Reduced Physiologically-Based Pharmacokinetic Model of Repaglinide: Impact of OATP1B1 and CYP2C8 Genotype and Source of In Vitro Data on the Prediction of Drug-Drug Interaction Risk

Purpose

To investigate the effect of OATP1B1 genotype as a covariate on repaglinide pharmacokinetics and drug-drug interaction (DDIs) risk using a reduced physiologically-based pharmacokinetic (PBPK) model.

Methods

Twenty nine mean plasma concentration-time profiles for SLCO1B1 c.521T>C were used to estimate hepatic uptake clearance (CL_uptake) in different genotype groups applying a population approach in NONMEM v.7.2.

Results

Estimated repaglinide CL_uptake corresponded to 217 and 113 μL/min/10⁶ cells for SLCO1B1 c.521TT/TC and CC, respectively. A significant effect of OATP1B1 genotype was seen on CL_uptake (48% reduction for CC relative to wild type). Sensitivity analysis highlighted the impact of CL_met and CL_diff uncertainty on the CL_uptake optimization using plasma data. Propagation of this uncertainty had a marginal effect on the prediction of repaglinide OATP1B1-mediated DDI with cyclosporine; however, sensitivity of the predicted magnitude of repaglinide metabolic DDI was high. In addition, the reduced PBPK model was used to assess the effect of both CYP2C8*3 and SLCO1B1 c.521T>C on repaglinide exposure by simulations; power calculations were performed to guide prospective DDI and pharmacogenetic studies.

Conclusions

The application of reduced PBPK model for parameter optimization and limitations of this process associated with the use of plasma rather than tissue profiles are illustrated.     

Associations of Angiopoietins With Heart Failure Incidence and Severity

BackgroundAngiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether angiopoietin signaling is causative, an adaptive response, or merely epiphenomenon of disease activity.Methods and ResultsIn a cohort free of cardiovascular disease at baseline (Multi-Ethnic Study of Atherosclerosis [MESA]), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension or left heart disease, associations between angiopoietins, invasive hemodynamics, and adverse clinical outcomes were evaluated. In MESA, Ang2 was associated with a higher incidence of heart failure or cardiovascular death (hazard ratio 1.21 per standard deviation, P < .001). Ang2 was associated with increased right atrial pressure (pulmonary arterial hypertension cohort) and increased wedge pressure and right atrial pressure (left heart disease cohort). Elevated Ang2 was associated with mortality in the pulmonary arterial hypertension cohort.ConclusionsAng2 was associated with incident heart failure or death among adults without cardiovascular disease at baseline and with disease severity in individuals with existing heart failure. Our finding that Ang2 is increased before disease onset and that elevations reflect disease severity, suggests Ang2 may contribute to heart failure pathogenesis.     

Exercise training soon after myocardial infarction

To assess the cardiovascular effects of exercise training soon after clinically uncomplicated myocardial infarction, 70 men (mean age 54 years) underwent gymnasium training (no. = 28), home training (no. = 12) or no training (no. = 30) 3 to 11 weeks after the acute event. During this 8 week interval functional capacity increased significantly (P < 0.001) in all three groups: gymnasium training, 66 percent; home training, 41 percent; and no training, 34 percent. Peak functional capacity at 11 weeks was 11.0 ± 1.6, 10.3 ± 1.4 and 9.4 ± 1.8 (mean ± standard deviation) multiples of resting energy expenditure (METs) in the three groups—values approximating those of sedentary men of similar age without coronary heart disease. Functional capacity increased more in the gymnasium training group than in the no training group, but this difference was statistically significant only in patients without exercise-induced ischemie S-T segment depression or angina pectoris (P < 0.01). Another “training effect”—diminished heart rate response to submaximal work—was also observed in all three groups. It is concluded that (1) symptom-limited treadmill exercise testing performed soon after clinically uncomplicated myocardial infarction is feasible and safe and provides useful guidelines for physical reconditioning. (2) Patients who demonstrate nonischemic responses to treadmill exercise testing soon after infarction may safely undergo unsupervised exercise training at home. (3) Formal exercise training may not be required to restore functional capacity to nearly normal values soon after clinically uncomplicated myocardial infarction.     

Delivering Social Work Education on Case Reviews and Inquiry Reports: An Exploratory Study of Students’ Perspectives in Northern Ireland

It is self-evident that we live in the age of inquiry where the negative impact of risk has been examined through numerous formal processes. In the wake of such scrutiny, there have been repeated recommendations for better training of the professionals charged with safeguarding the welfare of vulnerable individuals. Yet there has been very little examination of how student social workers, in particular, evaluate this training. This exploratory study responded to this gap through a mixed-methods design centring on the views of qualifying and post-qualifying social work students attending courses within two regional universities in Northern Ireland. The study found that, in the main, the cohorts responded favourably to certain aspects of the curriculum and how they were delivered. That said, the emotive nature of the case review and inquiry reports was inadequately addressed in the classroom and was not processed afterwards through a psycho-social framework. In effect, students were often left with residual anxieties that potentially hampered learning. On the basis of the findings, the study calls for further research into this highly significant area of professional competence.     

Disparities in Exposure to Automobile and Truck Traffic and Vehicle Emissions Near the Los Angeles–Long Beach Port Complex

Objectives. We assessed how traffic and mobile-source air pollution impacts are distributed across racial/ethnic and socioeconomically diverse groups in port-adjacent communities in southern Los Angeles County, which may experience divergent levels of exposure to port-related heavy-duty diesel truck traffic because of existing residential and land use patterns.Methods. We used spatial regression techniques to assess the association of neighborhood racial/ethnic and socioeconomic composition with residential parcel-level traffic and vehicle-related fine particulate matter exposure after accounting for built environment and land use factors.Results. After controlling for factors associated with traffic generation, we found that a higher percentage of nearby Black and Asian/Pacific Islander residents was associated with higher exposure, a higher percentage of Hispanic residents was associated with higher traffic exposure but lower vehicle particulate matter exposure, and areas with lower socioeconomic status experienced lower exposure.Conclusions. Disparities in traffic and vehicle particulate matter exposure are nuanced depending on the exposure metric used, the distribution of the traffic and emissions, and pollutant dispersal patterns. Future comparative research is needed to assess potential disparities in other transportation and goods movement corridors.Residential proximity to heavy traffic has been associated with adverse health effects, including asthma, reduced lung function, cardiac and pulmonary mortality, and adverse birth outcomes.1–3 Previous research suggests that non-White and lower income individuals may be exposed to higher levels of traffic-related air pollution4–8 and that disparities vary with social gradients associated with higher susceptibility to pollution.9,10 Environmental justice concerns are heightened in goods movement corridors in which substantial volumes of heavy-duty diesel trucks (HDDTs) transport shipping containers on arterials near residences and sensitive land uses through lower socioeconomic status communities.11,12Significant questions remain, however, regarding the existence and magnitude of race- and income-based disparities in traffic and air pollution exposure.13–16 Some studies have found little association between air pollution exposure and socioeconomic status after controlling for confounding factors17; others found greater air pollution and traffic exposure for higher socioeconomic groups.18,19 Such discrepancies could arise because of methodological differences and challenges in assessing inequities at various scales.11,20–22 Scale could be an important consideration in assessing traffic impacts because vehicle-related pollutants are highly localized, with pollutant concentrations decaying to background levels within 200 to 300 meters during the day,23–26 and because ambient air quality monitoring data are likely insufficient to characterize near-roadway pollutant gradients.Our study provides an important environmental justice case study by assessing how traffic and mobile-source air pollution impacts are distributed across groups in port-adjacent communities in southern Los Angeles County, which contain substantial racial/ethnic and socioeconomic diversity and may experience divergent levels of exposure to port-related HDDT traffic because of existing residential and land use patterns.12,27,28 We have contributed to the environmental justice literature by examining exposures at the parcel property assessment level to determine impacts at a finer spatial resolution,29 by using spatial regression techniques to account for spatial dependence of data when assessing disparities,30–33 and by using 3 parcel-level metrics of exposure that could have different spatial distributions and population impacts: total nearby vehicle miles traveled (VMT), nearby truck VMT, and the modeled concentrations of emissions from vehicles on neighborhood roadways. We hypothesized that the first 2 traffic exposure measures would provide a distance-based assessment of near-roadway exposure to traffic-related noise and air pollution and that the third would account for the air pollution “plume” after accounting for the geographic and temporal variation in traffic, wind, and other meteorological patterns.     

Diagnostic classification of arterial spin labeling and structural MRI in presenile early stage dementia

Because hypoperfusion of brain tissue precedes atrophy in dementia, the detection of dementia may be advanced by the use of perfusion information. Such information can be obtained noninvasively with arterial spin labeling (ASL), a relatively new MR technique quantifying cerebral blood flow (CBF). Using ASL and structural MRI, we evaluated diagnostic classification in 32 prospectively included presenile early stage dementia patients and 32 healthy controls. Patients were suspected of Alzheimer's disease (AD) or frontotemporal dementia. Classification was based on CBF as perfusion marker, gray matter (GM) volume as atrophy marker, and their combination. These markers were each examined using six feature extraction methods: a voxel‐wise method and a region of interest (ROI)‐wise approach using five ROI‐sets in the GM. These ROI‐sets ranged in number from 72 brain regions to a single ROI for the entire supratentorial brain. Classification was performed with a linear support vector machine classifier. For validation of the classification method on the basis of GM features, a reference dataset from the AD Neuroimaging Initiative database was used consisting of AD patients and healthy controls. In our early stage dementia population, the voxelwise feature‐extraction approach achieved more accurate results (area under the curve (AUC) range = 86 ? 91%) than all other approaches (AUC = 57 ? 84%). Used in isolation, CBF quantified with ASL was a good diagnostic marker for dementia. However, our findings indicated only little added diagnostic value when combining ASL with the structural MRI data (AUC = 91%), which did not significantly improve over accuracy of structural MRI atrophy marker by itself. Hum Brain Mapp 35:4916–4931, 2014. © 2014 Wiley Periodicals, Inc .     

Identification of novel double-stranded RNA mycoviruses of Fusarium virguliforme and evidence of their effects on virulence

Virulence and double-stranded RNA (dsRNA) profiles of 44 isolates of Fusarium virguliforme were compared. When grouped according to dsRNA profiles, isolates with large dsRNAs were significantly (P≤0.05) less virulent than isolates without dsRNAs. High-throughput sequence analysis of total RNA prepared from cultures with large dsRNAs identified two novel RNA viruses with genome sequences of approximately 9.3 kbp, which were named Fusarium virguliforme dsRNA mycovirus 1 and Fusarium virguliforme dsRNA mycovirus 2. The new viruses were most closely related to a group of unclassified viruses that included viruses of F. graminearum and Phlebiopsis gigantea and are related to members of the family Totiviridae.     

Radiation in orthopaedics (RIO) study: a national survey of UK orthopaedic surgeons

Objectives:Orthopaedic surgeons have a responsibility to minimise risks of ionising radiation to patients, themselves and staff. This study aims to establish the understanding of radiation practice, legislation and risk by orthopaedic surgeons.Methods:A nationwide online survey of UK-based orthopaedic surgeons was conducted. Participants answered 18 multiple-choice questions assessing level of radiation safety training, basic principles/knowledge of ionising radiation, relevant legislation and operating practice.Results:A total of 406 surgeons completed the survey. 92% reported using intraoperative ionising radiation at least once per week. 38% received no formal training on radiation safety. Knowledge of basic principles of radiation and legislation was limited. There was variable knowledge when labelling an image intensifier machine and choosing its safest orientation. Poor uptake of radiation protection equipment was noted. Only 19% agreed they had adequate training in ionising radiation safety and 27% reported receiving adequate training in equipment emitting ionising radiation in the operating theatre.Conclusion:Many orthopaedic surgeons in the UK do not believe they are adequately trained in radiation safety. There is a deficiency amongst practicing surgeons in basic knowledge, relevant legislation and practicalities of the use of ionising radiation in the operating room. This could potentially put patients and health-care professionals at additional risk. We recommend that a standardised national training programme on the basic principles and safety of ionising radiation is implemented for all practicing orthopaedic surgeons.Advances in knowledge:This paper is the first UK national survey amongst orthopaedic surgeons and is one of the largest reported internationally.     

Group treatment of dog phobia in people with mental handicaps

The present study describes the group treatment of dog phobia in people with mental handicaps. The method was based on that described by Dixon and Gunary (1986) and the aim was to see whether their procedure could be shortened and still remain effective. Eleven sessions were held with a group of six adults. The techniques used included graded exposure, modelling, and video feedback. Fear responses were rated during each session. The results demonstrated that following the sessions all members of the group showed an increased ability to cope with the close proximity of a dog, despite the procedure having been shortened. Some disadvantages of working with a heterogeneous group, and problems of maintenance and generalisation, are discussed.