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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  Salmonella Adhesion, Invasion and Cellular Immune Responses Are Differentially Affected by Iron Concentrations in a Combined In Vitro Gut Fermentation-Cell Model 
PLoS ONE  2014;9(3):e93549.
In regions with a high infectious disease burden, concerns have been raised about the safety of iron supplementation because higher iron concentrations in the gut lumen may increase risk of enteropathogen infection. The aim of this study was to investigate interactions of the enteropathogen Salmonella enterica ssp. enterica Typhimurium with intestinal cells under different iron concentrations encountered in the gut lumen during iron deficiency and supplementation using an in vitro colonic fermentation system inoculated with immobilized child gut microbiota combined with Caco-2/HT29-MTX co-culture monolayers. Colonic fermentation effluents obtained during normal, low (chelation by 2,2'-dipyridyl) and high iron (26.5 mg iron/L) fermentation conditions containing Salmonella or pure Salmonella cultures with similar iron conditions were applied to cellular monolayers. Salmonella adhesion and invasion capacity, cellular integrity and immune response were assessed. Under high iron conditions in pure culture, Salmonella adhesion was 8-fold increased compared to normal iron conditions while invasion was not affected leading to decreased invasion efficiency (−86%). Moreover, cellular cytokines IL-1β, IL-6, IL-8 and TNF-α secretion as well as NF-κB activation in THP-1 cells were attenuated under high iron conditions. Low iron conditions in pure culture increased Salmonella invasion correlating with an increase in IL-8 release. In fermentation effluents, Salmonella adhesion was 12-fold and invasion was 428-fold reduced compared to pure culture. Salmonella in high iron fermentation effluents had decreased invasion efficiency (−77.1%) and cellular TNF-α release compared to normal iron effluent. The presence of commensal microbiota and bacterial metabolites in fermentation effluents reduced adhesion and invasion of Salmonella compared to pure culture highlighting the importance of the gut microbiota as a barrier during pathogen invasion. High iron concentrations as encountered in the gut lumen during iron supplementation attenuated Salmonella invasion efficiency and cellular immune response suggesting that high iron concentrations alone may not lead to an increased Salmonella invasion.
doi:10.1371/journal.pone.0093549
PMCID: PMC3968171  PMID: 24676135
11.  Ordering a Dynamic Protein Via a Small Molecule Stabilizer 
Like many coactivators, the GACKIX domain of the master coactivator CBP/p300 recognizes transcriptional activators of diverse sequence composition via dynamic binding surfaces. The conformational dynamics of GACKIX that underlie its function also render it especially challenging for structural characterization. We find that the ligand discovery strategy of Tethering is an effective method for identifying small molecule fragments that stabilize the GACKIX domain and enables, for the first time, the crystallographic characterization of this important motif. The 2.0 Å resolution structure of GACKIX complexed to a small molecule was further analyzed by molecular dynamics simulations, revealing the importance of specific side chain motions that remodel the activator binding site in order to accommodate binding partners of distinct sequence and size. More broadly, these results suggest that Tethering can be a powerful strategy for identifying small molecule stabilizers of conformationally malleable proteins, thus facilitating their structural characterization and accelerating the discovery of small molecule modulators.
doi:10.1021/ja3122334
PMCID: PMC3607081  PMID: 23384013
12.  Group B Streptococcus and Streptococcus suis Capsular Polysaccharides Induce Chemokine Production by Dendritic Cells via Toll-Like Receptor 2- and MyD88-Dependent and -Independent Pathways 
Infection and Immunity  2013;81(9):3106-3118.
Streptococcus agalactiae (also known as group B Streptococcus [GBS]) and Streptococcus suis are encapsulated streptococci causing severe septicemia and meningitis. Bacterial capsular polysaccharides (CPSs) are poorly immunogenic, but anti-CPS antibodies are essential to the host defense against encapsulated bacteria. The mechanisms underlying anti-CPS antibody responses are not fully elucidated, but the biochemistry of CPSs, particularly the presence of sialic acid, may have an immunosuppressive effect. We investigated the ability of highly purified S. suis and GBS native (sialylated) CPSs to activate dendritic cells (DCs), which are crucial actors in the initiation of humoral immunity. The influence of CPS biochemistry was studied using CPSs extracted from different serotypes within these two streptococcal species, as well as desialylated CPSs. No interleukin-1β (IL-1β), IL-6, IL-12p70, tumor necrosis factor alpha (TNF-α), or IL-10 production was observed in S. suis or GBS CPS-stimulated DCs. Moreover, these CPSs exerted immunosuppressive effects on DC activation, as a diminution of gamma interferon (IFN-γ)-induced B cell-activating factor of the tumor necrosis factor family (BAFF) expression was observed in CPS-pretreated cells. However, S. suis and GBS CPSs induced significant production of CCL3, via partially Toll-like receptor 2 (TLR2)- and myeloid differentiation factor 88 (MyD88)-dependent pathways, and CCL2, via TLR-independent mechanisms. No major influence of CPS biochemistry was observed on the capacity to induce chemokine production by DCs, indicating that DCs respond to these CPSs in a patterned way rather than a structure-dedicated manner.
doi:10.1128/IAI.00113-13
PMCID: PMC3754219  PMID: 23774593
13.  Foot Type Biomechanics Part 2: Are structure and anthropometrics related to function? 
Gait & posture  2012;37(3):10.1016/j.gaitpost.2012.09.008.
Background
Many foot pathologies are associated with specific foot types. If foot structure and function are related, measurement of either could assist with differential diagnosis of pedal pathologies.
Hypothesis
Biomechanical measures of foot structure and function are related in asymptomatic healthy individuals.
Methods
Sixty-one healthy subjects' left feet were stratified into cavus (n = 12), rectus (n = 27) and planus (n = 22) foot types. Foot structure was assessed by malleolar valgus index, arch height index, and arch height flexibility. Anthropometrics (height and weight), age, and walking speed were measured. Foot function was assessed by center of pressure excursion index, peak plantar pressure, maximum force, and gait pattern parameters. Foot structure and anthropometric variables were entered into stepwise linear regression models to identify predictors of function.
Results
Measures of foot structure and anthropometrics explained 10–37% of the model variance (adjusted R2) for gait pattern parameters. When walking speed was included, the adjusted R2 increased to 45–77% but foot structure was no longer a factor. Foot structure and anthropometrics predicted 7–47% of the model variance for plantar pressure and 16–64% for maximum force parameters. All multivariate models were significant (p < 0.05), supporting acceptance of the hypothesis.
Discussion and conclusion
Foot structure and function are related in asymptomatic healthy individuals. The structural parameters employed are basic measurements that do not require ionizing radiation and could be used in a clinical setting. Further research is needed to identify additional predictive parameters (plantar soft tissue characteristics, skeletal alignment, and neuromuscular control) and to include individuals with pathology.
doi:10.1016/j.gaitpost.2012.09.008
PMCID: PMC3878980  PMID: 23107624
Foot and ankle; Gait; Foot type; Plantar pressures; Structure and function
14.  Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor Dabrafenib (GSK2118436) 
Purpose
Dabrafenib is a selective inhibitor of V600-mutant BRAF kinase, which recently demonstrated improved progression free survival (PFS) as compared with dacarbazine, in metastatic melanoma patients. The current study examined potential genetic markers associated with response and PFS in the phase I study of dabrafenib.
Experimental Design
Baseline (pre-treatment or archival) melanoma samples were evaluated in 41 patients using a custom genotyping melanoma-specific assay, sequencing of PTEN, and copy number analysis using multiplex ligation amplification and array based comparative genomic hybridization. Nine patients had on-treatment and/or progression samples available.
Results
All baseline patient samples had BRAFV600E/K confirmed. Baseline PTEN loss/mutation was not associated with best overall response (BOR) to dabrafenib, but it showed a trend for shorter median progression free survival (PFS) (18.3 [95% confidence interval (CI) 9.1–24.3] vs. 32.1 weeks [95% CI 24.1–33], p=0.059). Higher copy number of CCND1 (p=0.009) and lower copy number of CDKN2A (p=0.012) at baseline were significantly associated with decreased PFS. Although no melanomas had high level amplification of BRAF, the two patients with progressive disease as their best response had BRAF copy gain in their tumors.
Conclusions
Copy number changes in CDKN2A, CCND1, and mutation/copy number changes in PTEN correlated with the duration of PFS in patients treated with dabrafenib. The results suggest that these markers should be considered in the design and interpretation of future trials with selective BRAF inhibitors in advanced melanoma patients.
doi:10.1158/1078-0432.CCR-13-0827
PMCID: PMC3924894  PMID: 23833299
Melanoma; BRAF inhibitors; correlative studies; BRAF mutation; PTEN
15.  A Functional Magnetic Resonance Imaging Study of Working Memory in Youth after Sports-Related Concussion: Is It Still Working? 
Journal of Neurotrauma  2014;31(5):437-451.
Abstract
In children, the importance of detecting deficits after mild traumatic brain injury (mTBI) or concussion has grown with the increasing popularity of leisure physical activities and contact sports. Whereas most postconcussive symptoms (PCS) are similar for children and adults, the breadth of consequences to children remains largely unknown. To investigate the effect of mTBI on brain function, we compared working memory performance and related brain activity using blood-oxygen-level–dependent (BOLD) functional magnetic resonance imaging (fMRI) in 15 concussed youths and 15 healthy age-matched control subjects. Neuropsychological tests, self-perceived PCS, and levels of anxiety and depression were also assessed. Our results showed that, behaviorally, concussed youths had significantly worse performances on the working memory tasks, as well as on the Rey figure delayed recall and verbal fluency. fMRI results revealed that, compared to healthy children, concussed youths had significantly reduced task-related activity in bilateral dorsolateral prefrontal cortex, left premotor cortex, supplementary motor area, and left superior parietal lobule during performance of verbal and nonverbal working memory tasks. Additionally, concussed youths also showed less activation than healthy controls in the dorsal anterior cingulate cortex, left thalamus, and left caudate nucleus during the nonverbal task. Regression analysis indicated that BOLD signal changes in bilateral dorsolateral prefrontal cortex were significantly correlated with performance such that greater activities in these regions, relative to the control condition, were associated with greater accuracy. Our findings confirmed functional alterations in brain activity after concussion in youths, a result similar to that observed in adults. However, significant differences were noted. In particular, the observation of reduced working memory accuracy suggests that youths may be unable to engage compensatory strategies to maintain cognitive performance after mTBI. This has significant implications for safe return to daily activities, including competitive sport.
doi:10.1089/neu.2013.3052
PMCID: PMC3934544  PMID: 24070614
concussion; fMRI; working memory; youth
16.  Dementia Coding, Workup, and Treatment in the VA New England Healthcare System 
Growing evidence suggests that Alzheimer's disease and other types of dementia are underdiagnosed and poorly documented. In our study, we describe patterns of dementia coding and treatment in the Veteran's Administration New England Healthcare System. We conducted a retrospective cohort study with new outpatient ICD-9 codes for several types of dementia between 2002 and 2009. We examined healthcare utilization, medication use, initial dementia diagnoses, and changes in diagnoses over time by provider type. 8,999 veterans received new dementia diagnoses during the study period. Only 18.3% received a code for cognitive impairment other than dementia, most often “memory loss” (65.2%) prior to dementia diagnosis. Two-thirds of patients received their initial code from a PCP. The etiology of dementia was often never specified by ICD-9 code, even by specialists. Patients followed up exclusively by PCPs had lower rates of neuroimaging and were less likely to receive dementia medication. Emergency room visits and hospitalizations were frequent in all patients but highest in those seen by dementia specialists. Dementia medications are commonly used off-label. Our results suggest that, for the majority the patients, no prodrome of the dementia syndrome is documented with diagnostic code, and patients who do not see dementia specialists have less extensive diagnostic assessment and treatment.
doi:10.1155/2014/821894
PMCID: PMC3950831
17.  Pathogenesis of hyperinflation in chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable lung disease characterized by airflow limitation that is not fully reversible. In a significant proportion of patients with COPD, reduced lung elastic recoil combined with expiratory flow limitation leads to lung hyperinflation during the course of the disease. Development of hyperinflation during the course of COPD is insidious. Dynamic hyperinflation is highly prevalent in the advanced stages of COPD, and new evidence suggests that it also occurs in many patients with mild disease, independently of the presence of resting hyperinflation. Hyperinflation is clinically relevant for patients with COPD mainly because it contributes to dyspnea, exercise intolerance, skeletal muscle limitations, morbidity, and reduced physical activity levels associated with the disease. Various pharmacological and nonpharmacological interventions have been shown to reduce hyperinflation and delay the onset of ventilatory limitation in patients with COPD. The aim of this review is to address the more recent literature regarding the pathogenesis, assessment, and management of both static and dynamic lung hyperinflation in patients with COPD. We also address the influence of biological sex and obesity and new developments in our understanding of hyperinflation in patients with mild COPD and its evolution during progression of the disease.
doi:10.2147/COPD.S38934
PMCID: PMC3933347  PMID: 24600216
chronic obstructive pulmonary disease; hyperinflation; expiratory flow limitation; operational lung volumes
18.  Distribution of VGLUT3 in Highly Collateralized Axons from the Rat Dorsal Raphe Nucleus as Revealed by Single-Neuron Reconstructions 
PLoS ONE  2014;9(2):e87709.
This study aimed at providing the first detailed morphological description, at the single-cell level, of the rat dorsal raphe nucleus neurons, including the distribution of the VGLUT3 protein within their axons. Electrophysiological guidance procedures were used to label dorsal raphe nucleus neurons with biotinylated dextran amine. The somatodendritic and axonal arborization domains of labeled neurons were reconstructed entirely from serial sagittal sections using a computerized image analysis system. Under anaesthesia, dorsal raphe nucleus neurons display highly regular (1.72±0.50 Hz) spontaneous firing patterns. They have a medium size cell body (9.8±1.7 µm) with 2–4 primary dendrites mainly oriented anteroposteriorly. The ascending axons of dorsal raphe nucleus are all highly collateralized and widely distributed (total axonal length up to 18.7 cm), so that they can contact, in various combinations, forebrain structures as diverse as the striatum, the prefrontal cortex and the amygdala. Their morphological features and VGLUT3 content vary significantly according to their target sites. For example, high-resolution confocal analysis of the distribution of VGLUT3 within individually labeled-axons reveals that serotonin axon varicosities displaying VGLUT3 are larger (0.74±0.03 µm) than those devoid of this protein (0.55±0.03 µm). Furthermore, the percentage of axon varicosities that contain VGLUT3 is higher in the striatum (93%) than in the motor cortex (75%), suggesting that a complex trafficking mechanism of the VGLUT3 protein is at play within highly collateralized axons of the dorsal raphe nucleus neurons. Our results provide the first direct evidence that the dorsal raphe nucleus ascending projections are composed of widely distributed neuronal systems, whose capacity to co-release serotonin and glutamate varies from one forebrain locus to the other.
doi:10.1371/journal.pone.0087709
PMCID: PMC3913638  PMID: 24504335
19.  Regulation of Transcription by Small RNAs Complementary to Sequences Downstream from the 3’ Termini of Genes 
Nature chemical biology  2010;6(8):621-629.
Transcriptome studies reveal many noncoding transcripts overlapping 3’ gene termini. The function of these transcripts is unknown. Here we characterize transcription at the progesterone receptor (PR) locus and identify noncoding transcripts that overlap the 3’ end of the gene. Small RNAs complementary to sequences beyond the 3’ terminus of PR mRNA modulate expression of PR, recruit argonaute to a 3’-noncoding transcript, alter occupancy of RNA polymerase II, induce chromatin changes at the PR promoter, and affect responses to physiologic stimuli. We find that the promoter and 3’ terminal regions of the PR locus are in close proximity, providing a potential mechanism for RNA-mediated control of transcription over long genomic distances. Computational analysis led to identification of an inhibitory miRNA that targets the 3’ downstream region and modulates PR expression. These results extend the potential for small RNAs to regulate transcription to regions beyond the 3’ termini of mRNA.
doi:10.1038/nchembio.400
PMCID: PMC3909968  PMID: 20581822
20.  Does parental body mass index status modify the associations among birth weight, early growth and childhood adiposity? 
Paediatrics & Child Health  2013;18(2):e2-e9.
OBJECTIVES:
To examine the associations among birth weight, infant growth and childhood adiposity, and to test whether parental weight status modifies these associations.
METHODS:
The sample was comprised of 423 participants born at term who were an appropriate size for their gestational age from the Quebec Adipose and Lifestyle Investigation in Youth (QUALITY) study, a cohort of 630 children with a parental history of obesity. Infant growth velocity from zero to two years of age was estimated using slopes from simple linear regression for weight and body mass index (BMI) Z-scores. Child anthropometrics and body composition, and parental BMI were measured from eight to 10 years of age. Associations were modelled using multiple linear regressions.
RESULTS:
Increased birth weight and growth velocity independently predicted increased childhood adiposity. Effects of infant growth velocity on later adiposity were stronger with higher maternal BMI but not with higher paternal BMI. Similar interactions with birth weight were not found.
CONCLUSIONS:
Early childhood measures of growth and the mother’s BMI score should be included in investigations on obesity risk.
PMCID: PMC3567911  PMID: 24421668
Adiposity; Body mass index; Cohort study; Dual-energy x-ray absorptiometry; Parents; Weight gain
22.  Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs 
Biological chemistry  2011;392(4):315-325.
Spinocerebellar ataxia-3 (SCA3) (also known as Machado Joseph Disease) is an incurable neurodegenerative disorder caused by expression of a mutant variant of ataxin-3 protein (ATX3). Inhibiting expression of ATX-3 would provide a therapeutic strategy, but indiscriminant inhibition of both wild-type and mutant ATX3 might lead to undesirable side-effects. An ideal silencing agent would block expression of mutant ATX3 while leaving expression of wild-type ATX3 intact. We have previously observed that peptide nucleic acid (PNA) conjugates targeting the expanded CAG repeat within ATX3 mRNA block expression of both alleles. We now identify additional PNAs capable of inhibiting ATX3 expression that vary in length and in the nature of the conjugated cation chain. We can also achieve potent and selective inhibition using duplex RNAs containing one or more mismatches relative to the CAG repeat. Anti-CAG antisense bridged nucleic acid (BNA) oligonucleotides that lack a cationic domain are potent inhibitors but are not allele-selective. Allele-selective inhibitors of ATX-3 expression provide insights into the mechanism of selectivity and promising lead compounds for further development and in vivo investigation.
doi:10.1515/BC.2011.045
PMCID: PMC3908450  PMID: 21294677
Ataxin-3; Spinocerebellar ataxia-3; allele-selective; siRNA; peptide nucleic acid
23.  Strong Depth-Related Zonation of Megabenthos on a Rocky Continental Margin (∼700–4000 m) off Southern Tasmania, Australia 
PLoS ONE  2014;9(1):e85872.
Assemblages of megabenthos are structured in seven depth-related zones between ∼700 and 4000 m on the rocky and topographically complex continental margin south of Tasmania, southeastern Australia. These patterns emerge from analysis of imagery and specimen collections taken from a suite of surveys using photographic and in situ sampling by epibenthic sleds, towed video cameras, an autonomous underwater vehicle and a remotely operated vehicle (ROV). Seamount peaks in shallow zones had relatively low biomass and low diversity assemblages, which may be in part natural and in part due to effects of bottom trawl fishing. Species richness was highest at intermediate depths (1000–1300 m) as a result of an extensive coral reef community based on the bioherm-forming scleractinian Solenosmilia variabilis. However, megabenthos abundance peaked in a deeper, low diversity assemblage at 2000–2500 m. The S. variabilis reef and the deep biomass zone were separated by an extensive dead, sub-fossil S. variabilis reef and a relatively low biomass stratum on volcanic rock roughly coincident with the oxygen minimum layer. Below 2400 m, megabenthos was increasingly sparse, though punctuated by occasional small pockets of relatively high diversity and biomass. Nonetheless, megabenthic organisms were observed in the vast majority of photographs on all seabed habitats and to the maximum depths observed - a sandy plain below 3950 m. Taxonomic studies in progress suggest that the observed depth zonation is based in part on changing species mixes with depth, but also an underlying commonality to much of the seamount and rocky substrate biota across all depths. Although the mechanisms supporting the extraordinarily high biomass in 2000–2500 m depths remains obscure, plausible explanations include equatorwards lateral transport of polar production and/or a response to depth-stratified oxygen availability.
doi:10.1371/journal.pone.0085872
PMCID: PMC3899097  PMID: 24465758
24.  T cell unresponsiveness in a pediatric cystic fibrosis patient: a case report 
A girl was diagnosed with cystic fibrosis (CF) at birth, with repeatedly positive sweat tests and homozygous F508del mutations of her CF transmembrane conductance regulator (CFTR) gene. From an early age, her lung disease was more severe than her birth cohort peers despite aggressive treatment. At the age of 16 she was listed for lung transplantation, but prior to transplant was not on systemic corticosteroids or other immunosuppressive agents. In response to ex vivo stimulation, her pre-transplant peripheral blood T cells unexpectedly failed to produce detectable levels of IFN-γ, unlike cells from healthy controls or from another girl with CF and lung disease of comparable severity. Furthermore, naïve T cells freshly isolated from her peripheral blood showed a complete block of T cell differentiation into Th1, Th17 and Treg lineages, even in the presence of cytokines known to promote differentiation into the respective lineages. Her serology has been remarkably devoid of evidence of exposure to viruses that have been associated with T cell exhaustion. However, her freshly isolated naïve T cells showed sustained expression of markers of T cell exhaustion, which were further induced upon ex vivo stimulation, pointing to T cell exhaustion as the cause of the failure of naïve T cells to undergo differentiation in response to cytokine stimulation. Although excessive inflammation in CF lung can be both ineffective at clearing certain pathogens as well as destructive to the lung tissue itself, adequate inflammation is a component of an effective overall immune response to microbial pathogens. Our present findings suggest that intrinsic impairment of T cell differentiation may have contributed to the greater severity and more rapid progression of her CF lung disease than of the lung disease of most of her peers.
doi:10.1186/1710-1492-10-2
PMCID: PMC3896844  PMID: 24438707
T cell exhaustion; Cystic fibrosis; Naïve T cells; T cell differentiation
25.  Center-of-pressure total trajectory length is a complementary measure to maximum excursion to better differentiate multidirectional standing limits of stability between individuals with incomplete spinal cord injury and able-bodied individuals 
Background
Sensorimotor impairments secondary to a spinal cord injury affect standing postural balance. While quasi-static postural balance impairments have been documented, little information is known about dynamic postural balance in this population. The aim of this study was to quantify and characterize dynamic postural balance while standing among individuals with a spinal cord injury using the comfortable multidirectional limits of stability test and to explore its association with the quasi-static standing postural balance test.
Methods
Sixteen individuals with an incomplete spinal cord injury and sixteen able-bodied individuals participated in this study. For the comfortable multidirectional limits of stability test, participants were instructed to lean as far as possible in 8 directions, separated by 45° while standing with each foot on a forceplate and real-time COP visual feedback provided. Measures computed using the center of pressure (COP), such as the absolute maximal distance reached (COPmax) and the total length travelled by the COP to reach the maximal distance (COPlength), were used to characterize performance in each direction. Quasi-static standing postural balance with eyes open was evaluated using time-domain measures of the COP. The difference between the groups and the association between the dynamic and quasi-static test were analyzed.
Results
The COPlength of individuals with SCI was significantly greater (p ≤ 0.001) than that of able-bodied individuals in all tested directions except in the anterior and posterior directions (p ≤ 0.039), indicating an increased COP trajectory while progressing towards their maximal distance. The COPmax in the anterior direction was significantly smaller for individuals with SCI. Little association was found between the comfortable multidirectional limits of stability test and the quasi-static postural balance test (r ≥ −0.658).
Conclusion
Standing dynamic postural balance performance in individuals with an incomplete spinal cord injury can be differentiated from that of able-bodied individuals with the comfortable limits of stability test. Performance among individuals with an incomplete spinal cord injury is characterized by lack of precision when reaching. The comfortable limits of stability test provides supplementary information and could serve as an adjunct to the quasi-static test when evaluating postural balance in an incomplete spinal cord injury population.
doi:10.1186/1743-0003-11-8
PMCID: PMC3899383  PMID: 24438202
Movement; Outcome assessment; Postural balance; Rehabilitation; Spinal cord injuries

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