Megaprojects as niches of sociotechnical transitions: The case of digitalization in UK construction

Transitions are processes of systemic change where niches peripheral to a sociotechnical regime accumulate momentum, scale up and eventually transform its core. In contrast to this dominant narrative in transitions research, infrastructure systems exhibit the reverse process as change propagates from the regime core to its periphery. We explore this under-researched process in the case of digitalization in UK construction. We analyse six UK megaprojects that span more than 30 years as a single longitudinal embedded case, and show how the adoption of digital technologies driven by regime incumbents, seeds the processes of technology adaptation, aggregation, and system transformation. The adoption of digital technologies by incumbents is necessary to cope with megaproject scale and scope. Their adaptation to technology instigates organizational level change that starts at the regime core, accumulates with each project and makes these changes ripple across the industry and transform it

Labrador retrievers under primary veterinary care in the UK: demography, mortality and disorders

Abstract Background Labrador retrievers are reportedly predisposed to many disorders but accurate prevalence information relating to the general population are lacking. This study aimed to describe demography, mortality and commonly recorded diseases in Labrador retrievers under UK veterinary care. Methods The VetCompass™ programme collects electronic patient record data on dogs attending UK primary-care veterinary practices. Demographic analysis covered all33,320 Labrador retrievers in the VetCompass™ database under veterinary care during 2013 while disorder and mortality data were extracted from a random sample of 2074 (6.2%) of these dogs. Results Of the Labrador retrievers with information available, 15,427 (46.4%) were female and 15,252 (53.6%) were male. Females were more likely to be neutered than males (59.7% versus 54.8%, P <  0.001). The overall mean adult bodyweight was 33.0 kg (SD 6.1). Adult males were heavier (35.2 kg, SD 5.9 kg) than adult females (30.4 kg, SD 5.2 kg) (P <  0.001). The median longevity of Labrador retrievers overall was 12.0 years (IQR 9.9–13.8, range 0.0–16.0). The most common recorded colours were black (44.6%), yellow (27.8%) and liver/chocolate (reported from hereon as chocolate) (23.8%). The median longevity of non-chocolate coloured dogs (n = 139, 12.1 years, IQR 10.2–13.9, range 0.0–16.0) was longer than for chocolate coloured animals (n = 34, 10.7 years, IQR 9.0–12.4, range 3.8–15.5) (P = 0.028). Of a random sample of 2074 (6.2%) Labrador retrievers under care in 2013 that had full disorder data extracted, 1277 (61.6%) had at least one disorder recorded. The total number of dogs who died at any date during the study was 176. The most prevalent disorders recorded were otitis externa (n = 215, prevalence 10.4%, 95% CI: 9.1–11.8), overweight/obesity (183, 8.8%, 95% CI: 7.6–10.1) and degenerative joint disease (115, 5.5%, 95% CI: 4.6–6.6). Overweight/obesity was not statistically significantly associated with neutering in females (8.3% of entire versus 12.5% of neutered, P = 0.065) but was associated with neutering in males (4.1% of entire versus 11.4% of neutered, P < 0.001). The prevalence of otitis externa in black dogs was 12.8%, in yellow dogs it was 17.0% but, in chocolate dogs, it rose to 23.4% (P < 0.001). Similarly, the prevalence of pyo-traumatic dermatitis in black dogs was 1.1%, in yellow dogs it was 1.6% but in chocolate dogs it rose to 4.0% (P = 0.011). Conclusions The current study assists prioritisation of health issues within Labrador retrievers. The most common disorders were overweight/obesity, otitis externa and degenerative joint disease. Males were significantly heavier females. These results can alert prospective owners to potential health issues and inform breed-specific wellness checks

Complement C3 variant and the risk of age-related macular degeneration

Background: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.Methods: We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls.Results: The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9 x 10(sup -5)) and the Scottish group (244 cases and 351 controls, P=5.0 x 10(sup -5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%.Conclusions: Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease

The Parametric Inverse Problem in Transient Scattering

Scattering problems in many areas of applied physics are governed by the wave equation. In the most usual situation, we are given the incident wave (input) and the scatterer(s) and attempt, through analytical, experimental, or numerical methods, to produce the scattered waves (output). Such procedures can be carried out in either the frequency domain or the time domain and are categorized under the general heading of “forward problems.” In a less usual, but no less important situation, we are given the incident wave (input) and the scattered waves (output) and attempt to find the scatterer(s) that produced the output. In this case, we call the procedures “inverse” problems

Simultaneous temporal trends in dementia incidence and prevalence, 2005–2013 : a population-based retrospective cohort study in Saskatchewan, Canada

Original studies published over the last decade regarding time trends in dementia report mixed results. The aims of the present study were to use linked administrative health data for the province of Saskatchewan for the period 2005/2006 to 2012/2013 to: (1) examine simultaneous temporal trends in annual age- and sex-specific dementia incidence and prevalence among individuals aged 45 and older, and (2) stratify the changes in incidence over time by database of identification. Using a population-based retrospective cohort study design, data were extracted from seven provincial administrative health databases linked by a unique anonymized identification number. Individuals 45 years and older at first identification of dementia between April 1, 2005 and March 31, 2013 were included, based on case definition criteria met within any one of four administrative health databases (hospital, physician, prescription drug, and long-term care). Between 2005/2006 and 2012/2013, the 12-month age-standardized incidence rate of dementia declined significantly by 11.07% and the 12-month age-standardized prevalence increased significantly by 30.54%. The number of incident cases decreased from 3,389 to 3,270 and the number of prevalent cases increased from 8,795 to 13,012. Incidence rate reductions were observed in every database of identification. We observed a simultaneous trend of decreasing incidence and increasing prevalence of dementia over a relatively short 8-year time period from 2005/2006 to 2012/2013. These trends indicate that the average survival time of dementia is lengthening. Continued observation of these time trends is warranted given the short study period

Glucocorticoids rapidly inhibit cell migration through a novel, non-transcriptional HDAC6 pathway

Glucocorticoids (GCs) act through the glucocorticoid receptor (GR, also known as NR3C1) to regulate immunity, energy metabolism and tissue repair. Upon ligand binding, activated GR mediates cellular effects by regulating gene expression, but some GR effects can occur rapidly without new transcription. Here, we show that GCs rapidly inhibit cell migration, in response to both GR agonist and antagonist ligand binding. The inhibitory effect on migration is prevented by GR knockdown with siRNA, confirming GR specificity, but not by actinomycin D treatment, suggesting a non-transcriptional mechanism. We identified a rapid onset increase in microtubule polymerisation following GC treatment, identifying cytoskeletal stabilisation as the likely mechanism of action. HDAC6 overexpression, but not knockdown of αTAT1, rescued the GC effect, implicating HDAC6 as the GR effector. Consistent with this hypothesis, ligand-dependent cytoplasmic interaction between GR and HDAC6 was demonstrated by quantitative imaging. Taken together, we propose that activated GR inhibits HDAC6 function, and thereby increases the stability of the microtubule network to reduce cell motility. We therefore report a novel, non-transcriptional mechanism whereby GCs impair cell motility through inhibition of HDAC6 and rapid reorganization of the cell architecture

Principles of Stakes Fairness in Sport

Fairness in sport is not just about assigning the top prizes to the worthiest competitors. It is also about the way the prize structure itself is organised. For many sporting competitions, although it may be acceptable for winners to receive more than losers, it can seem unfair for winners to take everything and for losers to get nothing. Yet this insight leaves unanswered some difficult questions about what stakes fairness requires and which principles of stakes fairness are appropriate for particular competitions. In this article I specify a range of different principles of stakes fairness (ten in total) that could regulate sporting competitions. I also put forward a theoretical method for pairing up appropriate principles of stakes fairness with given sporting competitions. Specifically, I argue that the underlying rationales for holding sporting competitions can provide useful guides for identifying appropriate principles of stakes fairness. I then seek to clarify and work through some of the implications of this method for a sample of real world controversies over sporting prize structures. I also attempt to refine the method in response to two possible objections from indeterminacy and relativism. Finally, I compare and contrast my conclusions with more general philosophical debates about justice

Interpreting population reach of a large, successful physical activity trial delivered through primary care.

Abstract Background Failure to include socio-economically deprived or ethnic minority groups in physical activity (PA) trials may limit representativeness and could lead to implementation of interventions that then increase health inequalities. Randomised intervention trials often have low recruitment rates and rarely assess recruitment bias. A previous trial by the same team using similar methods recruited 30% of the eligible population but was in an affluent setting with few non-white residents and was limited to those over 60 years of age. Methods PACE-UP is a large, effective, population-based walking trial in inactive 45-75 year-olds that recruited through seven London general practices. Anonymised practice demographic data were available for all those invited, enabling investigation of inequalities in trial recruitment. Non-participants were invited to complete a questionnaire. Results From 10,927 postal invitations, 1150 (10.5%) completed baseline assessment. Participation rate ratios (95% CI), adjusted for age and gender as appropriate, were lower in men 0.59 (0.52, 0.67) than women, in those under 55 compared with those ≥65, 0.60 (0.51, 0.71), in the most deprived quintile compared with the least deprived 0.52 (0.39, 0.70) and in Asian individuals compared with whites 0.62 (0.50, 0.76). Black individuals were equally likely to participate as white individuals. Participation was also associated with having a co-morbidity or some degree of health limitation. The most common reasons for non-participation were considering themselves as being too active or lack of time. Conclusions Conducting the trial in this diverse setting reduced overall response, with lower response in socio-economically deprived and Asian sub-groups. Trials with greater reach are likely to be more expensive in terms of recruitment and gains in generalizability need to be balanced with greater costs. Differential uptake of successful trial interventions may increase inequalities in PA levels and should be monitored

Human physiologically based pharmacokinetic model for propofol

BACKGROUND: Propofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK) model for propofol. METHODS: PKQuest, a freely distributed software routine , was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1) the value of the propofol oil/water partition coefficient; 2) the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion. RESULTS: The PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance) is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters). The average weighted residual error (WRE) of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model. CONCLUSION: A PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a PBPK model is that it can be used to predict the changes in kinetics produced by variations in physiological parameters. As one example, the model simulation of the changes in pharmacokinetics for morbidly obese subjects is discussed

Cell lineage transport: a mechanism for molecular gradient formation

Gradient formation is a fundamental patterning mechanism during embryo development, commonly related to secreted proteins that move along an existing field of cells. Here, we mathematically address the feasibility of gradients of mRNAs and non-secreted proteins. We show that these gradients can arise in growing tissues whereby cells dilute and transport their molecular content as they divide and grow, a mechanism we termed ‘cell lineage transport.' We provide an experimental test by unveiling a distal-to-proximal gradient of Hoxd13 in the vertebrate developing limb bud driven by cell lineage transport, corroborating our model. Our study indicates that gradients of non-secreted molecules exhibit a power-law profile and can arise for a wide range of biologically relevant parameter values. Dilution and nonlinear growth confer robustness to the spatial gradient under changes in the cell cycle period, but at the expense of sensitivity in the timing of gradient formation. We expect that gradient formation driven by cell lineage transport will provide future insights into understanding the coordination between growth and patterning during embryonic development