Rotavirus vaccine coverage and factors associated with uptake using linked data: Ontario, Canada.

BACKGROUND: In August 2011, Ontario, Canada introduced a rotavirus immunization program using Rotarix™ vaccine. No assessments of rotavirus vaccine coverage have been previously conducted in Ontario. METHODS: We assessed vaccine coverage (series initiation and completion) and factors associated with uptake using the Electronic Medical Record Administrative data Linked Database (EMRALD), a collection of family physician electronic medical records (EMR) linked to health administrative data. Series initiation (1 dose) and series completion (2 doses) before and after the program's introduction were calculated. To identify factors associated with series initiation and completion, adjusted odds ratios (aOR) and 95% confidence intervals (95%CI) were calculated using logistic regression. RESULTS: A total of 12,525 children were included. Series completion increased each year of the program (73%, 79% and 84%, respectively). Factors associated with series initiation included high continuity of care (aOR = 2.15; 95%CI, 1.61-2.87), maternal influenza vaccination (aOR = 1.55; 95%CI,1.24-1.93), maternal immmigration to Canada in the last five years (aOR = 1.47; 95% CI, 1.05-2.04), and having no siblings (aOR = 1.62; 95%CI,1.30-2.03). Relative to the first program year, infants were more likely to initiate the series in the second year (aOR = 1.71; 95% CI 1.39-2.10) and third year (aOR = 2.02; 95% CI 1.56-2.61) of the program. Infants receiving care from physicians with large practices were less likely to initiate the series (aOR 0.91; 95%CI, 0.88-0.94, per 100 patients rostered) and less likely to complete the series (aOR 0.94; 95%CI, 0.91-0.97, per 100 patients rostered). Additional associations were identified for series completion. CONCLUSIONS: Family physician delivery achieved moderately high coverage in the program's first three years. This assessment demonstrates the usefulness of EMR data for evaluating vaccine coverage. Important insights into factors associated with initiation or completion (i.e. high continuity of care, smaller roster sizes, rural practice location) suggest areas for research and potential program supports.

Identifying individuals with physician-diagnosed chronic obstructive pulmonary disease in primary care electronic medical records: a retrospective chart abstraction study.

Little is known about using electronic medical records to identify patients with chronic obstructive pulmonary disease to improve quality of care. Our objective was to develop electronic medical record algorithms that can accurately identify patients with obstructive pulmonary disease. A retrospective chart abstraction study was conducted on data from the Electronic Medical Record Administrative data Linked Database (EMRALD®) housed at the Institute for Clinical Evaluative Sciences. Abstracted charts provided the reference standard based on available physician-diagnoses, chronic obstructive pulmonary disease-specific medications, smoking history and pulmonary function testing. Chronic obstructive pulmonary disease electronic medical record algorithms using combinations of terminology in the cumulative patient profile (CPP; problem list/past medical history), physician billing codes (chronic bronchitis/emphysema/other chronic obstructive pulmonary disease), and prescriptions, were tested against the reference standard. Sensitivity, specificity, and positive/negative predictive values (PPV/NPV) were calculated. There were 364 patients with chronic obstructive pulmonary disease identified in a 5889 randomly sampled cohort aged ≥ 35 years (prevalence = 6.2%). The electronic medical record algorithm consisting of ≥ 3 physician billing codes for chronic obstructive pulmonary disease per year; documentation in the CPP; tiotropium prescription; or ipratropium (or its formulations) prescription and a chronic obstructive pulmonary disease billing code had sensitivity of 76.9% (95% CI:72.2-81.2), specificity of 99.7% (99.5-99.8), PPV of 93.6% (90.3-96.1), and NPV of 98.5% (98.1-98.8). Electronic medical record algorithms can accurately identify patients with chronic obstructive pulmonary disease in primary care records. They can be used to enable further studies in practice patterns and chronic obstructive pulmonary disease management in primary care. CHRONIC LUNG DISEASE: NOVEL ALGORITHM SEARCH TECHNIQUE: Researchers develop an algorithm that can accurately search through electronic health records to find patients with chronic lung disease. Mining population-wide data for information on patients diagnosed and treated with chronic obstructive pulmonary disease (COPD) in primary care could help inform future healthcare and spending practices. Theresa Lee at the University of Toronto, Canada, and colleagues used an algorithm to search electronic medical records and identify patients with COPD from doctors' notes, prescriptions and symptom histories. They carefully adjusted the algorithm to improve sensitivity and predictive value by adding details such as specific medications, physician codes related to COPD, and different combinations of terminology in doctors' notes. The team accurately identified 364 patients with COPD in a randomly-selected cohort of 5889 people. Their results suggest opportunities for broader, informative studies of COPD in wider populations.

ADHD Treatment in Primary Care: Demographic Factors, Medication Trends, and Treatment Predictors.

BACKGROUND: The aim of this study is to determine the prevalence and characteristics of youth with attention-deficit hyperactivity disorder (ADHD) in Ontario, Canada, and to determine the predictors of psychotropic medication prescriptions in youth with ADHD. METHOD: This is a cross-sectional retrospective chart abstraction of more than 250 000 medical records from youth aged 1 to 24 years in a large geographical region in Ontario, Canada, linked to population-based health administrative data. A total of 10 000 charts were randomly selected and manually reviewed using predetermined criteria for ADHD and comorbidities. Prevalence, comorbidities, demographic indicators, and health service utilization characteristics were calculated. Predictors of treatment characteristics were determined using logistic regression modelling. RESULTS: The prevalence of ADHD was 5.4% (7.9% males, 2.7% females). Youth with ADHD had significant psychiatric comorbidities. The majority (70.0%) of ADHD patients received prescriptions for stimulant or nonstimulant ADHD medication. Antipsychotic prescriptions were provided to 11.9% of ADHD patients versus 0.9% of patients without ADHD. Antidepressant prescriptions were provided to 19.8% versus 5.4% of patients with and without ADHD, respectively. Predictors of antidepressant prescriptions were increasing age (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.07 to 1.21), psychiatric consultation (OR, 2.04; 95% CI, 1.16 to 3.58), and diagnoses of both anxiety and depression (OR, 18.4; 95% CI, 8.03 to 42.1), whereas the only predictor of antipsychotic prescriptions was psychiatric consultation (OR, 3.85; 95% CI, 2.11 to 7.02). CONCLUSIONS: Youth with ADHD have more psychiatric comorbidities than youth without ADHD. The majority of youth with ADHD received stimulant medications, and a significant number received additional psychotropic medications, with psychiatric consultation predicting medication use.

Primary Care Screening and Comorbidity Management in Rheumatoid Arthritis in Ontario, Canada.

OBJECTIVE: Quality measurement for rheumatoid arthritis (RA) patients has largely focused on care provided by rheumatologists. Our aim was to develop and assess quality measures related to the screening and management of comorbidity in RA patients in primary care. METHODS: We used the primary care Electronic Medical Record Administrative data Linked Database in Ontario, Canada. We harmonized Canadian general population and RA clinical recommendations to develop and assess screening, process, and outcome measures. For each RA patient, 10 non-RA patients were matched by age and sex. Stratified analyses were performed, comparing patients with RA to those without RA, to assess the performance of quality measures. RESULTS: We compared 1,405 RA patients to 14,050 matched non-RA patients (72.8% female; mean age 62.5 years). Compared to non-RA patients, RA patients more frequently had influenza (44.9% versus 40.0%) and pneumococcal (40.4% versus 34.1%) vaccinations and bone mineral density testing (67.4% versus 58.1%). Herpes zoster vaccinations were less frequent among RA patients (13.8% versus 19.5%), as was screening for cervical cancer (58.6% versus 64.0%). No significant differences were observed between RA and non-RA patients in screenings for breast (70.7% versus 73.8%) or colorectal (31.7% versus 34.5%) cancers. Only a quarter of RA patients had a comprehensive cardiovascular risk assessment. No definitive differences were detected in the management of patients who had co-occurring cardiovascular disease or diabetes mellitus. CONCLUSION: For both RA and non-RA patients, compliance with Canadian recommendations for preventive medical services and screening for comorbid conditions in primary care was less than optimal. This indicates key targets for improvement.

Patterns of Care Among Patients Referred to Rheumatologists in Ontario, Canada.

OBJECTIVE: Our aim was to characterize referrals to rheumatologists, the early care management of patients with rheumatic diseases, and timeliness of care and treatment. METHODS: We conducted a retrospective observational study involving patients with first-time rheumatology referrals between 2000 and 2013 in the primary care Electronic Medical Record Administrative data Linked Database (EMRALD) in Ontario, Canada. Referrals were characterized in terms of diagnoses, patient demographics, diagnostic tests, treatment initiated by family physicians and rheumatologists, and other specialists seen prior to rheumatology consultation. Timeliness of referrals, rheumatologist consultations, and treatment were determined overall and for each diagnostic category. RESULTS: Among 2,430 patients referred to a rheumatologist, 69% were female, with an average age of 53 years. The principal diagnosis associated with the referral included osteoarthritis (32%), systemic inflammatory rheumatic diseases (31%), regional musculoskeletal conditions (16%), chronic pain conditions (14%), osteoporosis (2%), and other/miscellaneous (5%). Family physicians most frequently prescribed nonsteroidal antiinflammatory drugs/cyclooxygenase 2 inhibitors (38%), and their pre-referral diagnostic testing practice varied considerably. The duration of time from symptom onset to rheumatology consultation varied by diagnoses, with the shortest being for patients with systemic rheumatic diseases; for rheumatoid arthritis (RA), the median time to consultation was 327 days. Most of the delay occurred prior to referral; 36% of RA patients initiated a disease-modifying antirheumatic drug within 6 months of symptom onset. CONCLUSION: Approximately 1 in 3 referrals to rheumatologists were for a systemic inflammatory rheumatic disease. We observed substantial delays to rheumatology consultations and variations in patterns of care that could be amenable to quality improvement interventions.

Improving stroke prevention therapy for patients with atrial fibrillation in primary care: protocol for a pragmatic, cluster-randomized trial.

BACKGROUND: The prevalence of atrial fibrillation (AF) is growing as the population ages, and at least 15% of ischemic strokes are attributed to AF. However, many high-risk AF patients are not offered guideline-recommended stroke prevention therapy due to a variety of system, provider, and patient-level barriers. METHODS: We will conduct a pragmatic, cluster-randomized controlled trial randomizing primary care clinics to test a "toolkit" of quality improvement interventions in primary care. In keeping with the recommendations of the chronic care model to simultaneously activate patients and facilitate proactive care by providers, the toolkit includes provider-focused strategies (education, audit and feedback, electronic decision support, and reminders) plus patient-directed strategies (educational letters and reminders). The trial will include two feedback cycles at baseline and approximately 6 months and a final data collection at approximately 12 months. The study will be powered to show a difference of 10% in the primary outcome of proportion of patients receiving guideline-recommended stroke prevention therapy. Analysis will follow the intention-to-treat principle and will be blind to treatment allocation. Unit of analysis will be the patient; models will use generalized estimating equations to account for clustering at the clinical level. DISCUSSION: Stroke prevention therapy using anticoagulation in patients with AF is known to reduce strokes by two thirds or more in clinical trials, but most studies indicate under-use of this treatment in real-world practice. If the toolkit successfully improves care for patients with AF, stakeholders will be engaged to facilitate broader application to maximize the potential to improve patient outcomes. The intervention toolkit tested in this project could also provide a model to improve quality of care for other chronic cardiovascular conditions managed in primary care. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01927445 ). Registered August 14, 2014 at https://clinicaltrials.gov/ .

Identifying Patients With Atrial Fibrillation in Administrative Data.

BACKGROUND: Identifying patients with atrial fibrillation (AF) using administrative data is important for epidemiologic and outcomes research. Although administrative data cover large populations, it is necessary to assess their validity in identifying AF patients. METHODS: We used Ontario family physician electronic medical records from the Electronic Medical Record Administrative data Linked Database (EMRALD) as a reference standard to assess the accuracy of administrative data algorithms in identifying patients with AF. From a random sample of 7500 adult patients, patients with AF as recorded in family physician records were identified. RESULTS: The optimal algorithm consisted of any of: hospitalization or an emergency room code for AF or prescription for an AF-specific antiarrhythmic agent or billing code for cardioversion, or prescription for an anticoagulant that was accompanied by a physician billing code. for arrhythmia. The algorithm sensitivity was 80.7% (95% confidence interval [CI], 75.1-86.3), specificity 99.1% (95% CI, 98.9-99.3), positive predictive value 71.1% (95% CI, 65.1-77.1), and negative predictive value 99.5% (95% CI, 99.3-99.7). This algorithm, applied to the Ontario population, resulted in a calculated increase in AF prevalence from 1.68% to 2.36% over the years 2000-2014. Anticoagulation rates for AF patients increased from 53% in 2011 to 60% in 2014. Among AF patients receiving anticoagulants, novel oral anticoagulant utilization increased from < 5% in 2011 to > 50% in 2014. CONCLUSIONS: Identifying patients with AF can be done using administrative data, and the algorithm can be used to assess trends in disease burden over time and patterns of care in large populations.

Wait times to rheumatology care for patients with rheumatic diseases: a data linkage study of primary care electronic medical records and administrative data.

BACKGROUND: The Wait Time Alliance recently established wait time benchmarks for rheumatology consultations in Canada. Our aim was to quantify wait times to primary and rheumatology care for patients with rheumatic diseases. METHODS: We identified patients from primary care practices in the Electronic Medical Record Administrative data Linked Database who had referrals to Ontario rheumatologists over the period 2000-2013. To assess the full care pathway, we identified dates of symptom onset, presentation in primary care and referral from electronic medical records. Dates of rheumatologist consultations were obtained by linking with physician service claims. We determined the duration of each phase of the care pathway (symptom onset to primary care encounter, primary care encounter to referral, and referral to rheumatologist consultation) and compared them with established benchmarks. RESULTS: Among 2430 referrals from 168 family physicians, 2015 patients (82.9%) were seen by 146 rheumatologists within 1 year of referral. Of the 2430 referrals, 2417 (99.5%) occurred between 2005 and 2013. The main reasons for referral were osteoarthritis (32.4%) and systemic inflammatory rheumatic diseases (30.6%). Wait times varied by diagnosis and geographic region. Overall, the median wait time from referral to rheumatologist consultation was 74 (interquartile range 27-101) days; it was 66 (interquartile range 18-84) days for systemic inflammatory rheumatic diseases. Wait time benchmarks were not achieved, even for the most urgent types of referral. For systemic inflammatory rheumatic diseases, most of the delays occurred before referral. INTERPRETATION: Rheumatology wait times exceeded established benchmarks. Targeted efforts are needed to promote more timely access to both primary and rheumatology care. Routine linkage of electronic medical records with administrative data may help fill important gaps in knowledge about waits to primary and specialty care.

Validation of infant immunization billing codes in administrative data.

Ontario has a single payer provincial health insurance program. Administrative data may provide a potentially robust source of information for post-marketing vaccine studies. Vaccine-specific immunization billing codes were introduced in 2011. Our objective was to validate Ontario's universal health care administrative datasets to assess infant immunization status. Electronic medical record data from the Electronic Medical Record Administrative data Linked Database (EMRALD) was used as the reference standard to calculate performance characteristics of the Ontario Health Insurance Plan (OHIP) database vaccine-specific and general immunization codes for 4 primary infant immunizations: diphtheria, tetanus, acellular pertussis, inactivated polio, Haemophilus influenzae type B (DTaP-IPV-Hib) combination vaccine, pneumococcal conjugate vaccine, measles, mumps, rubella (MMR) vaccine, and meningococcal conjugate serogroup C vaccine. OHIP billing claims had specificity ranging from 81% to 92%, sensitivity 70% to 83%, positive predictive value (PPV) 97% to 99%, and negative predictive value (NPV) 13% to 46% for identifying the various specific vaccines in administrative data. For cohorts vaccinated in the new code introduction phase, using both the vaccine-specific and general codes had higher sensitivity than the vaccine-specific codes alone. In conclusion, immunization billing claims from administrative data in Ontario had high specificity and PPV, moderate sensitivity, and low NPV. This study identifies some of the applications of utilizing administrative data for post-marketing vaccine studies. However, limitations of these data decrease their utility for measuring vaccine coverage and effectiveness. Therefore, the establishment of a comprehensive and linkable immunization registry should be a provincial priority.

Development of a novel therapeutic suppressor of brain proinflammatory cytokine up-regulation that attenuates synaptic dysfunction and behavioral deficits.

We report the development of a novel, aqueous-soluble, safe, small molecule, experimental therapeutic that suppresses injury-induced, proinflammatory cytokine increases in the brain, with resultant attenuation of synaptic protein biomarker loss and improvement in hippocampus-dependent behavioral deficits. A GMP production scheme for the active pharmaceutical ingredient, compound 17, is presented. The development and large-scale availability of this novel compound allow exploration of new, potentially disease-modifying, therapeutic approaches to CNS disorders.

Cooperative effect of gefitinib and fumitremorgin c on cell growth and chemosensitivity in estrogen receptor alpha negative fulvestrant-resistant MCF-7 cells.

The selective ER downregulator, fulvestrant, is currently approved as a second line endocrine therapy after onset of resistance to prior antiestrogen therapy in postmenopausal breast cancer patients. Resistance to antihormonal therapies is common and, therefore, we anticipate that fulvestrant-resistance will occur as well. The current study was undertaken to investigate the underlying molecular changes after fulvestrant-resistance and find new therapeutic targets and agents for fulvestrant-resistant breast cancer cells. We developed a unique fulvestrant-resistant cell line (MCF-7/F), derived from MCF-7 estrogen receptor alpha (ERalpha)-positive human breast cancer cells, by culturing them in 1 microM fulvestrant containing medium for approximately 18 months. MCF-7/F cells became irreversibly ERalpha negative as withdrawal of fulvestrant did not alter the ERalpha-negative phenotype, determined by real-time PCR, Western blot analysis, and ERE-luciferase transfection assays. MCF-7/F cells grew in a hormone-independent manner. Interestingly, MCF-7/F cells overexpressed both epidermal growth factor receptor (EGFR) and breast cancer resistant protein (BCRP). Gefitinib, a specific EGFR tyrosine kinase inhibitor, preferentially inhibited the growth of MCF-7/F cells relative to MCF-7 cells by inhibiting both MAPK44/42 and Akt phosphorylation. MCF-7/F cells became less sensitive to chemotherapeutic agents such as mitoxantrone. Moreover, fumitremorgin C, a specific BCRP inhibitor, significantly increased the efficacy of mitoxantrone in MCF-7/F cells. Gefitinib increased the inhibitory effect of mitoxantrone on cell growth. Similarly, fumitremorgin C increased the inhibitory effect of gefitinib on cell growth, suggesting that there is a bidirectional crosstalk between EGFR and BCRP. More importantly, these results provide a molecular basis for using gefitinib, BCRP inhibitors, and chemotherapeutic agents as combination therapy approaches in fulvestrant-resistant breast cancer.

De novo and molecular target-independent discovery of orally bioavailable lead compounds for neurological disorders.

There is immediate potential to enhance success and innovation in drug development by pairing newly emerging approaches in medicinal chemistry and computational biology with knowledge gained from the recent era of high throughput screens and the early years of modern drug discovery when in vivo efficacy was an early "Go/No Go" project management decision. Focused, in-parallel synthetic chemistry platforms, combined with computational analyses serving as decision aids in planning, minimize the total number of compounds synthesized while maximizing the probability of creating bioavailable compounds that sample diverse chemical space. Incorporating a hierarchal strategy that emphasizes early selection of synthesized compounds based on biological or biophysical endpoints presents fewer and more relevant compounds for secondary evaluation of in vivo efficacy using animal screens with disease relevant or clinically translatable endpoints. We summarize here an interdisciplinary approach at the chemistry-biology interface that is used for the rapid discovery of novel lead compounds for neurodegenerative disorders, such as Alzheimer's disease (AD). The chemistry platform uses established chemistries amenable to in-parallel strategies to create synthetic diversifications of the privileged pyridazine chemotype that sample a restricted chemical space. The hierarchal biology platform uses primary screens for in vitro activity and selectivity with the target cell type, and rapid secondary screens for in vivo efficacy and toxicity in animal models with good phenotypic penetrance for disease relevant pathophysiological endpoints or clinically translatable surrogate endpoints. For the AD case study, novel lead compounds were developed in less than two years by a small academic group, and corporate sponsored clinical trials are planned.

Glia as a therapeutic target: selective suppression of human amyloid-beta-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration.

A corollary of the neuroinflammation hypothesis is that selective suppression of neurotoxic products produced by excessive glial activation will result in neuroprotection. We report here that daily oral administration to mice of the brain-penetrant compound 4,6-diphenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)pyridazine (MW01-5-188WH), a selective inhibitor of proinflammatory cytokine production by activated glia, suppressed the human amyloid-beta (Abeta) 1-42-induced upregulation of interleukin-1beta, tumor necrosis factor-alpha, and S100B in the hippocampus. Suppression of neuroinflammation was accompanied by restoration of hippocampal synaptic dysfunction markers synaptophysin and postsynaptic density-95 back toward control levels. Consistent with the neuropathophysiological improvements, MW01-5-188WH therapy attenuated deficits in Y maze behavior, a hippocampal-linked task. Oral MW01-5-188WH therapy begun 3 weeks after initiation of intracerebroventricular infusion of human Abeta decreased the numbers of activated astrocytes and microglia and the cytokine levels in the hippocampus without modifying amyloid plaque burden or altering peripheral tissue cytokine upregulation in response to an in vivo inflammatory challenge. The results provide a novel integrative chemical biology proof in support of the neuroinflammation hypothesis of disease progression, demonstrate that neurodegeneration can be attenuated independently of plaque modulation by targeting innate brain proinflammatory cytokine responses, and indicate the feasibility of developing efficacious, safe, and selective therapies for neurodegenerative disorders by targeting key glial activation pathways.

Apoptotic action of 17beta-estradiol in raloxifene-resistant MCF-7 cells in vitro and in vivo.

BACKGROUND: Resistance to tamoxifen, a selective estrogen receptor modulator (SERM), involves changes that prevent apoptosis and enhance cell proliferation and survival. Paradoxically, estrogen treatment inhibits the growth of long-term tamoxifen-treated breast tumors. Because of the increasing use of raloxifene, another SERM, to prevent osteoporosis and potentially reduce breast cancer risk, some women will develop raloxifene-resistant breast cancer. We developed a raloxifene-resistant MCF-7 cell model (MCF-7/Ral) and investigated the nature of raloxifene-resistant breast cancer and its response to estradiol. METHODS: Raloxifene resistance and hormone responsiveness were assessed by proliferation assays and cell cycle analysis in parental MCF-7 and MCF-7/Ral cells. Nuclear factor kappaB (NF-kappaB) activity was investigated with a transient transfection assay. Apoptosis was investigated by annexin V staining, mRNA was measured by real-time polymerase chain reaction, and protein was measured by western blotting. Tumorigenesis was studied by injecting MCF-7 or MCF-7/Ral cells into ovariectomized athymic mice (10 per group) and monitoring tumor size weekly. All statistical tests were two-sided. RESULTS: Basal NF-kappaB activity was higher in MCF-7/Ral cells (1.6 U, 95% confidence interval [CI] = 1.2 to 2.0 U) than in MCF-7 cells (0.8 U, 95% CI = 0.4 to 1.1 U; P =.004). When cultured with 1 microM raloxifene, MCF-7/Ral cells grew statistically significantly (P<.001) faster than MCF-7 cells. Estradiol treatment of MCF-7/Ral cells arrested cells in G(2)/M phase of the cell cycle, decreased NF-kappaB activity (0.2 U, 95% CI = 0.2 to 0.3 U; P<.001), increased expression of Fas protein and mRNA (4.5-fold, 95% CI = 2.8- to 6.3-fold versus 0.5-fold, 95% CI = 0.3- to 0.8-fold for control treatment; P<.001), and induced apoptosis. Treatment with either raloxifene or tamoxifen stimulated MCF-7/Ral tumor growth, suggesting that such tumors were resistant to both drugs. When a 9-week raloxifene or tamoxifen treatment was followed by a 5-week estradiol treatment, estradiol statistically significantly reduced the size of tumors stimulated by raloxifene or tamoxifen (at week 14, P =.004 for raloxifene and P<.001 for tamoxifen). CONCLUSIONS: Growth of raloxifene-resistant MCF-7/Ral cells in vitro and in vivo is repressed by estradiol treatment by a mechanism involving G2/M-phase arrest, decreased NF-kappaB activity, and increased Fas expression to induce apoptosis.