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1.  Mucosal and systemic antibody responses to potential Pseudomonas aeruginosa vaccine protein antigens in young children with cystic fibrosis following colonization and infection 
Pseudomonas aeruginosa is an important prognostic determinant in cystic fibrosis (CF). Little is known however, about P. aeruginosa induced local mucosal and systemic immune responses. Twenty CF children were categorized according to their P. aeruginosa status: (1) chronic lower respiratory tract infection (LRTI), (2) prior successfully treated initial LRTI, (3) isolated upper respiratory tract (URT) colonization, and (4) no known URT colonization or previous LRTI. Their antibody responses, and those of six non-CF disease controls, in serum and bronchoalveolar lavage (BAL) fluid to potential P. aeruginosa vaccine antigens outer membrane protein F (OprF), outer membrane protein H (OprH), catalase A (KatA) and a whole killed cell (WKC) extract were evaluated. Outer membrane protein G (OprG) responses were also measured in blood. Natural exposure, colonization and infection resulted in detectable antibody levels in BAL and serum in all CF groups. Both chronically infected and URT colonized CF children had substantially elevated immunoglobulin A antibody levels in the BAL fluid and sera toward the WKC extract and OprF antigen compared with the other groups of CF children and non-CF controls. The serum levels of specific P. aeruginosa antibodies involving immunoglobulin G and M isotypes increased with chronic LRTI, especially antibody levels to KatA, OprH and WKC extract, which were substantially greater in chronically infected children compared with all other groups. In conclusion, natural exposure, URT colonization and LRTI with P. aeruginosa all induce substantial mucosal and systemic antibody responses to potential vaccine antigens with chronically infected CF children having the highest levels.
doi:10.4161/hv.23226
PMCID: PMC3891706  PMID: 23249482
cystic fibrosis; Pseudomonas aeruginosa; OprF; OprH; OprG; KatA; mucosal and systemic antibody; vaccine
2.  The 2012 SAGE wait times program: Survey of Access to GastroEnterology in Canada 
BACKGROUND:
Periodically surveying wait times for specialist health services in Canada captures current data and enables comparisons with previous surveys to identify changes over time.
METHODS:
During one week in April 2012, Canadian gastroenterologists were asked to complete a questionnaire (online or by fax) recording demographics, reason for referral, and dates of referral and specialist visits for at least 10 consecutive new patients (five consultations and five procedures) who had not been seen previously for the same indication. Wait times were determined for 18 indications and compared with those from similar surveys conducted in 2008 and 2005.
RESULTS:
Data regarding adult patients were provided by 173 gastroenterologists for 1374 consultations, 540 procedures and 293 same-day consultations and procedures. Nationally, the median wait times were 92 days (95% CI 85 days to 100 days) from referral to consultation, 55 days (95% CI 50 days to 61 days) from consultation to procedure and 155 days (95% CI 142 days to 175 days) (total) from referral to procedure. Overall, wait times were longer in 2012 than in 2005 (P<0.05); the wait time to same-day consultation and procedure was shorter in 2012 than in 2008 (78 days versus 101 days; P<0.05), but continued to be longer than in 2005 (P<0.05). The total wait time remained longest for screening colonoscopy, increasing from 201 days in 2008 to 279 days in 2012 (P<0.05).
DISCUSSION:
Wait times for gastroenterology services continue to exceed recommended targets, remain unchanged since 2008 and exceed wait times reported in 2005.
PMCID: PMC3731118  PMID: 23472243
Access; Audit; Canada; Endoscopy; Gastroenterology; Wait time
3.  Patient-identified quality indicators for colonoscopy services 
BACKGROUND:
Current quality improvement tools for endoscopy services, such as the Global Rating Scale (GRS), emphasize the need for patient-centred care. However, there are no studies that have investigated patient expectations and/or perceptions of quality indicators in endoscopy services.
OBJECTIVES:
To identify quality indicators for colonoscopy services from the patient perspective; to rate indicators of importance; to determine factors that influence indicator ratings; and to compare the identified indicators with those of the GRS.
METHODS:
A two-phase mixed methods study was undertaken in Montreal (Quebec), Calgary (Alberta) and Hamilton (Ontario) among patients ≥18 years of age who spoke and read English or French. In phase 1, focus group participants identified quality indicators that were then used to construct a survey questionnaire. In phase 2, survey questionnaires, which were completed immediately after colonoscopy, prompted respondents to rate the 20 focus group-derived indicators according to their level of importance (low, medium, high) and to list up to nine additional items. Multiple logistic regression analysis was used to determine the factors that influenced focus group-derived indicator ratings. Patient-identified indicators were compared with those used in the GRS to identify novel indicators.
RESULTS:
Three quality indicator themes were identified by 66 participants in 12 focus groups: communication, comfort and service environment. Of the 828 surveys distributed, 402 (48.6%) were returned and 65% of focus group-derived indicators were rated highly important by at least 55% of survey respondents. Indicator ratings differed according to age, sex, site and perceived colorectal cancer risk. Of the 29 patient-identified indicators, 17 (58.6%) were novel.
CONCLUSIONS:
Patients identified 17 novel quality indicators, suggesting that patients and health professionals differ in their perspectives with respect to quality in colonoscopy services.
PMCID: PMC3545623  PMID: 23378980
Colorectal cancer screening; Indicators; Quality
4.  Report on the Expert Forum on Using Information Technology to Facilitate Uptake and Impact of Colorectal Cancer Screening Guidelines 
The present report summarizes the proceedings of the pan-Canadian Expert Forum on Using Information Technology to Facilitate Uptake and Impact of Colorectal Cancer Screening Guidelines, which was held in Montreal, Quebec, November 18 to 19, 2011. The meeting assembled a multidisciplinary group of family physicians, gastroenterologists, nurses, patients, foundation representatives, screening program administrators and researchers to discuss the development of a mechanism or strategy that would permit the collection of comparable data by all colorectal cancer (CRC) screening programs, which would not only support the needs of each program but also provide a national perspective. The overarching theme of the meeting was ‘designing a national approach to computerized electronic data collection and dissemination for CRC screening that would improve knowledge transfer across the continuum of preventive health care’. The forum encouraged presentations on clinical, research and technical topics. The meeting fostered valuable cross-disciplinary communication and delivered the message that it is essential to develop a national health informatics approach for CRC screening data collection and dissemination to support provincial CRC screening programs.
PMCID: PMC3551566  PMID: 23248792
Colorectal cancer; Information technology; National registry; Report; Screening
5.  A survey of the practice of after-hours and emergency endoscopy in Canada 
OBJECTIVE:
To determine staffing and practice patterns for after-hours endoscopy service in Canada
METHODS:
A link to a web-based survey was sent by e-mail to all clinical members of the Canadian Association of Gastroenterology in February 2011. A priori, it was planned to compare variations in practice among gastroenterologists (GIs) performing endoscopy in different regions of Canada, between pediatric and adult GIs, and between university and community hospitals.
RESULTS:
Of 422 potential respondents, 168 (40%) responded. Of the 139 adult GIs, 61% performed after-hours endoscopy in the endoscopy suite where daytime procedures were performed, 62% had a trained endoscopy nurse available for all procedures, 38% had access to propofol sedation, 12% reprocessed the endoscopes themselves or with the help of a resident, 4% had out-of-hospital patients come directly to their endoscopy suite and 53% were highly satisfied. The adult endoscopists practising at community hospitals were more likely to have an anesthetist attend the procedure. Regional differences were noted, with more involvement of anesthetists (13%) and availability of propofol (50%) in Ontario, more frequent reprocessing of endoscopes in the central reprocessing units in British Columbia (78%) and almost universal availability of a trained endoscopy nurse (96%) with concomitant higher endoscopist satisfaction (84% highly satisfied) in Alberta.
CONCLUSIONS:
More than one-third of surveyed endoscopists across the country do not have a trained endoscopy nurse to assist in after-hours endoscopy – the time period when urgent patients often present and typically require therapeutic endoscopic interventions. There are significant regional differences in the practice of after-hours endoscopy in Canada.
PMCID: PMC3551559  PMID: 23248785
Emergency care; Endoscopy; Staffing; Standards
6.  Evaluation and management of skeletal health in celiac disease: Position statement 
OBJECTIVE:
To review the evaluation and management of skeletal health in patients with celiac disease (CD), and to make recommendations on screening, diagnosis, treatment and follow-up of low bone mineral density (BMD) in CD patients.
METHODS:
A multidisciplinary team developed clinically relevant questions for review. An electronic search of the literature was conducted using the MEDLINE and EMBASE databases from 1996 to 2010. All original studies, reviews and guidelines, both pediatric and adult, were included. A document summarizing the results of the review and proposed recommendations was prepared and underwent multiple revisions until consensus was reached.
RESULTS:
At diagnosis, approximately one-third of adult CD patients have osteoporosis, one-third have osteopenia and one-third have normal BMD. Children with CD have low bone mass at diagnosis. Adult and pediatric CD patients are at increased risk of fractures.
DISCUSSION:
For adults, serum calcium, albumin, 25(OH) vitamin D3, parathyroid hormone and 24 h urine calcium testing should be performed at diagnosis; patients with ‘classic’ CD and those at risk for osteoporosis should undergo a dual x-ray absorptiometry scan. An abnormal baseline dual x-ray absorptiometry scan should be repeated one to two years after initiation of a gluten-free diet (GFD). For children, BMD should be assessed one year after diagnosis if GFD adherence is not strict. A GFD is the most important treatment for bone loss. Supplemental antiresorptives may be justified in those who remain at high fracture risk (eg, postmenopausal women, older men) after implementation of a GFD.
CONCLUSION:
Current evidence does not support the screening of all CD patients for low BMD at diagnosis. Follow-up BMD assessment should be performed one to two years after initiation of a GFD.
PMCID: PMC3495700  PMID: 23166906
Bone; Celiac disease; Osteoporosis
7.  Approach to diagnosing celiac disease in patients with low bone mineral density or fragility fractures 
Canadian Family Physician  2013;59(10):1055-1061.
Abstract
Objective
To provide clinicians with an update on the diagnosis of celiac disease (CD) and to make recommendations on the indications to screen for CD in patients presenting with low bone mineral density (BMD) or fragility fractures.
Quality of evidence
A multidisciplinary task force developed clinically relevant questions related to the diagnosis of CD as the basis for a literature search of the MEDLINE, EMBASE, and CENTRAL databases (January 2000 to January 2009) using the key words celiac disease, osteoporosis, osteopenia, low bone mass, and fracture. The existing literature consists of level I and II studies.
Main message
The estimated prevalence of asymptomatic CD is 2% to 3% in individuals with low BMD. Routine screening for CD is not justified in patients with low BMD. However, targeted screening for CD is recommended for patients who have T-scores of −1.0 or less at the spine or hip, or a history of fragility fractures in association with any CD-related symptoms or conditions; family history of CD; or low urinary calcium levels, vitamin D insufficiency, and raised parathyroid hormone levels despite adequate intake of calcium and vitamin D. Celiac disease testing should be performed while the subject is consuming a gluten-containing diet; initial screening should be performed with human recombinant immunoglobulin (Ig) A tissue transglutaminase or other IgA tissue transglutaminase assays, in association with IgA endomysial antibody immunofluorescence. Duodenal biopsy is necessary to confirm the diagnosis of CD. Human leukocyte antigen typing might assist in confirming or ruling out the diagnosis of CD in cases where serology and histology are discordant. Definitive diagnosis is based on clinical, serologic, and histologic features, combined with a positive response to a gluten-free diet.
Conclusion
Current evidence does not support routine screening for CD in all patients with low BMD. A targeted case-finding approach is appropriate for patients who are at higher risk of CD.
PMCID: PMC3796969  PMID: 24130278
8.  Approche au diagnostic de la maladie cœliaque chez les patients ayant une faible densité minérale osseuse ou des fractures de fragilité 
Canadian Family Physician  2013;59(10):e441-e448.
Résumé
Objectif
Présenter aux cliniciens une mise à jour sur le diagnostic de la maladie cœliaque (MC), ainsi que des recommandations sur les indications de procéder au dépistage de la MC chez les patients présentant une faible densité minérale osseuse (DMO) ou des fractures de fragilité.
Qualité des données
Un groupe de travail multidisciplinaire a élaboré des questions cliniquement pertinentes relativement au diagnostic de la MC servant de fondement à une recherche documentaire dans les bases de données MEDLINE, EMBASE et CENTRAL (de janvier 2000 à janvier 2009) à l’aide des mots clés en anglais celiac disease, osteoporosis, osteopenia, low bone mass et fracture. Les ouvrages scientifiques existants comportent des études de niveaux I et II.
Message principal
La prévalence estimée de la MC asymptomatique est de 2 % à 3 % chez les personnes qui ont une faible DMO. Par ailleurs, un dépistage ciblé est recommandé pour les patients qui ont des T-scores de −1,0 ou moins à la colonne vertébrale ou aux hanches ou des antécédents de fractures de fragilité associées à des symptômes ou à des problèmes reliés à la MC, des antécédents familiaux de MC ou de bas niveaux de calcium urinaire, une insuffisance en vitamine D et des niveaux à la hausse d’hormones parathyroïdiennes en dépit d’un apport suffisant en calcium et en vitamine D. Le dépistage de la MC devrait se faire pendant que le sujet consomme un régime alimentaire contenant du gluten. On procède au dépistage initial par le dosage d’immunoglobuline (Ig) A antitransglutaminase en utilisant la transglutaminase tissulaire humaine recombinante ou une autre transglutaminase tissulaire, en association avec l’immunofluorescence des IgA anti-endomysium. Une biopsie du duodénum est nécessaire pour confirmer le diagnostic de la MC. Le typage des antigènes des leucocytes humains peut aider à confirmer ou à exclure le diagnostic de la MC dans les cas où la sérologie et l’histologie ne concordent pas. Le diagnostic définitif se fonde sur les caractéristiques cliniques, sérologiques et histologiques combinées à une réponse positive à une alimentation sans gluten.
PMCID: PMC3796989
9.  Safety of esophagogastroduodenoscopy within 30 days of myocardial infarction: A retrospective cohort study from a Canadian tertiary centre 
Patients who experience gastrointestinal bleeding after myocardial infarction (MI) often have comorbidities that could place them at increased risk of complications if evaluative endoscopy were to be performed. Although esophagogastroduodenoscopy is considered to be generally safe in high-risk individuals, some post-MI patients may be more susceptible to a variety of cardiopulmonary complications. This cohort study examined cardiopulmonary safety in post-MI patients and evaluated specific predictors of complications of post-MI endoscopy.
BACKGROUND:
Patients who experience myocardial infarction (MI) are at risk of gastrointestinal (GI) bleeding complications. Endoscopic evaluation may lead to cardiopulmonary complications. Guidelines and studies regarding the safety of endoscopy in this population are limited.
OBJECTIVE:
To evaluate the safety of endoscopy in a retrospective cohort of post-MI patients at a Canadian tertiary centre.
METHODS:
Using hospital diagnostic/procedure codes, the charts of patients meeting the inclusion criteria of having ST elevation MI or non-ST elevation MI, and GI bleeding detected at endoscopy were reviewed. The information retrieved included demographics, medical history, medications, endoscopy details and cardiopulmonary/GI events.
RESULTS:
A total of 121 patients experienced an MI and underwent endoscopy within 30 days. However, only 44 met the inclusion criteria and were reviewed. The mean age of the patients was 75 years, and 55% were female. The mean hemoglobin level was 86 g/L, and 38 of 44 patients required a transfusion. Comorbidities included hypertension (82%), diabetes (46%), heart failure (55%), stroke (21%), lung disease (27%), previous MI (46%), cardiac bypass surgery (30%), history of GI bleed (25%), history of ulcer (18%) and ejection fraction <50% (48%). The median number of days to endoscopy after MI was three. Complications included seven patients with acute coronary syndrome, one with arrhythmia, one with respiratory failure, one with aspiration pneumonia and two with perforation. Age, hemoglobin level or timing of endoscopy did not significantly predict a complication.
CONCLUSIONS:
Patients with GI bleeding after MI often have comorbidities and are on antiplatelet agents. Endoscopy is a valuable tool in the diagnosis and management of bleeding complications, but must be weighed against the potential risk of other complications, which in the present study occurred in more than 25% of procedures.
PMCID: PMC3299238  PMID: 22408766
Acute myocardial infarction; Complication; Gastrointestinal endoscopy; Safety
10.  Effectiveness of disseminating consensus management recommendations for ulcer bleeding: a cluster randomized trial 
Background:
International guidelines for the management of nonvariceal upper gastrointestinal bleeding have not been widely adopted in clinical practice. We sought to determine whether a national, multifaceted intervention could improve adherence to guidelines, especially for patients at high risk of nonvariceal upper gastrointestinal bleeding.
Methods:
In this randomized trial, we stratified hospitals by region and size and allocated sites to either the control or experimental group. Health care workers in the experimental group were given published guidelines, generic algorithms, stratification scoring systems and written reminders and attended multidisciplinary guideline education groups and case-based workshops. These interventions were implemented over a 12-month period after randomization, with performance feedback and benchmarking. The primary outcome of adherence rates to key guidelines in endoscopic and pharmacologic management, determined by chart review, was adjusted according to site characteristics and possible within-site dependencies. We also report the rates of adherence to other recommendations.
Results:
Forty-three sites were randomized to the experimental (n = 21) or control (n = 22) groups. In our primary analysis, we compared patients before (experimental group: n = 402 patients; control group: n = 424 patients) and after (experimental group: n = 361 patients; control group: n = 389 patients) intervention. Patient-level analysis revealed no significant difference in adherence rates to the guidelines after the intervention (experimental group: 9.8%; control group: 4.8%; p = 0.99) after adjustment for the rate of adherence before the intervention (experimental group: 13.2%; control group: 7.1%). The adherence rates to other guidelines were similar and decreased over time, varying between 5% and 93%.
Interpretation:
This national knowledge translation–based trial suggests poor adherence to guidelines on nonvariceal upper gastrointestinal bleeding. Adherence was not improved by an educational intervention, which highlights both the complexity and poor predictability of attempting to alter the behaviour of health care providers (Trial registration: ClinicalTrials.gov, no. MCT-88113).
doi:10.1503/cmaj.120095
PMCID: PMC3576461  PMID: 23318399
11.  Indicators of safety compromise in gastrointestinal endoscopy 
The growth in the use of endoscopy to diagnose and treat many gastointestinal disorders, and its central role in cancer screening programs, has led to a significant increase in the number of procedures performed. This growth, however, has also led to many variations in, among others, the provision of services, the choice of sedative medications and the training of providers. The recognition of the significance of quality in endoscopy has prompted several countries, including Canada, to initiate efforts to adopt nationwide quality improvement programs. The Canadian Association of Gastroenterology formed a committee to review endoscopy and quality with the aim of stimulating improvement. This article focuses specifically on patient safety indicators that were developed at a consensus conference aimed at generating a broad range of recommendations for selected endoscopic procedures, which if adopted, could lead to significant changes in how endoscopy services are provided.
INTRODUCTION:
The importance of quality indicators has become increasingly recognized in gastrointestinal endoscopy. Patient safety requires the identification and monitoring of occurrences associated with harm or the potential for harm. The identification of relevant indicators of safety compromise is, therefore, a critical element that is key to the effective implementation of endoscopy quality improvement programs.
OBJECTIVE:
To identify key indicators of safety compromise in gastrointestinal endoscopy.
METHODS:
The Canadian Association of Gastroenterology Safety and Quality Indicators in Endoscopy Consensus Group was formed to address issues of quality in endoscopy. A subcommittee was formed to identify key safety indicators. A systematic literature review was undertaken, and articles pertinent to safety in endoscopy were identified and reviewed. All complications and measures used to document safety were recorded. From this, a preliminary list of 16 indicators was compiled and presented to the 35-person consensus group during a three-day meeting. A revised list of 20 items was subsequently put to the consensus group for vote for inclusion on the final list of safety indicators. Items were retained only if the consensus group highly agreed on their importance.
RESULTS:
A total of 19 indicators of safety compromise were retained and grouped into the three following categories: medication-related – the need for CPR, use of reversal agents, hypoxia, hypotension, hypertension, sedation doses in patients older than 70 years of age, allergic reactions and laryngospasm/bronchospasm; procedure-related early – perforation, immediate postpolypectomy bleeding, need for hospital admission or transfer to emergency department from the gastroenterology unit, instrument impaction, severe persistent abdominal pain requiring evaluation proven to not be perforation; and procedure-related delayed – death within 30 days of procedure, 14-day unplanned hospitalization, 14-day unplanned contact with a health provider, gastrointestinal bleeding within 14 days of procedure, infection or symptomatic metabolic complications.
CONCLUSIONS:
The 19 indicators of safety compromise in endoscopy, identified by a rigorous, evidence-based consensus process, provide clear outcomes to be recorded by all facilities as part of their continuing quality improvement programs.
PMCID: PMC3275408  PMID: 22312605
Digestive system; Endoscopy; Health care; Quality assurance; Surgical complications; Safety
12.  Canadian Association of Gastroenterology consensus guidelines on safety and quality indicators in endoscopy 
Several organizations worldwide have developed procedure-based guidelines and/or position statements regarding various aspects of quality and safety indicators, and credentialing for endoscopy. Although important, they do not specifically address patient needs or provide a framework for their adoption in the context of endoscopy services. The consensus guidelines reported in this article, however, aimed to identify processes and indicators relevant to the provision of high-quality endoscopy services that will support ongoing quality improvement across many jurisdictions, specifically in the areas of ethics, facility standards and policies, quality assurance, training and education, reporting standards and patient perceptions.
BACKGROUND:
Increasing use of gastrointestinal endoscopy, particularly for colorectal cancer screening, and increasing emphasis on health care quality, highlight the need for clearly defined, evidence-based processes to support quality improvement in endoscopy.
OBJECTIVE:
To identify processes and indicators of quality and safety relevant to high-quality endoscopy service delivery.
METHODS:
A multidisciplinary group of 35 voting participants developed recommendation statements and performance indicators. Systematic literature searches generated 50 initial statements that were revised iteratively following a modified Delphi approach using a web-based evaluation and voting tool. Statement development and evidence evaluation followed the AGREE (Appraisal of Guidelines, REsearch and Evaluation) and GRADE (Grading of Recommendations, Assessment, Development and Evaluation) guidelines. At the consensus conference, participants voted anonymously on all statements using a 6-point scale. Subsequent web-based voting evaluated recommendations for specific, individual quality indicators, safety indicators and mandatory endoscopy reporting fields. Consensus was defined a priori as agreement by 80% of participants.
RESULTS:
Consensus was reached on 23 recommendation statements addressing the following: ethics (statement 1: agreement 100%), facility standards and policies (statements 2 to 9: 90% to 100%), quality assurance (statements 10 to 13: 94% to 100%), training, education, competency and privileges (statements 14 to 19: 97% to 100%), endoscopy reporting standards (statements 20 and 21: 97% to 100%) and patient perceptions (statements 22 and 23: 100%). Additionally, 18 quality indicators (agreement 83% to 100%), 20 safety indicators (agreement 77% to 100%) and 23 recommended endoscopy-reporting elements (agreement 91% to 100%) were identified.
DISCUSSION:
The consensus process identified a clear need for high-quality clinical and outcomes research to support quality improvement in the delivery of endoscopy services.
CONCLUSIONS:
The guidelines support quality improvement in endoscopy by providing explicit recommendations on systematic monitoring, assessment and modification of endoscopy service delivery to yield benefits for all patients affected by the practice of gastrointestinal endoscopy.
PMCID: PMC3275402  PMID: 22308578
Digestive system; Endoscopy; Guideline; Health care; Quality assurance
13.  Acute Hypersensitivity of Pluripotent Testicular Cancer-Derived Embryonal Carcinoma to Low-Dose 5-Aza Deoxycytidine Is Associated with Global DNA Damage-Associated p53 Activation, Anti-Pluripotency and DNA Demethylation 
PLoS ONE  2012;7(12):e53003.
Human embryonal carcinoma (EC) cells are the stem cells of nonseminoma testicular germ cells tumors (TGCTs) and share remarkable similarities to human embryonic stem (ES) cells. In prior work we found that EC cells are hypersensitive to low nanomolar doses of 5-aza deoxycytidine (5-aza) and that this hypersensitivity partially depended on unusually high levels of the DNA methyltransferase, DNMT3B. We show here that low-dose 5-aza treatment results in DNA damage and induction of p53 in NT2/D1 cells. In addition, low-dose 5-aza results in global and gene specific promoter DNA hypomethylation. Low-dose 5-aza induces a p53 transcriptional signature distinct from that induced with cisplatin in NT2/D1 cells and also uniquely downregulates genes associated with pluripotency including NANOG, SOX2, GDF3 and Myc target genes. Changes in the p53 and pluripotency signatures with 5-aza were to a large extent dependent on high levels of DNMT3B. In contrast to the majority of p53 target genes upregulated by 5-aza that did not show DNA hypomethylation, several other genes induced with 5-aza had corresponding decreases in promoter methylation. These genes include RIN1, SOX15, GPER, and TLR4 and are novel candidate tumors suppressors in TGCTs. Our studies suggest that the hypersensitivity of NT2/D1 cells to low-dose 5-aza is multifactorial and involves the combined activation of p53 targets, repression of pluripotency genes, and activation of genes repressed by DNA methylation. Low-dose 5-aza therapy may be a general strategy to treat those tumors that are sustained by cells with embryonic stem-like properties.
GEO number for the microarray data: GSE42647.
doi:10.1371/journal.pone.0053003
PMCID: PMC3531428  PMID: 23300844
14.  A literature review of quality in lower gastrointestinal endoscopy from the patient perspective 
Colorectal cancer (CRC) is the third most frequently diagnosed cancer, and the second leading cause of cancer death among men and women in Canada. Prompted by nationally accepted CRC guidelines, the use of colonoscopy – widely regarded to be the optimal method of CRC screening – has increased dramatically in recent years. However, when evaluating colonoscopy performance and the delivery of high-quality care, it is important to also consider factors relevant to the patients who require colonoscopy services. Understanding the patient perspective on what comprises quality in colonoscopy/endoscopy is essential to tailoring improvements in the standards of practice and quality of care. Accordingly, this study systematically reviewed the literature pertaining to aspects of colonoscopy and endoscopy that may be considered to be important to patients.
BACKGROUND:
Given the limited state of health care resources, increased demand for colorectal cancer (CRC) screening raises concerns about the quality of endoscopy services. Little is known about quality in colonoscopy and endoscopy from the patient perspective.
OBJECTIVE:
To systematically review the literature on quality that is relevant to patients who require colonoscopy or endoscopy services.
METHODS:
A systematic PubMed search was performed on articles that were published between January 2000 and February 2011. Keywords included “colonoscopy” or “sigmoidoscopy” or “endoscopy” AND “quality”; “colonoscopy” or “sigmoidoscopy” or “endoscopy” AND “patient satisfaction” or “willingness to return”. The included articles were qualitative and quantitative English language studies regarding aspects of colonoscopy and/or endoscopy services that were evaluated by patients in which data were collected within one year of the colonoscopy/endoscopy procedure.
RESULTS:
In total, 28 quantitative studies were identified, of which eight (28.6%) met the inclusion criteria (four cross-sectional, three prospective cohort and one single-blinded controlled study). Aspects of quality included comfort, management of pain and anxiety, endoscopy unit staff manner, skills and specialty, procedure and results discussion with the doctor, physical environment, wait times for the appointment and procedure, and discharge. Qualitative studies eliciting the patient perspective on what constituted quality in colonoscopy/endoscopy were not found.
CONCLUSIONS:
Factors related to comfort, staff, communication and the service environment were evaluated from the patient perspective using closed-ended questions that were designed by clinicians and researchers. Future research using qualitative methodology to elicit the patient perspective on quality in colonoscopy and/or endoscopy services is needed.
PMCID: PMC3266160  PMID: 22175059
Colonoscopy; Endoscopy; Patient perspective; Quality; Review
15.  Between Celiac Disease and Irritable Bowel Syndrome: The “No Man’s Land” of Gluten Sensitivity 
The repertoire of gastrointestinal (GI) symptoms is finite; however, the etiologies and mechanisms underlying symptom generation and perception are diverse and, in many cases, unknown. This review examines the clinical and experimental evidence exploring the putative relationship between gluten sensitivity (GS) and the generation of GI symptoms. It explores the hypothesis that, in a proportion of patients, GS causes functional bowel disorder (FBD)-like symptoms. We propose a model for investigating and understanding the induction of GI symptoms and dysfunction by gluten in FBD and organic disease. We hypothesize that, even in the absence of fully developed celiac disease, gluten can induce symptoms similar to FBD. We discuss the hypothesis that GS and post-infectious irritable bowel syndrome (IBS) provide two triggers that can explain at least part of the spectrum that constitutes IBS, further advancing an understanding of the role of mucosal responses to luminal factors in FBDs. We propose that the animal model of GS in human leukocyte antigen (HLA)-DQ8 mice allows investigation of mucosal pathophysiological changes that occur before the onset of full-blown inflammation in a GS host. A better understanding of how gluten can cause symptoms in sensitive individuals will illuminate the interaction between host genotype, diet, and intestinal microbiota in generating one of the most common GI conditions.
doi:10.1038/ajg.2009.188
PMCID: PMC3480312  PMID: 19455131
16.  Patient accounts of diagnostic testing for familial hypercholesterolaemia: comparing responses to genetic and non-genetic testing methods 
BMC Medical Genetics  2012;13:87.
Background
Continuing developments in genetic testing technology together with research revealing gene-disease associations have brought closer the potential for genetic screening of populations. A major concern, as with any screening programme, is the response of the patient to the findings of screening, whether the outcome is positive or negative. Such concern is heightened for genetic testing, which it is feared may elicit stronger reactions than non-genetic testing.
Methods
This paper draws on thematic analysis of 113 semi-structured interviews with 39 patients being tested for familial hypercholesterolaemia (FH), an inherited predisposition to early-onset heart disease. It examines the impact of disease risk assessments based on both genetic and non-genetic information, or solely non-genetic information.
Results
The impact of diagnostic testing did not seem to vary according to whether or not genetic information was used. More generally, being given a positive or negative diagnosis of FH had minimal discernible impact on people's lives as they maintained the continuity of their beliefs and behaviour.
Conclusions
The results suggest that concerns about the use of genetic testing in this context are unfounded, a conclusion that echoes findings from studies in this and other health contexts.
doi:10.1186/1471-2350-13-87
PMCID: PMC3495051  PMID: 22994377
Behaviour change; Genetics; Genetic testing; Health behaviour; Risk; Qualitative
17.  Effect on Adherence to Nicotine Replacement Therapy of Informing Smokers Their Dose Is Determined by Their Genotype: A Randomised Controlled Trial 
PLoS ONE  2012;7(4):e35249.
Background
The behavioural impact of pharmacogenomics is untested. We tested two hypotheses concerning the behavioural impact of informing smokers their oral dose of NRT is tailored to analysis of DNA.
Methods and Findings
We conducted an RCT with smokers in smoking cessation clinics (N = 633). In combination with NRT patch, participants were informed that their doses of oral NRT were based either on their mu-opioid receptor (OPRM1) genotype, or their nicotine dependence questionnaire score (phenotype). The proportion of prescribed NRT consumed in the first 28 days following quitting was not significantly different between groups: (68.5% of prescribed NRT consumed in genotype vs 63.6%, phenotype group, difference  =  5.0%, 95% CI −0.9,10.8, p  =  0.098). Motivation to make another quit attempt among those (n  =  331) not abstinent at six months was not significantly different between groups (p  =  0.23). Abstinence at 28 days was not different between groups (p = 0.67); at six months was greater in genotype than phenotype group (13.7% vs 7.9%, difference  =  5.8%, 95% CI 1.0,10.7, p  =  0.018).
Conclusions
Informing smokers their oral dose of NRT was tailored to genotype not phenotype had a small, statistically non-significant effect on 28-day adherence to NRT. Among those still smoking at six months, there was no evidence that saying NRT was tailored to genotype adversely affected motivation to make another quit attempt. Higher abstinence rate at six months in the genotype arm requires investigation.
Trial registration
Controlled-Trials.com ISRCTN14352545.
doi:10.1371/journal.pone.0035249
PMCID: PMC3324463  PMID: 22509402
18.  Testing for gluten-related disorders in clinical practice: The role of serology in managing the spectrum of gluten sensitivity 
Immunoglobulin A tissue transglutaminase is the single most efficient serological test for the diagnosis of celiac disease. It is well known that immunoglobulin A tissue transglutaminase levels correlate with the degree of intestinal damage, and that values can fluctuate in patients over time. Serological testing can be used to identify symptomatic individuals that need a confirmatory biopsy, to screen at-risk populations or to monitor diet compliance in patients previously diagnosed with celiac disease. Thus, interpretation of serological testing requires consideration of the full clinical scenario. Antigliadin tests are no longer recommended for the diagnosis of classical celiac disease. However, our understanding of the pathogenesis and spectrum of gluten sensitivity has improved, and gluten-sensitive irritable bowel syndrome patients are increasingly being recognized. Studies are needed to determine the clinical utility of antigliadin serology in the diagnosis of gluten sensitivity.
PMCID: PMC3088693  PMID: 21523259
Antigliadin antibodies; Antitissue transglutaminase; Celiac disease; Diagnosis; Gluten intolerance; Serology
19.  The function of ‘functional’: a mixed methods investigation 
Objective
The term ‘functional’ has a distinguished history, embodying a number of physiological concepts, but has increasingly come to mean ‘hysterical’. The DSM-V working group proposes to use ‘functional’ as the official diagnostic term for medically unexplained neurological symptoms (currently known as ‘conversion disorder’). This study aimed to explore the current neurological meanings of the term and to understand its resilience.
Design
Mixed methods were used, first interviewing the neurologists in a large UK region and then surveying all neurologists in the UK on their use of the term.
Results
The interviews revealed four dominant uses—‘not organic’, a physical disability, a brain disorder and a psychiatric problem—as well as considerable ambiguity. Although there was much dissatisfaction with the term, the ambiguity was also seen as useful when engaging with patients. The survey confirmed these findings, with a majority adhering to a strict interpretation of ‘functional’ to mean only ‘not organic’, but a minority employing it to mean different things in different contexts - and endorsing the view that ‘functional’ would one day be a neurological construct again.
Conclusions
‘Functional’ embodies real divisions in neurologists' conceptualisation of unexplained symptoms and, perhaps, between those of patients and neurologists: its diversity of meanings allows it to be a common term while meaning different things to different people, or at different times, and thus conceal some of the conflict in a particularly contentious area. This flexibility may help explain the term's longevity.
doi:10.1136/jnnp-2011-300992
PMCID: PMC3277687  PMID: 22250186
20.  Point-of-care, peer-comparator colonoscopy practice audit: The Canadian Association of Gastroenterology Quality Program – Endoscopy 
BACKGROUND
Point-of-care practice audits allow documentation of procedural outcomes to support quality improvement in endoscopic practice.
OBJECTIVE
To evaluate a colonoscopists’ practice audit tool that provides point-of-care data collection and peer-comparator feedback.
METHODS
A prospective, observational colonoscopy practice audit was conducted in academic and community endoscopy units for unselected patients undergoing colonoscopy. Anonymized colonoscopist, patient and practice data were collected using touchscreen smart-phones with automated data upload for data analysis and review by participants. The main outcome measures were the following colonoscopy quality indicators: colonoscope insertion and withdrawal times, bowel preparation quality, sedation, immediate complications and polypectomy, and biopsy rates.
RESULTS
Over a span of 16 months, 62 endoscopists reported on 1279 colonoscopy procedures. The mean cecal intubation rate was 94.9% (10th centile 84.2%). The mean withdrawal time was 8.8 min and, for nonpolypectomy colonoscopies, 41.9% of colonoscopists reported a mean withdrawal time of less than 6 min. Polypectomy was performed in 37% of colonoscopies. Independent predictors of polypectomy included the following: endoscopy unit type, patient age, interval since previous colonoscopy, bowel preparation quality, stable inflammatory bowel disease, previous colon polyps and withdrawal time. Withdrawal times of less than 6 min were associated with lower polyp removal rates (mean difference −11.3% [95% CI −2.8% to −19.9%]; P=0.01).
DISCUSSION
Cecal intubation rates exceeded 90% and polypectomy rates exceeded 30%, but withdrawal times were frequently shorter than recommended. There are marked practice variations consistent with previous observations.
CONCLUSION
Real-time, point-of-care practice audits with prompt, confidential access to outcome data provide a basis for targeted educational programs to improve quality in colonoscopy practice.
PMCID: PMC3027329  PMID: 21258663
Colonoscopy; Health care; Practice audit; Quality assurance; Quality indicators
21.  Comparison of a Sleep Item From the General Health Questionnaire-12 With the Jenkins Sleep Questionnaire as Measures of Sleep Disturbance 
Journal of Epidemiology  2011;21(6):474-480.
Background
The objective of this study was to examine whether a widely available single-item measure of sleep disturbances is an acceptable alternative to a multi-item sleep questionnaire.
Methods
Data were derived from Finnish Helsinki Health Study postal questionnaires administered in 2000–2002 (n = 7777, response rate 67%). The measures were the 4-item Jenkins Sleep Questionnaire (JSQ) on difficulties initiating and maintaining sleep, and nonrestorative sleep, and an item on sleep loss due to worry, from the General Health Questionnaire-12 (GHQ-12). Receiver operating characteristics (ROC) curve analyses were done to compare the predictive performance of the GHQ-12 item with the JSQ scale. Using the above 2 measures of sleep, logistic regression models were used to examine associations between sociodemographic factors, working conditions, health-related factors, and sleep disturbance.
Results
The estimated area under the ROC curve was 0.68 among both women and men, which suggests that the ability of the GHQ-12 item to discriminate true positives from false positives was modest. However, the associations of sleep disturbance with its key determinants were largely similar using the GHQ-12 and the JSQ.
Conclusions
A widely available, GHQ-12-based, single-item sleep measure was not an adequate substitute for a multi-item measure of overall sleep disturbance. Although the measures produced largely similar associations for key determinants of poor sleep, the discrepancies between responses must be considered when analyzing data from a measure that uses a single sleep item.
doi:10.2188/jea.JE20110023
PMCID: PMC3899464  PMID: 21986193
sleep; validation; GHQ-12; JSQ; single-item; multi-item
22.  Use of Sugar on the Healing of Diabetic Ulcers: A Review 
With the advent of several innovative wound care management tools, the choice of products and treatment modalities available to clinicians continues to expand. High costs associated with wound care, especially diabetic foot wounds, make it important for clinician scientists to research alternative therapies and optimally incorporate them into wound care protocols appropriately. This article reviews using sugar as a treatment option in diabetic foot care and provides a guide to its appropriate use in healing foot ulcers. In addition to a clinical case study, the physiological significance and advantages of sugar are discussed.
PMCID: PMC2956799  PMID: 20920433
diabetic foot ulcers; sugar; wound healing
23.  A one-year economic evaluation of six alternative strategies for the management of uninvestigated upper gastrointestinal symptoms in Canadian primary care 
BACKGROUND:
The cost-effectiveness of initial strategies in managing Canadian patients with uninvestigated upper gastrointestinal symptoms remains controversial.
OBJECTIVE:
To assess the cost-effectiveness of six management approaches to uninvestigated upper gastrointestinal symptoms in the Canadian setting.
METHODS:
The present study analyzed data from four randomized trials assessing homogeneous and complementary populations of Canadian patients with uninvestigated upper gastrointestinal symptoms with comparable outcomes. Symptom-free months, quality-adjusted life-years (QALYs) and direct costs in Canadian dollars of two management approaches based on the Canadian Dyspepsia Working Group (CanDys) Clinical Management Tool, and four additional strategies (two empirical antisecretory agents, and two prompt endoscopy) were examined and compared. Prevalence data, probabilities, utilities and costs were included in a Markov model, while sensitivity analysis used Monte Carlo simulations. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were determined.
RESULTS:
Empirical omeprazole cost $226 per QALY ($49 per symptom-free month) per patient. CanDys omeprazole and endoscopy approaches were more effective than empirical omeprazole, but more costly. Alternatives using H2-receptor antagonists were less effective than those using a proton pump inhibitor. No significant differences were found for most incremental cost-effectiveness ratios. As willingness to pay (WTP) thresholds rose from $226 to $24,000 per QALY, empirical antisecretory approaches were less likely to be the most cost-effective choice, with CanDys omeprazole progressively becoming a more likely option. For WTP values ranging from $24,000 to $70,000 per QALY, the most clinically relevant range, CanDys omeprazole was the most cost-effective strategy (32% to 46% of the time), with prompt endoscopy-proton pump inhibitor favoured at higher WTP values.
CONCLUSIONS:
Although no strategy was the indisputable cost-effective option, CanDys omeprazole may be the strategy of choice over a clinically relevant range of WTP assumptions in the initial management of Canadian patients with uninvestigated dyspepsia.
PMCID: PMC2947002  PMID: 20711528
Antisecretory therapy; Cost-effectiveness; Dyspepsia; Economic modelling; Endoscopy; Helicobacter pylori
24.  Neurologists' understanding and management of conversion disorder 
Background
Conversion disorder is largely managed by neurologists, for whom it presents great challenges to understanding and management. This study aimed to quantify these challenges, examining how neurologists understand conversion disorder, and what they tell their patients.
Methods
A postal survey of all consultant neurologists in the UK registered with the Association of British Neurologists.
Results
349 of 591 practising consultant neurologists completed the survey. They saw conversion disorder commonly. While they endorsed psychological models for conversion, they diagnosed it according to features of the clinical presentation, most importantly inconsistency and abnormal illness behaviour. Most of the respondents saw feigning as entangled with conversion disorder, with a minority seeing one as a variant of the other. They were quite willing to discuss psychological factors as long as the patient was receptive but were generally unwilling to discuss feigning even though they saw it as their responsibility. Those who favoured models in terms of feigning were older, while younger, female neurologists preferred psychological models, believed conversion would one day be understood neurologically and found communicating with their conversion patients easier than it had been in the past.
Discussion
Neurologists accept psychological models for conversion disorder but do not employ them in their diagnosis; they do not see conversion as clearly different from feigning. This may be changing as younger, female neurologists endorse psychological views more clearly and find it easier to discuss with their patients.
doi:10.1136/jnnp.2010.233114
PMCID: PMC3191819  PMID: 21325661
25.  Trial Protocol: Communicating DNA-based risk assessments for Crohn's disease: a randomised controlled trial assessing impact upon stopping smoking 
BMC Public Health  2011;11:44.
Background
Estimates of the risk of developing Crohn's disease (CD) can be made using DNA testing for mutations in the NOD2 (CARD15) gene, family history, and smoking status. Smoking doubles the risk of CD, a risk that is reduced by stopping. CD therefore serves as a timely and novel paradigm within which to assess the utility of predictive genetic testing to motivate behaviour change to reduce the risk of disease. The aim of the study is to describe the impact upon stopping smoking of communicating a risk of developing CD that incorporates DNA analysis. We will test the following main hypothesis:
Smokers who are first degree relatives (FDRs) of CD probands are more likely to make smoking cessation attempts following communication of risk estimates of developing CD that incorporate DNA analysis, compared with an equivalent communication that does not incorporate DNA analysis.
Methods/design
A parallel groups randomised controlled trial in which smokers who are FDRs of probands with CD are randomly allocated in families to undergo one of two types of assessment of risk for developing CD based on either:
i. DNA analysis, family history of CD and smoking status, or
ii. Family history of CD and smoking status
The primary outcome is stopping smoking for 24 hours or longer in the six months following provision of risk information. The secondary outcomes are seven-day smoking abstinence at one week and six month follow-ups. Randomisation of 470 smoking FDRs of CD probands, with 400 followed up (85%), provides 80% power to detect a difference in the primary outcome of 14% between randomised arms, at the 5% significance level.
Discussion
This trial provides one of the strongest tests to date of the impact of communicating DNA-based risk assessment on risk-reducing behaviour change. Specific issues regarding the choice of trial design are discussed.
Trial Registration
ISRCTN: ISRCTN21633644
doi:10.1186/1471-2458-11-44
PMCID: PMC3036624  PMID: 21247480

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