Health system costs of potentially inappropriate prescribing in Ontario, Canada: A protocol for a population-based cohort study

All rights reserved. No commercial use is permitted unless otherwise expressly granted. Introduction Adverse drug events (ADEs) are common in older persons and contribute significantly to emergency department visits, hospitalisations and mortality. ADEs are often due to potentially inappropriate prescriptions (PIP) or potentially inappropriate omissions (PIO), and are avoidable if inappropriate prescriptions or omissions are identified and prevented. Identifying PIP/PIO at the population level through the application of PIP/PIO assessment tools to health administrative data can provide a unique opportunity to assess the economic burden of PIP/PIO on the healthcare system beyond medication costs which is yet to be done. The objective of this study is to assess the economic burden associated with PIP/PIO and to estimate the incremental costs associated with distinct PIP/PIO in the province of Ontario. Methods and analysis We will conduct a retrospective cohort study using Ontario's health administrative databases. Eligible patients aged 66 years and older who were prescribed at least one medication between 1 April 2003 and 31 March 2014 (approximately 2.4 million patients) will be included. Population attributable fraction methodology will be used to assess the overall burden of PIP in Ontario, while regression analyses will be used to estimate the incremental costs of having specific PIP criteria and aid in prioritising targets for intervention. Ethics and dissemination This study was approved by the Institutional Review Board at Sunnybrook Health Sciences Centre, Toronto, Canada. Dissemination will occur via publication, presentation at national and international conferences, and knowledge exchange with various stakeholders

Overcoming multiple drug resistance mechanisms in medulloblastoma

Introduction: Medulloblastoma (MB) is the most common malignant paediatric brain tumour. Recurrence and progression of disease occurs in 15-20% of standard risk and 30-40% of high risk patients. We analysed whether circumvention of chemoresistance pathways (drug export, DNA repair and apoptotic inhibition) can restore chemotherapeutic efficacy in a panel of MB cell lines. Results: We demonstrate, by immunohistochemistry in patient tissue microarrays, that ABCB1 is expressed in 43% of tumours and is significantly associated with high-risk. We show that ABCB1, O6-methylguanine-DNA-methyltransferase (MGMT) and BCL2 family members are differentially expressed (by quantitative reverse transcription polymerase chain reaction, Western blotting and flow cytometry) in MB cell lines. Based on these findings, each pathway was then inhibited or circumvented and cell survival assessed using clonogenic assays. Inhibition of ABCB1 using vardenafil or verapamil resulted in a significant increase in sensitivity to etoposide in ABCB1-expressing MB cell lines. Sensitivity to temozolomide (TMZ) was MGMT-dependent, but two novel imidazotetrazine derivatives (N-3 sulfoxide and N-3 propargyl TMZ analogues) demonstrated ≥7 fold and ≥3 fold more potent cytotoxicity respectively compared to TMZ in MGMT-expressing MB cell lines. Activity of the BAD mimetic ABT-737 was BCL2A1 and ABCB1 dependent, whereas the pan-BCL2 inhibitor obatoclax was effective as a single cytotoxic agent irrespective of MCL1, BCL2, BCL2A1, or ABCB1 expression. Conclusions: ABCB1 is associated with high-risk MB; hence, inhibition of ABCB1 by vardenafil may represent a valid approach in these patients. Imidazotetrazine analogues of TMZ and the BH3 mimetic obatoclax are promising clinical candidates in drug resistant MB tumours expressing MGMT and BCL2 anti-apoptotic members respectively

Metallothionein in human oesophagus, Barrett's epithelium and adenocarcinoma

The potential of the metal-binding protein, metallothionein, in assessing the progression of normal oesophagus through Barrett's to adenocarcinoma was investigated. Metallothionein was quantitatively determined in resected tissues from patients undergoing oesophagectomy for high grade dysplasia/adenocarcinoma and in biopsies from patients with Barrett's syndrome. In 10 cancer patients, metallothionein concentrations in adenocarcinoma were not significantly different from normal oesophagus, although six had elevated metallothionein concentrations in the metaplastic tissue bordering the adenocarcinoma. In 17 out of 20 non-cancer patients with Barrett's epithelium, metallothionein was significantly increased by 108% (P<0.004). There was no association between the metallothionein levels in Barrett's epithelium and the presence of inflammatory cells, metaplasia or dysplasia. Metallothionein is a marker of progression from normal to Barrett's epithelium but is not increased in oesophageal adenocarcinoma

Predicting mental imagery based BCI performance from personality, cognitive profile and neurophysiological patterns

Mental-Imagery based Brain-Computer Interfaces (MI-BCIs) allow their users to send commands to a computer using their brain-activity alone (typically measured by ElectroEncephaloGraphy— EEG), which is processed while they perform specific mental tasks. While very promising, MI-BCIs remain barely used outside laboratories because of the difficulty encountered by users to control them. Indeed, although some users obtain good control performances after training, a substantial proportion remains unable to reliably control an MI-BCI. This huge variability in user-performance led the community to look for predictors of MI-BCI control ability. However, these predictors were only explored for motor-imagery based BCIs, and mostly for a single training session per subject. In this study, 18 participants were instructed to learn to control an EEG-based MI-BCI by performing 3 MI-tasks, 2 of which were non-motor tasks, across 6 training sessions, on 6 different days. Relationships between the participants’ BCI control performances and their personality, cognitive profile and neurophysiological markers were explored. While no relevant relationships with neurophysiological markers were found, strong correlations between MI-BCI performances and mental-rotation scores (reflecting spatial abilities) were revealed. Also, a predictive model of MI-BCI performance based on psychometric questionnaire scores was proposed. A leave-one-subject-out cross validation process revealed the stability and reliability of this model: it enabled to predict participants’ performance with a mean error of less than 3 points. This study determined how users’ profiles impact their MI-BCI control ability and thus clears the way for designing novel MI-BCI training protocols, adapted to the profile of each user

B7 costimulation and intracellular indoleamine-2,3-dioxygenase (IDO) expression in peripheral blood of healthy pregnant and non-pregnant women.

BACKGROUND: B7 costimulatory molecules are expressed on antigen presenting cells (APCs) and are important regulators of T cell activation. We investigated the role of the B7 family of costimulatory molecules in the development of the systemic maternal immune tolerance during healthy pregnancy (HP). We also aimed to investigate the intracellular expression of indoleamine-2,3-dioxygenase (IDO) and plasma levels of tryptophane (TRP), kynurenine (KYN) and kynurenic acid (KYNA), important molecules with immunoregulatory properties, in order to describe their potential contribution to the pregnancy-specific maternal immune tolerance. METHODS: We determined the frequency of activated (CD11b+) monocytes expressing B7-1, B7-2, B7-H1, and B7-H2, and that of T cells and CD4+ T helper cells expressing CD28, CTLA-4, PD-1, and ICOS in peripheral blood samples of healthy pregnant (HP) and non-pregnant (NP) women using flow cytometry. We also examined the intracellular expression of IDO applying flow cytometry and plasma levels of TRP, KYN and KYNA using high-performance liquid chromatography. RESULTS: A significant increase in the prevalence of CD28+ T cells was observed in HP compared to NP women. At the same time a decrease was shown in the expression of CTLA-4 on these cells. The frequency of CD80+ monocytes was lower in HP women. The prevalence of IDO-expressing T cells and monocytes was higher in HP compared to NP women. Plasma KYN, KYNA and TRP levels were lower, while at the same time, the KYN/TRP ratio was higher in HP than in NP women. CONCLUSIONS: Costimulation via CD28 may not contribute to the immunosuppressive environment, at least in the third trimester of pregnancy. The development of the pregnancy-specific immune tolerance in the mechanism of B7 costimulation may be more related to the altered expression of B7 proteins on APCs rather than that of their receptors on T cells. The elevated intracellular IDO expression in monocytes and T cells, as well as higher plasma enzymatic IDO activity are likely to contribute to the systemic immunosuppressive environment in the third trimester characteristic for healthy gestation

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Prefrontal Cortex Glutamate Correlates with Mental Perspective-Taking

Background: Dysfunctions in theory of mind and empathic abilities have been suggested as core symptoms in major psychiatric disorders including schizophrenia and autism. Since self monitoring, perspective taking and empathy have been linked to prefrontal (PFC) and anterior cingulate cortex (ACC) function, neurotransmitter variations in these areas may account for normal and pathological variations of these functions. Converging evidence indicates an essential role of glutamatergic neurotransmission in psychiatric diseases with pronounced deficits in empathy. However, the role of the glutamate system for different dimensions of empathy has not been investigated so far. Methodology/Principal Findings: Absolute concentrations of cerebral glutamate in the ACC, left dorsolateral PFC and left hippocampus were determined by 3-tesla proton magnetic resonance spectroscopy (1H-MRS) in 17 healthy individuals. Three dimensions of empathy were estimated by a self-rating questionnaire, the Interpersonal Reactivity Index (IRI). Linear regression analysis showed that dorsolateral PFC glutamate concentration was predicted by IRI factor ‘‘perspective taking’’ (T = 22.710, p = 0.018; adjusted alpha-level of 0.017, Bonferroni) but not by ‘‘empathic concern’ ’ or ‘‘personal distress’’. No significant relationship between IRI subscores and the glutamate levels in the ACC or left hippocampus was detected. Conclusions/Significance: This is the first study to investigate the role of the glutamate system for dimensions of theory of mind and empathy. Results are in line with recent concepts that executive top-down control of behavior is mediated b

Female Fertility Affects Men's Linguistic Choices

We examined the influence of female fertility on the likelihood of male participants aligning their choice of syntactic construction with those of female confederates. Men interacted with women throughout their menstrual cycle. On critical trials during the interaction, the confederate described a picture to the participant using particular syntactic constructions. Immediately thereafter, the participant described to the confederate a picture that could be described using either the same construction that was used by the confederate or an alternative form of the construction. Our data show that the likelihood of men choosing the same syntactic structure as the women was inversely related to the women's level of fertility: higher levels of fertility were associated with lower levels of linguistic matching. A follow-up study revealed that female participants do not show this same change in linguistic behavior as a function of changes in their conversation partner's fertility. We interpret these findings in the context of recent data suggesting that non-conforming behavior may be a means of men displaying their fitness as a mate to women

Comparing Respondent-Driven Sampling and Targeted Sampling Methods of Recruiting Injection Drug Users in San Francisco

The objective of this article is to compare demographic characteristics, risk behaviors, and service utilization among injection drug users (IDUs) recruited from two separate studies in San Francisco in 2005, one which used targeted sampling (TS) and the other which used respondent-driven sampling (RDS). IDUs were recruited using TS (n = 651) and RDS (n = 534) and participated in quantitative interviews that included demographic characteristics, risk behaviors, and service utilization. Prevalence estimates and 95% confidence intervals (CIs) were calculated to assess whether there were differences in these variables by sampling method. There was overlap in 95% CIs for all demographic variables except African American race (TS: 45%, 53%; RDS: 29%, 44%). Maps showed that the proportion of IDUs distributed across zip codes were similar for the TS and RDS sample, with the exception of a single zip code that was more represented in the TS sample. This zip code includes an isolated, predominantly African American neighborhood where only the TS study had a field site. Risk behavior estimates were similar for both TS and RDS samples, although self-reported hepatitis C infection was lower in the RDS sample. In terms of service utilization, more IDUs in the RDS sample reported no recent use of drug treatment and syringe exchange program services. Our study suggests that perhaps a hybrid sampling plan is best suited for recruiting IDUs in San Francisco, whereby the more intensive ethnographic and secondary analysis components of TS would aid in the planning of seed placement and field locations for RDS