Implementing and evaluating far-field 3D X-ray diffraction at the I12 JEEP beamline, Diamond Light Source.

Three-dimensional X-ray diffraction (3DXRD) is shown to be feasible at the I12 Joint Engineering, Environmental and Processing (JEEP) beamline of Diamond Light Source. As a demonstration, a microstructually simple low-carbon ferritic steel was studied in a highly textured and annealed state. A processing pipeline suited to this beamline was created, using software already established in the 3DXRD user community, enabling grain centre-of-mass positions, orientations and strain tensor elements to be determined. Orientations, with texture measurements independently validated from electron backscatter diffraction (EBSD) data, possessed a ∼0.1° uncertainty, comparable with other 3DXRD instruments. The spatial resolution was limited by the far-field detector pixel size; the average of the grain centre of mass position errors was determined as ±âˆ¼80 µm. An average per-grain error of ∼1 × 10-3 for the elastic strains was also measured; this could be reduced in future experiments by improving sample preparation, geometry calibration, data collection and analysis techniques. Application of 3DXRD onto I12 shows great potential, where its implementation is highly desirable due to the flexible, open architecture of the beamline. User-owned or designed sample environments can be used, thus 3DXRD could be applied to previously unexplored scientific areas.

Applications of multivariate statistical methods and simulation libraries to analysis of electron backscatter diffraction and transmission Kikuchi diffraction datasets.

Multivariate statistical methods are widely used throughout the sciences, including microscopy, however, their utilisation for analysis of electron backscatter diffraction (EBSD) data has not been adequately explored. The basic aim of most EBSD analysis is to segment the spatial domain to reveal and quantify the microstructure, and links this to knowledge of the crystallography (e.g. crystal phase, orientation) within each segmented region. Two analysis strategies have been explored; principal component analysis (PCA) and k-means clustering. The intensity at individual (binned) pixels on the detector were used as the variables defining the multidimensional space in which each pattern in the map generates a single discrete point. PCA analysis alone did not work well but rotating factors to the VARIMAX solution did. K-means clustering also successfully segmented the data but was computational more expensive. The characteristic patterns produced by either VARIMAX or k-means clustering enhance weak patterns, remove pattern overlap, and allow subtle effects from polarity to be distinguished. Combining multivariate statistical analysis (MSA) approaches with template matching to simulation libraries can significantly reduce computational demand as the number of patterns to be matched is drastically reduced. Both template matching and MSA approaches may augment existing analysis methods but will not replace them in the majority of applications.

Movement Disorders in Children and Adolescents Receiving Antipsychotic Pharmacotherapy: A Population-Based Study.

OBJECTIVES: To describe a cohort of young users of risperidone and quetiapine in the province of Manitoba (Canada) and assess the risk for movement disorders in the two treatments. METHODS: This was a population-based study conducted on all residents of the province of 19 years of age and younger who received prescriptions for risperidone or quetiapine between April 1, 1996, and March 31, 2011. Incident rates of antipsychotic use were reported. The risk for movement disorders in patients treated with quetiapine compared with those treated with risperidone was assessed by time-to-event analysis using Cox proportional hazards models. RESULTS: Between April 1, 1996, and March 31, 2011, 23,888 youth (age ≤19 years) were prescribed an antipsychotic agent. Among them, 8756 were identified as new incident users. After applying exclusion criteria, 2594 individuals comprised the cohort of users of risperidone and quetiapine. The use of quetiapine was associated with a lower risk of extrapyramidal symptoms (EPSs) adverse events. The unadjusted and adjusted hazard ratios (95% confidence interval [CI]) for quetiapine versus risperidone were 0.83 (0.56-1.25) and 0.53 (0.34-0.83), respectively. CONCLUSION: EPS diagnoses have been detected in children treated with quetiapine; however, the risk of movement disorders appears to be higher with treatment with risperidone. Clinicians should always take into consideration the risk-benefit before treating children with antipsychotic medications and should be vigilant of the onset of drug-induced adverse events.

The contrasting roles of creep and stress relaxation in the time-dependent deformation during in-situ cooling of a nickel-base single crystal superalloy.

Time dependent plastic deformation in a single crystal nickel-base superalloy during cooling from casting relevant temperatures has been studied using a combination of in-situ neutron diffraction, transmission electron microscopy and modelling. Visco-plastic deformation during cooling was found to be dependent on the stress and constraints imposed to component contraction during cooling, which mechanistically comprises creep and stress relaxation. Creep results in progressive work hardening with dislocations shearing the γ' precipitates, a high dislocation density in the γ channels and near the γ/γ' interface and precipitate shearing. When macroscopic contraction is restricted, relaxation dominates. This leads to work softening from a decreased dislocation density and the presence of long segment stacking faults in γ phase. Changes in lattice strains occur to a similar magnitude in both the γ and γ' phases during stress relaxation, while in creep there is no clear monotonic trend in lattice strain in the γ phase, but only a marginal increase in the γ' precipitates. Using a visco-plastic law derived from in-situ experiments, the experimentally measured and calculated stresses during cooling show a good agreement when creep predominates. However, when stress relaxation dominates accounting for the decrease in dislocation density during cooling is essential.

Sustained Use of Benzodiazepines and Escalation to High Doses in a Canadian Population.

OBJECTIVE: "Antibenzodiazepine" campaigns have been conducted worldwide to limit the prescribing of these drugs because of concerns about inappropriate use and addiction. The causal relationship between long-term use and escalation to high doses has not been proven. This study assessed the extent of dose escalation among individuals who were long-term users of benzodiazepines or Z-hypnotics. METHODS: A population-based study was conducted in the Canadian province of Manitoba using administrative health databases. Sustained use was defined as continuous use for at least two years (N=12,598). Dose escalation, measured in diazepam milligram equivalents (DMEs) per day and observed at six-month intervals, was assessed by using latent-class trajectory analysis. Characteristics of individuals with sustained use were described. RESULTS: The analysis revealed four distinct groups. Two groups (<8% of the cohort) showed escalation to high doses (over 40 DMEs). More than 55% of high-dose escalators were in the 0- to 44-year age group, 75% lived in urban areas, and approximately 75% had a diagnosis of depression. Clonazepam was the drug most commonly involved with dose escalation; among individuals escalating to doses higher than 60 DMEs, 91% were using clonazepam. Rates of "doctor shopping" and "pharmacy hopping" were higher among younger adults, compared with older adults. Younger adults also had higher rates of concomitant antidepressant therapy. CONCLUSIONS: A limited segment of a population that received benzodiazepine prescriptions was classified as sustained users, and a small proportion of that group escalated to doses higher than those recommended by product monographs and clinical guidelines.

Use of benzodiazepines and related drugs in Manitoba: a population-based study.

BACKGROUND: Despite their favourable toxicology profile, benzodiazepines and the related Z-drugs (zopiclone, zolpidem and zaleplon) have been associated with physiological tolerance, dependence and addiction. Evidence of harm (e.g., falls, motor vehicle collisions and cognitive disturbances) has been reported in older populations. The aim of this study was to determine the relation between users' characteristics and the use of benzodiazepines and Z-drugs in Manitoba over a 16-year period. METHODS: This time-series analysis was based on prescription data from Apr. 1, 1996, to Mar. 31, 2012, obtained from the Drug Product Information Network database of Manitoba. We obtained sociodemographic information on benzodiazepine and Z-drug users from the Population Registry and determined changes in utilization rates over time using generalized estimating equations. RESULTS: Overall, the prevalence of benzodiazepine use remained stable at about 61.0 per 1000 population between 1996/97 and 2011/12; however, the prevalence of Z-drug use increased steadily from 10.9 to 37.0 per 1000 over the same period. In older people (≥ 65 years), the incidence of benzodiazepine use decreased from 55.5 to 30.3 users per 1000, whereas the incidence of Z-drug use increased from 7.3 to 20.3 users per 1000 over the study period. Among those 18-64 years of age, the incidence of benzodiazepine use decreased from 30.1 to 27.6 users per 1000, but the increase in incidence of Z-drug use was more than 2-fold. The youngest population (≤ 17 years) showed the lowest rates of use of these drugs. The highest rates of use were observed among older women and the low-income population. INTERPRETATION: Over the study period, benzodiazepines have been prescribed less frequently to older patients in Manitoba; however, zopiclone prescribing has continued to increase for all age groups. The reasons for this increase remain to be determined.

A population-based study of the use of selective serotonin reuptake inhibitors before and after introduction of generic equivalents.

OBJECTIVE: Generic drugs are less expensive than their branded equivalents, but receive limited promotion. This study sought to examine how user rates of individual selective serotonin reuptake inhibitors (SSRIs) changed after the introduction of their generic equivalents. METHOD: Administrative health and census data were used to examine the rates of use of all 6 SSRIs from 1996 to 2009 in the province of Manitoba (population of 1.2 million). The primary outcome measure was a comparison of the rates of use in the pre- and post-generic periods, using generalized estimating equations. Secondary analyses were stratified by specialty of physician prescriber. RESULTS: Escalating rates of use of branded SSRIs in the pre-generic period significantly decreased after generic versions became available (all Ps < 0.001). Incident use of sertraline and paroxetine continued to decrease throughout the post-generic period (1.5% and 1.9% quarterly decreasing rates, respectively). During the years when generic sertraline, fluoxetine, and fluvoxamine were available, their use declined while branded paroxetine and citalopram use continued to increase. Use of branded citalopram, sertraline, and paroxetine prescribed by general practitioners (GPs) increased at rates significantly higher than when prescribed by psychiatrists (all Ps < 0.001). CONCLUSION: The introduction of cheaper generic alternatives of SSRIs paradoxically resulted in their use diminishing rather than increasing. With the exception of escitalopram, branded SSRIs tended to be preferentially used, compared with available less expensive generic SSRIs. These patterns were more pronounced for prescriptions by GPs.

Ten years of antipsychotic prescribing to children: a Canadian population-based study.

OBJECTIVE: To report the prescribing of antipsychotics to the youth population of the Canadian province of Manitoba during the course of a decade. METHODS: Use of antipsychotics in children and adolescents (aged 18 years or younger) was described using data collected from the administrative health databases of Manitoba Health and the Statistics Canada census between the fiscal years of 1999 and 2008. RESULTS: The prevalence of antipsychotic use in this segment of the population increased with the introduction of the second-generation antipsychotics (SGAs) from 1.9 per 1000 in 1999 to 7.4 per 1000 in 2008. The male-to-female antipsychotic usage ratio increased from 1.9 to 2.7 as the male youth population represented the fastest-growing subgroup of antipsychotic users in the entire population of Manitoba. The total number of prescriptions also increased significantly despite the lack of approved indications in this population. Proportion of use remained equally split between high- and low-income users. More than 70% of antipsychotic prescriptions to children and adolescents were written by general practitioners. The most common diagnoses linked to antipsychotic use were attention-deficit hyperactivity disorder and conduct disorders. Use of antipsychotics in combination with methylphenidate increased from 13% to 43%. CONCLUSION: Extensive off-label use of SGAs has been observed in the youth population of Manitoba for treatment of aggressive behaviours across a range of diagnoses. It is important to monitor antipsychotic prescribing to children as more reports of significant adverse events associated with antipsychotics become available.

Safety and efficacy of an ocular insert for apomorphine-induced emesis in dogs.

OBJECTIVE: To evaluate the safety and efficacy of an ocular insert designed to provide controlled release of apomorphine for the induction of emesis in dogs. ANIMALS: 5,001 dogs treated with ocular apomorphine inserts and 32 dogs treated with IV administration of apomorphine. PROCEDURES: Data collected on a case report form included breed, body weight, time to emesis after placement of the insert, and any information available regarding the nature of the toxicosis and clinical signs. A list of potential adverse effects was provided, and attending clinicians graded their occurrence by use of a subjective scale. Similar report forms were used for dogs that received apomorphine IV. Treatment was considered successful if emesis occurred within 15 minutes of administration. Safety was assessed by evaluation of the frequency and severity of adverse effects. RESULTS: For the ocular insert and IV injection groups, the success rates were 83.5% and 90.6% respectively, and were not significantly different. Adverse effects were more frequent in the IV group, whereas ocular irritation was most frequent in the insert group. CONCLUSIONS AND CLINICAL RELEVANCE: Overall, the ocular inserts provided an alternative to parenteral administration of apomorphine with comparable efficacy and a lower prevalence of adverse effects.

Utilization and costs of antipsychotic agents: a Canadian population-based study, 1996-2006.

OBJECTIVE: This study evaluated the prescribing patterns and costs for antipsychotic agents in the population of the Canadian province of Manitoba over the past decade. METHODS: A population-based study of antipsychotic utilization and costs was conducted on data collected from the administrative databases of the Manitoba Population Health Data Repository and the Statistics Canada census between index years 1996 and 2006 (April 1, 1995, through March 31, 2006). RESULTS: The total annual number of antipsychotic prescriptions dispensed in Manitoba increased by 227% between 1996 and 2006, and the prevalence of antipsychotic users increased by 62% over the same time interval. The fastest-growing segment of antipsychotic users in Manitoba appears to be young males, who increased from .16% in 1996 to .88% in 2006. The highest numbers of prescriptions were reported for schizophrenia, dementia, and conduct disorder. Annual expenditures for antipsychotics increased from $1.7 million in 1996 to $22.0 million in 2006 (expenditures are in Canadian dollars). The cost of second-generation agents reached 80% of total antipsychotic expenditures in 2006; risperidone was the most prescribed agent in all age groups of patients. The per-patient annual cost of antipsychotic pharmacotherapy increased by approximately 680% between 1996 and 2006 in Manitoba. CONCLUSIONS: The number of antipsychotic prescriptions and the prevalence of users of antipsychotic medications increased significantly in Manitoba over the study period, despite a steady-state population of approximately 1.2 million. Incremental costs relative to the use of antipsychotic medications can be explained by the market penetration of the second-generation agents and their expanded use in the treatment of various diagnoses.

Evaluation of an interchangeability switch in patients treated with clozapine: A retrospective review.

OBJECTIVE: To report the findings of a switch from brand-name to generic clozapine in a Canadian outpatient population. METHOD: The medical records of 58 outpatients diagnosed with schizophrenia and other psychotic disorders and stabilized on brand-name clozapine therapy were reviewed retrospectively. Patients were switched from brand-name to generic clozapine on their next dispensing supply after September 29, 2003. Data regarding clozapine dose regimens, physicians' visits, hospitalizations, and adverse events were collected from the patients' charts for the 6 months preceding and the 6 months after the switch from brand-name to generic clozapine. Relevant measurement changes in those data associated with the switch are evaluated. RESULTS: No significant changes in dose, number of physician's visits, or hospitalization rates were observed as a consequence of the switch from brand-name to generic clozapine. In addition, there were no reported increases in the frequency of the most common adverse events, including decreases in white blood cell counts. None of the patients received a "nonrechallengeable" status, and no discontinuation of clozapine therapy occurred for any reason (toxicity or treatment failure) in the 6 months after the formulation switch. CONCLUSION: In the current outpatient population, retrospective evaluation of the conversion from brand-name clozapine to the first generic alternative available on the Canadian market did not reveal any significant treatment changes.

Erythropoietin-alpha dosage requirements in a provincial hemodialysis population: effect of switching from subcutaneous to intravenous administration.

BACKGROUND: The purpose of this initiative was to compare erythropoietin-alpha doses in hemodialysis patients who changed from subcutaneous to intravenous administration. The Manitoba Renal Program switched routes due to concern about erythropoietin-associated pure red cell aplasia. METHODS: We compared the erythropoietin-alpha dosage requirements during subcutaneous administration (3 months pre-switch) and intravenous administration (months 4-6 post-switch). We also compared: hemoglobin, transferrin saturation (Tsat%), ferritin, and percent of patients receiving intravenous iron. The same erythropoietin-alpha regimen was initially used when patients were switched. RESULTS: Of the 628 patients receiving erythropoietin-alpha, the data were complete for 400. The dose increased 26% (mean +/- SD, 10,425 +/- 7,330 vs. 13,125 +/- 8,638 IU/week; p < 0.0001), despite similar hemoglobin, (mean +/- SD, 11.5 +/- 1.1g/dl (114.9 +/- 11.2 g/l) vs. 11.3 +/- 1.0 g/dl (113.5 +/- 10.4 g/l); p = 0.0450) and iron parameters (Tsat 30.9%, ferritin 464 ng/ml (microg/l) vs. Tsat 28.7%, ferritin 538 ng/ml (microg/l)). For the subgroup of 84 patients who maintained target hemoglobin (10-11 g/dl or 110-120 g/l) for both periods, the dose increased 26% (mean +/- SD, 8,393 +/- 6,242 vs. 10,589 +/- 7,049 IU/week; p < 0.0001) without a change in hemoglobin, (mean +/- SD, 11.5 +/- 0.3 g/dl (115.2 +/- 3.0 g/l) vs. 11.5 +/- 0.3 g/dl (114.9 +/- 3.3 g/l); p = 0.5789). When stratified by subcutaneous dose, patients with the lowest dose (<5,000 IU/week) demonstrated the greatest increase (89%), and those with the highest dose (>20,000 IU/week) experienced no increase (-3%). CONCLUSION: Overall, erythropoietin-alpha doses increased by 26% when patients were converted from subcutaneous to intravenous administration.

Conversion from subcutaneous to intravenous erythropoietin in a hemodialysis population.

The purpose of this study was to compare erythropoietin dosage requirements during subcutaneous versus intravenous administration in a hemodialysis population. Hemodialysis patients receiving subcutaneous epoetin alfa were switched to the intravenous route using a prospective, crossover design. Baseline anemia parameters were measured at months -2, -1, and 0 when patients were receiving subcutaneous dosing and compared to months 4, 5, and 6 after the switch to intravenous dosing. Ninety-eight patients were enrolled into the study with an average age of 54.8 years. Over the course of the study, 34 patients were excluded from analysis, leaving 64 patients with complete hemoglobin and erythropoietin dosing data throughout the subcutaneous and intravenous evaluation periods. In these patients, the dose of erythropoietin increased significantly from the subcutaneous to the intravenous period (7567.7 to 10229.2 IU/wk). The conversion of hemodialysis patients from the subcutaneous to the intravenous route of administration significantly increased epoetin alfa dosage requirements.

Predictors of receipt of a fluoroquinolone versus trimethoprim-sulfamethoxazole for treatment of acute pyelonephritis in women in Manitoba, Canada.

PURPOSE: The increasing and comparatively high proportion of uropathogens in Canada resistant to trimethoprim-sulfamethoxazole (TMP-SMX) may be partially responsible for the increasing use of fluoroquinolones. A number of patient-specific variables have been identified as risk factors for infections caused by antibiotic-resistant pathogens. However, variables unrelated to need, have also been associated with receipt of broad-spectrum antibiotics. We identified patient variables associated with receipt of a fluoroquinolone versus TMP-SMX for treatment of acute pyelonephritis. METHODS: Healthcare claims from the province of Manitoba, Canada for the period February 1996 to March 1999 were examined to identify episodes of pyelonephritis in non-pregnant females between 18 and 65 years of age treated with TMP-SMX or a fluoroquinolone. Patient variables were identified based on healthcare claims review and data from Statistics Canada. Logistic regression was used to model the probability of receipt of a fluoroquinolone. RESULTS: A total of 1084 women met inclusion criteria; 653 treated with TMP-SMX and 431 treated with a fluoroquinolone. Age, income, rural residence, recent antibiotic use, recent hospitalization and presentation to an emergency room (ER) were positively associated with receipt of a fluoroquinolone. CONCLUSIONS: Patient variables reportedly associated with an increased probability of resistant organisms (e.g., age, recent antibiotic use and recent hospitalization) were significantly associated with an increased probability of receipt of fluoroquinolones. However, variables unrelated to antibiotic resistance (e.g., income, rural residence and presentation to an ER) were also significantly associated with receipt of a fluoroquinolone.