Identification of a Potent, Selective, and Brain-Penetrant Rho Kinase Inhibitor and its Activity in a Mouse Model of Huntington's Disease.

The Rho kinase (ROCK) pathway is implicated in the pathogenesis of several conditions, including neurological diseases. In Huntington's disease (HD), ROCK is implicated in mutant huntingtin (HTT) aggregation and neurotoxicity, and members of the ROCK pathway are increased in HD mouse models and patients. To validate this mode of action as a potential treatment for HD, we sought a potent, selective, central nervous system (CNS)-penetrant ROCK inhibitor. Identifying a compound that could be dosed orally in mice with selectivity against other AGC kinases, including protein kinase G (PKG), whose inhibition could potentially activate the ROCK pathway, was paramount for the program. We describe the optimization of published ligands to identify a novel series of ROCK inhibitors based on a piperazine core. Morphing of the early series developed in-house by scaffold hopping enabled the identification of a compound exhibiting high potency and desired selectivity and demonstrating a robust pharmacodynamic (PD) effect by the inhibition of ROCK-mediated substrate (MYPT1) phosphorylation after oral dosing.

Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington's Disease.

Using an iterative structure-activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC50, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington's disease.

An open-label, randomised controlled trial on the effectiveness of the Orve + wrap® versus Forced Air Warming in restoring normothermia in the postanaesthetic care unit.

AIMS AND OBJECTIVES: To determine the clinical effectiveness and safety of the Orve + wrap® thermal blanket. BACKGROUND: Inadvertent perioperative hypothermia is a common problem in postanaesthetic care units and can have significant effects on patients' postoperative morbidity. Despite its commercial availability, there is no clinical evidence on the effectiveness of Orve + wrap®. DESIGN: A single centre prospective, open-label, noninferiority randomised controlled trial. METHODS: Postoperative hypothermic (35.0-35.9°C) patients who had undergone elective surgery were randomised to receive either Orve + wrap® or Forced Air Warming during their PACU stay. Patient temperatures were recorded every 10 min using zero-heat-flux thermometry. This study is reported using CONSORT Extension checklist for noninferiority and equivalence trials. RESULTS: Between December 2016-October 2018, 129 patients were randomised to receive either Orve + wrap® blanket (n = 65, 50.3%) or Forced Air Warming (n = 64, 49.7%). The mean 60-min postoperative temperature of patients receiving Orve + wrap® blanket was 36.2 and 36.3°C for the patients receiving Forced Air Warming. The predefined noninferiority margin of a mean difference in temperature of 0.3°C was not reached between the groups at 60 min. Additionally, there were no statistical differences between adverse event rates across these groups. CONCLUSIONS: In the context of this study, warming patients with the Orve + wrap® was noninferior to Forced Air Warming. There were comparable rates of associated postoperative consequences of warming (shivering, hypotension, arrhythmias or surgical site infections), between the groups. RELEVANCE TO CLINICAL PRACTICE: The Orve + wrap® potentially provides an alternative warming method to Forced Air Warming for patients requiring short-term postoperative warming. However, there are still a number of unknowns regarding the Orve + wrap® performance and further exploration is required.

Access to Soft-Surface, Green Exercise Trails in Mountainous, Urban Municipalities.

Soft-surface exercise infrastructure (ie off-road, mountain, and dirt trails) has been a particularly valuable community asset in mountainous, urban municipalities. This off-road, trail infrastructure can encourage individuals to engage in green exercise (ie physical activity done outside while in nature, for example, mountainous trails and near waterways). Green exercise can be helpful for encouraging individuals to participate in exercise who otherwise may not; it is especially helpful for promoting mental well-being and a sense of being connected to the environment. This study characterizes trail access and predictors among urban, mountainous municipalities in the Utah Wasatch Front region. Access was determined using two-standard deviation ellipses (2SDE) activity space analysis, and predictors were identified using multiple linear regression. About 42% municipalities had no trailhead access (ie no trailhead within its corresponding activity space). Trail density and trailheads were significantly correlated (r = 0.49, P = .004). There was a significant trail density cluster in the southern area of the study region, centered all over the city of Alpine. Reduced-model regression yielded trailheads and home income as being significant predictors of trail density, and trail density and elevation as being significant predictors for trailheads. Results demonstrate patterns of access to green exercise trails that align with socioeconomic and municipal elevation. The results of this research should be insightful for those who work in exercise promotion and urban planners.

Awareness and Perceptions of Type 2 Diabetes Risk Factors, Preventability, and Complications Among College Students in Visakhapatnam, India.

In India, often referred to as the "diabetes capital of the world," it is imperative to establish the level of knowledge among Asian Indians of Type 2 Diabetes (DM2) in order to plan effective public health programs aimed at prevention of DM2. Using an original survey of 983 college students in Visakhapatnam, Andhra Pradesh, we evaluated individuals' knowledge of DM2 including prevalence, risk factors, and prevention. To date, there are only a few studies that look at awareness of diabetes on the community level, and no previous studies have involved sampling college students. Our findings show that although awareness of diabetes is high, only half of the students sampled were aware that DM2 could be prevented and 60% were unaware that little or no exercise was a risk factor. The results suggest that diabetes awareness programs are needed among the college age population in India to prevent DM2.

Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors.

Potent and selective class IIa HDAC tetrasubstituted cyclopropane hydroxamic acid inhibitors were identified with high oral bioavailability that exhibited good brain and muscle exposure. Compound 14 displayed suitable properties for assessment of the impact of class IIa HDAC catalytic site inhibition in preclinical disease models.