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1.  The Effects of Cold Exposure on Leukocytes, Hormones and Cytokines during Acute Exercise in Humans 
PLoS ONE  2014;9(10):e110774.
The purpose of the study was to examine the effects of exercise on total leukocyte count and subsets, as well as hormone and cytokine responses in a thermoneutral and cold environment, with and without an individualized pre-cooling protocol inducing low-intensity shivering. Nine healthy young men participated in six experimental trials wearing shorts and t-shirts. Participants exercised for 60 min on a treadmill at low (LOW: 50% of peak VO2) and moderate (MOD: 70% VO2peak) exercise intensities in a climatic chamber set at 22°C (NT), and in 0°C (COLD) with and without a pre-exercise low-intensity shivering protocol (SHIV). Core and skin temperature, heart rate and oxygen consumption were collected continuously. Blood samples were collected before and at the end of exercise to assess endocrine and immunological changes. Core temperature in NT was greater than COLD and SHIV by 0.4±0.2°C whereas skin temperature in NT was also greater than COLD and SHIV by 8.5±1.4°C and 9.3±2.5°C respectively in MOD. Total testosterone, adenocorticotropin and cortisol were greater in NT vs. COLD and SHIV in MOD. Norepinephrine was greater in NT vs. other conditions across intensities. Interleukin-2, IL-5, IL-7, IL-10, IL-17, IFN-γ, Rantes, Eotaxin, IP-10, MIP-1β, MCP-1, VEGF, PDGF, and G-CSF were elevated in NT vs. COLD and/or SHIV. Furthermore, IFN-γ, MIP-1β, MCP-1, IL-10, VEGF, and PDGF demonstrate greater concentrations in SHIV vs. COLD, mainly in the MOD condition. This study demonstrated that exercising in the cold can diminish the exercise-induced systemic inflammatory response seen in a thermoneutral environment. Nonetheless, prolonged cooling inducing shivering thermogenesis prior to exercise, may induce an immuno-stimulatory response following moderate intensity exercise. Performing exercise in cold environments can be a useful strategy in partially inhibiting the acute systemic inflammatory response from exercise but oppositely, additional body cooling may reverse this benefit.
doi:10.1371/journal.pone.0110774
PMCID: PMC4206434  PMID: 25338085
2.  Development and Validation of Questionnaires Exploring Health Care Professionals' Intention to Use Wiki-Based Reminders to Promote Best Practices in Trauma 
JMIR Research Protocols  2014;3(4):e50.
Background
Little is known about factors influencing professionals’ use of wikis.
Objective
We developed and validated two questionnaires to assess health care professionals’ intention to use wiki-based reminders for the management of trauma patients.
Methods
We developed questionnaires for emergency physicians (EPs) and allied health professions (AHPs) based on the Theory of Planned Behavior and adapted them to the salient beliefs of each, identified in an earlier study. Items measured demographics and direct and indirect theoretical constructs. We piloted the questionnaires with 2 focus groups (5 EPs and 5 AHPs) to identify problems of wording and length. Based on feedback, we adjusted the wording and combined certain items. A new convenience sample of 25 EPs and 26 AHPs then performed a test-retest of the questionnaires at a 2-week interval. We assessed internal consistency using Cronbach alpha coefficients and temporal stability of items with an agreement intraclass correlation coefficient (ICC).
Results
Five EPs and 5 AHPs (3 nurses, 1 respiratory therapist, and 1 pharmacist) formed 2 focus groups; 25 EPs and 26 AHPs (12 nurses, 7 respiratory therapists, and 7 pharmacists) completed the test and retest. The EP questionnaire test-retest scores for consistency (Cronbach alpha) and stability (ICC) were intention (test: Cronbach alpha=.94; retest: Cronbach alpha=.98; ICC=.89), attitude (.74, .72, .70), subjective norm (.79, .78, .75), perceived behavioral control (.67, .65, .66), attitudinal beliefs (.94, .86, .60), normative beliefs (.83, .87, .79), and control beliefs barriers (.58, .67, .78) and facilitators (.97, .85, .30). The AHP questionnaire scores for consistency and stability were: intention (test Cronbach alpha=.69, retest Cronbach alpha=.81, ICC=.48), attitude (.85, .87, .83), subjective norm (.47, .82, .62), perceived behavioral control (.55, .62, .60), attitudinal beliefs (.92, .91, .82), normative beliefs (.85, .90, .74), and control beliefs barriers (.58, .55, .66) and facilitators (.72, .94, –.05). To improve the psychometric properties of both questionnaires, we reformulated poorly consistent or unstable items.
Conclusions
Our new theory-based questionnaires to measure health care professionals’ intention to use wiki-based reminders have adequate validity and reliability for use in large surveys. In the long run, they can be used to develop a theory-based implementation intervention for a wiki promoting best practices in trauma care.
doi:10.2196/resprot.3762
PMCID: PMC4213801  PMID: 25281856
knowledge translation; wiki; collaborative writing applications; decision support tools; health informatics; Theory of Planned Behavior; trauma care; traumatic brain injury; interprofessional collaboration
3.  Treating an Established Episode of Delirium in Palliative Care: Expert Opinion and Review of the Current Evidence Base With Recommendations for Future Development 
Context
Delirium is a highly prevalent complication in patients in palliative care settings, especially in the end-of-life context.
Objectives
To review the current evidence base for treating episodes of delirium in palliative care settings and propose a framework for future development.
Methods
We combined multidisciplinary input from delirium researchers and other purposely selected stakeholders at an international delirium study planning meeting. This was supplemented by a literature search of multiple databases and relevant reference lists to identify studies regarding therapeutic interventions for delirium.
Results
The context of delirium management in palliative care is highly variable. The standard management of a delirium episode includes the investigation of precipitating and aggravating factors followed by symptomatic treatment with drug therapy. However, the intensity of this management depends on illness trajectory and goals of care in addition to the local availability of both investigative modalities and therapeutic interventions. Pharmacologically, haloperidol remains the practice standard by consensus for symptomatic control. Dosing schedules are derived from expert opinion and various clinical practice guidelines as evidence-based data from palliative care settings are limited. The commonly used pharmacologic interventions for delirium in this population warrant evaluation in clinical trials to examine dosing and titration regimens, different routes of administration, and safety and efficacy compared with placebo.
Conclusion
Delirium treatment is multidimensional and includes the identification of precipitating and aggravating factors. For symptomatic management, haloperidol remains the practice standard. Further high-quality collaborative research investigating the appropriate treatment of this complex syndrome is needed.
doi:10.1016/j.jpainsymman.2013.07.018
PMCID: PMC4081457  PMID: 24480529
Delirium; palliative care; evidence-based medicine; therapeutics; decision making; hospices
4.  Applying Theory to Understand and Modify Nurse Intention to Adhere to Recommendations regarding the Use of Filter Needles: An Intervention Mapping Approach 
Nursing Research and Practice  2014;2014:356153.
The manipulation of glass ampoules involves risk of particle contamination of parenteral medication, and the use of filter needles has often been recommended in order to reduce the number of particles in these solutions. This study aims to develop a theory-based intervention to increase nurse intention to use filter needles according to clinical guideline recommendations produced by a large university medical centre in Quebec (Canada). Using the Intervention Mapping framework, we first identified the psychosocial determinants of nurse intention to use filter needles according to these recommendations. Second, we developed and implemented an intervention targeting nurses from five care units in order to increase their intention to adhere to recommendations on the use of filter needles. We also assessed nurse satisfaction with the intervention. In total, 270 nurses received the intervention and 169 completed the posttest questionnaire. The two determinants of intention, that is, attitude and perceived behavioral control, were significantly higher after the intervention, but only perceived behavioral control remained a predictor of intention. In general, nurses were highly satisfied with the intervention. This study provides support for the use of Intervention Mapping to develop, implement, and evaluate theory-based interventions in order to improve healthcare professional adherence to clinical recommendations.
doi:10.1155/2014/356153
PMCID: PMC4121269  PMID: 25120927
5.  Involving patient in the early stages of health technology assessment (HTA): a study protocol 
Background
Public and patient involvement in the different stages of the health technology assessment (HTA) process is increasingly encouraged. The selection of topics for assessment, which includes identifying and prioritizing HTA questions, is a constant challenge for HTA agencies because the number of technologies requiring an assessment exceeds the resources available. Public and patient involvement in these early stages of HTA could make assessments more relevant and acceptable to them. Involving them in the development of the assessment plan is also crucial to optimize their influence and impact on HTA research. The project objectives are: 1) setting up interventions to promote patient participation in three stages of the HTA process: identification of HTA topics, prioritization, and development of the assessment plan of the topic prioritized; and 2) assessing the impact of patient participation on the relevance of the topics suggested, the prioritization process, and the assessment plan from the point of view of patients and other groups involved in HTA.
Methods
Patients and their representatives living in the catchment area of the HTA Roundtable of Université Laval’s Integrated University Health Network (covering six health regions of the Province of Quebec, Canada) will be involved in the following HTA activities: 1) identification of potential HTA topics in the field of cancer; 2) revision of vignettes developed to inform the prioritization of topics; 3) participation in deliberation sessions for prioritizing HTA topics; and 4) development of the assessment plan of the topic prioritized. The research team will coordinate the implementation of these activities and will evaluate the process and outcomes of patient involvement through semi-structured interviews with representatives of the different stakeholder groups, structured observations, and document analysis, mainly involving the comparison of votes and topics suggested by various stakeholder groups.
Discussion
This project is designed as an integrated approach to knowledge translation and will be conducted through a close collaboration between researchers and knowledge users at all stages of the project. In response to the needs expressed by HTA producers, the knowledge produced will be directly useful in guiding practices regarding patient involvement in the early phases of HTA.
doi:10.1186/1472-6963-14-273
PMCID: PMC4072844  PMID: 24950739
Public and patient participation; Research priorities; Health technology assessment; Public involvement; Knowledge translation
6.  Systematic Review of Factors Influencing the Adoption of Information and Communication Technologies by Healthcare Professionals 
Journal of medical systems  2010;36(1):241-277.
This systematic review of mixed methods studies focuses on factors that can facilitate or limit the implementation of information and communication technologies (ICTs) in clinical settings. Systematic searches of relevant bibliographic databases identified studies about interventions promoting ICT adoption by healthcare professionals. Content analysis was performed by two reviewers using a specific grid. One hundred and one (101) studies were included in the review. Perception of the benefits of the innovation (system usefulness) was the most common facilitating factor, followed by ease of use. Issues regarding design, technical concerns, familiarity with ICT, and time were the most frequent limiting factors identified. Our results suggest strategies that could effectively promote the successful adoption of ICT in healthcare professional practices.
doi:10.1007/s10916-010-9473-4
PMCID: PMC4011799  PMID: 20703721 CAMSID: cams382
Systematic review; Adoption factors; Information and communication technologies (ICTs); ICT adoption by healthcare professionals
7.  Interventions for promoting information and communication technologies adoption in healthcare professionals 
Background
Information and communication technologies (ICT) are defined as digital and analogue technologies that facilitate the capturing, processing, storage and exchange of information via electronic communication. ICTs have the potential to improve information management, access to health services, quality of care, continuity of services, and cost containment. Knowledge is lacking on conditions for successful ICT integration into practice.
Objectives
To carry out a systematic review of the effectiveness of interventions to promote the adoption of ICT by healthcare professionals.
Search methods
Specific strategies, defined with the help of an information specialist, were used to search the Cochrane Effective Practice and Organisation of Care Group (EPOC) register and additional relevant databases. We considered studies published from January 1990 until October 2007.
Selection criteria
Randomised controlled trials (RCTs), controlled clinical trials (CCTs), controlled before/after studies (CBAs), and interrupted time series (ITS) that reported objectively measured outcomes concerning the effect of interventions to promote adoption of ICT in healthcare professionals’ practices.
Data collection and analysis
Two reviewers independently assessed each potentially relevant study for inclusion. We resolved discrepancies by discussion or a third reviewer. Two teams of two reviewers independently extracted data and assessed the quality of included studies. A meta-analysis of study outcomes was not possible, given the small number of included studies and the heterogeneity of intervention and outcomes measures. We conducted qualitative analyses, and have presented the results in a narrative format.
Main results
Ten studies met the inclusion criteria. Nine of them were RCTs. All studies involved physicians as participants (including postgraduate trainees), and one study also included other participants. Only two studies measured patient outcomes. Searching skills and/or frequency of use of electronic databases, mainly MEDLINE, were targeted in eight studies. Use of Internet for audit and feedback, and email for provider-patient communication, were targeted in two studies. Four studies showed small to moderate positive effects of the intervention on ICT adoption. Four studies were unable to demonstrate significant positive effects, and the two others showed mixed effects. No studies looked at the long-term effect or sustainability of the intervention.
Authors’ conclusions
There is very limited evidence on effective interventions promoting the adoption of ICTs by healthcare professionals. Small effects have been reported for interventions targeting the use of electronic databases and digital libraries. The effectiveness of interventions to promote ICT adoption in healthcare settings remains uncertain, and more well designed trials are needed.
doi:10.1002/14651858.CD006093.pub2
PMCID: PMC3973635  PMID: 19160265 CAMSID: cams377
Databases, Bibliographic [utilization]; Health Personnel [*statistics & numerical data]; Information Storage and Retrieval [*utilization]; Professional Practice [*statistics & numerical data]; Randomized Controlled Trials as Topic
8.  Wikis and Collaborative Writing Applications in Health Care: A Scoping Review 
Background
Collaborative writing applications (eg, wikis and Google Documents) hold the potential to improve the use of evidence in both public health and health care. The rapid rise in their use has created the need for a systematic synthesis of the evidence of their impact as knowledge translation (KT) tools in the health care sector and for an inventory of the factors that affect their use.
Objective
Through the Levac six-stage methodology, a scoping review was undertaken to explore the depth and breadth of evidence about the effective, safe, and ethical use of wikis and collaborative writing applications (CWAs) in health care.
Methods
Multiple strategies were used to locate studies. Seven scientific databases and 6 grey literature sources were queried for articles on wikis and CWAs published between 2001 and September 16, 2011. In total, 4436 citations and 1921 grey literature items were screened. Two reviewers independently reviewed citations, selected eligible studies, and extracted data using a standardized form. We included any paper presenting qualitative or quantitative empirical evidence concerning health care and CWAs. We defined a CWA as any technology that enables the joint and simultaneous editing of a webpage or an online document by many end users. We performed qualitative content analysis to identify the factors that affect the use of CWAs using the Gagnon framework and their effects on health care using the Donabedian framework.
Results
Of the 111 studies included, 4 were experimental, 5 quasi-experimental, 5 observational, 52 case studies, 23 surveys about wiki use, and 22 descriptive studies about the quality of information in wikis. We classified them by theme: patterns of use of CWAs (n=26), quality of information in existing CWAs (n=25), and CWAs as KT tools (n=73). A high prevalence of CWA use (ie, more than 50%) is reported in 58% (7/12) of surveys conducted with health care professionals and students. However, we found only one longitudinal study showing that CWA use is increasing in health care. Moreover, contribution rates remain low and the quality of information contained in different CWAs needs improvement. We identified 48 barriers and 91 facilitators in 4 major themes (factors related to the CWA, users’ knowledge and attitude towards CWAs, human environment, and organizational environment). We also found 57 positive and 23 negative effects that we classified into processes and outcomes.
Conclusions
Although we found some experimental and quasi-experimental studies of the effectiveness and safety of CWAs as educational and KT interventions, the vast majority of included studies were observational case studies about CWAs being used by health professionals and patients. More primary research is needed to find ways to address the different barriers to their use and to make these applications more useful for different stakeholders.
doi:10.2196/jmir.2787
PMCID: PMC3929050  PMID: 24103318
collaborative writing applications; collaborative authoring; knowledge management; crowdsourcing; medical informatics; ehealth; Internet; Wiki; Wikipedia; Google Docs; Google Knol; Web 2.0; knowledge translation; evidence-based medicine; participatory med
9.  Cold exposure enhances fat utilization but not non-esterified fatty acids, glycerol or catecholamines availability during submaximal walking and running 
Cold exposure modulates the use of carbohydrates (CHOs) and fat during exercise. This phenomenon has mostly been observed in controlled cycling studies, but not during walking and running when core temperature and oxygen consumption are controlled, as both may alter energy metabolism. This study aimed at examining energy substrate availability and utilization during walking and running in the cold when core temperature and oxygen consumption are maintained. Ten lightly clothed male subjects walked or ran for 60-min, at 50% and 70% of maximal oxygen consumption, respectively, in a climatic chamber set at 0°C or 22°C. Thermal, cardiovascular, and oxidative responses were measured every 15-min during exercise. Blood samples for serum non-esterified fatty acids (NEFAs), glycerol, glucose, beta-hydroxybutyrate (BHB), plasma catecholamines, and serum lipids were collected immediately prior, and at 30- and 60-min of exercise. Skin temperature strongly decreased while core temperature did not change during cold trials. Heart rate (HR) was also lower in cold trials. A rise in fat utilization in the cold was seen through lower respiratory quotient (RQ) (−0.03 ± 0.02), greater fat oxidation (+0.14 ± 0.13 g · min−1) and contribution of fat to total energy expenditure (+1.62 ± 1.99 kcal · min−1). No differences from cold exposure were observed in blood parameters. During submaximal walking and running, a greater reliance on derived fat sources occurs in the cold, despite the absence of concurrent alterations in NEFAs, glycerol, or catecholamine concentrations. This disparity may suggest a greater reliance on intra-muscular energy sources such as triglycerides during both walking and running.
doi:10.3389/fphys.2013.00099
PMCID: PMC3650516  PMID: 23675353
exercise; thermal responses; energy metabolism; glucose; fat
10.  Proprotein Convertase 1/3 (PC1/3) in the Rat Alveolar Macrophage Cell Line NR8383: Localization, Trafficking and Effects on Cytokine Secretion 
PLoS ONE  2013;8(4):e61557.
The proprotein convertase 1/3 (PC1/3) is an important post-translational processing enzyme for the activation of precursor proteins within the regulated secretory pathway. Well characterized for its role in the neural and endocrine systems, we recently reported an unconventional role of PC1/3 as a modulator of the Toll-like receptor innate immune response. There are only a few reports that have studied PC1/3 expression in macrophages, and more investigation is needed to better characterize its function. These studies would greatly benefit from model cell lines. Our study aims to identify and characterize PC1/3 in a relevant model macrophage cell line and to determine the links between PC1/3 and innate immune cellular responses. We describe the rat alveolar cell line, NR8383, as expressing PC1/3 and the most common Toll-like receptors. In NR8383 cells, PC1/3 is localized at the Trans-Golgi network and traffics to lysosome related vesicles upon lipopolysaccharide stimulation. Moreover, we report the co-localization of PC1/3 and Toll-like receptor 4 upon lipopolysaccharide stimulation. Down regulation of PC1/3 by shRNA produce a similar phenotype in NR8383 to what we previously reported in isolated peritoneal macrophages. PC1/3 shRNA induced changes in the cellular organization and expression of the specific trafficking regulator RAB GTPase. As a consequence, NR8383 down-regulated for PC1/3, present an abnormal cytokine secretion profile. We conclude that the NR8383 cell line represents a good model to study PC1/3 in macrophages and we present PC1/3 as an important regulator of vesicle trafficking and secretion in macrophages.
doi:10.1371/journal.pone.0061557
PMCID: PMC3634814  PMID: 23637853
11.  Involving patients in HTA activities at local level: a study protocol based on the collaboration between researchers and knowledge users 
Background
The literature recognizes a need for greater patient involvement in health technology assessment (HTA), but few studies have been reported, especially at the local level. Following the decentralisation of HTA in Quebec, Canada, the last few years have seen the creation of HTA units in many Quebec university hospital centres. These units represent a unique opportunity for increased patient involvement in HTA at the local level. Our project will engage patients in an assessment being carried out by a local HTA team to assess alternatives to isolation and restraint for hospitalized or institutionalized adults. Our objectives are to: 1) validate a reference framework for exploring the relevance and applicability of various models of patient involvement in HTA, 2) implement strategies that involve patients (including close relatives and representatives) at different stages of the HTA process, 3) evaluate intervention processes, and 4) explore the impact of these interventions on a) the applicability and acceptability of recommendations arising from the assessment, b) patient satisfaction, and c) the sustainability of this approach in HTA.
Methods
For Objective 1, we will conduct individual interviews with various stakeholders affected by the use of alternatives to isolation and restraint for hospitalized or institutionalized adults. For Objective 2, we will implement three specific strategies for patient involvement in HTA: a) direct participation in the HTA process, b) consultation of patients or their close relatives through data collection, and c) patient involvement in the dissemination of HTA results. For Objectives 3 and 4, we will evaluate the intervention processes and the impact of patient involvement strategies on the recommendations arising from the HTA and the understanding of the ethical and social implications of the HTA.
Discussion
This project is likely to influence future HTA practices because it directly targets knowledge users' need for strategies that increase patient involvement in HTA. By documenting the processes and outcomes of these involvement strategies, the project will contribute to the knowledge base related to patient involvement in HTA.
doi:10.1186/1472-6963-12-14
PMCID: PMC3274445  PMID: 22248231
Health technology assessment; patient involvement; decision making; knowledge users; alternatives to isolation and restraint
12.  Introducing patient perspective in health technology assessment at the local level 
Background
Recognizing the importance of increased patient participation in healthcare decisions leads decision makers to consider effective ways to incorporate patient perspectives in Health Technology Assessment (HTA) processes. The implementation of local health HTA units in university hospitals in Quebec provides a unique opportunity to foster an increased participation of patients in decisions regarding health technologies and clinical interventions. This project explores strategies that could be effective in involving patients in HTA activities at the local level. To do so, three objectives are pursued: 1) To synthesise international knowledge and experiences on patient and public involvement in HTA activities; 2) To explore the perceptions of stakeholders (administrators, clinical managers, healthcare professionals, HTA producers, and patients) regarding strategies for involving patients in various HTA activities; and 3) To produce a consensual strategic framework that could guide interventions for involving patients in HTA activities at the local level.
Methods
A systematic review of the literature will be conducted to synthesise international knowledge and experiments regarding the implication of patients and public in HTA. Then, focus groups will be carried out with representatives of various stakeholder groups in order to explore their perceptions regarding patient participation in HTA. Based on findings from the systematic review and the focus groups, a framework to support patient participation in HTA activities will be proposed. It will then be validated during a deliberative meeting with the research team, composed of scientists and decision makers, and representatives from different groups involved in HTA in Quebec. This deliberative meeting will aim at identifying the type and the degree of participation as well as the adequate timing for involving patients in local HTA activities.
Discussion
Given the actual state of evidence, integrating patient perspective in HTA activities has the potential to improve the quality of healthcare services. This study provides an opportunity to bridge the gap between HTA producers and its ultimate end-user: the patient. It will provide guidance to support local HTA units in Quebec and elsewhere in their decisions regarding patient participation. The framework developed could be applied to design and implement strategies for involving patients in HTA activities.
doi:10.1186/1472-6963-9-54
PMCID: PMC2671501  PMID: 19327160
13.  New Real-Time PCR Assay for Rapid Detection of Methicillin- Resistant Staphylococcus aureus Directly from Specimens Containing a Mixture of Staphylococci 
Journal of Clinical Microbiology  2004;42(5):1875-1884.
Molecular methods for the rapid identification of methicillin-resistant Staphylococcus aureus (MRSA) are generally based on the detection of an S. aureus-specific gene target and the mecA gene. However, such methods cannot be applied for the direct detection of MRSA from nonsterile specimens such as nasal samples without the previous isolation, capture, or enrichment of MRSA because these samples often contain both coagulase-negative staphylococci (CoNS) and S. aureus, either of which can carry mecA. In this study, we describe a real-time multiplex PCR assay which allows the detection of MRSA directly from clinical specimens containing a mixture of staphylococci in <1 h. Five primers specific to the different staphylococcal cassette chromosome mec (SCCmec) right extremity sequences, including three new sequences, were used in combination with a primer and three molecular beacon probes specific to the S. aureus chromosomal orfX gene sequences located to the right of the SCCmec integration site. Of the 1,657 MRSA isolates tested, 1,636 (98.7%) were detected with the PCR assay, whereas 26 of 569 (4.6%) methicillin-susceptible S. aureus (MSSA) strains were misidentified as MRSA. None of the 62 nonstaphylococcal bacterial species or the 212 methicillin-resistant or 74 methicillin-susceptible CoNS strains (MRCoNS and MSCoNS, respectively) were detected by the assay. The amplification of MRSA was not inhibited in the presence of high copy numbers of MSSA, MRCoNS, or MSCoNS. The analytical sensitivity of the PCR assay, as evaluated with MRSA-negative nasal specimens containing a mixture of MSSA, MRCoNS, and MSCoNS spiked with MRSA, was ∼25 CFU per nasal sample. This real-time PCR assay represents a rapid and powerful method which can be used for the detection of MRSA directly from specimens containing a mixture of staphylococci.
doi:10.1128/JCM.42.5.1875-1884.2004
PMCID: PMC404602  PMID: 15131143
14.  A quantitative ranking of Canada's research output of original human studies for the decade 1989 to 1998 
BACKGROUND: Since 1987 research articles have been catalogued with the author's affiliation address in the 40 databases of the Medical Literature Analysis and Retrieval System (MEDLARS) of the National Library of Medicine, Bethesda, Md. The present study was conducted to examine the Canadian entries in MEDLARS to interpret past and future trends and to combine the MEDLARS demographic data with data from other sources to rank Canadian research output of human studies both nationally and internationally. METHODS: The PubMed Web site of the National Library of Medicine was used to count medical articles archived in MEDLARS and published from Jan. 1, 1989, through Dec. 31, 1998. The articles attributed to Canadian authors were compared by country, province, city, medical school, hospital, article type, journal and medical specialty. RESULTS: During the study period Canadian authors contributed on average 3% (standard deviation [SD] 0.2%) of the worldwide MEDLARS content each year, which translated to a mean of 11,067 (SD 1037) articles per year; 49% were human studies, of which 13% were clinical or controlled trials, and 55% involved people aged 18 years or less. In total, 68% of the articles were by authors affiliated with Canadian medical schools; those affiliated with the University of Toronto accounted for the greatest number (8604), whereas authors affiliated with McGill University had the greatest rate of annual increase in the quantity published (8%). Over one-third (38%) of the articles appeared in Canadian journals. When counted by specialty, 17% of the articles were by authors with clinical specialties, 5% by those with surgical specialties and 3% by those with laboratory specialties. INTERPRETATION: The annual rate of increase in research output for Canada was more than 3 times higher than that seen world wide. Canada is now ranked seventh among countries contributing human studies to MEDLARS. The increase indicates that Canada's medical schools are productive, competitive in making contributions to medical science and are supporting Canadian journals.
PMCID: PMC1232227  PMID: 11216196
15.  Validating a conceptual model for an inter-professional approach to shared decision making: a mixed methods study 
Rationale, aims and objectives
Following increased interest in having inter-professional (IP) health care teams engage patients in decision making, we developed a conceptual model for an IP approach to shared decision making (SDM) in primary care. We assessed the validity of the model with stakeholders in Canada.
Methods
In 15 individual interviews and 7 group interviews with 79 stakeholders, we asked them to: (1) propose changes to the IP-SDM model; (2) identify barriers and facilitators to the model's implementation in clinical practice; and (3) assess the model using a theory appraisal questionnaire. We performed a thematic analysis of the transcripts and a descriptive analysis of the questionnaires.
Results
Stakeholders suggested placing the patient at its centre; extending the concept of family to include significant others; clarifying outcomes; highlighting the concept of time; merging the micro, meso and macro levels in one figure; and recognizing the influence of the environment and emotions. The most common barriers identified were time constraints, insufficient resources and an imbalance of power among health professionals. The most common facilitators were education and training in inter-professionalism and SDM, motivation to achieve an IP approach to SDM, and mutual knowledge and understanding of disciplinary roles. Most stakeholders considered that the concepts and relationships between the concepts were clear and rated the model as logical, testable, having clear schematic representation, and being relevant to inter-professional collaboration, SDM and primary care.
Conclusions
Stakeholders validated the new IP-SDM model for primary care settings and proposed few modifications. Future research should assess if the model helps implement SDM in IP clinical practice.
doi:10.1111/j.1365-2753.2010.01515.x
PMCID: PMC3170704  PMID: 20695950
conceptual model; decision coaching; inter-professionalism; primary care; shared decision making; validity
16.  Identifying risk profiles for childhood obesity using recursive partitioning based on individual, familial, and neighborhood environment factors 
Background
Few studies consider how risk factors within multiple levels of influence operate synergistically to determine childhood obesity. We used recursive partitioning analysis to identify unique combinations of individual, familial, and neighborhood factors that best predict obesity in children, and tested whether these predict 2-year changes in body mass index (BMI).
Methods
Data were collected in 2005–2008 and in 2008–2011 for 512 Quebec youth (8–10 years at baseline) with a history of parental obesity (QUALITY study). CDC age- and sex-specific BMI percentiles were computed and children were considered obese if their BMI was ≥95th percentile. Individual (physical activity and sugar-sweetened beverage intake), familial (household socioeconomic status and measures of parental obesity including both BMI and waist circumference), and neighborhood (disadvantage, prestige, and presence of parks, convenience stores, and fast food restaurants) factors were examined. Recursive partitioning, a method that generates a classification tree predicting obesity based on combined exposure to a series of variables, was used. Associations between resulting varying risk group membership and BMI percentile at baseline and 2-year follow up were examined using linear regression.
Results
Recursive partitioning yielded 7 subgroups with a prevalence of obesity equal to 8%, 11%, 26%, 28%, 41%, 60%, and 63%, respectively. The 2 highest risk subgroups comprised i) children not meeting physical activity guidelines, with at least one BMI-defined obese parent and 2 abdominally obese parents, living in disadvantaged neighborhoods without parks and, ii) children with these characteristics, except with access to ≥1 park and with access to ≥1 convenience store. Group membership was strongly associated with BMI at baseline, but did not systematically predict change in BMI.
Conclusion
Findings support the notion that obesity is predicted by multiple factors in different settings and provide some indications of potentially obesogenic environments. Alternate group definitions as well as longer duration of follow up should be investigated to predict change in obesity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12966-015-0175-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12966-015-0175-7
PMCID: PMC4336734
Built environment; Body mass index; Familial risk; Food environment; Neighborhood characteristics; Obesity; Physical activity; Recursive partitioning analysis; Socioecological model
17.  E1-Mediated Recruitment of a UAF1-USP Deubiquitinase Complex Facilitates Human Papillomavirus DNA Replication 
Journal of Virology  2014;88(15):8545-8555.
ABSTRACT
The human papillomavirus (HPV) E1 helicase promotes viral DNA replication through its DNA unwinding activity and association with host factors. The E1 proteins from anogenital HPV types interact with the cellular WD repeat-containing factor UAF1 (formerly known as p80). Specific amino acid substitutions in E1 that impair this interaction inhibit maintenance of the viral episome in immortalized keratinocytes and reduce viral DNA replication by up to 70% in transient assays. In this study, we determined by affinity purification of UAF1 that it interacts with three deubiquitinating enzymes in C33A cervical carcinoma cells: USP1, a nuclear protein, and the two cytoplasmic enzymes USP12 and USP46. Coimmunoprecipitation experiments indicated that E1 assembles into a ternary complex with UAF1 and any one of these three USPs. Moreover, expression of E1 leads to a redistribution of USP12 and USP46 from the cytoplasm to the nucleus. Chromatin immunoprecipitation studies further revealed that E1 recruits these threes USPs to the viral origin in association with UAF1. The function of USP1, USP12, and USP46 in viral DNA replication was investigated by overproduction of catalytically inactive versions of these enzymes in transient assays. All three dominant negative USPs reduced HPV31 DNA replication by up to 60%, an effect that was specific, as it was not observed in assays performed with a truncated E1 lacking the UAF1-binding domain or with bovine papillomavirus 1 E1, which does not bind UAF1. These results highlight the importance of the USP1, USP12, and USP46 deubiquitinating enzymes in anogenital HPV DNA replication.
IMPORTANCE Human papillomaviruses are small DNA tumor viruses that induce benign and malignant lesions of the skin and mucosa. HPV types that infect the anogenital tract are the etiological agents of cervical cancer, the majority of anal cancers, and a growing proportion of head-and-neck cancers. Replication of the HPV genome requires the viral protein E1, a DNA helicase that also interacts with host factors to promote viral DNA synthesis. We previously reported that the E1 helicase from anogenital HPV types associates with the WD40 repeat-containing protein UAF1. Here, we show that UAF1 bridges the interaction of E1 with three deubiquitinating enzymes, USP1, USP12, and USP46. We further show that these deubiquitinases are recruited by E1/UAF1 to the viral origin of DNA replication and that overexpression of catalytically inactive versions of these enzymes reduces viral DNA replication. These results highlight the need for an E1-associated deubiquitinase activity in anogenital HPV genome replication.
doi:10.1128/JVI.00379-14
PMCID: PMC4135941  PMID: 24850727
18.  Impact of milk consumption on cardiometabolic risk in postmenopausal women with abdominal obesity 
Nutrition Journal  2015;14:12.
Background
The impact of dairy intake on cardiometabolic risk factors associated with metabolic syndrome (MetS) needs further research.
Objective
To investigate the impact of milk consumption on a wide array of cardiometabolic risk factors associated with MetS (blood lipids, cholesterol homeostasis, glucose homeostasis, systemic inflammation, blood pressure, endothelial function) in postmenopausal women with abdominal obesity.
Methods
In this randomized, crossover study, 27 women with abdominal obesity consumed two 6-week diets based on the National Cholesterol Education Program (NCEP), one with 3.2 servings/d of 2% fat milk per 2000 kcal (MILK) and one without milk or other dairy (NCEP). The macronutrient composition of both diets was comparable (55% carbohydrates, 15% proteins, 30% fat and 10% saturated fat).
Results
The MILK diet had no significant effect on LDL-C, triglycerides, LDL size, CRP and cell adhesion molecule concentrations and on indicators of insulin sensitivity. The MILK diet reduced HDL-C, adiponectin, endothelin and fasting glucose levels as well blood pressure (all P ≤ 0.01), but those changes were comparable to those seen with the NCEP milk-free diet (all between-diet P ≥ 0.07). Finally, the MILK diet was associated with lower VLDL apolipoprotein B fractional catabolic rate (−13.4%; P = 0.04) and plasma sterol concentrations (−12.0%; P = 0.04) compared with the control NCEP milk-free diet.
Conclusions
These data suggest that short-term consumption of low fat milk in the context of a prudent NCEP diet has no favorable nor deleterious effect on cardiometabolic risk factors associated with MetS in postmenopausal women with abdominal obesity.
Electronic supplementary material
The online version of this article (doi:10.1186/1475-2891-14-12) contains supplementary material, which is available to authorized users.
doi:10.1186/1475-2891-14-12
PMCID: PMC4328687  PMID: 25604722
Milk; Dairy; Metabolic syndrome; Blood pressure; Cardiovascular disease; Randomized controlled study; Postmenopausal women
19.  RNAi Factors are Present and Active in Human Cell Nuclei 
Cell reports  2014;6(1):211-221.
Summary
RNAi is widely appreciated as a powerful regulator of mRNA translation in the cytoplasm of mammalian cells. However, the presence and activity of RNAi factors in the mammalian nucleus has been the subject of considerable debate. Here we show that Argonaute-2 (Ago2) and RNAi factors Dicer, TRBP and TRNC6A/GW182 are in the human nucleus and associate together in multi-protein complexes. Small RNAs can silence nuclear RNA and guide site-specific cleavage of the targeted RNA, demonstrating that RNAi can function in the human nucleus. Nuclear Dicer is active and miRNAs are bound to nuclear Ago2, consistent with the existence of nuclear miRNA pathways. Notably, we do not detect loading of duplex small RNAs in nuclear extracts and known loading factors are absent. These results extend RNAi into the mammalian nucleus and suggest that regulation of RNAi via small RNA loading of Ago2 differs between the cytoplasm and the nucleus.
doi:10.1016/j.celrep.2013.12.013
PMCID: PMC3916906  PMID: 24388755
20.  Further improvement in reducing superficial contamination in NIRS using double short separation measurements 
NeuroImage  2013;85(0 1):10.1016/j.neuroimage.2013.01.073.
Near-Infrared Spectroscopy (NIRS) allows the recovery of the evoked hemodynamic response to brain activation. In adult human populations, the NIRS signal is strongly contaminated by systemic interference occurring in the superficial layers of the head. An approach to overcome this difficulty is to use additional NIRS measurements with short optode separations to measure the systemic hemodynamic fluctuations occurring in the superficial layers. These measurements can then be used as regressors in the post-experiment analysis to remove the systemic contamination and isolate the brain signal. In our previous work, we showed that the systemic interference measured in NIRS is heterogeneous across the surface of the scalp. As a consequence, the short separation measurement used in the regression procedure must be located close to the standard NIRS channel from which the evoked hemodynamic response of the brain is to be recovered. Here, we demonstrate that using two short separation measurements, one at the source optode and one at the detector optode, further increases the performance of the short separation regression method compared to using a single short separation measurement. While a single short separation channel produces an average reduction in noise of 33% for HbO, using a short separation channel at both source and detector reduces noise by 59% compared to the standard method using a general linear model (GLM) without short separation. For HbR, noise reduction of 3% is achieved using a single short separation and this number goes to 47% when two short separations are used. Our work emphasizes the importance of integrating short separation measurements both at the source and at the detector optode of the standard channels from which the hemodynamic response is to be recovered. While the implementation of short separation sources presents some difficulties experimentally, the improvement in noise reduction is significant enough to justify the practical challenges.
doi:10.1016/j.neuroimage.2013.01.073
PMCID: PMC3665655  PMID: 23403181
Near-Infrared Spectroscopy; Systemic Interference; Short Optode Separations; Kalman filtering; State-Space analysis
21.  Motion artifacts in functional near-infrared spectroscopy: a comparison of motion correction techniques applied to real cognitive data 
NeuroImage  2013;85(0 1):10.1016/j.neuroimage.2013.04.082.
Motion artifacts are a significant source of noise in many functional near-infrared spectroscopy (fNIRS) experiments. Despite this, there is no well-established method for their removal. Instead, functional trials of fNIRS data containing a motion artifact are often rejected completely. However, in most experimental circumstances the number of trials is limited, and multiple motion artifacts are common, particularly in challenging populations. Many methods have been proposed recently to correct for motion artifacts, including principle component analysis, spline interpolation, Kalman filtering, wavelet filtering and correlation-based signal improvement. The performance of different techniques has been often compared in simulations, but only rarely has it been assessed on real functional data. Here, we compare the performance of these motion correction techniques on real functional data acquired during a cognitive task, which required the participant to speak aloud, leading to a low-frequency, low-amplitude motion artifact that is correlated with the hemodynamic response. To compare the efficacy of these methods, objective metrics related to the physiology of the hemodynamic response have been derived. Our results show that it is always better to correct for motion artifacts than reject trials, and that wavelet filtering is the most effective approach to correcting this type of artifact, reducing the area under the curve where the artifact is present in 93% of the cases. Our results therefore support previous studies that have shown wavelet filtering to be the most promising and powerful technique for the correction of motion artifacts in fNIRS data. The analyses performed here can serve as a guide for others to objectively test the impact of different motion correction algorithms and therefore select the most appropriate for the analysis of their own fNIRS experiment.
doi:10.1016/j.neuroimage.2013.04.082
PMCID: PMC3762942  PMID: 23639260
functional near-infrared spectroscopy; fNIRS; motion artifact; hemodynamic response; motion correction
22.  Evaluation of [64Cu]Cu-DOTA and [64Cu]Cu-CB-TE2A Chelates for Targeted Positron Emission Tomography with an αvβ6-Specific Peptide 
Molecular imaging  2009;8(2):111-121.
Significant upregulation of the integrin αvβ6 has been described as a prognostic indicator in several cancers, making it an attractive target for tumor imaging. This study compares variants of a PEGylated αvβ6-targeting peptide, bearing either an [18F]fluorobenzoyl prosthetic group ([18F]FBA-PEG-A20FMDV2) or different [64Cu]copper chelators (DOTA-PEG-A20FMDV2, CB-TE2A-PEG-A20FMDV2). The compounds were evaluated in vitro by enzyme-linked immunosorbent assay (against the integrin αvβ6 and the closely related integrin αvβ3) and by cell labeling (αvβ6-positive DX3puroβ6/αvβ6-negative DX3puro) and in vivo using micro-positron emission tomography in a mouse model bearing paired DX3puroβ6/Dx3puro xenografts. In vitro, all three compounds showed excellent αvβ6-specific binding (50% inhibitory concentration [IC50](αvβ6) = 3 to 6 nmol/L; IC50(αvβ3) > 10 µmol/L). In vivo, they displayed comparable, preferential uptake for the αvβ6-expressing xenograft over the αvβ6-negative control (> 4:1 ratio at 4 hours postinjection). Whereas [64Cu]Cu-DOTA-PEG-A20FMDV2 resulted in increased levels of radioactivity in the liver, [64Cu]Cu-CB-TE2A-PEG-A20FMDV2 did not. Significantly, both 64Cu-labeled tracers showed unexpectedly high and persistent levels of radioactivity in the kidneys (> 40% injected dose/g at 4 and 12 hours postinjection). The findings underscore the potential influence of the prosthetic group on targeted in vivo imaging of clinically relevant markers such as αvβ6. Despite identical targeting peptide moiety and largely equal in vitro behavior, both 64Cu-labeled tracers displayed inferior pharmacokinetics, making them in their present form less suitable candidates than the 18F-labeled tracer for in vivo imaging of αvβ6.
PMCID: PMC4287215  PMID: 19397856
23.  Adiponectin Is a Candidate Biomarker of Lower Extremity Bone Density in Men With Chronic Spinal Cord Injury 
Adipose tissue is a major regulator of bone metabolism and in the general population obesity is associated with greater bone mineral density (BMD). However, bone-fat interactions are multifactorial, and may involve pathways that influence both bone formation and resorption with competing effects on the skeleton. One such pathway involves adipocyte production of adipokines that regulate bone metabolism. In this study we determined the association between BMD, walking status, and circulating adipokines (adiponectin and leptin) in 149 men with chronic spinal cord injury (SCI). Although adipokine levels did not vary significantly based on walking status, there was a significant inverse association between adiponectin and BMD in wheelchair users independent of body composition. We found no association between adiponectin and BMD in the walkers and no association between leptin and BMD in either group. These findings suggest that for subjects with chronic SCI, walking may mitigate the effect of adiponectin mediated bone loss. For wheelchair users, adipose-derived adiponectin may contribute to SCI-induced osteoporosis because the osteoprotective benefits of obesity appear to require mechanical loading during ambulation.
doi:10.1002/jbmr.2020
PMCID: PMC3979427  PMID: 23787489
OSTEOPOROSIS; ADIPONECTIN; BIOMARKER; SPINAL CORD INJURY; REHABILITATION MEDICINE
24.  Quantitation of nanoparticle accumulation in flow using optimized microfluidic chambers 
Journal of drug targeting  2013;22(1):48-56.
Background
The vascular cell adhesion molecule-1 (VCAM-1) targeting peptide sequence, VHPKQHR, is a promising moiety for targeting atherosclerosis through incorporation into nanoparticles such as dendrimers and liposomes.
Purpose
We aim to develop VCAM-1-targeted nanoparticles that effectively accumulate on the endothelium under shear conditions and to develop robust microfluidic chambers able to house sufficient cells for flow cytometric measurements.
Methods
Carboxyfluorescein-labeled monomeric VHP-peptide, tetrameric VHP-dendrimers (bisbidentate or radial architecture, with or without N-terminal acetylation) and VHP-peptide liposomes were prepared. Human umbilical vein endothelial cells were treated with nano-particles under 0 or 2.9 dyne/cm2 shear, and particle binding was quantified. Flow chambers cured at various temperatures, with or without glass backings were fabricated, characterized for deformation and applied in experiments.
Results
Although liposomes accumulated with highest efficiency, dendrimers also demonstrated specific binding. N-terminal acetylation significantly reduced dendrimer binding, and despite shorter movement range, bisbidentate dendrimers outperformed radial dendrimers, suggesting multiple epitope presence within its estimated arm-span of 57 Å. Under shear, while liposome binding increased 300%, dendrimer binding to cells decreased 65%. Through higher temperature curing and glass backing insertion, polydimethylsiloxane flow chambers maintaining rectangular cross-section with aspect-ratio as low as 1:111 were achieved.
Conclusion
Optimized dendrimers and liposomal nanocarriers specifically accumulated onto cells within microfluidic chambers.
doi:10.3109/1061186X.2013.837468
PMCID: PMC4004627  PMID: 24079404
Atherosclerosis; dendrimers; in vitro model; liposomes; peptide; targeted drug delivery
25.  Genetic Variants and Early Cigarette Smoking and Nicotine Dependence Phenotypes in Adolescents 
PLoS ONE  2014;9(12):e115716.
Background
While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes.
Methods
In a prospective study of 1294 adolescents aged 12–13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7–8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator).
Results
The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076.
Conclusions
Because the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3).
Impact
Dopaminergic pathways may be salient during early smoking and the development of ND.
doi:10.1371/journal.pone.0115716
PMCID: PMC4278712  PMID: 25545355

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