Effects of hypnotic drugs on performance before and after sleep

The effects of various hypnotics on sleep stage parameters and on the parameters of effectiveness were evaluated along with the effects of several commonly used yet distinctly different hypnotics on daytime performance. The effects on daytime performance of two nonhypnotics commonly used in the space program were also examined

Evaluation of the EndoPAT as a Tool to Assess Endothelial Function

Endothelial dysfunction is a potential target for (pharmaceutical) intervention of several systemic pathological conditions. We investigated the feasibility of the EndoPAT to evaluate acute changes in endothelial function with repeated noninvasive measurements and assessed its discriminating power in different populations. Endothelial function was stable over a longer period of time in renally impaired patients (coefficient of variation 13%). Endothelial function in renally impaired and type 2 diabetic patients was not decreased compared to healthy volunteers (2.9 ± 1.4 and 1.8 ± 0.3, resp., versus 1.8 ± 0.5, P > 0.05). The EndoPAT did not detect an effect of robust interventions on endothelial function in healthy volunteers (glucose load: change from baseline 0.08 ± 0.50, 95% confidence interval −0.44 to 0.60; smoking: change from baseline 0.49 ± 0.92, 95% confidence interval −0.47 to 1.46). This suggests that at present the EndoPAT might not be suitable to assess (changes in) endothelial function in early-phase clinical pharmacology studies. Endothelial function as measured by the EndoPAT could be physiologically different from endothelial function as measured by conventional techniques. This should be investigated carefully before the EndoPAT can be considered a useful tool in drug development or clinical practice

A mixed-methods feasibility study of a goal-focused manualised intervention to support people with dementia to stay living independently at home with support from family carers: NIDUS (New Interventions for Independence in Dementia Study) Family

Objectives: To examine the feasibility and acceptability of NIDUS-Family, a 6–8 session manualised, individually tailored, modular intervention supporting independence at home for people with dementia; and explore participants’ and facilitators’ experiences of the intervention. / Method: In this single group multi-site feasibility study, trained, supervised non-clinically qualified graduates (facilitators) delivered NIDUS-Family to family carer and people living with dementia dyads. We recruited participants from GP practices and memory services in London and Bradford. We completed quantitative outcomes pre- and post-intervention; and conducted qualitative interviews with participants and facilitators. Our pre-specified main outcomes were proportion of potential participants approached who agreed to participate, intervention adherence and acceptability to family carers, and facilitator fidelity to the manual. / Results: We recruited 16 dyads (57% of those approached); 12 (75%) completed the intervention. Of 12 participants rating intervention acceptability, 9 (75%) agreed or strongly agreed that it had helped; 2 (18%) neither agreed nor disagreed and 1 (8%) disagreed. Mean facilitator fidelity was high (81.5%). Dyads set on average 3.9 goals; these most commonly related to getting out and about and increasing activity/hobby participation (n = 10); carer wellbeing (n = 6), managing physical complaints (n = 6); meal preparation/cooking (n = 5); and reducing irritability, frustration or aggression (n = 5). Almost all secondary outcomes changed in a direction indicating improvement. In our qualitative analysis we identified three overarching themes; relationships facilitate change, goal-focused versus manualised approach and balancing the needs of carers and people with dementia. / Conclusion: NIDUS-Family was feasible and acceptable to participants. Following refinements, testing in a pragmatic trial is underway

Improving recognition of delirium in clinical practice: a call for action

The purpose of this correspondence article is to report opinion amongst experts in the delirium field as to why, despite on-going training for all health professionals, delirium continues to be under recognised. Consensus was obtained by means of two conference workshops and an online survey of members of the European Delirium Association. Major barriers to recognition at an individual level include ignorance about the benefit of treating delirium. At an organisational level, reflecting socio-cultural attitudes, barriers include a low strategic and financial priority and the fact that delirium is an orphan condition falling between specialties

Feasibility and acceptability of NIDUS-Professional, a training and support intervention for homecare workers caring for clients living with dementia: a cluster-randomised feasibility trial protocol.

INTRODUCTION: Most people living with dementia want to remain living in their own homes, and are supported to do so by family carers and homecare workers. There are concerns that homecare is often unable to meet the needs of this client group, with limited evidence regarding effective interventions to improve it for people living with dementia. We have developed a training and support programme for homecare workers (NIDUS-Professional) to be delivered alongside support sessions for people living with dementia and their family carers (NIDUS-Family). We aim to assess (1) its acceptability among homecare workers and employing agencies, and (2) the feasibility of homecare workers, people living with dementia and their family carers completing the outcomes of intervention in a future randomised controlled trial. METHODS AND ANALYSIS: This is a cluster-randomised (2:1) single-blind, multisite feasibility trial. We aim to recruit 60-90 homecare workers, 30-60 clients living with dementia and their family carers through 6-9 English homecare agencies. In the intervention arm, homecare staff will be offered six group sessions on video call over three months, followed by monthly group sessions over the subsequent three-month period. Outcome measures will be collected at baseline and at six months. ETHICS AND DISSEMINATION: The study received ethical approval on 7 January 2020 from the Camden & King's Cross Research Ethics Committee. Study reference: 19/LO/1667. Findings will be disseminated through a peer-reviewed journal, conference presentation and blog to research and clinical audiences; we will attend forums to present findings to participating homecare agencies and their clients. TRIAL REGISTRATION NUMBER: ISRCTN15757555

Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway

The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. © 2013 Bhowmick et al