Phytochemical characterization and toxicological activity attributed to the acetonic extract of South American Vassobia breviflora.

The particular plant species found in southern Brazil, Vassobia breviflora (Solanaceae) has only a few apparent studies examining its biological effect. Thus, the aim of the present study was to determine the activity of the acetone extract fraction derived from V. breviflora. Four compounds were identified by ESI-qTOF-MS: eucalrobusone R, aplanoic acid B, pheophorbide A, and pheophytin A. In addition, 5 compounds were identified by HPLC-PDA-MS/MS: all-trans-lutein, 15-cis-lutein, all-trans-ß-carotene, 5,8-epoxy-ß-carotene, and cis-ß-carotene. Cell lines A549 (lung cancer), A375 (melanoma cancer) and HeLa (cervical cancer) were incubated with different concentrations of each studied extract using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and 2'-7'dichlorofluorescin diacetate (DCFH-DA) assays. The acetonic extract exhibited cytotoxic activity at a concentration of 0.03 mg/ml in the HeLa strain and 0.1 mg/ml in the others. In addition to increased production of reactive oxygen species (ROS). Antibacterial activity was assessed utilizing minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) in 9 ATCCs strains and 7 clinical isolates, as well as determination of biofilm production. Data demonstrated that MIC and MBC were approximately 256 mg/ml in most of the strains tested and antibiofilm effect at S. aureus, S. epidermidis, A. baumannii, and E. faecalis, concentrations below the MIC. Genotoxic activity on plasmid DNA did not produce significant elevated levels in breaks in the isolated genetic material.

Insights on the Bioaccessibility of Natural Pigments from Diatom Chaetoceros calcitrans.

This study aimed to investigate the bioaccessibility of carotenoids and chlorophylls from the biomass of microalgae Chaetoceros calcitrans. The samples were submitted to an in vitro digestion protocol, and the compounds were determined by HPLC-PDA-MS/MS. A total of 13 compounds were identified in all tests. After in vitro digestion, the relative bioaccessibility of carotenoids and chlorophylls ranged from 4 to 58%. The qualitative profile of carotenoids reflected the initial sample, with all-E-zeaxanthin (57.2%) being the most bioaccessible compound, followed by all-E-neochrome (31.26%), the latter being reported for the first time in the micellar fraction. On the other hand, among the chlorophylls only pheophytin a (15.01%) was bioaccessible. Furthermore, a chlorophyll derivative (Hydroxypheophytin a') was formed after in vitro digestion. Considering all compounds, xanthophylls (12.03%) and chlorophylls (12.22%) were significantly (p < 0.05) more bioaccessible than carotenes (11.22%). Finally, the considerable individual bioaccessibilities found, especially for zeaxanthin, demonstrate the bioactive potential of this bioresource. However, the large reduction in the totality of compounds after in vitro digestion suggests that additional technological strategies should be explored in the future to increase the efficiency of micellarization and enhance its bioactive effects.

Trends and uptake of new formulations of controlled-release oxycodone in Canada.

PURPOSE: This study investigated the impact of changing availability of tamper-deterrent and non-tamper-deterrent oxycodone on prescribing patterns of controlled-release oxycodone across Canada. METHODS: We conducted a population-based, serial cross-sectional study of controlled-release oxycodone dispensing from community pharmacies across Canada between October 2007 and April 2016. We calculated rates of dispensing (tablets per 100 population) and reported the relative market share of generic non-tamper-deterrent controlled-release oxycodone. All analyses were reported nationally and stratified by province. RESULTS: After the introduction of a tamper-deterrent formulation, the national rate of controlled-release oxycodone dispensing fell by 44.6% (from 26.4 to 14.6 tablets per 100 population from February 2012 to April 2016). Between December 2012 and July 2013, there was moderate uptake of generic non-tamper-deterrent controlled-release oxycodone (968 452 tablets; 16.0% in July 2013), which appeared to have little impact on the overall rate of controlled-release oxycodone dispensing in Canada. However, the uptake of generic non-tamper-deterrent oxycodone varied considerably by province. By April 2016, 55.0% of all controlled-release oxycodone tablets dispensed in Quebec were for the generic formulation. Elsewhere in Canada, this prevalence was less than 30%, ranging between 1.6% (Prince Edward Island) and 26.9% (British Columbia) at the end of our study period. CONCLUSIONS: The changing availability of tamper-deterrent and non-tamper-deterrent formulations of controlled-release oxycodone in Canada has had variable influence on the rate of use of these products across Canada. Future research should explore whether the availability of generic controlled-release oxycodone has led to measurable changes in the safety of oxycodone use in Canada.

Government Direct-to-Consumer Education to Reduce Prescription Opioid Use: A Cluster Randomized Clinical Trial.

Importance: Direct-to-consumer education reduces chronic sedative use. The effectiveness of this approach for prescription opioids among patients with chronic noncancer pain remains untested. Objectives: To evaluate the effectiveness of a government-led educational information brochure mailed to community-dwelling, long-term opioid consumers to reduce prescription opioid use compared with usual care. Design, Setting, and Participants: This cluster randomized clinical trial was conducted from July 2018 to January 2019 in Manitoba, Canada. All adults with long-term opioid prescriptions were enrolled (n = 4225). Participants were identified via the Manitoba Drug Program Information Network. Individuals receiving palliative care or with a diagnosis of cancer or dementia were excluded. Data were analyzed from July 2019 to March 2020. Intervention: Participants were clustered according to their primary care clinic and randomized to the intervention (a codesigned direct-to-consumer educational brochure sent by mail) or usual care (comparator group). Main Outcomes and Measures: The main outcome was discontinuation of opioid prescriptions at the participant level after 6 months, ascertained by pharmacy drug claims. Secondary outcomes included dose reduction (in morphine milligram equivalents [MME]) and/or therapeutic switch. Reduction in opioid use was assessed using generalized estimating equations to account for clustering, with prespecified subgroup analyses by age and sex. Analysis was intention to treat. Results: Of 4206 participants, 2409 (57.3%) were male; mean (SD) age was 60.0 (14.4) years. Mean (SD) baseline opioid use was comparable between groups (intervention, 157.7 [179.7] MME/d; control, 153.4 [181.8] MME/d). After 6 months, 235 of 2136 participants (11.0%) in 127 clusters in the intervention group no longer filled opioid prescriptions compared with 228 of 2070 (11.0%) in 124 clusters in the comparator group (difference, 0.0%; 95% CI, -1.9% to 1.9%). More participants in the intervention group than in the control group reduced their dose (1410 [66.0%] vs 1307 [63.1%]; difference, 2.8% [95% CI, 0.0%-5.7%]). Receipt of the brochure led to greater dose reductions for participants who were male (difference, 3.9%; 95% CI, 0.1%-7.7%), aged 18 to 64 years (difference, 3.7%; 95% CI, 0.2%-7.2%), or living in urban areas (difference, 5.9%; 95% CI, 1.9%-9.9%) compared with usual care. Conclusions and Relevance: In this cluster randomized clinical trial, no significant difference in the prevalence of opioid cessation was observed after 6 months between the intervention and usual care groups; however, the intervention resulted in more adults reducing their opioid dose compared with usual care. Trial Registration: ClinicalTrials.gov Identifier: NCT03400384.

Alternative green solvents associated with ultrasound-assisted extraction: A green chemistry approach for the extraction of carotenoids and chlorophylls from microalgae.

This study proposes a method for the ultrasonic extraction of carotenoids and chlorophyll from Scenedesmus obliquus and Arthrospira platensis microalgae with green solvents. Ethanol and ethanolic solutions of ionic liquids were tested with a variety of extraction parameters, including number of extractions, time of extraction, and solid-liquid ratio R(S/L), to determine the optimal conditions. After selecting the most effective green solvent (ethanol), the process conditions were established: R(S/L) of 1:10, three extraction cycles at 3 min each), giving an extraction yield of 2602.36 and 764.21 µgcarotenoids.gdried biomass-1; and 22.01 and 5.81 mgchlorophyll.gdried biomass-1 in S. obliquus and A. platensis, respectively. The carotenoid and chlorophyll extracts obtained using ethanol were shown to be potent scavengers of peroxyl radical, being 5.94 to 26.08 times more potent α-tocopherol. These findings pave the way for a green strategy for valorizing microalgal biocompounds through efficient and environmentally friendly technological processes.

Measuring the value of solidarity: The abem financial assistance program for out-of-pocket payments on pharmacy medicines in Portugal.

OBJECTIVE: Out-of-pocket payments for prescribed medicines are still comparatively high in Portugal. The abem program was launched in Portugal in May 2016 to aid vulnerable groups by completely covering out-of-pocket costs of prescribed medicines in community pharmacies. This study assesses the impact of the program on poverty and catastrophic health expenditures. METHODS: A longitudinal study was carried out with the analysis of several program databases (from the beginning of the program in May 2016 to September 2018) covering the cohorts of beneficiaries, daily data on medicines dispensed, social referencing entities, and solidarity pharmacies. The study provides estimates of standard poverty measures (intensity and severity) as well as the incidence of catastrophic health expenditures. RESULTS: More than 6000 beneficiaries were supported (56.8% female, 34.7% aged 65 or over), encompassing 127,510 medicines (mainly nervous system and cardiovascular system) with an average 26.9% co-payment (payments totalling €1.5 million). The program achieved substantial reductions in poverty (3.4% in intensity, 5.6% in severity), and eliminated cases with catastrophic health expenditures in medicines that would have affected 7.5% of the beneficiaries. CONCLUSIONS: Findings confirm a continuous increase in the number of beneficiaries, enabling access to medicines especially for the vulnerable elderly, and a sizable impact on eliminating out-of-pocket payments for medicines in the target population.

The utility of administrative data for surveillance of comorbidity in multiple sclerosis: a validation study.

BACKGROUND: Although comorbidity is important in multiple sclerosis (MS), few validated methods for its assessment exist. We validated and applied administrative case definitions for several comorbidities in MS. METHODS: Using provincial administrative data we identified persons with MS and a matched general population cohort. Case definitions for chronic lung disease (CLD), epilepsy, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and migraine were developed using administrative data, and validated against medical records. We applied these definitions to estimate the age-standardized prevalence of these comorbidities in the MS and matched cohorts. RESULTS: Versus medical records, administrative case definitions showed moderate agreement for CLD (ĸ = 0.41), migraine (ĸ = 0.51), and epilepsy (ĸ = 0.44), fair agreement for IBS (ĸ = 0.36) and could not be calculated for IBD (small sample size). The 2005 prevalence of CLD was similar in the MS (15.6%) and general populations (14.4%). The prevalence of the remaining comorbidities was higher in the MS than the general populations: epilepsy (4.12 vs. 1.12%), IBD (0.78 vs. 0.65%), IBS (12.2 vs. 6.80%) and migraine (23.0 vs. 16.5%). CONCLUSIONS: Administrative data are valid for tracking CLD, epilepsy, and migraine in MS. The prevalence of epilepsy, IBD, IBS and migraine is increased in MS versus the general population.

Mental comorbidity and multiple sclerosis: validating administrative data to support population-based surveillance.

BACKGROUND: While mental comorbidity is considered common in multiple sclerosis (MS), its impact is poorly defined; methods are needed to support studies of mental comorbidity. We validated and applied administrative case definitions for any mental comorbidities in MS. METHODS: Using administrative health data we identified persons with MS and a matched general population cohort. Administrative case definitions for any mental comorbidity, any mood disorder, depression, anxiety, bipolar disorder and schizophrenia were developed and validated against medical records using a a kappa statistic (k). Using these definitions we estimated the prevalence of these comorbidities in the study populations. RESULTS: Compared to medical records, administrative definitions showed moderate agreement for any mental comorbidity, mood disorders and depression (all k ≥ 0.49), fair agreement for anxiety (k = 0.23) and bipolar disorder (k = 0.30), and near perfect agreement for schizophrenia (k = 1.0). The age-standardized prevalence of all mental comorbidities was higher in the MS than in the general populations: depression (31.7% vs. 20.5%), anxiety (35.6% vs. 29.6%), and bipolar disorder (5.83% vs. 3.45%), except for schizophrenia (0.93% vs. 0.93%). CONCLUSIONS: Administrative data are a valid means of surveillance of mental comorbidity in MS. The prevalence of mental comorbidities, except schizophrenia, is increased in MS compared to the general population.

Rising prevalence of vascular comorbidities in multiple sclerosis: validation of administrative definitions for diabetes, hypertension, and hyperlipidemia.

BACKGROUND: Despite the importance of comorbidity in multiple sclerosis (MS), methods for comorbidity assessment in MS are poorly developed. OBJECTIVE: We validated and applied administrative case definitions for diabetes, hypertension, and hyperlipidemia in MS. METHODS: Using provincial administrative data we identified persons with MS and a matched general population cohort. Case definitions for diabetes, hypertension, and hyperlipidemia were derived using hospital, physician, and prescription claims, and validated in 430 persons with MS. We examined temporal trends in the age-adjusted prevalence of these conditions from 1984-2006. RESULTS: Agreement between various case definitions and medical records ranged from kappa (κ) =0.51-0.69 for diabetes, κ =0.21-0.71 for hyperlipidemia, and κ =0.52-0.75 for hypertension. The 2005 age-adjusted prevalence of diabetes was similar in the MS (7.62%) and general populations (8.31%; prevalence ratio [PR] 0.91; 0.81-1.03). The age-adjusted prevalence did not differ for hypertension (MS: 20.8% versus general: 22.5% [PR 0.91; 0.78-1.06]), or hyperlipidemia (MS: 13.8% versus general: 15.2% [PR 0.90; 0.67-1.22]). The prevalence of all conditions rose in both populations over the study period. CONCLUSION: Administrative data are a valid means of tracking diabetes, hypertension, and hyperlipidemia in MS. The prevalence of these comorbidities is similar in the MS and general populations.

Closing the gap in postfracture care at the population level: a randomized controlled trial.

BACKGROUND: Postfracture care is suboptimal, and strategies to address this major gap in care are necessary. We investigated whether notifications sent by mail to physicians and patients would lead to improved postfracture care. METHODS: We conducted a randomized controlled trial (ClinicalTrials.gov identifier NCT00594789) in the province of Manitoba, Canada, from June 2008 to May 2010. Using medical claims data, we identified 4264 men and women age 50 years or older who recently reported major fractures, and who had not undergone recent bone mineral density testing or treatment for osteoporosis. Participants were randomized to three groups: group 1 received usual care (n = 1480), patients in group 2 had mailed notification of the fracture sent to their primary care physicians (n = 1363), and group 3 had notifications sent to both physicians and patients (n = 1421). Bone mineral density testing and the start of pharmacologic treatment for osteoporosis within the following 12 months were documented. RESULTS: Among participants in group 1 (usual care), 15.8% of women and 7.6% of men underwent testing for bone mineral density or started pharmacologic treatment for osteoporosis. Outcome measures improved among participants in group 2 (30.3% of women and 19.0% of men, both p < 0.001) and group 3 (34.0% of women and 19.8% of men, both p < 0.001). No additional benefit was seen with patient notification in addition to physician notification. Combining groups 2 and 3, the absolute increase for the combined end point of bone mineral density testing or pharmacologic treatment was 14.9% (16.4% among women, 11.8% among men). The number needed to notify to change patient care was 7 (6 for women, 6 for men). The adjusted odds ratio (OR) to change patient care in group 2 was 2.45 (95% confidence interval [CI] 2.01-2.98); for group 3 the OR was 2.82 (95% CI 2.33-3.43). INTERPRETATION: This notification system provides a relatively simple way to enhance post-fracture care.

Osteoporosis-related fracture case definitions for population-based administrative data.

BACKGROUND: Population-based administrative data have been used to study osteoporosis-related fracture risk factors and outcomes, but there has been limited research about the validity of these data for ascertaining fracture cases. The objectives of this study were to: (a) compare fracture incidence estimates from administrative data with estimates from population-based clinically-validated data, and (b) test for differences in incidence estimates from multiple administrative data case definitions. METHODS: Thirty-five case definitions for incident fractures of the hip, wrist, humerus, and clinical vertebrae were constructed using diagnosis codes in hospital data and diagnosis and service codes in physician billing data from Manitoba, Canada. Clinically-validated fractures were identified from the Canadian Multicentre Osteoporosis Study (CaMos). Generalized linear models were used to test for differences in incidence estimates. RESULTS: For hip fracture, sex-specific differences were observed in the magnitude of under- and over-ascertainment of administrative data case definitions when compared with CaMos data. The length of the fracture-free period to ascertain incident cases had a variable effect on over-ascertainment across fracture sites, as did the use of imaging, fixation, or repair service codes. Case definitions based on hospital data resulted in under-ascertainment of incident clinical vertebral fractures. There were no significant differences in trend estimates for wrist, humerus, and clinical vertebral case definitions. CONCLUSIONS: The validity of administrative data for estimating fracture incidence depends on the site and features of the case definition.

Guidance for formulating ingredients/products from Chlorella vulgaris and Arthrospira platensis considering carotenoid and chlorophyll bioaccessibility and cellular uptake.

This study aimed to investigate the impact of different microalgal matrices on the bioaccessibility and uptake by Caco-2 cells of carotenoids and chlorophylls. In this way, the microalgal ingredients/products (whole dry biomass [WDB], whole ultrasonicated paste [WUP], and liposoluble pigment emulsion [LPE]) obtained from Chlorella vulgaris and Arthrospira platensis were submitted to in vitro simulated digestion. Apical uptake of pigments in micelles generated during the simulated digestion by Caco-2 human intestinal cells was determined. The influence of simulated digestion on carotenoid and chlorophyll stability and bioaccessibility was assessed by HPLC-PDA-MS/MS and the carotenoids and chlorophylls' bioaccessibility and cellular uptake were shown to be boosted according to the matrix (LPE > WUP > WDB). Our findings showed that Chlorella vulgaris and Arthrospira platensis could be considered in formulations when carotenoids and chlorophylls are the target molecules in the ingredients/products.

Closing the postfracture care gap using administrative health databases: design and implementation of a randomized controlled trial.

Postfracture care is suboptimal, and strategies to address this major care gap are urgently required. Case management is effective but is resource intensive and difficult to deliver to a widely scattered population. We describe the design and successful implementation of a randomized controlled trial (NCT00594789), which uses provincial administrative health databases to notify eligible physicians and patients after a major osteoporotic fracture that such fractures warrant additional assessment or pharmacologic treatment to prevent subsequent fractures. Men and women aged 50 yr or older residing in the Province of Manitoba, Canada, with a recently reported clinical fracture (hip, spine, humerus, and forearm) from medical claims data, and without recent bone mineral density (BMD) testing (in the last 3 yr) or osteoporosis therapy (in the last year), were randomized to 3 groups: group 1 received usual care, group 2 (physicians only) had mailed notification to the primary care physicians (alert letter, BMD requisition, and management flowchart), and group 3 (physicians and patient) had both physician notifications and patient notification (alert letter). During the initial 10 mo (from June 2008 to March 2009), 2901 fracture patients meeting the inclusion criteria were randomized. Groups were well balanced. Direct costs related to the initiative (programming, case identification, and mailings) were Canadian dollars (CAD$)12,379 during the pilot phase, which translates to CAD$6.50 per notification (groups 2 and 3). Ongoing costs (which exclude the initial programming costs) are estimated at CAD$1.25 per notification. This postfracture intervention, based on medical claims data, provides an easy way to enhance postfracture care. The approach is scalable, can be delivered to a widely scattered population, and requires minimal infrastructure. This low-cost intervention may complement more resource-intensive programs based on case managers.

Considerations for Developing a Reassessment Process: Report from the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration's Reassessment and Uptake Working Group.

The Canadian Real-world Evidence for Value in Cancer Drugs (CanREValue) Collaboration was established to develop a framework for generating and using real-world evidence (RWE) to inform the reassessment of cancer drugs following initial health technology assessment (HTA). The Reassessment and Uptake Working Group (RWG) is one of the five established CanREValue Working Groups. The RWG aims to develop considerations for incorporating RWE for HTA reassessment and strategies for using RWE to reassess drug funding decisions. Between February 2018 and December 2019, the RWG attended four teleconferences (with follow-up surveys) and two in-person meetings to discuss recommendations for the development of a reassessment process and potential barriers and facilitators. Modified Delphi methods were used to gather input. A draft report of recommendations (to December 2018) was shared for public consultation (December 2019 to January 2020). Initial considerations for developing a reassessment process were proposed. Specifically, reassessment can be initiated by diverse stakeholders, including decision makers from public drug plans or industry stakeholders. The reassessment process should be modelled after existing deliberation and recommendation frameworks used by HTA agencies. Proposed reassessment outcome categories include maintaining status quo, revisiting funding criteria, renegotiating price, or disinvesting. Overall, these initial considerations will serve as the basis for future advancements by the Collaboration.

Leveraging policy to reduce chronic opioid use by educating and empowering community dwelling adults: a study protocol for the TAPERING randomized controlled trial.

BACKGROUND: Opioid use has risen to epidemic proportions across Canada, with increasing evidence of harms including accidental overdose and death. Policy-makers have called for effective approaches to promote opioid reduction. One promising method from deprescribing randomized trials is to empower patients through direct-to-patient education. The current trial will evaluate the effectiveness of a government-led mail-out of educational information to adult community-dwelling, chronic opioid users on the reduction of opioids compared to usual care. METHODS: This is a pragmatic, prospective, cluster randomized, parallel-arm controlled trial, comparing mailed distribution of a direct-to-patient educational brochure for chronic opioid use (intervention arm) to usual care (control arm). Eligible participants from across Manitoba, Canada, will be identified by the Provincial Drug Programs Branch within the Manitoba Health, Seniors and Active Living Department of the Manitoba Government, allocated to primary care providers, and the latter will be randomized in clusters of family medicine practices to achieve a 1:1 ratio. The primary outcome is complete cessation of opioids after 6 months assessed using Drug Program Information Network data. Secondary outcomes include ≥ 25% dose reduction in the mean morphine milligram equivalent (MME) daily dose, reduction of daily dose to < 90 mg MME, or therapeutic switch to another opioid or non-opioid medication. Data will be analyzed using intent-to-treat generalized estimating equations. DISCUSSION: This trial will test the efficacy of a population-based, wide-scale, government-led direct-to-patient educational initiative to drive reductions in chronic opioid use by community-dwelling adults across Manitoba. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03400384 . Registered on 18 January 2018.

Single-site vs multisite bone density measurement for fracture prediction.

BACKGROUND: Bone density measurement with dual-energy x-ray absorptiometry is widely used for fracture risk assessment. Discordance between measurement sites is common, but it is unclear how this affects fracture prediction. METHODS: We performed a historical cohort study among 16 505 women 50 years or older at the time of baseline dual-energy x-ray absorptiometry of the spine and hip (mean +/- SD observation period, 3.2 +/- 1.5 years). The study population was drawn from a database that contains all clinical dual-energy x-ray absorptiometry test results for the province of Manitoba, Canada. Each subject's longitudinal health service record was assessed for the presence of fracture codes after bone density testing. The likelihood ratio test was used to assess the improvement in fracture prediction from Cox proportional hazards models using bone density covariates from a single site or from combined sites. RESULTS: Age-adjusted hazard ratios (HRs) per standard deviation for osteoporotic fracture ranged from 1.61 (95% confidence interval [CI], 1.39-1.87) for the lumbar spine to 1.85 (95% CI, 1.70-2.01) for the total hip, with intermediate values for the femur neck (HR, 1.76 [95% CI, 1.62-1.92]) and trochanter (HR, 1.77 [95% CI, 1.63-1.92]). For fracture prediction, use of the minimum bone density measurement was no better than use of a hip measurement alone. When the total hip measurement was included in a fracture prediction model for the overall population, none of the other measurements added substantial information. The spine was the most useful site for the prediction of spine fractures alone. CONCLUSIONS: Proximal femur bone density measurements consistently outperformed lumbar spine measurements for global fracture prediction. In this cohort, the total hip was the best site for overall fracture assessment.

Number of osteoporotic sites and fracture risk assessment: a cohort study from the Manitoba Bone Density Program.

UNLABELLED: Site-discordance in BMD assessment is common and significantly affects patient categorization. Greater number of osteoporotic sites correlates with lower T scores at each index site. This largely explains the positive association between number of osteoporotic sites and fracture risk. INTRODUCTION: Site-discordance in BMD is common when used to classify patients based on a cut-off T score of -2.5. It is unclear whether fracture risk assessment is improved by considering BMD information from multiple sites. Our objective was to assess the contribution of number of osteoporotic sites to overall fracture risk. MATERIALS AND METHODS: The study population was drawn from the regionally based clinical database of the Manitoba Bone Density Program that includes all clinical DXA test results for the Province of Manitoba, Canada. Analyses were limited to 16,505 women>or=50 years of age at the time of baseline DXA of the spine (L1-L4) and hip (three sites). During follow-up (3.2+/-1.5 years), longitudinal health service records showed 765 women with at least one osteoporotic fracture code (hip, forearm, spine, or humerus). RESULTS: Of 5012 women classified as osteoporotic by at least one site (T score -2.5 or lower), almost one half (2370; 47%) were abnormal at only a single site. Among the 1856 women with an osteoporotic total hip measurement, mean total hip T scores decreased as the number of additional osteoporotic sites increased (-2.58, no other osteoporotic sites; -2.69, one other site; -2.87, two other sites; -3.17, three other sites; Spearman r=-0.44, p<0.0001). Age-adjusted fracture risk from a Cox proportional hazards model increased as the number of osteoporotic sites increased (p<0.0001), but number of osteoporotic sites was no longer an independent predictor after total hip BMD was included as a covariate (p=0.19). Covariate adjustment for other sites of BMD measurement attenuated, but did not eliminate, the effect of number of osteoporotic sites. CONCLUSIONS: Site-discordance is common and significantly affects patient categorization when different skeletal sites are used for diagnosis. Greater number of osteoporotic sites correlates with lower T scores at each index site. This largely explains the positive association between number of osteoporotic sites and fracture risk.

Effectiveness of bone density measurement for predicting osteoporotic fractures in clinical practice.

CONTEXT: Bone density measurement with dual-energy x-ray absorptiometry is widely used for fracture risk assessment. It has not been established that published gradients of fracture risk from study populations can be directly applied to clinical populations. OBJECTIVE: The objective of the study was to assess osteoporotic fracture prediction with dual-energy x-ray absorptiometry in a large clinical cohort. DESIGN: This was a historical cohort study (mean observation period 3.2 +/- 1.5 yr). PATIENTS: The study population was drawn from the population-based database of the Manitoba Bone Density Program. Analyses were limited to women aged 50 yr or older at baseline (n = 16,505). MAIN OUTCOME MEASURE: Each subject's longitudinal health service record was assessed for the presence of nontrauma fracture codes (hip, spine, wrist, and humerus) after bone density testing. Age-adjusted hazard ratios for fracture were derived from Cox proportional hazards models. RESULTS: Site-specific and overall fracture rates were significantly associated with each site of bone density measurement (all P < 0.00001). The 95% confidence intervals overlapped those from a widely cited metaanalysis of fracture prediction from different sites. Although fracture prediction was not significantly different between the three hip measurement sites, each hip site was better than the lumbar spine for predicting overall fractures (nonoverlapping 95% confidence intervals). The manufacturer sd (equivalent to a unit change in T-score) resulted in a significantly smaller gradient of risk for the spine than when the population sd was used. CONCLUSIONS: Bone density measurements are effective for predicting fractures in clinical practice. However, hip measurements were superior to the spine in overall osteoporotic fracture prediction.

Antidepressant utilization in British Columbia from 1996 to 2004: increasing prevalence but not incidence.

OBJECTIVES: Expenditures on antidepressants in Canada are rapidly increasing; yet few studies have analyzed the characteristics of antidepressant users. This study investigated the prevalence and incidence of antidepressant use in British Columbia over eight years. METHODS: Antidepressant utilization and demographic data were assessed for the population of British Columbia from 1996 to 2004. Prescription claims were identified within the PharmaNet database for serotonin reuptake inhibitors (SSRI), tricyclics, monoamine oxidase inhibitors, bupropion (categorized separately for smoking cessation), and "novel" antidepressants, such as venlafaxine. Incident utilization (dispensed "first" antidepressant after two years without an antidepressant claim) and prevalent utilization were analyzed. All cohort members were required to have continuous registration with British Columbia medical services for at least two years before the first antidepressant claim. RESULTS: Prevalence of antidepressant use doubled, from 34 to 72 users per 1,000 population, between 1996 and 2004. The prevalence of particular classes of antidepressants also changed over time. Prevalence of novel antidepressants and SSRIs increased, although incidence of SSRIs decreased. Prevalent and incident use of bupropion for smoking cessation peaked in 1999 but then declined. Quarterly incident antidepressant use increased in 1998 and 1999 (6.5 and 11.3 users per 1,000) but decreased through 2004 (4.2 users per 1,000). Those aged 20 to 44 years and those aged 45 to 64 years showed the greatest peak in incident antidepressant use. A socioeconomic gradient in prescribing was observed. CONCLUSIONS: Prevalent antidepressant use has increased dramatically since 1996. By contrast, incident use increased from 1998 to 1999 but then decreased through 2004. Many complex factors likely contribute to antidepressant prescribing patterns.

Changes in the dispensing of opioid medications in Canada following the introduction of a tamper-deterrent formulation of long-acting oxycodone: a time series analysis.

BACKGROUND: In February 2012, a reformulated tamper-deterrent form of long-acting oxycodone, OxyNeo, was introduced in Canada. We investigated the impact of the introduction of OxyNeo on patterns of opioid prescribing. METHODS: We conducted population-based, cross-sectional analyses of opioid dispensing in Canada between 2008 and 2016. We estimated monthly community pharmacy dispensing of oral formulations of codeine, morphine, hydromorphone and oxycodone, and a transdermal formulation of fentanyl, and converted quantities to milligrams of morphine equivalents (MMEs) per 1000 population. We used time series analysis to evaluate the effect of the introduction of OxyNeo on these trends. RESULTS: National dispensing of long-acting opioids fell by 14.9% between February 2012 and April 2016, from 36 098 MMEs to 30 716 MMEs per 1000 population (p < 0.01). This effect varied across Canada and was largest in Ontario (reduction of 22.8%) (p = 0.01) and British Columbia (reduction of 30.0%) (p = 0.01). The national rate of oxycodone dispensing fell by 46.4% after the introduction of OxyNeo (p < 0.001); this was partially offset by an increase of 47.8% in hydromorphone dispensing (p < 0.001). Although dispensing of immediate-release opioids was a substantial contributor to overall population opioid exposure across Canada, it was unaffected by the introduction of OxyNeo (p > 0.05 in all provinces). INTERPRETATION: The findings suggest that the introduction of a tamper-deterrent formulation of long-acting oxycodone in Canada, against a background of changing public drug benefits, was associated with sustained changes in selection of long-acting opioids but only small changes in the quantity of long-acting opioids dispensed. This illustrates the limited effect a tamper-deterrent formulation and associated coverage policy can have when other, non-tamper-deterrent alternatives are readily available.