Dopamine-mediated plasticity preserves excitatory connections to direct pathway striatal projection neurons and motor function in a mouse model of Parkinson's disease.

The cardinal symptoms of Parkinson's disease (PD) such as bradykinesia and akinesia are debilitating, and treatment options remain inadequate. The loss of nigrostriatal dopamine neurons in PD produces motor symptoms by shifting the balance of striatal output from the direct (go) to indirect (no-go) pathway in large part through changes in the excitatory connections and intrinsic excitabilities of the striatal projection neurons (SPNs). Here, we report using two different experimental models that a transient increase in striatal dopamine and enhanced D1 receptor activation, during 6-OHDA dopamine depletion, prevent the loss of mature spines and dendritic arbors on direct pathway projection neurons (dSPNs) and normal motor behavior for up to 5 months. The primary motor cortex and midline thalamic nuclei provide the major excitatory connections to SPNs. Using ChR2-assisted circuit mapping to measure inputs from motor cortex M1 to dorsolateral dSPNs, we observed a dramatic reduction in both experimental model mice and controls following dopamine depletion. Changes in the intrinsic excitabilities of SPNs were also similar to controls following dopamine depletion. Future work will examine thalamic connections to dSPNs. The findings reported here reveal previously unappreciated plasticity mechanisms within the basal ganglia that can be leveraged to treat the motor symptoms of PD.

Burden of health behaviours and socioeconomic position on health care expenditure in Ontario.

Background: Smoking, unhealthy alcohol consumption, poor diet and physical inactivity are leading risk factors for morbidity and mortality, and contribute substantially to overall healthcare costs. The availability of health surveys linked to health care provides population-based estimates of direct healthcare costs. We estimated health behaviour and socioeconomic-attribute healthcare costs, and how these have changed during a period when government policies have aimed to reduce their burden.  Methods: The Ontario samples of the Canadian Community Health Surveys (conducted in 2003, 2005, and 2007-2008) were linked at the individual level to all records of health care use of publicly funded healthcare. Generalized linear models were estimated with a negative binomial distribution to ascertain the relationship of health behaviours and socioeconomic risk factors on health care costs. The multivariable cost model was applied to unlinked, Ontario CCHS samples for each year from 2004 to 2013 to examine the evolution of health behaviour and socioeconomic-attributable direct health care expenditures over a 10-year period. Results: We included 80,749 respondents, aged 25 years and older, and 312,952 person-years of follow-up. The cost model was applied to 200,324 respondents aged 25 years and older (CCHS 2004 to 2013). During the 10-year period from 2004 to 2013, smoking, unhealthy alcohol consumption, poor diet and physical inactivity attributed to 22% of Ontario's direct health care costs. Ontarians in the most disadvantaged socioeconomic position contributed to 15% of the province's direct health care costs. Combined, these health behaviour and socioeconomic risk factors were associated with 34% ($134 billion) of direct health care costs (2004 to 2013). Over this time period, we estimated a 1.9% reduction in health care expenditure ($5.0 billion) attributable to improvements in some health behaviours, most importantly reduced rates of smoking. Conclusions: Adverse health behaviours and socioeconomic position cause a large direct health care system cost burden.

How pharmacoepidemiology networks can manage distributed analyses to improve replicability and transparency and minimize bias.

Several pharmacoepidemiology networks have been developed over the past decade that use a distributed approach, implementing the same analysis at multiple data sites, to preserve privacy and minimize data sharing. Distributed networks are efficient, by interrogating data on very large populations. The structure of these networks can also be leveraged to improve replicability, increase transparency, and reduce bias. We describe some features of distributed networks using, as examples, the Canadian Network for Observational Drug Effect Studies, the Sentinel System in the USA, and the European Research Network of Pharmacovigilance and Pharmacoepidemiology. Common protocols, analysis plans, and data models, with policies on amendments and protocol violations, are key features. These tools ensure that studies can be audited and repeated as necessary. Blinding and strict conflict of interest policies reduce the potential for bias in analyses and interpretation. These developments should improve the timeliness and accuracy of information used to support both clinical and regulatory decisions.

Protocol for a scoping review of post-trial extensions of randomised controlled trials using individually linked administrative and registry data.

INTRODUCTION: Well-conducted randomised controlled trials (RCTs) provide the least biased estimates of intervention effects. However, RCTs are costly and time-consuming to perform and long-term follow-up of participants may be hampered by lost contacts and financial constraints. Advances in computing and population-based registries have created new possibilities for increasing the value of RCTs by post-trial extension using linkage to routinely collected administrative/registry data in order to determine long-term interventional effects. There have been recent important examples, including 20+ years follow-up studies of trials of pravastatin and mammography. Despite the potential value of post-trial extension, there has been no systematic study of this literature. This scoping review aims to characterise published post-trial extension studies, assess their value, and identify any potential challenges associated with this approach. METHODS AND ANALYSIS: This review will use the recommended methods for scoping reviews. We will search MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. A draft search strategy is included in this protocol. Review of titles and abstracts, full texts of potentially eligible studies and data/information extraction will be conducted independently by pairs of investigators. Eligible studies will be RCTs that investigated healthcare interventions that were extended by individual linkage to administrative/registry/electronic medical records data after the completion of the planned follow-up period. Information concerning the original trial, characteristics of the extension study, any clinical, policy or ethical implications and methodological or practical challenges will be collected using standardised forms. ETHICS AND DISSEMINATION: As this study uses secondary data, and does not include person-level data, ethics approval is not required. We aim to disseminate these findings through journals and conferences targeting triallists and researchers involved in health data linkage. We aim to produce guidance for investigators on the conduct of post-trial extensions using routinely collected data.

Association Between Incretin-Based Drugs and the Risk of Acute Pancreatitis.

IMPORTANCE: The association between incretin-based drugs, such as dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, and acute pancreatitis is controversial. OBJECTIVE: To determine whether the use of incretin-based drugs, compared with the use of 2 or more other oral antidiabetic drugs, is associated with an increased risk of acute pancreatitis. DESIGN, SETTING, AND PARTICIPANTS: A large, international, multicenter, population-based cohort study was conducted using combined health records from 7 participating sites in Canada, the United States, and the United Kingdom. An overall cohort of 1 532 513 patients with type 2 diabetes initiating the use of antidiabetic drugs between January 1, 2007, and June 30, 2013, was included, with follow-up until June 30, 2014. EXPOSURES: Current use of incretin-based drugs compared with current use of at least 2 oral antidiabetic drugs. MAIN OUTCOMES AND MEASURES: Nested case-control analyses were conducted including hospitalized patients with acute pancreatitis matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and follow-up duration. Hazard ratios (HRs) and 95% CIs for hospitalized acute pancreatitis were estimated and compared current use of incretin-based drugs with current use of 2 or more oral antidiabetic drugs. Secondary analyses were performed to assess whether the risk varied by class of drug (DPP-4 inhibitors and GLP-1 agonists) or by duration of use. Site-specific HRs were pooled using random-effects models. RESULTS: Of 1 532 513 patients included in the analysis, 781 567 (51.0%) were male; mean age was 56.6 years. During 3 464 659 person-years of follow-up, 5165 patients were hospitalized for acute pancreatitis (incidence rate, 1.49 per 1000 person-years). Compared with current use of 2 or more oral antidiabetic drugs, current use of incretin-based drugs was not associated with an increased risk of acute pancreatitis (pooled adjusted HR, 1.03; 95% CI, 0.87-1.22). Similarly, the risk did not vary by drug class (DPP-4 inhibitors: pooled adjusted HR, 1.09; 95% CI, 0.86-1.22; GLP-1 agonists: pooled adjusted HR, 1.04; 95% CI, 0.81-1.35) and there was no evidence of a duration-response association. CONCLUSIONS AND RELEVANCE: In this large population-based study, use of incretin-based drugs was not associated with an increased risk of acute pancreatitis compared with other oral antidiabetic drugs.

Sex ratios at birth after induced abortion.

BACKGROUND: Skewed male:female ratios at birth have been observed among certain immigrant groups. Data on abortion practices that might help to explain these findings are lacking. METHODS: We examined 1 220 933 births to women with up to 3 consecutive singleton live births between 1993 and 2012 in Ontario. Records of live births, and induced and spontaneous abortions were linked to Canadian immigration records. We determined associations of male:female infant ratios with maternal birthplace, sex of the previous living sibling(s) and prior spontaneous or induced abortions. RESULTS: Male:female infant ratios did not appreciably depart from the normal range among Canadian-born women and most women born outside of Canada, irrespective of the sex of previous children or the characteristics of prior abortions. However, among infants of women who immigrated from India and had previously given birth to 2 girls, the overall male:female ratio was 1.96 (95% confidence interval [CI] 1.75-2.21) for the third live birth. The male:female infant ratio after 2 girls was 1.77 (95% CI 1.26-2.47) times higher if the current birth was preceded by 1 induced abortion, 2.38 (95% CI 1.44-3.94) times higher if preceded by 2 or more induced abortions and 3.88 (95% CI 2.02-7.50) times higher if the induced abortion was performed at 15 weeks or more gestation relative to no preceding abortion. Spontaneous abortions were not associated with male-biased sex ratios in subsequent births. INTERPRETATION: High male:female ratios observed among infants born to women who immigrated from India are associated with induced abortions, especially in the second trimester of pregnancy.

A 3-year study of high-cost users of health care.

BACKGROUND: Characterizing high-cost users of health care resources is essential for the development of appropriate interventions to improve the management of these patients. We sought to determine the concentration of health care spending, characterize demographic characteristics and clinical diagnoses of high-cost users and examine the consistency of their health care consumption over time. METHODS: We conducted a retrospective analysis of all residents of Ontario, Canada, who were eligible for publicly funded health care between 2009 and 2011. We estimated the total attributable government health care spending for every individual in all health care sectors. RESULTS: More than $30 billion in annual health expenditures, representing 75% of total government health care spending, was attributed to individual costs. One-third of high-cost users (individuals with the highest 5% of costs) in 2009 remained in this category in the subsequent 2 years. Most spending among high-cost users was for institutional care, in contrast to lower-cost users, among whom spending was predominantly for ambulatory care services. Costs were far more concentrated among children than among older adults. The most common reasons for hospital admissions among high-cost users were chronic diseases, infections, acute events and palliative care. INTERPRETATION: Although high health care costs were concentrated in a small minority of the population, these related to a diverse set of patient health care needs and were incurred in a wide array of health care settings. Improving the sustainability of the health care system through better management of high-cost users will require different tactics for different high-cost populations.

Asthma and chronic obstructive pulmonary disease (COPD) prevalence and health services use in Ontario Métis: a population-based cohort study.

INTRODUCTION: Chronic respiratory diseases cause a significant health and economic burden around the world. In Canada, Aboriginal populations are at increased risk of asthma and chronic obstructive pulmonary disease (COPD). There is little known, however, about these diseases in the Canadian Métis population, who have mixed Aboriginal and European ancestry. A population-based study was conducted to quantify asthma and COPD prevalence and health services use in the Métis population of Ontario, Canada's largest province. METHODS: The Métis Nation of Ontario Citizenship Registry was linked to provincial health administrative databases to measure and compare burden of asthma and COPD between the Métis and non-Métis populations of Ontario between 2009 and 2012. Asthma and COPD prevalence, health services use (general physician and specialist visits, emergency department visits, hospitalizations), and mortality were measured. RESULTS: Prevalences of asthma and COPD were 30% and 70% higher, respectively, in the Métis compared to the general Ontario population (p<0.001). General physician and specialist visits were significantly lower in Métis with asthma, while general physician visits for COPD were significantly higher. Emergency department visits and hospitalizations were generally higher for Métis compared to non-Métis with either disease. All-cause mortality in Métis with COPD was 1.3 times higher compared to non-Métis with COPD (p = 0.01). CONCLUSION: There is a high burden of asthma and COPD in Ontario Métis, with significant prevalence and acute health services use related to these diseases. Lower rates of physician visits suggest barriers in access to primary care services.

Prescription medicines: decision-making preferences of patients who receive different levels of public subsidy.

OBJECTIVE: To compare the relative importance of medicine attributes and decision-making preferences of patients with higher or lower levels of insurance coverage in a publicly funded health care system. DESIGN AND SETTING: Cross-sectional telephone survey of randomly selected regular medicine users aged ≥18 years in the Hunter Valley, NSW, Australia. MAIN VARIABLES STUDIED: Questions about 27 medicine attributes and active involvement in decisions to start a new medicine. RESULTS: After adjustment, there were few differences between the 408 concession card holders (high insurance) and 410 general beneficiaries (low insurance) in their assessment of the importance of medicine attributes. For both groups, the explanation of treatment options, establishing the need for the medicine, and medicine efficacy and safety were the most important considerations. Medicine costs, the treatment burden and medicine familiarity were less important; the views of family and friends ranked lowest. There was a statistically significantly greater influence of the regular doctor for the concession card holders than general beneficiaries (93.6 vs. 84%, adjusted OR 2.80, 95% CI 1.31, 5.99). Concession card holders were more likely to favour doctors having more say in the decision-making process (crude OR 1.69, 95% CI 1.28, 2.24), and more likely to report the most recent treatment decision being made by the doctor alone, compared with general beneficiaries (61.2 vs. 40.3%). CONCLUSION: Medicine need, efficacy and safety are viewed as paramount for most patients, irrespective of insurance status. While patients report the importance of participation in treatment decisions, delegation of decision making to the doctor was common in practice.

Multispecialty physician networks in Ontario.

BACKGROUND: Large multispecialty physician group practices, with a central role for primary care practitioners, have been shown to achieve high-quality, low-cost care for patients with chronic disease. We assessed the extent to which informal multispecialty physician networks in Ontario could be identified by using health administrative data to exploit natural linkages among patients, physicians, and hospitals based on existing patient flow. METHODS: We linked each Ontario resident to his or her usual provider of primary care over the period from fiscal year 2008/2009 to fiscal year 2010/2011. We linked each specialist to the hospital where he or she performed the most inpatient services. We linked each primary care physician to the hospital where most of his or her ambulatory patients were admitted for non-maternal medical care. Each resident was then linked to the same hospital as his or her usual provider of primary care. We computed "loyalty" as the proportion of care to network residents provided by physicians and hospitals within their network. Smaller clusters were aggregated to create networks based on a minimum population size, distance, and loyalty. Networks were not constrained geographically. RESULTS: We identified 78 multispecialty physician networks, comprising 12,410 primary care physicians, 14,687 specialists, and 175 acute care hospitals serving a total of 12,917,178 people. Median network size was 134,723 residents, 125 primary care physicians, and 143 specialists. Virtually all eligible residents were linked to a usual provider of primary care and to a network. Most specialists (93.5%) and primary care physicians (98.2%) were linked to a hospital. Median network physician loyalty was 68.4% for all physician visits and 81.1% for primary care visits. Median non-maternal admission loyalty was 67.4%. Urban networks had lower loyalties and were less self-contained but had more health care resources. INTERPRETATION: We demonstrated the feasibility of identifying informal multispecialty physician networks in Ontario on the basis of patterns of health care-seeking behaviour. Networks were reasonably self-contained, in that individual residents received most of their care from providers within their respective networks. Formal constitution of networks could foster accountability for efficient, integrated care through care management tools and quality improvement, the ideas behind "accountable care organizations."

Sex ratios among Canadian liveborn infants of mothers from different countries.

BACKGROUND: There has been much discussion about whether female feticide occurs in certain immigrant groups in Canada. We examined data on live births in Ontario and compared sex ratios in different groups according to the mother's country or region of birth and parity. METHODS: We completed a population-based study of 766,688 singleton live births between 2002 and 2007. We used birth records provided by Ontario Vital Statistics for live births in the province between 23 and 41 weeks' gestation. We categorized each newborn according to the mother's country or region of birth, namely Canada (n = 486,599), Europe (n = 58,505), South Korea (n = 3663), China (n = 23,818), Philippines (n = 15,367), rest of East Asia (n = 18,971), Pakistan (n = 18,018), India (n = 31,978), rest of South Asia (n = 20,695) and other countries (n = 89,074). We calculated male:female ratios and 95% confidence intervals (CIs) for all live births by these regions and stratified them by maternal parity at the time of delivery (0, 1, 2 or ≥ 3). RESULTS: Among infants of nulliparous women, the male:female ratio was about 1.05 overall. As parity increased, the ratio remained unchanged among infants of Canadian-born women. In contrast, the male:female ratio was significantly higher among infants of primiparous women born in South Korea (1.20, 95% CI 1.09-1.34) and India (1.11, 95% CI 1.07-1.15) than among infants of Canadian-born primiparous women. Among multiparous women, those born in India were significantly more likely than Canadian-born women to have a male infant (parity 2, ratio 1.36, 95% CI 1.27-1.46; parity ≥ 3, ratio 1.25, 95% CI 1.09-1.43). INTERPRETATION: Our study of male:female ratios in Ontario showed that multiparous women born in India were significantly more likely than multiparous women born in Canada to have a male infant.

The health services burden of heart failure: an analysis using linked population health data-sets.

BACKGROUND: The burden of patients with heart failure on health care systems is widely recognised, although there have been few attempts to quantify individual patterns of care and differences in health service utilisation related to age, socio-economic factors and the presence of co-morbidities. The aim of this study was to assess the typical profile, trajectory and resource use of a cohort of Australian patients with heart failure using linked population-based, patient-level data. METHODS: Using hospital separations (Admitted Patient Data Collection) with death registrations (Registry of Births, Deaths and Marriages) for the period 2000-2007 we estimated age- and gender-specific rates of index admissions and readmissions, risk factors for hospital readmission, mean length of stay (LOS), median survival and bed-days occupied by patients with heart failure in New South Wales, Australia. RESULTS: We identified 29,161 index admissions for heart failure. Admission rates increased with age, and were higher for males than females for all age groups. Age-standardised rates decreased over time (256.7 to 237.7/100,000 for males and 235.3 to 217.1/100,000 for females from 2002-3 to 2006-7; p = 0.0073 adjusted for gender). Readmission rates (any cause) were 27% and 73% at 28-days and one year respectively; readmission rates for heart failure were 11% and 32% respectively. All cause mortality was 10% and 28% at 28 days and one year. Increasing age was associated with more heart failure readmissions, longer LOS and shorter median survival. Increasing age, increasing Charlson comorbidity score and male gender were risk factors for hospital readmission. Cohort members occupied 954,888 hospital bed-days during the study period (any cause); 383,646 bed-days were attributed to heart failure admissions. CONCLUSIONS: The rates of index admissions for heart failure decreased significantly in both males and females over the study period. However, the impact on acute care hospital beds was substantial, with heart failure patients occupying almost 200,000 bed-days per year in NSW over the five year study period. The strong age-related trends highlight the importance of stabilising elderly patients before discharge and community-based outreach programs to better manage heart failure and reduce readmissions.

A prompt to the web: the media and health information seeking behaviour.

UNLABELLED: OBJECTIVE, DESIGN, SETTING AND PARTICIPANTS: The objective was to investigate media influence on consumers' health related behaviours. A cross-sectional survey of randomly selected adults (18+ years) residing in the Hunter Region of New South Wales Australia was conducted. The sample was selected using a combination of the white pages and random digit dialling. MAIN OUTCOME MEASURES: The proportions of respondents who recalled seeing or hearing about conditions or treatments in the media over the 12 months prior to interview (August 2009-August 2010) and their subsequent health related behaviour. RESULTS: Although most survey participants reported seeking health information from their doctors, around two-thirds of survey participants (551, 68.8%) recalled hearing, seeing or reading about one or more medical conditions (total = 1097 instances) in the mainstream media over the past 12 months. Almost 40% of respondents (307, 38.4%) stated that they had looked for more information about a condition as a result of hearing about it in the media, and most used the internet (269, 87.4%). More than a quarter of respondents (215, 26.9%) indicated that they had asked their doctor about a condition they had heard about in the media. Around half of those who asked their doctor (109, 50.6%) reported that their inquiry resulted in them receiving treatment, of whom almost half (53, 48.3%) reported being prescribed a medicine. CONCLUSION: The survey results show that consumers become aware of medicines through traditional media and then to learn more often turn to the internet where quality of information may be poor.