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Abstract Background HER2-positive breast cancers exhibit high rates of innate and acquired resistance to trastuzumab (TZ), a HER2-directed antibody used as a first line treatment for this disease. TZ resistance may in part be mediated by frequent co-expression of EGFR and by sustained activation of the mammalian target of rapamycin (mTOR) pathway. Here, we assessed feasibility of combining the EGFR inhibitor gefitinib and the mTOR inhibitor everolimus (RAD001) for treating HER2 overexpressing breast cancers with different sensitivity to TZ. Methods The gefitinib and RAD001 combination was broadly evaluated in TZ sensitive (SKBR3 and MCF7-HER2) and TZ resistant (JIMT-1) breast cancer models. The effects on cell growth were measured in cell based assays using the fixed molar ratio design and the median effect principle. In vivo studies were performed in Rag2M mice bearing established tumors. Analysis of cell cycle, changes in targeted signaling pathways and tumor characteristics were conducted to assess gefitinib and RAD001 interactions. Results The gefitinib and RAD001 combination inhibited cell growth in vitro in a synergistic fashion as defined by the Chou and Talalay median effect principle and increased tumor xenograft growth delay. The improvement in therapeutic efficacy by the combination was associated in vitro with cell line dependent increases in cytotoxicity and cytostasis while treatment in vivo promoted cytostasis. The most striking and consistent therapeutic effect of the combination was increased inhibition of the mTOR pathway (in vitro and in vivo) and EGFR signaling in vivo relative to the single drugs. Conclusions The gefitinib and RAD001 combination provides effective control over growth of HER2 overexpressing cells and tumors irrespective of the TZ sensitivity status.

Background: Satisfaction with treatment has been identified as an important contributing factor to adherence with oral anticoagulant (OAC) therapy in patients with atrial fibrillation (AF). We aimed to evaluate the satisfaction level of patients with AF regarding OAC use over time, using validated patient-reported outcome instruments, and to identify associated patient characteristics. Methods: Participants were recruited from specialized AF clinics in Canada. Eligible AF patients who were prescribed OACs were followed for up to 2 years. Participants were interviewed via telephone every 3-4 months using a structured survey. The Treatment Satisfaction Questionnaire for Medication (TSQM II) and the Anti-Clot Treatment Scale (ACTS) were used to measure satisfaction over time. Results: Among the 306 participants, satisfaction scores on the TSQM II and ACTS instruments were high. Unadjusted analyses showed significantly greater satisfaction with the burden of therapy with direct OACs (DOACs) compared to that with warfarin (small-magnitude effect) and greater satisfaction with the convenience of rivaroxaban, compared with that of all other OACs (moderate-magnitude effect). After adjustment for all other variables, vitamin K antagonist therapy was associated with greater global satisfaction than was DOAC treatment. Satisfaction with benefit and burden as measured by the ACTS scale, and global satisfaction on the TSQM II scale, tended to increase over time. Patient factors that were somewhat consistently associated with greater satisfaction were female sex and younger age. Conclusions: Patients with AF were highly satisfied with their therapy, with few differences among OAC classes and individual OACs. Individual patients may or may not be more satisfied with DOAC than VKA therapy, and regardless of the OAC prescribed, the may require significant support to maintain therapy adherence. Résumé: Contexte: La satisfaction à l’égard du traitement a été désignée comme un facteur important contribuant à l’adhésion au traitement par anticoagulants oraux (ACO) chez les patients atteints de fibrillation auriculaire (FA). Notre objectif était d’évaluer le degré de satisfaction des patients atteints de FA concernant l’utilisation des ACO au fil du temps, à l’aide d’instruments validés mesurant les résultats signalés par les patients, et de déterminer les caractéristiques connexes des patients. Méthodologie: Les participants ont été recrutés dans des cliniques spécialisées en FA au Canada. Les patients admissibles atteints de FA qui se sont fait prescrire des ACO ont été suivis pendant une période allant jusqu’à 2 ans. Les participants ont été interrogés par téléphone tous les 3 ou 4 mois à l’aide d’une enquête structurée. Le questionnaire Treatment Satisfaction Questionnaire for Medication – Version II (TSQM II) et l’échelle Anti-Clot Treatment Scale (ACTS) ont été utilisés pour mesurer la satisfaction au fil du temps. Résultats: Parmi les 306 participants, les taux de satisfaction indiqués par les instruments TSQM II et ACTS étaient élevés. Les analyses non corrigées ont montré une satisfaction liée au fardeau du traitement significativement plus élevée avec les ACO directs qu’avec la warfarine (effet de faible ampleur) et une plus grande satisfaction concernant la commodité du rivaroxaban par rapport à celle de tous les autres ACO (effet de moyenne ampleur). Après ajustement pour tenir compte de toutes les autres variables, le traitement par antivitamines K (AVK) était associé à une plus grande satisfaction globale que le traitement par ACO direct. La satisfaction à l’égard des avantages et du fardeau, mesurée par l’échelle ACTS, et la satisfaction globale sur l’échelle TSQM II, ont eu tendance à augmenter avec le temps. Les facteurs liés aux patients qui ont été associés de manière assez constante à une plus grande satisfaction étaient le sexe féminin et un âge plus jeune. Conclusions: Les patients atteints de FA étaient très satisfaits de leur traitement, et peu de différences existaient entre les classes d’ACO et les ACO individuels. Chaque patient peut être ou non plus satisfait du traitement par ACO direct que par AVK et, quel que soit l’ACO prescrit, il peut avoir besoin d’un soutien important pour maintenir l’adhésion au traitement.

In France, in the last few years, a lot of ponds have been removed during operations of river restoration, remobilizing the sediments that had been deposited behind the dam over the years. Pond sediments are complicated mixtures predominantly consisting of rocks and soils particles from the watershed, atmospheric dust brought by winds, algae and organic remains or particles that were produced by processes in the water column, such as amorphous silica or calcite. Sediments “can be dressed” with chemical elements of various kinds, including pollutants that settle on the bottom of the ponds. It is therefore important to understand what types of substances can be found in pond and to understand the effect of operations of river restoration on water quality. We applied the X-ray fluorescence spectrometry (XRF), where sample is irradiated with X-rays from a radioactive source, which excites the elements in the sample and generates secondary fluorescent X-rays. Elements emit energy of unique wavelengths, which allows their qualitative and quantitative determination. Commonly, elements from atomic number 11 (Na) to 92 (U) can be detected. Using this methodology, analyses were made on sediments samples from a pond located in the centre of France: results show that the pond is relatively free of pollutants. Starting from this reference, we will think which substances can be remobilized after operations of rivers restoration.

Description of the problem: Development of evidence-based educational activities is needed to provide educators with the tools to aid learners in strengthening patient consultation skills in the primary care practice setting, an emerging area of practice in Canada. Objective: The objective was to develop an educational activity to bring self-awareness to fourth year pharmacy student and pharmacy resident consultation skills and to determine learner perceptions of this educational activity, including identifying the key areas of skill development that learners found were positively impacted. Description of the innovation: An innovative learning activity utilizing audio-video technology to enable recording and reviewing of learner-led patient consultations was developed and implemented within the University of British Columbia Pharmacists Clinic. Learners had the opportunity to lead 60-minute patient consultations. With patient and learner consent, patient consultations were recorded for learner viewing and self-assessment. Pharmacist preceptors supervised and assessed learner performance. Learners completed an online anonymous survey after the learning activity to evaluate its value. Critical analysis: Between September 2018 and July 2019, eight pharmacy learners, consisting of student pharmacists (5) and post-graduate pharmacy residents (3) completed the learning activity and provided their feedback. The majority of learners (87.5%) felt the learning activity was beneficial to the development of patient consultation skills. Learners gained awareness of areas requiring improvement which included appropriate questioning, clear and concise language, time management and non-verbal habits. Next steps: Adapting and modifying this learning activity to align with specific practice settings and learning objectives is feasible for other primary care practice sites offering experiential practicums.

Objective: To summarize available literature describing third-party payer reimbursement models for pharmacist-led preventive health services as part of workplace health initiatives. Methods: A combination of search terms related to pharmacists, preventive health, and third-party reimbursement were searched in MEDLINE, EMBASE, and PubMed. Included studies described community pharmacist-led cardiovascular and diabetes preventive health service to employees older than 18 years of age as part of a workplace health program with corresponding third-party reimbursement models. Programs that were reimbursed by government resources or studies lacking reimbursement model details were excluded. One reviewer performed level 1 screening and three reviewers analyzed included studies. Results: The search criteria yielded 863 results. Sixteen articles were reviewed after level 1 screening and 13 were ineligible and excluded. Three studies with varying quality of reporting were included. Reimbursement models varied from $40 USD for a 20-minute visit to $391 to $552 USD total per patient with an average of 6 visits per patient. Conclusion: There is a lack of quality literature describing third-party reimbursement models for pharmacist-led preventive health services, which hinders the ability to implement a standardized model. High quality studies evaluating the cost of reimbursing pharmacist-led cardiovascular preventive health services compared to the savings to the third-party payer should be performed to inform the standardization of payment models.

Background: Burnout syndrome is well-documented among healthcare professionals across various practice settings. There has been recent expansion of Canadian pharmacists into team-based primary care and burnout in this setting has not been assessed. Our objective was to assess workplace burnout and to identify factors that play a role in perpetuating or diminishing it. Method: An online survey to assess burnout was developed using the Maslach Burnout Inventory (MBI) tool and questions regarding pharmacist background and practice. Invitations to complete the survey were sent to Canadian pharmacists working in team-based primary care settings on November 26, 2019 via a national primary healthcare listserv. Results: A total of 31/433 completed responses were collected. The main analysis focused on the personal accomplishment (PA) domain as it had an adequate response rate. The PA domain had a median score of 5.0 (95% CI 4.69-5.22). We compared medians of the PA domain across different groups of each categorical variable. We found that the number of years working in primary care settings was positively associated with a higher PA domain score (p= 0.029). Discussion: PA was higher in pharmacists who have been practicing in a primary care setting for longer; however, burnout rates could not be properly assessed due to the limited response rate. Conclusion: This is the first study to assess burnout among Canadian team-based primary care pharmacists. Personal accomplishment was higher in those who have been practicing in a primary care setting for longer. Future studies should consider alternate methods to evaluate burnout in this population. Article Type: Original Research

Magnetic resonance imaging-only radiotherapy treatment planning (MRI-only RTP) and positron emission tomography (PET)–MRI imaging require generation of synthetic computed tomography (sCT) images from MRI images. In this study, initial dosimetric evaluation was performed for a previously developed MRI-based attenuation correction (MRAC) method for use in MRI-only RTP of the brain. MRAC-based sCT images were retrospectively generated from Dixon MR images of 20 patients who had previously received external beam radiation therapy (EBRT). Bone segmentation performance and Dice similarity coefficient of the sCT conversion method were evaluated for bone volumes on CT images. Dose calculation accuracy was assessed by recalculating the CT-based EBRT plans using the sCT images as the base attenuation data. Dose comparison was done for the sCT- and CT-based EBRT plans in planning target volume (PTV) and organs at risk (OAR). Parametric dose comparison showed mean relative differences of

Since Aikhenvald 2004, evidentiality has been severed from epistemic modality. We studied the evidential and epistemic modal aspects of the Estonian evidential -vat experimentally and on the basis of a corpus study. We designed two experiments to separate the two categories. Four-, six-, and nine-year-old children were first asked to identify the source of the information provided with the morpheme. Then they performed a forced choice task guided by grammar: affirmative indicative, negative, and evidential sentences. Four-year-olds did not understand the evidential and modal -vat. Six year-olds showed an increased understanding of the evidential meaning but not the modal meaning or use. Nine-year-olds demonstrated full understanding of the evidential and an increased understanding of the epistemic modal aspect of the evidential. Estonian children thus develop the correct understanding of the morpheme -vat as an epistemic modal only after learning its evidential meaning.