, in literature there is a limited number of HRA studies that use the so called Performance Shaping Factors or Influencing Factors to describe the working context. These factors (IFs) are those human, environmental, organizational or task specific factors that positively or negatively affect surgeons’ performance and the Error Probability. This study aims at developing an ad hoc taxonomy of Influencing Factors for surgery and it is meant to represent a first contribution towards the application of IF-based HRA in healthcare. The study methodology is twofold: firstly, literature review was used to identify and select personal and organizational factors that shape surgical performance; secondly, a field study was carried out to validate the preliminary list of IFs. Minimally Invasive Surgery (MIS) has been chosen as the field study domain. Ten factors have been extracted from the literature and classified according to the SHEL model. All the IFs in the taxonomy were observed throughout observation sessions. Furthermore, the observations prompted the addition of one more factor, namely “distractions”. In order to arrive at a stronger validation of the taxonomy, further research is needed to develop extensive validation of the conceptualization, clustering and assessment of IFs, by eliciting surgeons’ perceptions through multiple qualitative and quantitative methods