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Introduction: Canadians are the second largest consumers of prescription opioids per capita in the world. Emergency physicians tend to prescribe stronger and larger quantities of opioids, while family physicians write the most opioid prescriptions overall. These practices have been shown to precipitate future dependence, toxicity and the need for hospitalization. Despite this emerging evidence, there is a paucity of research on emergency physicians’ opioid prescribing practices in Canada. The objectives of this study were to describe our local emergency physicians’ opioid prescribing patterns both in the emergency department and upon discharge, and to explore factors that impact their prescribing decisions. Methods: Emergency physicians from two urban, adult emergency departments in St. John's, Newfoundland were anonymously surveyed using a web-based survey tool. All 42 physicians were invited to participate via email during the six-week study period and reminders were sent at weeks two and four. Results: A total of 21 participants responded to the survey. Over half of respondents (57.14%) reported that they “often” prescribe opioids for the treatment of acute pain in the emergency department, and an equal number of respondents reported doing so “sometimes” at discharge. Eighty-five percent of respondents reported most commonly prescribing intravenous morphine for acute pain in the emergency department, and over thirty-five percent reported most commonly prescribing oral morphine upon discharge. Patient age and risk of misuse were the most frequently cited factors that influenced respondents’ prescribing decisions. Only 4 of the 22 respondents reported using evidence-based guidelines to tailor their opioid prescribing practices, while an overwhelming majority (80.95%) believe there is a need for evidence-based opioid prescribing guidelines for the treatment of acute pain. Sixty percent of respondents completed additional training in safe opioid prescribing, yet less than half of respondents (42.86%) felt they could help to mitigate the opioid crisis by prescribing fewer opioids in the emergency department. Conclusion: Emergency physicians frequently prescribe opioids for the treatment of acute pain and new evidence suggests that this practice can lead to significant morbidity. While further research is needed to better understand emergency physicians’ opioid prescribing practices, our findings support the need for evidence-based guidelines for the treatment of acute pain to ensure patient safety.
As the central component of heightened vascularization in glioblastoma (GBM), endothelial cells (EC) are arguably the most responsive stromal cells in the tumour microenvironment during conventional treatment using ionizing radiation (IR). Although the inherent tumor tropism and angiogenic property of mesenchymal stem cells (MSC) has been documented in many cancer types including GBM, little is known about the function of MSC that are recruited to the GBM tumor microenvironment. The purpose of this study was to elucidate the effect of MSC on irradiated EC. Here we studied the influence of IR, MSC or MSC condition media (CM) on human umbilical vein endothelial cells (HUVECs). IR was found to up-regulate mRNA levels of CXCL5, CXCL10, ICAM1, VCAM1, VEGF-c and tissue factor (TF) in a dose-dependent manner whereas MSC co-culture boosted the expression of ICAM1, VCAM1, VEGF-c, TF, and MCP3. An additive effect of IR and MSC-culture was most detected with respect to ICAM1, TF and CXCL5 under 2Gy. MSC co-culture decreased IR-induced phospho-p53 in HUVECs at 15Gy. In addition, IR decreased the level of phospho-Akt in HUVECs as well as cell proliferation. Notably, both effects were countered by MSC CM. Interestingly, up-regulation of the same set of IR-driven genes in GBM was positively correlated with poor survival in the TCGA GBM database, a correlation that was lost if using gene list that was obtained from IR and MSC combine. These findings suggest that MSC promotes angiogenesis in GBM by overturning the IR-induced active state of endothelial cells and rendering them radio-resistant.
Few studies have investigated the impact of parental suicide attempt (SA) on offspring outcomes other than mental health. We investigated the association of parental SA with offspring educational attainment in the Avon Longitudinal Study of Parents and Children (ALSPAC).
Parental SA was prospectively recorded from pregnancy until the study children were 11 years old. National school test results (ages 11–16 years) were obtained by record linkage. Multilevel regression models quantified the association between parental SA and offspring outcomes.
Data were available for 6667 mother–child and 3054 father–child pairs. Adolescents whose mothers had attempted suicide were less likely than their peers to achieve the expected educational level by age 14 years [adjusted odds ratio (aOR) 0.63, 95% confidence interval (CI) 0.41–0.95] in models controlling for relevant confounders, including parental education and depression. At age 16 years, adolescents whose mothers had attempted suicide were less likely to obtain the expected educational level (five or more qualifications at grade A*–C) (aOR 0.66, 95% CI 0.43–1.00) in models controlling for relevant confounders and parental education; however, after additionally controlling for maternal depression the results were consistent with chance (aOR 0.74, 95% CI 0.48–1.13). Findings in relation to paternal SA were consistent with those of maternal SA but power was limited due to lower response rate amongst fathers.
Maternal SA was associated with diminished educational performance at age 14 years. Educational attainment during adolescence can have substantial effect on future opportunities and well-being and these offspring may benefit from interventions.
A randomised controlled trial (RCT) of high-dose v. low-dose fish oil in recent-onset rheumatoid arthritis (RA) demonstrated that the group allocated to high-dose fish oil had increased remission and decreased failure of disease-modifying anti-rheumatic drug (DMARD) therapy. This study examines the relationships between plasma phospholipid levels of the n-3 fatty acids in fish oil, EPA and DHA, and remission and DMARD use in recent-onset RA. EPA and DHA were measured in blood samples from both groups of the RCT. The data were analysed as a single cohort, and Cox proportional hazards models were used to examine relationships between plasma phospholipid (PL) EPA and DHA and various outcome measures. When analysed as a single cohort, plasma PL EPA was related to time to remission, with a one unit increase in EPA (1 % total fatty acids) associated with a 12 % increase in the probability of remission at any time during the study period (hazard ratio (HR)=1·12; 95 % CI 1·02, 1·23; P=0·02). Adjustment for smoking, anti-cyclic citrullinated peptide antibodies and ‘shared epitope’ HLA-DR allele status did not change the HR. Plasma PL EPA, adjusted for the same variables, was negatively related to time to DMARD failure (HR=0·85; 95 % CI 0·72, 0·99; P=0·047). The HR for DHA and time to remission or DMARD failure were similar in magnitude to those for EPA, but not statistically significant. Biomarkers of n-3 status, such as plasma PL EPA, have the potential to predict clinical outcomes relevant to standard drug treatment of RA patients.
Randomised controlled trials (RCT) examining the effects of fish oil supplementation on cardiac outcomes have yielded varying results over time. Although RCT are placed at the top of the evidence hierarchy, this methodology arose in the framework of pharmaceutical development. RCT with pharmaceuticals differ in important ways from RCT involving fish oil interventions. In particular, in pharmaceutical RCT, the test agent is present only in the intervention group and not in the control group, whereas in fish oil RCT, n-3 fats are present in the diet and in the tissues of both groups. Also, early phase studies with pharmaceuticals determine pharmacokinetics and pharmacodynamics to design the dose of the RCT intervention so that it is in a predicted linear dose–response range. None of this happens in fish oil RCT, and there is evidence that both baseline n-3 intake and tissue levels may be sufficiently high in the dose–response range that it is not possible to demonstrate a clinical effect with a RCT. When these issues are considered, it is possible that the changing pattern of fish consumption and fish oil use over time, especially in cardiac patients, can explain the disparity where benefit was observed in the early fish oil trials but not in the more recent trials.
High-redshift quasars are unique probes of the evolution of supermassive black holes and the intergalactic medium at the end of the epoch of reionization. We present the optical spectra of eight new z ~ 6 quasars selected from the Panoramic Survey Telescope & Rapid Response System 1 (Pan-STARRS1). Details of the selection strategy can be found in Bañados et al. (2014). With this work we increase the number of known quasars at z < 5.7 by more than 10%. The quasars discovered here span a large range of luminosities (19.6 ≤ zP1 ≤ 21.2) and are remarkably heterogeneous in their spectral features: half of them show bright emission lines whereas the other half show weak or no Lyα emission line. We find a larger fraction of weak–line emission quasars than in lower redshift studies, although still based on low number statistics, this may imply that the quasar population could be more diverse than previously thought.
The Nuclear Decommissioning Authority (NDA) is developing a safety case for the long-term management of higher activity wastes. This includes safety assessments of transport to and operations at the repository. One of the main faults and hazards to be considered is waste package response to impact accidents.
The criteria of impact performance for waste packages are based upon activity release of particulates generated from the break up of the waste form during impact. The NDA approach to impact performance is based upon waste package response from finite element modelling in combination with break-up tests.
Previous break up research commissioned by the NDA has concentrated on commercial graphite and glass samples. These extended studies, undertaken by the National Nuclear Laboratory in collaboration with the Department of Aerosol Technology of the Fraunhofer Institute of Toxicology and Experimental Medicine, provide break-up data specific to nuclear facilities and waste materials. These include archived unirrradiated graphite used to construct Magnox reactor cores and reflectors, simulant high level waste glass, selected grout formulations and selected metal-in-grout formulations.
Children whose parents die by, or attempt, suicide are believed to be at greater risk of suicidal behaviours and affective disorders. We systematically reviewed the literature on these associations and, using meta-analysis, estimated the strength of associations as well as investigated potential effect modifiers (parental and offspring gender, offspring age).
We comprehensively searched the literature (Medline, PsycINFO, EMBASE, Web of Science), finding 28 articles that met our inclusion criteria, 14 of which contributed to the meta-analysis. Crude odds ratio and adjusted odds ratio (aOR) were pooled using fixed-effects models.
Controlling for relevant confounders, offspring whose parents died by suicide were more likely than offspring of two living parents to die by suicide [aOR 1.94, 95% confidence interval (CI) 1.54–2.45] but there were heterogeneous findings in the two studies investigating the impact on offspring suicide attempt (aOR 1.31, 95% CI 0.73–2.35). Children whose parents attempted suicide were at increased risk of attempted suicide (aOR 1.95, 95% CI 1.48–2.57). Limited evidence indicated that exposure to parental death by suicide is associated with subsequent risk of affective disorders. Maternal suicidal behaviour and younger age at exposure were associated with larger effect estimates but there was no evidence that the association differed in sons versus daughters.
Parental suicidal behaviour is associated with increased risk of offspring suicidal behaviour. Findings suggest that maternal suicidal behaviour is a more potent risk factor than paternal, and that children are more vulnerable than adolescents and adults. However, there is no evidence of a stronger association in either male or female offspring.
Granular materials are now recognized as a distinct state of matter, and studies of their behavior form a fascinating interdisciplinary branch of science. The intrinsic dissipative nature of the interactions between the constituent macroscopic particles gives rise to several basic properties specific to granular substances, setting granular matter apart from the conventional gaseous, liquid, or solid states.
Thin layers of granular materials subjected to vertical vibration exhibit a diversity of patterns. The particular pattern is determined by the interplay between driving frequency f and the acceleration amplitude Γ. Interfaces in vibrated granular layers, existing for large enough amplitude of vibration, separate large domains of flat layers oscillating with opposite phase. These two phases are related to the period-doubling character of the flat layer motion at large plate acceleration. Interfaces are either smooth or “decorated” by periodic undulations depending on parameters of vibration. An additional subharmonic driving results in a controlled displacement of the interface with respect to the center of the experimental cell. The speed and the direction of the interface motion are sensitive to the phase and amplitude of the subharmonic driving.
The image sequence above shows interface nucleation and propagation towards the center of the cell, with dimensionless time tf labeled in each image. The interface forms at the right side wall of the cell due to small-amplitude phase-shifted subharmonic driving. After the additional driving stops, the interface moves towards the center, creating small-scale localized structures in the process.
We probe the transitions between solid-like and fluid-like granular states in the presence of shaking in the horizontal and vertical directions. These transitions are fundamental to other aspects of granular flow such as avalanche flow, in which there is a free surface. Key control parameters include accelerations in the vertical and horizontal directions, Γi = Aiω2i/g, for shaking of the form si = Ai cos(ωit + φi), i = h, v. Here, g is the acceleration of gravity. Also important is the relative phase between the two modes of shaking. We focus on low to moderate dimensionless accelerations, 0 < Γv,h < 1.6. We consider first the case Γv = 0, i.e. pure horizontal shaking. In this case, there is a hysteretic transition between solid and fluid states, where the fluid state consists of a sloshing layer of material of height H plus additional transverse flow. The hysteresis is lifted in the presence of a modest amount of fluidization by gas flow, or if a slight overburden is provided. We also identify a time scale, τ, for the transition between the phases that diverges inversely as the distance ε = (Γh–Γhc)/Γhc, from the appropriate transition points, i.e. as τ α ε-1. We identify a new convective mechanism, associated with horizontal shearing at the walls, as the mechanism that drives the transverse convective flow. For combined horizontal and vertical shaking, there exist a related set of novel dynamics and stability properties. These include the spontaneous formation of a static heap and a transition to flow, similar to the flow state under horizontal shaking, when the vertical acceleration Γv < 1. A simple friction model provides a good description of the steady states and a reasonably good description of the transition to flow. Horizontal and vertical shaking frequencies that differ by a small amount can lead to a novel switching state, as the relative phase, φh—φv, shifts over time.
The production of potent toxins by bloom-, scum- and mat-forming cyanobacteria, in fresh-, brackish and marine waters, appears to be a
global phenomenon. Cyanobacterial toxins can also be produced by cyanobacteria from terrestrial sources. The range and number of
known cyanobacterial toxins are increasing apace as associated poisoning incidents are investigated, and increasingly powerful analytical
methods are applied to complement toxicity-based studies on both natural samples and laboratory isolates of cyanobacteria. Water quality
management to reduce toxic cyanobacterial mass developments, and schemes to mitigate the potential effects of cyanobacterial toxins,
require an understanding of the occurrence and properties of the toxins and of the exposure routes via which the toxins present risks to
health. Here, we review advances in the recognition of cyanobacterial toxins and their toxicity, and of the exposure routes with reference
to human health, namely via skin contact, inhalation, haemodialysis and ingestion (the oral route).
The effect of intake on urea production, entry into the digestive tract and return of N to the ornithine cycle was studied in four sheep. Each sheep received 0–6, 1–2 and 1.8 × estimated maintenance energy intake quantities of grass pellets for 9 d. After 4 d of adjustment, N balance measurements were conducted between days 5 and 8. From day 7 to day 9 animals were continuously infused, via the jugular vein, with [15N15N]urea and three urine samples were collected at approximately 2h intervals 48–54h after the start of infusion. Total urea and enrichments of [15N15N]- and [14N15N]urea in the urine samples were determined. Urea production was calculated from the isotopic dilution of [15N15N]urea and entry into the gastrointestinal tract (GIT) obtained from the difference between this and urinary urea elimination. Urea which enters the GIT undergoes hydrolysis to liberate NH3 which may be reabsorbed and enter the ornithine cycle, in which case the product is [14N15N]urea, based on the probabilities of labelled and unlabelled N providing ureagenic precursors. The quantity of urea-N which returns to the ornithine cycle from the GIT can thus be calculated. Existing models based on this approach yield overestimates of the fate of individual urea molecules due to a failure to allow for multiple recycling of [14N15N]urea species through the GIT. Refinements introduced to cover this resulted in a 33–48 % reduction in calculated return of label for the current study. The present model also predicted that 95 % of the label movements across the GIT could be accommodated by three or fewer entries and returns of urea-N and 99 % by recycling for a maximum of six occasions. Urea-N production increased with intake (P < 0.001) and exceeded digestible N values at all intakes. Urea which entered the digestive tract, both in absolute terms (P < 0.001) and as a proportion of production (0.62, 0.69, 0.73; P = 0.027), increased with intake. The proportion of entry into the digestive tract which was returned to the ornithine cycle remained reasonably constant (0.37–0.41) across all intakes but the absolute amount increased (5.6, 9.2 and 15.0gN/d; P < 0.001) with intake. If allowance is included for losses of 15N in faeces then the approach offers a relatively simple means of estimating anabolic reuse of urea by digestive tract micro-organisms and can complement data obtained from the technically more demanding arterio-venous and multiple-isotope techniques used hitherto.
The hepatic responses of late gestation, dry dairy cows to acute (6 h) infusions of an amino acid (AA) mixture (Synthamin; 0.0, 1.1, 2.2, 4.4, 8.8 and 17.6 mmol/min) into the mesenteric vein were determined. Neither blood flow nor O2 consumption across the portal-drained viscera (PDV) and liver was significantly altered by infusion. Similarly, there were no effects on net absorption, or hepatic removal, of acetate, propionate, butyrate or NH3. Glucose PDV appearance was unchanged but hepatic glucose production increased (P = 0.032) by 0.2 mmol/min per mmol/min of AA infused. Additional extraction of alanine, glycine (both infused) and glutamine (not infused) by the liver was sufficient to account for most of the extra C required for glucose synthesis. The N that would be liberated from these glucogenic AA would also account for a large proportion of the increase in urea-N produced in response to the AA infusion. This supports the concept of a correlation between gluconeogenesis and ureagenesis. Furthermore, the amide-N liberated from the extracted glutamine would contribute up to 0.17 of hepatic NH3 flux and assist in balancing N inputs into the carbamoyl phosphate and arginosuccinate entry points of the ornithine cycle. Rates of fractional extraction of the various AA by the liver were best fitted by linear equations, indicating that even at the highest rates of administration (approximately twice maximal physiological absorption) the transport systems were not saturated. Hepatic fractional extractions of infused essential AA were highest for methionine (0.83) and phenylalanine (0.87) with the lowest proportion removed observed for valine (0.25), leucine (0.30), lysine (0.31) and isoleucine (0.49). For the non-essential AA, the highest apparent fractional extractions were for glycine (0–73), arginine (0.79) and tyrosine (0.63) followed by alanine (0.54), proline (0.47) and serine (0–37). Hepatic removal of AA-N exceeded the increase in urea-N formation such that, at the highest rate of infusion, approximately 10 mmol/min of the extracted AA was apparently available for hepatic anabolism, more than is required to account for assumed increases in liver mass and export protein synthesis. Similarly, the amount of AA available for peripheral tissue protein gain, when assessed against phenylalanine supply as the limitation, would be the equivalent of a maximum of 0.5 g protein retained/min (6 mmol AA-N/min). This would provide sufficient AA for replenishment of peripheral (muscle) protein stores plus support of the placenta and fetus.