Wellbeing and Social Network Characteristics in Rural Communities: Findings from a Cohort in Social Housing in Cornwall, United Kingdom.

The mental wellbeing of those living in resource poor and rural localities is a public health priority. Despite evidence of a link between social networks and mental wellbeing, little is known about this relationship in the context of rural and resource poor environments. The current study uses novel social network methodology to investigate the extent to which social network size and composition is related to mental wellbeing in a social housing community in rural England.

Real-time monitoring of COVID-19 dynamics using automated trend fitting and anomaly detection.

As several countries gradually release social distancing measures, rapid detection of new localized COVID-19 hotspots and subsequent intervention will be key to avoiding large-scale resurgence of transmission. We introduce ASMODEE (automatic selection of models and outlier detection for epidemics), a new tool for detecting sudden changes in COVID-19 incidence. Our approach relies on automatically selecting the best (fitting or predicting) model from a range of user-defined time series models, excluding the most recent data points, to characterize the main trend in an incidence.

Fostering Engagement With Health and Housing Innovation: Development of Participant Personas in a Social Housing Cohort.

Background: Personas, based on customer or population data, are widely used to inform design decisions in the commercial sector. The variety of methods available means that personas can be produced from projects of different types and scale.

Objective: This study aims to experiment with the use of personas that bring together data from a survey, household air measurements and electricity usage sensors, and an interview within a research and innovation project, with the aim of supporting eHealth and eWell-being product, process, and service development through broadening the engagement with and understanding of the data about the local community.

Guidelines for Modeling and Reporting Health Effects of Climate Change Mitigation Actions.

Background: Modeling suggests that climate change mitigation actions can have substantial human health benefits that accrue quickly and locally. Documenting the benefits can help drive more ambitious and health-protective climate change mitigation actions; however, documenting the adverse health effects can help to avoid them. Estimating the health effects of mitigation (HEM) actions can help policy makers prioritize investments based not only on mitigation potential but also on expected health benefits.

Population Pharmacokinetic Analysis of Bortezomib in Pediatric Leukemia Patients: Model-Based Support for Body Surface Area-Based Dosing Over the 2- to 16-Year Age Range.

This population analysis described the pharmacokinetics of bortezomib after twice-weekly, repeat-dose, intravenous administration in pediatric patients participating in 2 clinical trials: the phase 2 AALL07P1 (NCT00873093) trial in relapsed acute lymphoblastic leukemia and the phase 3 AAML1031 (NCT01371981) trial in de novo acute myelogenous leukemia. The sources of variability in the pharmacokinetic parameters were characterized and quantified to support dosing recommendations. Patients received intravenous bortezomib 1.

Identification of Criticality in Neuronal Avalanches: II. A Theoretical and Empirical Investigation of the Driven Case.

The observation of apparent power laws in neuronal systems has led to the suggestion that the brain is at, or close to, a critical state and may be a self-organised critical system. Within the framework of self-organised criticality a separation of timescales is thought to be crucial for the observation of power-law dynamics and computational models are often constructed with this property. However, this is not necessarily a characteristic of physiological neural networks-external input does not only occur when the network is at rest/a steady state.

Interdependency and hierarchy of exact and approximate epidemic models on networks.

Over the years numerous models of S I S (susceptible --> infected --> susceptible) disease dynamics unfolding on networks have been proposed. Here, we discuss the links between many of these models and how they can be viewed as more general motif-based models. We illustrate how the different models can be derived from one another and, where this is not possible, discuss extensions to established models that enables this derivation.

Identification of Criticality in Neuronal Avalanches: I. A Theoretical Investigation of the Non-driven Case.

In this paper, we study a simple model of a purely excitatory neural network that, by construction, operates at a critical point. This model allows us to consider various markers of criticality and illustrate how they should perform in a finite-size system. By calculating the exact distribution of avalanche sizes, we are able to show that, over a limited range of avalanche sizes which we precisely identify, the distribution has scale free properties but is not a power law.

Mainstreaming carbon management in healthcare systems: a bottom-up modeling approach.

Increasing greenhouse gas emissions threaten human health and the environment. In response, healthcare managers face significant challenges in balancing operational decisions about patient care with carbon mitigation targets. We explore a bottom-up modeling framework to aid in the decision-making for both carbon and cost in healthcare, using data from a case study in Cornwall, UK.

Epidemic threshold and control in a dynamic network.

In this paper we present a model describing susceptible-infected-susceptible-type epidemics spreading on a dynamic contact network with random link activation and deletion where link activation can be locally constrained. We use and adapt an improved effective degree compartmental modeling framework recently proposed by Lindquist et al. [J.

Water quality characteristics of discharge from reforested loose-dumped mine spoil in eastern Kentucky.

Surface mining is a common method for extracting coal in the coal fields of eastern Kentucky. Using the Forestry Reclamation Approach (FRA), which emphasizes the use of minimally compacted or loose-dumped spoil as a growth medium for trees, reclamation practitioners are successfully reestablishing forests. Yet, questions remain regarding the effects FRA has on the quality of waters discharged to receiving streams.

Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X7 receptor antagonists leading to the discovery of the clinical candidate CE-224,535.

High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X(7) receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X(7)R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis.

Absolute oral bioavailability of traxoprodil in cytochrome P450 2D6 extensive and poor metabolisers.

Background: Traxoprodil, a substituted 4-phenylpiperidine, is an N-methyl-D-aspartate (NMDA) receptor antagonist that is selective for receptors containing the NR2B subunit. In vivo and in vitro studies examining the disposition of traxoprodil have demonstrated that it is mainly metabolised by cytochrome P450 (CYP) 2D6, a major drug-metabolising enzyme that exhibits a genetic polymorphism.

Objective: To assess the single-dose absolute oral bioavailability of traxoprodil in healthy male volunteers phenotyped as either CYP2D6 extensive or poor metabolisers.

Preclinical pharmacokinetics and metabolism of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3-a]pyridine, a novel and selective p38alpha inhibitor: identification of an active metabolite in preclinical species and human liver microsomes.

The disposition of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3-a]pyridine (1), a potent and selective inhibitor of mitogen activated protein (MAP) kinase p38alpha, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 1 demonstrated generally favorable pharmacokinetic properties in all species examined. Following intravenous (i.

Structure-activity relationships of triazolopyridine oxazole p38 inhibitors: identification of candidates for clinical development.

The synthesis, structure-activity relationship, in vivo activity, and metabolic profile for a series of triazolopyridine-oxazole based p38 inhibitors are described. The deficiencies of the lead structure in the series, CP-808844, were overcome by changes to the C4 aryl group and the triazole side-chain culminating in the identification of several potential clinical candidates.

Influence of lipophilicity on the interactions of N-alkyl-4-phenyl-1,2,3,6-tetrahydropyridines and their positively charged N-alkyl-4-phenylpyridinium metabolites with cytochrome P450 2D6.

The relationship between lipophilicity and CYP2D6 affinity of cyclic tertiary (N-alkyl-4-phenyl-1,2,3,6-tetrahydropyridines) and quaternary (N-alkyl-4-phenylpyridinium) amines was examined. The 1,2,3,6-tetrahydropyridine scaffold was chosen due to its common occurrence in the structures of CYP2D6 ligands such as the Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the dehydrated haloperidol metabolite N-[4-(4-fluorophenyl)-4-oxobutyl]-4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (HPTP). Likewise, the pyridinium framework is found in and 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium and N-methyl-4-phenylpyridinium (MPP(+)), the positively charged metabolites of MPTP and haloperidol.

Assessment of the contributions of CYP3A4 and CYP3A5 in the metabolism of the antipsychotic agent haloperidol to its potentially neurotoxic pyridinium metabolite and effect of antidepressants on the bioactivation pathway.

As a plausible explanation for the large interindividual variability in the pharmacokinetics of the neuroleptic agent haloperidol, the contributions of CYP3A isozymes (CYP3A4 and the polymorphic CYP3A5) predominantly involved in haloperidol bioactivation to the neurotoxic pyridinium species 4-(4-Chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HPP(+)) were assessed in human liver microsomes and heterologously expressed enzymes. Based on recent reports on drug-drug interactions between haloperidol and antidepressants including selective serotonin reuptake inhibitors, the inhibitory effects of antidepressants on the CYP3A4/5-mediated haloperidol bioactivation were also evaluated. HPP(+) formation followed Michaelis-Menten kinetics in microsomes, recombinant CYP3A4, and CYP3A5 with K(m) values of 24.

On the diversity of oxidative bioactivation reactions on nitrogen-containing xenobiotics.

The unexpected occurrence of idiosyncratic drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use or failure to release/withdrawal. This leads to considerable uncertainty in drug development and has led to attempts to try to predict a drug's potential to cause such reactions. The biotransformation of relatively inert drugs to highly reactive metabolites, commonly referred to as "bioactivation", is now recognized to be an obligatory step in several kinds of drug-induced adverse reactions.