Adverse Events Associated With Disease-Modifying Drugs for Multiple Sclerosis: A Multiregional Population-Based Study

BACKGROUND AND OBJECTIVES: It is not possible to fully establish the safety of a disease-modifying drug (DMD) for multiple sclerosis (MS) from randomized controlled trials as only very common adverse events occurring over the short-term can be captured, and the quality of reporting has been variable. We examined the relationship between the DMDs for MS and potential adverse events in a multiregion population-based study. METHODS: We identified people with MS using linked administrative health data from 4 Canadian provinces. MS cases were followed from the most recent of first MS or related demyelinating disease event on January 1, 1996, until the earliest of emigration, death, or December 31, 2017. DMD exposure primarily comprised ß-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab. We examined associations between DMD exposure and infection-related hospitalizations and physician visits using recurrent events proportional means models and between DMD exposure and 15 broad categories of incident adverse events using stratified multivariate Cox proportional hazard models. RESULTS: We identified 35,894 people with MS. While virtually all DMDs were associated with a 42%-61% lower risk of infection-related hospitalizations, there was a modest increase in infection-related physician visits by 10%-33% for select DMDs. For incident adverse events, most elevated risks involved a second-generation DMD, with alemtuzumab's hazard of thyroid disorders being 19.42 (95% CI 9.29-36.51), hypertension 4.96 (95% CI 1.78-13.84), and cardiovascular disease 3.72 (95% CI 2.12-6.53). Natalizumab's highest risk was for cardiovascular disease (adjusted hazard ratio [aHR] 1.61; 95% CI 1.24-2.10). For the oral DMDs, fingolimod was associated with higher hazards of cerebrovascular (aHR 2.04; 95% CI 1.27-3.30) and ischemic heart diseases (aHR 1.64; 95% CI 1.10-2.44) and hypertension (aHR 1.73; 95% CI 1.30-2.31); teriflunomide with higher hazards of thyroid disorders (aHR 2.30; 95% CI 1.11-4.74), chronic liver disease (aHR 1.94; 95% CI 1.19-3.18), hypertension (aHR 1.76; 95% CI 1.32-2.37), and hyperlipidemia (aHR 1.61; 95% CI 1.07-2.44); and from complementary analyses (in 1 province), dimethyl fumarate with acute liver injury (aHR 6.55; 95% CI 1.96-21.87). DISCUSSION: Our study provides an extensive safety profile of several different DMDs used to treat MS in the real-world setting. Our findings not only complement those observed in short-term clinical trials but also provide new insights that help inform the risk-benefit profile of the DMDs used to treat MS in clinical practice. The results of this study highlight the continued need for long-term, independent safety studies of the DMDs used to treat MS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with MS, while DMD exposure reduces the risk of infection-related hospitalizations, there are increased risks of infection-related physician visits and incident adverse events for select DMDs.

4D Additive-Subtractive Manufacturing of Shape Memory Ceramics.

The development of high-temperature structural materials, such as ceramics, is limited by their extremely high melting points and the difficulty in building complicated architectures. Four-dimensional (4D) printing helps enhance the geometrical flexibility of ceramics. However, ceramic 4D printing systems are limited by the separate processes for shape and material transformations, low accuracy of morphing systems, low resolution of ceramic structures, and their time-intensive nature. Here, a paradigm for a one-step shape/material transformation, high-2D/3D/4D-precision, high-efficiency, and scalable 4D additive-subtractive manufacturing of shape memory ceramics is developed. Original/reverse and global/local multimode shape memory capabilities are achieved using macroscale SiOC-based ceramic materials. The uniformly deposited Al2 O3 -rich layer on the printed SiOC-based ceramic lattice structures results in an unusually high flame ablation performance of the complex-shaped ceramics. The proposed framework is expected to broaden the applications of high-temperature structural materials in the aerospace, electronics, biomedical, and art fields.

Inequities in Rural and Urban Health Care Utilization Among Individuals Diagnosed With Inflammatory Bowel Disease: A Retrospective Population-Based Cohort Study From Saskatchewan, Canada.

Background: Rural dwellers with inflammatory bowel disease (IBD) face barriers to accessing specialized health services. We aimed to contrast health care utilization between rural and urban residents diagnosed with IBD in Saskatchewan, Canada. Methods: We completed a population-based retrospective study from 1998/1999 to 2017/2018 using administrative health databases. A validated algorithm was used to identify incident IBD cases aged 18+. Rural/urban residence was assigned at IBD diagnosis. Outpatient (gastroenterology visits, lower endoscopies, and IBD medications claims) and inpatient (IBD-specific and IBD-related hospitalizations, and surgeries for IBD) outcomes were measured after IBD diagnosis. Cox proportional hazard, negative binomial, and logistic models were used to evaluate associations adjusting by sex, age, neighbourhood income quintile, and disease type. Hazard ratios (HR), incidence rate ratios (IRR), odds ratios (OR), and 95% confidence intervals (95% CI) were reported. Results: From 5,173 incident IBD cases, 1,544 (29.8%) were living in rural Saskatchewan at IBD diagnosis. Compared to urban dwellers, rural residents had fewer gastroenterology visits (HR = 0.82, 95% CI: 0.77-0.88), were less likely to have a gastroenterologist as primary IBD care provider (OR = 0.60, 95% CI: 0.51-0.70), and had lower endoscopies rates (IRR = 0.92, 95% CI: 0.87-0.98) and more 5-aminosalicylic acid claims (HR = 1.10, 95% CI: 1.02-1.18). Rural residents had a higher risk and rates of IBD-specific (HR = 1.23, 95% CI: 1.13-1.34; IRR = 1.22, 95% CI: 1.09-1.37) and IBD-related (HR = 1.20, 95% CI: 1.11-1.31; IRR = 1.23, 95% CI: 1.10-1.37) hospitalizations than their urban counterparts. Conclusion: We identified rural-urban disparities in IBD health care utilization that reflect rural-urban inequities in the access to IBD care. These inequities require attention to promote health care innovation and equitable management of patients with IBD living in rural areas.

Patterns of antiemetic medication use during pregnancy: A multi-country retrospective cohort study.

OBJECTIVE: To compare patterns in use of different antiemetics during pregnancy in Canada, the United Kingdom, and the United States, between 2002 and 2014. METHODS: We constructed population-based cohorts of pregnant women using administrative healthcare data from five Canadian provinces (Alberta, British Columbia, Manitoba, Ontario, and Saskatchewan), the Clinical Practice Research Datalink from the United Kingdom, and the IBM MarketScan Research Databases from the United States. We included pregnancies ending in live births, stillbirth, spontaneous abortion, or induced abortion. We determined maternal use of antiemetics from pharmacy claims in Canada and the United States and from prescriptions in the United Kingdom. RESULTS: The most common outcome of 3 848 734 included pregnancies (started 2002-2014) was live birth (66.7% of all pregnancies) followed by spontaneous abortion (20.2%). Use of antiemetics during pregnancy increased over time in all three countries. Canada had the highest prevalence of use of prescription antiemetics during pregnancy (17.7% of pregnancies overall, 13.2% of pregnancies in 2002, and 18.9% in 2014), followed by the United States (14.0% overall, 8.9% in 2007, and 18.1% in 2014), and the United Kingdom (5.0% overall, 4.2% in 2002, and 6.5% in 2014). Besides use of antiemetic drugs being considerably lower in the United Kingdom, the increase in its use over time was more modest. The most commonly used antiemetic was combination doxylamine/pyridoxine in Canada (95.2% of pregnancies treated with antiemetics), ondansetron in the United States (72.2%), and prochlorperazine in the United Kingdom (63.5%). CONCLUSIONS: In this large cohort study, we observed an overall increase in antiemetic use during pregnancy, and patterns of use varied across jurisdictions. Continued monitoring of antiemetic use and further research are warranted to better understand the reasons for differences in use of these medications and to assess their benefit-risk profile in this population.

The multiomics landscape of serum exosomes during the development of sepsis.

INTRODUCTION: Sepsis is an infection-induced severe inflammatory disorder leading to multiple organ dysfunction. It remains a highly lethal condition for which early diagnosis and therapy achieve unsatisfactory results. Circulating exosomes containing biomarkers and mediators of sepsis have recently received attention, but the progress has been far from optimal. OBJECTIVES: The present study focuses on the profiles of molecular dynamics in serum exosomes and explores the potential molecular mechanisms on serum exosomes during the process of sepsis. METHODS: We used high-performance liquid chromatography-tandem mass spectrometry and RNA-seq to detect the dynamic profiles of exosome proteins and RNAs (including mRNAs, lncRNAs and miRNAs) in serum exosomes from 3 healthy individuals and 9 septic patients at the different stages. Then integrative multiomics analyses were performed and the results were validated by qRT-PCR, LiquiChip assay and metabolomics analysis on mice subjected to cecal ligation and puncture (CLP) modeling. RESULTS: A total of 354 proteins, 195 mRNAs, 82 lncRNAs and 55 miRNAs were identified as differentially expressed molecules in serum exosomes from septic patients. Integrative multiomics analysis showed that exosome components were associated with cytokine storm, complement and clotting cascades, the endothelial barrier, 20S proteasome-dependent protein degradation and vitamin metabolism. Importantly, pretreatment with serum exosomes derived from mice subjected to CLP significantly restrained proinflammatory cytokine expression and alleviated tissue injury in septic mice. Further metabolomics analysis demonstrated that pretreatment with septic serum exosomes significantly affected the metabolites associated with vitamin digestion and absorption in CLP mice. CONCLUSION: Our study for the first time describes the landscape of the molecular dynamics of serum exosomes during the development of sepsis and proposes some hypothetical molecular mechanisms by integrative multiomics analysis, which may provide helpful diagnostic and therapeutic insights for the ongoing battle against sepsis.

Increasing Prevalence and Stable Incidence Rates of Inflammatory Bowel Disease Among First Nations: Population-Based Evidence From a Western Canadian Province.

BACKGROUND: There is limited to no evidence of the prevalence and incidence rates of inflammatory bowel disease (IBD) among Indigenous peoples. In partnership with Indigenous patients and family advocates, we aimed to estimate the prevalence, incidence, and trends over time of IBD among First Nations (FNs) since 1999 in the Western Canadian province of Saskatchewan. METHODS: We conducted a retrospective population-based study linking provincial administrative health data from the 1999-2000 to 2016-2017 fiscal years. An IBD case definition requiring multiple health care contacts was used. The prevalence and incidence data were modeled using generalized linear models and a negative binomial distribution. Models considered the effect of age groups, sex, diagnosis type (ulcerative colitis [UC], Crohn disease [CD]), and fiscal years to estimate prevalence and incidence rates and trends over time. RESULTS: The prevalence of IBD among FNs increased from 64/100,000 (95% confidence interval [CI], 62-66) in 1999-2000 to 142/100,000 (95% CI, 140-144) people in 2016-2017, with an annual average increase of 4.2% (95% CI, 3.2%-5.2%). Similarly, the prevalence of UC and CD, respectively, increased by 3.4% (95% CI, 2.3%-4.6%) and 4.1% (95% CI, 3.3%-4.9%) per year. In contrast, the incidence rates of IBD, UC, and CD among FNs depicted stable trends over time; no statistically significant changes were observed in the annual change trend tests. The ratio of UC to CD was 1.71. CONCLUSIONS: We provided population-based evidence of the increasing prevalence and stable incidence rates of IBD among FNs. Further studies are needed in other regions to continue understanding the patterns of IBD among Indigenous peoples.

Harmine is an effective therapeutic small molecule for the treatment of cardiac hypertrophy.

Harmine is a ß-carboline alkaloid isolated from Banisteria caapi and Peganum harmala L with various pharmacological activities, including antioxidant, anti-inflammatory, antitumor, anti-depressant, and anti-leishmanial capabilities. Nevertheless, the pharmacological effect of harmine on cardiomyocytes and heart muscle has not been reported. Here we found a protective effect of harmine on cardiac hypertrophy in spontaneously hypertensive rats in vivo. Further, harmine could inhibit the phenotypes of norepinephrine-induced hypertrophy in human embryonic stem cell-derived cardiomyocytes in vitro. It reduced the enlarged cell surface area, reversed the increased calcium handling and contractility, and downregulated expression of hypertrophy-related genes in norepinephrine-induced hypertrophy of human cardiomyocytes derived from embryonic stem cells. We further showed that one of the potential underlying mechanism by which harmine alleviates cardiac hypertrophy relied on inhibition of NF-κB phosphorylation and the stimulated inflammatory cytokines in pathological ventricular remodeling. Our data suggest that harmine is a promising therapeutic agent for cardiac hypertrophy independent of blood pressure modulation and could be a promising addition of current medications for cardiac hypertrophy.

Denitrifying anaerobic methane oxidation process responses to the addition of growth factor betaine in the MFC-granular sludge coupling system: Enhancing mechanism and metagenomic analysis.

To solve the problem of the slow growth of denitrifying anaerobic methane oxidation (DAMO) bacteria during the enrichment process, betaine was added as a growth factor and its influence on the mechanism of DAMO process along with the metagenomic analysis of the process in a MFC-granular sludge coupling system was explored. When the addition of betaine was increased to 0.5 g/L and 1.0 g/L, the NO3--N removal increased to 210 mg/L. Also, the increasing betaine dosage in 1st to 4th chambers resulted in a significant increase in dissolved methane concentration which reached a maximum value of 16.6 ± 1.19 mg/L. When the dosage of betaine was increased from 0 g/L to 1.0 g/L, the dominant bacterial phyla in the 1st to 4th chambers changed to Proteobacteria (20.8-50.7%) from Euryarchaeota (42.0-54.1%) and Methanothrix which was significantly decreased by 17.9-37.4%. There was a slight decline in the DAMO microorganism abundance, possibly due to the increased methyl donors limiting the DAMO microorganism growth. Denitrification metabolism pathway module (increased from 0.10% to 0.15%) of Nitrogen metabolism and Formaldehyde assimilation, and serine pathway of Methane metabolism presented an ascendant trend with the increased betaine dosage as determined by the metagenomics analysis of KEGG metabolism pathway.

Genome-wide analysis and expression profiles of PdeMYB transcription factors in colored-leaf poplar (Populus deltoids).

BACKGROUND: MYB transcription factors, comprising one of the largest transcription factor families in plants, play many roles in secondary metabolism, especially in anthocyanin biosynthesis. However, the functions of the PdeMYB transcription factor in colored-leaf poplar remain elusive. RESULTS: In the present study, genome-wide characterization of the PdeMYB genes in colored-leaf poplar (Populus deltoids) was conducted. A total of 302 PdeMYB transcription factors were identified, including 183 R2R3-MYB, five R1R2R3-MYB, one 4R-MYB, and 113 1R-MYB transcription factor genes. Genomic localization and paralogs of PdeMYB genes mapped 289 genes on 19 chromosomes, with collinearity relationships among genes. The conserved domain, gene structure, and evolutionary relationships of the PdeMYB genes were also established and analyzed. The expression levels of PdeMYB genes were obtained from previous data in green leaf poplar (L2025) and colored leaf poplar (QHP) as well as our own qRT-PCR analysis data in green leaf poplar (L2025) and colored leaf poplar (CHP), which provide valuable clues for further functional characterization of PdeMYB genes. CONCLUSIONS: The above results provide not only comprehensive insights into the structure and functions of PdeMYB genes but also provide candidate genes for the future improvement of leaf colorization in Populus deltoids.

Effect of hydraulic retention time on the denitrification performance and metabolic mechanism of a multi-chambered bio-electrochemical system.

The effects of hydraulic retention time (HRT) on the denitrification performance of the multi-chambered bio-electrochemistry system and the metabolic mechanism of the microbial community were investigated. Results indicated that the NO3--N and NO2--N removal efficiency was up to 99.5% and 99.9%, respectively. The electricity generation performance of the system was optimum at 24 h HRT, with the maximum power density and output voltage of the fourth chamber to be 471.2 mW/m3 and 602.4 mV, respectively. With the decrease of HRT from 24 h to 8 h, the protein-like substance in extracellular polymeric substance (EPS) of granular sludge was reduced and the fluorescence intensities were weakened. Besides, the abundance of metabolism pathway was the highest at 50.0% and 49.9%, respectively, and the methane metabolism (1.8% and 2.0%, respectively) and the nitrogen metabolism (0.8% and 0.9%, respectively) in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway played important roles in providing guaranteed stability and efficient removal of organic matter and nitrogen from the system.

Comparison of Pregnancy Outcomes of Patients Treated With Ondansetron vs Alternative Antiemetic Medications in a Multinational, Population-Based Cohort.

Importance: Ondansetron is frequently used to treat nausea and vomiting during pregnancy. Although some studies reported important safety signals, few studies have been sufficiently large to assess rare pregnancy outcomes. Objective: To study the association between ondansetron exposure during pregnancy and the risks of spontaneous abortion, stillbirth, and major congenital malformations. Design, Setting, and Participants: This is a cohort study conducted in 3 countries, with a meta-analysis. Participants included women and girls aged 12 to 55 years who experienced spontaneous abortion, induced abortion, stillbirth, or live birth between April 2002 and March 2016, as recorded in administrative data from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, and Ontario), the US IBM MarketScan Research Databases, and the UK Clinical Practice Research Datalink. The statistical analysis was completed in October 2020. Exposures: Exposure to ondansetron during pregnancy was compared with exposure to other commonly used antiemetics to minimize confounding by indication. Main Outcomes and Measures: The primary outcome was fetal death, defined as either spontaneous abortion or stillbirth. Secondary outcomes were the 2 components of the primary outcome and major congenital malformations identified during the year after a live birth. Adjusted hazard ratios were estimated using Cox proportional hazards models with time-dependent drug exposures and were adjusted using high-dimensional propensity scores. For major congenital malformations, adjusted odds ratios were estimated from logistic models. Site-level results were pooled using random-effects meta-analysis. Sensitivity analyses considered second-line antiemetic exposure and exposure specifically during 4 to 10 weeks of gestation. Results: Data from 456 963 pregnancies were included in this study of fetal death (249 787 [54.7%] in Canada, 197 913 [43.3%] in the US, and 9263 [2.0%] in the UK; maternal age, ≤24 years, 93 201 patients [20.4%]; 25-29 years, 149 117 patients [32.6%]; 30-34 years, 142 442 patients [31.2%]; and ≥35 years, 72 203 patients [15.8%]). Fetal death occurred in 12 907 (7.9%) of 163 810 pregnancies exposed to ondansetron, and 17 476 (5.7%) of 306 766 pregnancies exposed to other antiemetics. The adjusted hazard ratios were 0.91 (95% CI, 0.67-1.23) for fetal death with time-dependent ondansetron exposure during pregnancy, 0.82 (95% CI, 0.64-1.04) for spontaneous abortion, and 0.97 (95% CI, 0.79-1.20) for stillbirth. For major congenital malformations, the estimated odds ratio was 1.06 (95% CI, 0.91-1.22). Results of sensitivity analyses were generally consistent with those of the primary analyses. Conclusions and Relevance: In this large, multicenter cohort study, there was no association between ondansetron exposure during pregnancy and increased risk of fetal death, spontaneous abortion, stillbirth, or major congenital malformations compared with exposure to other antiemetic drugs.

TMBIM6, a potential virus target protein identified by integrated multiomics data analysis in SARS-CoV-2-infected host cells.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we collected open access data to analyze the mechanisms associated with SARS-CoV-2 infection. Gene set enrichment analysis (GSEA) revealed that apoptosis-related pathways were enriched in the cells after SARS-CoV-2 infection, and the results of differential expression analysis showed that biological functions related to endoplasmic reticulum stress (ERS) and lipid metabolism were disordered. TMBIM6 was identified as a potential target for SARS-CoV-2 in host cells through weighted gene coexpression network analysis (WGCNA) of the time course of expression of host and viral proteins. The expression and related functions of TMBIM6 were subsequently analyzed to illuminate how viral proteins interfere with the physiological function of host cells. The potential function of viral proteins was further analyzed by GEne Network Inference with Ensemble of trees (GENIE3). This study identified TMBIM6 as a target protein associated with the pathogenesis of SARS-CoV-2, which might provide a novel therapeutic approach for COVID-19 in the future.

Performance and functional microbial communities of denitrification process of a novel MFC-granular sludge coupling system.

The performance, microbial communities and functional gene metabolism of the novel microbial fuel cell (MFC)-granular sludge coupling system was investigated. The results showed that COD and nitrogen removal can be up to 1.3-2.0 kg COD/L, 20-30 mg NO2--N/L, and 60-70 mg NO3--N/L, respectively. Proteobacteria, Chloroflexi, and Firmicutes were the dominant bacterial phyla, and the denitrification process was mainly consisted of the dominant denitrifying bacteria: Thauera (26.21%) and Pseudomonas (14.79%) in the first compartment, combining with denitrifying anaerobic methane oxidation bacteria: NC10 phylum of 0.072% (the first compartment) and 0.089% (the fourth compartment), Candidatus Methylomirabilis oxyfera of 0.044% (the first compartment) and 0.048% (the fourth compartment). According to functional gene classification for Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, metabolism was the main cluster for the whole sequence in the KEGG (7.17-11.41%), indicating that the dominant metabolic pathway played an important role in the degradation of pollutants.

Data-Independent Acquisition-Based Quantitative Proteomics Analysis Reveals Dynamic Network Profiles during the Macrophage Inflammatory Response.

Understanding of the molecular regulatory mechanisms underlying the inflammatory response is incomplete. The present study focuses on characterizing the proteome in a model of inflammation in macrophages treated with lipopolysaccharide (LPS). A total of 3597 proteins are identified in macrophages with the data-independent acquisition (DIA) method. Bioinformatic analyses reveal discrete modules and the underlying molecular mechanisms, as well as the signaling network that modulates the development of inflammation. It is found that a total of 87 differentially expressed proteins are shared by all stages of LPS-induced inflammation in macrophages and that 18 of these proteins participate in metabolic processes by forming a tight interaction network. Data support the hypothesis that ribosome proteins play a key role in regulating the macrophage response to LPS. Interestingly, conjoint analyses of the transcriptome and proteome in macrophages treated with LPS reveal that the genes upregulated at both the mRNA and protein levels are mainly involved in inflammation and the immune response, whereas the genes downregulated are significantly enriched in metabolism-related processes. These results not only provide a more comprehensive understanding of the molecular mechanisms of inflammation mediated by bacterial infection but also provide a dynamic proteomic resource for further studies.

Higher health care use before a clinically isolated syndrome with or without subsequent MS.

BACKGROUND: To establish whether a unique multiple sclerosis (MS) prodrome exists by comparing health care utilization in the five-year period before initial presentation with optic neuritis (ON) or transverse myelitis (TM) among those who were and were not subsequently diagnosed with MS. METHODS: Using population-based administrative health data we conducted a retrospective cohort study in three Canadian provinces. We identified individuals with a clinically isolated syndrome (ON or TM), who were eventually diagnosed with MS (CIS-MS) or not (CIS-non MS), and a control cohort matched on age, sex and region without a CIS. We compared rates of hospitalization, physician services use and prescription drug use in the five years before the first ON or TM claim (labeled years -1,-2,-3,-4,-5) using negative binomial regression models adjusted for age, sex, socioeconomic status and index year. RESULTS: We identified 1,155 CIS-MS cases, 20,638 CIS-non MS cases, and 108,726 matched controls. Compared to matched controls, the CIS-MS cohort had a higher hospitalization rate (years -5 and -1), physician visits (all years) and prescription drug use (years -4 and -1). Compared to matched controls, the CIS-non MS cohort had a higher rate of hospitalizations (all years), physician visits (all years) and prescription drug use (all years). CONCLUSION: Health care use was higher in individuals with a CIS than without a CIS in the five years before an incident demyelinating event, regardless of whether they were subsequently diagnosed with MS. This suggests that there is a prodromal period before CIS which is not unique to MS.

Five years before multiple sclerosis onset: Phenotyping the prodrome.

BACKGROUND: The multiple sclerosis (MS) prodrome is poorly characterized. OBJECTIVE: To phenotype the MS prodrome via health care encounters. METHODS: Using data from a population-based cohort study linking administrative and clinical data in four Canadian provinces, we compared physician and hospital encounters and prescriptions filled (via International Classification of Diseases chapters, physician specialty or drug classes) for MS subjects in the 5 years before the first demyelinating claim in an administrative cohort or the clinical symptom onset in an MS clinic-derived cohort, to age-, sex- and geographically matched controls. Rate ratios (RRs), 95% confidence intervals (95% CIs) and proportions were estimated. RESULTS: The administrative and clinical cohorts included 13,951/66,940 and 3202/16,006 people with and without MS (cases/controls). Compared to controls, in the 5 years before the first demyelinating claim or symptom onset, cases had more physician and hospital encounters for the nervous (RR (range) = 2.31; 95% CI: 1.05-5.10 to 4.75; 95% CI: 3.11-7.25), sensory (RR (range) = 1.40; 95% CI: 1.34-1.46 to 2.28; 95% CI: 1.72-3.02), musculoskeletal (RR (range) = 1.19; 95% CI: 1.07-1.33 to 1.70; 95% CI: 1.57-1.85) and genito-urinary systems (RR (range) = 1.17; 95% CI: 1.05-1.30 to 1.59; 95% CI: 1.48-1.70). Cases had more psychiatrist and urologist encounters (RR (range) = 1.48; 95% CI: 1.36-1.62 to 1.80; 95% CI: 1.61-2.01), and higher proportions of musculoskeletal, genito-urinary or hormonal-related prescriptions (1.1-1.5 times higher, all p < 0.02). However, cases had fewer pregnancy-related encounters than controls (RR = 0.78; 95% CI: 0.71-0.86 to 0.88; 95% CI: 0.84-0.92). CONCLUSION: Phenotyping the prodrome 5 years before clinical recognition of MS is feasible.

Mining healthcare data for markers of the multiple sclerosis prodrome.

BACKGROUND: Previous studies suggest the existence of a prodromal period in multiple sclerosis, but little is known about the phenotypic characteristics. This study aims to characterize the multiple sclerosis (MS) prodrome using data mining analytics in the healthcare setting. METHODS: We identified people with MS and matched general population controls using health administrative data in two Canadian provinces (British Columbia and Saskatchewan). Using a training dataset (66.6% of British Columbia's cohort), L1 penalized logistic regression models were fitted to predict MS from physician and hospital encounters (via International Classification of Diseases [ICD] codes) and prescriptions filled (as drug classes) during the five years before the MS case's first demyelinating event. Internal and external validation of identified predictors was performed using logistic regression on the remaining British Columbia (33.4%) and Saskatchewan data. Adjusted odds ratios (aORs) and Area under the Curve (AUC) metrics for the models' predictive performance were reported. RESULTS: We identified 8,669 MS cases and 40,867 controls. Good predictive performance was observed for physician data (internal/external validation AUC = 0.81/0.79). Physician-generated ICD codes that were associated with MS and validated in both provinces included disorders of the central and peripheral nervous system, disorders of the eye, and cerebrovascular disease (aOR = 1.3-7.0). Overall, hospital and prescription data showed very poor and poor predictive performance (internal/external validation AUCs = 0.54/0.55 and 0.66/0.61, respectively). However, hospitalizations related to the urinary system or spinal cord diseases, or prescriptions for urinary antispasmodics or anti-vertigo preparations, were associated with 2 to 3-fold higher odds of MS (aOR = 2.3-3.3). CONCLUSIONS: Findings provide insight into the clinical characteristics of the MS prodrome. Diagnostic codes from physician encounters were capable of differentiating between MS cases and controls.

Trends in Blood Glucose Test Strip Utilization: A Population-Wide Analysis in Saskatchewan, Canada.

OBJECTIVES: To describe trends in blood glucose test strip (TS) utilization and cost in Saskatchewan. METHODS: A retrospective analysis of TS use between January 1, 1996, and December 31, 2013, was conducted using population-based health administrative databases in Saskatchewan. The prescription drug database was used to describe the annual number of TS dispensations, the number of strips dispensed, the number of unique beneficiaries and the total costs. A patient-level analysis was also carried out to describe the patterns of TS use (i.e. light, moderate or heavy) by the entire cohort and by diabetes treatments. Potential cost savings due to a newly implemented restriction policy were estimated based on the most recent data (2013). RESULTS: TS utilization increased dramatically between 1996 and 2013 in terms of the number of users and the average number of TSs received. The percentage of TS users receiving fewer than 4 TSs per week (i.e. light users) decreased by 20%, while the percentage of heavy users (i.e. those receiving more than 8 TSs per week) increased by 19%. During the same period, the use of high-risk oral hypoglycemic medications declined by 30% among all TS users. Heavy TS use was observed in at least one-third of all users, irrespective of treatment type. CONCLUSIONS: If Saskatchewan's newly imposed coverage limits had been applied in 2013, the costs of strips exceeding those limits would have totalled $2.5 million. Although TS use aligns with chronic disease care paradigms, the substantial costs and lack of evidence of patient outcomes demand better strategies to help reduce unnecessary use.

Determinants of self-perceived health for Canadians aged 40 and older and policy implications.

BACKGROUND: Perceived health status indicates people's overall perception of their health, including both physical and psychological dimensions. The aim of this study was to examine the determinants of self-perceived health for Canadians aged 40 and older using data from the Canadian Community Health Survey (2010). METHODS: Multiple logistic regression models were employed to identify factors associated with self-perceived health in two age groups: Adults aged 65+ and Adults aged 40-64. RESULTS: We found that higher income was significantly associated with better health status while chronic conditions and stress were associated with worse health status. In the 40-64 and 65+ age groups, individuals in the highest income bracket were 4.65 and 1.94 times, respectively, more likely to report better health than individuals in the lowest income bracket. The difference in the level of income associated health inequities between the two age groups point to the need for understanding the reasons behind lower inequities among seniors and how much the social protections provided by the Canadian government to seniors contribute to lowering inequities. CONCLUSIONS: Though Canada has a national public health insurance system providing coverage to all Canadians, health inequities associated with income persist providing further evidence of the importance of the social determinants of health. Examining the extent of these inequities and what factors influence them helps direct policy attention. In addition to documenting inequities, this paper discusses policy options for reducing the identified inequities.

Adherence to disease-modifying therapies for multiple sclerosis and subsequent hospitalizations.

PURPOSE: The aim of this study was to examine the association between optimal adherence to first-line disease-modifying therapies (DMT) for multiple sclerosis (MS) and hospitalizations. METHODS: We used population-based administrative data from three Canadian provinces. All individuals receiving DMT (interferon-B-1b, interferon-B-1a, or glatiramer acetate) between January 1, 1996, and December 31, 2011 (British Columbia); March 31, 2012 (Manitoba); or March 31, 2014, (Saskatchewan) were included. Adherence was estimated for the first year of DMT (year 0), using the medication possession ratio (MPR). The association between optimal adherence (MPR ≥ 80%) and all-cause and MS-specific hospitalizations in the subsequent 1, 2, and 5 years was assessed using Hurdle Poisson and logistic regression. Rate and odds ratios were adjusted (aRR and aOR) for sociodemographic factors and prior health-care utilization. RESULTS: Overall, 4746 subjects were followed for a mean 7.8 (SD 4.0) years; 3598 (76%) were women. Optimal DMT adherence was achieved in 3564/4746 (75.1%) subjects. Subsequent all-cause and MS-specific hospitalizations were lower for subjects with optimal versus suboptimal adherence, but none reached statistical significance (1-year period, aRR = 0.77, 95%CI: 0.47-1.26; aOR = 0.80, 95%CI: 0.52-1.25). Similar findings were observed in the 2-year and 5-year periods. Prior health-care utilization (hospitalizations and medications) was associated with future hospitalizations; for every additional medication class, the 5-year all-cause hospitalization rate and likelihood of an MS-specific hospitalization increased by 5% and 11%, respectively (aRR = 1.05, 95%CI: 1.02-1.07; and aOR = 1.11, 95%CI: 1.07-1.14). CONCLUSIONS: Hospitalization rates were lower in subjects with optimal DMT adherence, but findings were not statistically significant. Prior hospitalization and polypharmacy were associated with increased risk for future hospitalizations in MS. Copyright © 2017 John Wiley & Sons, Ltd.