Virtual screening of the corporate compound collection yielded compound 1 as a subtype selective muscarinic M 1 receptor agonist hit. Initial optimization of the N-capping group of the central piperidine ring resulted in compounds 2 and 3 with significantly improved potency and selectivity. Subsequent optimization of substituents on the phenyl ring of the benzimidazolone moiety led to the discovery of novel muscarinic M 1 receptor agonists 4 and 5 with excellent potency, general and subtype selectivity, and pharmacokinetic (PK) properties including good central nervous system (CNS) penetration and oral bioavailability. Compound 5 showed robust in vivo activities in animal models of cognition enhancement. The combination of high potency, excellent selectivity, and good PK properties makes compounds 4 and 5 valuable tool compounds for investigating and validating potential therapeutic benefits resulting from selective M 1 activation.

Background and Purpose— Delirium is associated with increased mortality, length of stay, and poor functional outcome following critical illness. The epidemiology of delirium in stroke is poorly described. We sought to collate evidence around occurrence (incidence or prevalence) of delirium in acute stroke. Methods— We searched multiple cross-disciplinary electronic databases using a prespecified search strategy, complemented by hand searching. Eligible studies described delirium in acute (first 6 weeks) stroke. We compared delirium occurrence using random-effects models to describe summary estimates. We assessed risk of bias using the Newcastle-Ottawa tool, incorporating this in sensitivity analyses. We performed subgroup analyses for delirium diagnostic method (confusion assessment method scoring, clinical diagnosis, other), duration and timing of delirium assessment (>1 or <1 week), and performed meta-regression based on the year of publication. Results— Of 8822 titles, we included 32 papers (6718 participants) in the quantitative analysis. Summary estimate for occurrence of delirium was 25% (95% CI, 20%–30%; moderate quality evidence). Limiting to studies at low risk of bias (22 studies, 4422 participants), the occurrence rate was 23% (95% CI, 17%–28%). Subgroup summary estimates suggest that delirium occurrence may vary with assessment method: confusion assessment method, 21% (95% CI, 16%–27%); clinical diagnosis, 27% (95% CI, 19%–38%); other, 32% (95% CI, 22%–43%) but not with duration and timing of assessment. Meta-regression suggested decline in occurrence of delirium comparing historical to more recent studies (slope, 0.03 [SE, 0.004]; P <0.0001). Conclusions— Delirium is common, affecting 1 in 4 acute stroke patients. Reported rates of delirium may be dependent on assessment method. Our estimate of delirium occurrence could be used for audit, to plan intervention studies, and inform clinical practice. Clinical Trial Registration— URL: http://www.crd.york.ac.uk/PROSPERO/ . Unique identifier: CRD42015029251.

Background and objectives COVID-19 has had a negative effect on mental health across the world's population. Healthcare workers in particular have experienced increased levels of psychological distress, depression and anxiety. Any perceived stress to an individual can provoke psychological defence mechanisms. Using psychoanalytic theory, a defence mechanism is described as an unconscious psychological strategy, with or without resulting behaviour, which aims to reduce or eliminate anxiety arising from unacceptable or potentially harmful stimuli. This paper aims to describe a range of psychological defence mechanisms encountered within colleagues in relation to the COVID-19 pandemic. Methods Using the methodology of a case series, specific defence mechanisms are explored with reference to further literature in the field. Results The author has encountered varying psychological defence mechanisms, both within himself and in other members of the multidisciplinary team. These have been illustrated in the attached clinical vignettes, relating to the specific psychological coping mechanisms of; denial, hypochondriasis, altruism, sublimation and humour. Conclusion We encourage acknowledgement of psychological defence mechanisms and their implications on day to day practice. Whilst defence mechanisms can have a number of negative consequences as described in this article, they also have an important role, particularly in the case of mature defence mechanisms, as protective factors against psychological distress and symptom formation. Deeper understanding of the gold-standard hierarchical organization of defence mechanisms could help increase utilisation of specific therapeutic interventions for enhancing changes from immature to mature defensive responses to stressful experiences as the COVID-19 pandemic progresses.

Inhabited Television" combines multiuser virtual environments with television, so that online audience-members can participate in TV shows staged in a virtual world. It is presented simultaneously both to conventional passive viewers and to online participants. In many cases it benefits from being broadcast live. This paper is based on our fourth major experiment with Inhabited TV, a live virtual game show called "Out Of This World". For this event we adopted non-automated approaches to camera control and mixing to allow an exploration of appropriate forms of presentation for inhabited television. We describe the techniques which were used to create and enhance the live video output which was produced during the show: appropriate world design; dynamic constraints on participant movements; and a performance-oriented virtual camera control interface. This camera control interface includes explicit support for a range of spatial and temporal control styles. We also give evaluative feedback on the camera control interface and the event's (television-based) approach to mixing and directing, drawing on a social scientific field study conducted on-site during the preparation for, and performances of, the show.