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1.  Use of collagenase ointment in conjunction with negative pressure wound therapy in the care of diabetic wounds: a case series of six patients 
Diabetic Foot & Ankle  2015;6:10.3402/dfa.v6.24999.
Diabetic wounds with additional comorbidities are costly, time intensive, and difficult to heal. Often, multiple modalities may be necessary to achieve wound resolution, relying on the synergistic advantage of each therapy to affect wound healing. The selectivity of Clostridium collagenase is physiologically effective at degrading non-viable collagen fibers while preserving living collagen tissue. Additionally, negative pressure wound therapy (NPWT) has long been used to aid wound healing while concurrently depreciating biological wound burden time.
Six patients were selected from those appearing to our university based limb salvage service. Inclusion criteria included patients with a recurrent mixed fibrotic and granular wound base, in which NPWT was indicated, without exclusion criteria. Patients enrolled were administered clostridial collagenase ointment at each regularly scheduled NPWT dressing change. Patients were followed until healing, with visual representations of wound progression and time to full healing recorded.
Tandem application of these therapies appeared to expedite wound healing by clearing degenerative fibrous tissue and expediting wound granulation without additional complication. Unfortunately, not all patients were able to reach full healing; with two patients experiencing ulcer recurrence, likely a result of their significant comorbid nature.
In our experience, we have noticed a specific subgroup of patients who benefit greatly when collagenase enzymatic debridement therapy is combined with NPWT. It is our belief that this combination therapy combines the molecular clearing of non-viable collagen with the wound granulation necessary to advance complex wounds to the next step in healing despite the current paucity in literature discussing this specific pairing.
PMCID: PMC4309834  PMID: 25630362
diabetes; ulcers; wound healing; negative pressure wound therapy; collagenase
2.  Reduction of pain via platelet-rich plasma in split-thickness skin graft donor sites: a series of matched pairs 
Diabetic Foot & Ankle  2015;6:10.3402/dfa.v6.24972.
In the past decade, autologous platelet-rich plasma (PRP) therapy has seen increasingly widespread integration into medical specialties. PRP application is known to accelerate wound epithelialization rates, and may also reduce postoperative wound site pain. Recently, we observed an increase in patient satisfaction following PRP gel (Angel, Cytomedix, Rockville, MD) application to split-thickness skin graft (STSG) donor sites. We assessed all patients known to our university-based hospital service who underwent multiple STSGs up to the year 2014, with at least one treated with topical PRP. Based on these criteria, five patients aged 48.4±17.6 (80% male) were identified who could serve as their own control, with mean time of 4.4±5.1 years between operations. In both therapies, initial dressing changes occurred on postoperative day (POD) 7, with donor site pain measured by Likert visual pain scale. Paired t-tests compared the size and thickness of harvested skin graft and patient pain level, and STSG thickness and surface area were comparable between control and PRP interventions (p>0.05 for all). Donor site pain was reduced from an average of 7.2 (±2.6) to 3 (±3.7), an average reduction in pain of 4.2 (standard error 1.1, p=0.0098) following PRP use. Based on these results, the authors suggest PRP as a beneficial adjunct for reducing donor site pain following STSG harvest.
PMCID: PMC4306752  PMID: 25623477
skin grafts; platelet-rich plasma; diabetic foot; pain reduction
3.  Frailty and Technology: A Systematic Review of Gait Analysis in Those with Frailty 
Gerontology  2013;60(1):79-89.
New technologies for gait assessment areemerging and have provided new avenues for accurately measuring gait characteristics in home and clinic. However, potential meaningful clinical gait parameters beyond speed have received little attention in frailty research.
To study gait characteristics in different frailty status groups for identifying the most useful parameters and assessment protocols for frailty diagnosis.
We searched PubMed, Embase, PsycINFO, CINAHL, Web of Science, Cochrane Library, and Age Line. Articles were selected according to the following criteria: (1) population: individuals defined as frail, prefrail, or transitioning to frail, and (2) outcome measures: quantitative gait variables as obtained by biomechanical analysis. Effect sizes (d) were calculated for the ability of parameters to discriminate between different frailty status groups.
Eleven publications met inclusion criteria. Frailty definitions, gait protocols and parameters were inconsistent, which made comparison of outcomes difficult. Effect sizes were calculated only for the three studies which compared at least two different frailty status groups. Gait speed shows the highest effect size to discriminate between frailty subgroups, in particular during habitual walking (d = 0.76–6.17). Gait variability also discriminates between different frailty status groups in particular during fast walking. Prominent parameters related to prefrailty are reduced cadence (d = 1.43) and increased step width variability (d = 0.64), whereas frailty (vs. prefrail status) is characterized by reduced step length during habitual walking (d = 1.32) and increased double support during fast walking (d = 0.78). Interestingly, one study suggested that dual-task walking speed can be used to predict prospective frailty development.
Gait characteristics in people with frailty are insufficiently analyzed in the literature and represent a major area for innovation. Despite the paucity of work, current results suggest that parameters beyond speed could be helpful in identifying different categories of frailty. Increased gait variability might reflect a multisystem reduction and may be useful in identifying frailty. In addition, a demanding task such as fast walking or adding a cognitive distractor might enhance the sensitivity and specificity of frailty risk prediction and classification, and is recommended for frailty assessment using gait analysis.
PMCID: PMC4017858  PMID: 23949441
Gait; Technology; Analysis; Assessment; Measurement; Frailty; Older adults
4.  Tissue-specific Leptin promoter DNA methylation is associated with maternal and infant perinatal factors 
Leptin a regulator of body weight is involved in reproductive and developmental functions. Leptin promoter DNA methylation (LEP) regulates gene expression in a tissue-specific manner and has been linked to adverse pregnancy outcomes. In non-pathologic human pregnancies, we assessed LEP methylation, genotyped the single nucleotide polymorphism (SNP) rs2167270 in placental (n=81), maternal and cord blood samples (n=60), and examined the association between methylation, genotype, and perinatal factors. Maternal blood LEP methylation was lower in pre-pregnancy obese women (P=0.01). Cord blood LEP methylation was higher in small for gestational age (SGA) (P=4.6×10−3) and A/A genotype (P=1.6×10−4), lower (−1.47, P=0.03) in infants born to pre-pregnancy obese mothers and correlated (P=0.01) with maternal blood LEP. Gender was associated with placental LEP methylation (P=0.05). These results suggest that LEP epigenetic control may be influenced by perinatal factors including: maternal obesity, infant growth, genotype and gender in a tissue-specific manner and may have multigenerational implications.
PMCID: PMC3795868  PMID: 23911897
leptin; epigenetics; DNA methylation; rs2167270; pregnancy; maternal obesity; small for gestational age
5.  The roles of DNA methylation of NR3C1 and 11β-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior 
Epigenetics  2013;8(12):1321-1329.
Exposure to maternal mood disorder in utero may program infant neurobehavior via DNA methylation of the glucocorticoid receptor (NR3C1) and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2), two placental genes that have been implicated in perturbations of the hypothalamic pituitary adrenocortical (HPA) axis. We tested the relations among prenatal exposure to maternal depression or anxiety, methylation of exon 1F of NR3C1 and 11β-HSD-2, and newborn neurobehavior. Controlling for relevant covariates, infants whose mothers reported depression during pregnancy and showed greater methylation of placental NR3C1 CpG2 had poorer self-regulation, more hypotonia, and more lethargy than infants whose mothers did not report depression. On the other hand, infants whose mothers reported anxiety during pregnancy and showed greater methylation of placental 11β-HSD-2 CpG4 were more hypotonic compared with infants of mothers who did not report anxiety during pregnancy. Our results support the fetal programming hypothesis and suggest that fetal adjustments to cues from the intrauterine environment, in this case an environment that could be characterized by increased exposure to maternal cortisol, may lead to poor neurodevelopmental outcomes.
PMCID: PMC3933492  PMID: 24135662
DNA methylation; maternal depression; maternal anxiety; newborn neurobehavior
6.  Genetic and Epigenetic Variation of the Glucocorticoid Receptor (NR3C1) in Placenta and Infant Neurobehavior 
Developmental psychobiology  2012;55(7):673-683.
The intrauterine environment can impact the developing infant by altering the function of the placenta through changes to the epigenetic regulatory features of this tissue. Genetic variation, too, may impact infant development or may modify the relationship between epigenetic alterations and infant outcomes. To examine the association of this variation with early life infant neurodevelopment, we examined the extent of DNA methylation of the glucocorticoid receptor gene (NR3C1) promoter and a common SNP in the promoter region in a series of 186 placentas from healthy newborn infants. We associated these molecular features with specific summary measures from the NICU Network Neurobehavioral Scales. After controlling for genotype and confounders, we identified significant associations of NR3C1 methylation with infant quality of movement (P=0.05) and with infant attention (P=0.05), and a potential interaction between methylation and genotype on infant attention score. These results suggest that epigenetic alteration of the NR3C1 gene in the placentas of genetically susceptible infants can have impacts on neurodevelopment which may have lifelong impact on neurobehavioral and mental health outcomes. Further research is needed to more precisely define these relationships and the interaction between epigenetic alterations and genetic variations on infant health.
PMCID: PMC3458180  PMID: 22714792
Epigenetic; glucocorticoid receptor; placenta; neurodevelopment; human; attention; quality of movement
7.  Diabetic Peripheral Neuropathy and Gait: Does Footwear Modify This Association? 
Gait-related fall risk is the leading cause of mortality among patients with diabetes, especially those older than 65 years. Deterioration in balance and loss of protective sensation in lower extremities contribute significantly to fall risk in patients with diabetic peripheral neuropathy (DPN). This study aimed to explore the impact of neuropathy and foot ulcer on gait.
We recruited 39 participants (age, 56.9 ± 8.2 years; body mass index, 29.6.3 ± 4.7 kg/m2), including 15 DPN patients without foot ulcers, 16 DPN patients with foot ulcers, and 8 healthy aged-matched controls. Patients with active foot ulcers wore an offloading device during gait examination, including removable cast walker.
Results suggest that neuropathy alters gait mainly by increasing gait initiation, gait variability (coefficient of variation of gait velocity), and double support (DS) time, while reducing knee range of motion and center of mass sway (p < .05). Interestingly, the presence of foot ulcer does not impact gait velocity (p > .1) but enhances some of the gait parameters such as gait variability and DS time.
This study demonstrates that neuropathy deteriorates gait, but the presence of foot ulcers does not alter gait parameters further than neuropathy. In addition, patients with foot ulcers demonstrated a better gait compared with DPN patients without ulcers. We speculate that offloading footwear may be enhancing the somatosensory feedback from sensate skin, thereby positively affecting gait parameters. A study with a larger sample is required to explore the effect of prescribed footwear in the DPN population in order to validate the findings of this research study.
PMCID: PMC3876356  PMID: 24124939
diabetes; foot ulcer; gait; offloading; wearable sensors
8.  Novel Wearable Technology for Assessing Spontaneous Daily Physical Activity and Risk of Falling in Older Adults with Diabetes 
As baby boomers age and their expected life span increases, there is an unprecedented need to better manage the health care of elders with diabetes who are at increased risk of falling due to diabetes complications, frailty, or other conditions. New clinical and research tools are needed to measure functioning accurately and to identify early indicators of risk of falling, thus translating into more effective and earlier intervention.
The objective of this pilot study was to validate a significant change in hardware and algorithm to track activity patterns using a single triaxial accelerometer through validation of timed up and go and standard measures of balance and gait. We recruited a convenience sample of eight older adults with diabetes and peripheral neuropathy (age, 77 ± 7 years old) who were asked to wear the sensor for imposed daytime activity performed in our gait laboratory. Subjects were stratified into risk of falling categories based on Tinetti scores. We examined the accuracy of the suggested technology for discrimination of high- versus low-risk groups.
The system was accurate in identifying the number of steps taken and walking duration (random error <5%). The proposed algorithm allowed accurate identification and stratification of those at highest risk of falling, suggesting that subjects with high risk of falling required a substantially longer duration for rising from a chair when compared with those with low risk of falling (p < .05).
Our new single triaxial accelerometer algorithm successfully tracked postural transition, allowing accurate identification of those at high risk of falling, and could be useful for intermittent or even continuous monitoring of older adults with diabetes. Other potential applications could include activity monitoring of the diabetes population with lower extremity disease and of patients undergoing surgical procedures or as an objective measure during rehabilitation.
J Diabetes Sci Technol 2013;7(5):1147–1160
PMCID: PMC3876357  PMID: 24124940
body-worn sensor; diabetes care; foot ulcer; home telemonitoring; physical activity monitoring; risk of falling; wearable technology
9.  Placental FKBP5 Genetic and Epigenetic Variation Is Associated with Infant Neurobehavioral Outcomes in the RICHS Cohort 
PLoS ONE  2014;9(8):e104913.
Adverse maternal environments can lead to increased fetal exposure to maternal cortisol, which can cause infant neurobehavioral deficits. The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function. FK506 binding protein (FKBP5) is a negative regulator of cortisol response, FKBP5 methylation has been linked to brain morphology and mental disorder risk, and genetic variation of FKBP5 was associated with post-traumatic stress disorder in adults. We hypothesized that placental FKBP5 methylation and genetic variation contribute to gene expression control, and are associated with infant neurodevelopmental outcomes assessed using the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). In 509 infants enrolled in the Rhode Island Child Health Study, placental FKBP5 methylation was measured at intron 7 using quantitative bisulfite pyrosequencing. Placental FKBP5 mRNA was measured in a subset of 61 infants by quantitative PCR, and the SNP rs1360780 was genotyped using a quantitative allelic discrimination assay. Relationships between methylation, expression and NNNS scores were examined using linear models adjusted for confounding variables, then logistic models were created to determine the influence of methylation on membership in high risk groups of infants. FKBP5 methylation was negatively associated with expression (P = 0.08, r = −0.22); infants with the TT genotype had higher expression than individuals with CC and CT genotypes (P = 0.06), and those with CC genotype displayed a negative relationship between methylation and expression (P = 0.06, r = −0.43). Infants in the highest quartile of FKBP5 methylation had increased risk of NNNS high arousal compared to infants in the lowest quartile (OR 2.22, CI 1.07–4.61). TT genotype infants had increased odds of high NNNS stress abstinence (OR 1.98, CI 0.92–4.26). Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta’s ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes.
PMCID: PMC4130612  PMID: 25115650
10.  A Population-Based Investigation into the Self-Reported Reasons for Sleep Problems 
PLoS ONE  2014;9(7):e101368.
Typologies of sleep problems have usually relied on identifying underlying causes or symptom clusters. In this study the value of using the patient's own reasons for sleep disturbance are explored. Using secondary data analysis of a nationally representative psychiatric survey the patterning of the various reasons respondents provided for self-reported sleep problems were examined. Over two thirds (69.3%) of respondents could identify a specific reason for their sleep problem with worry (37.9%) and illness (20.1%) representing the most commonly reported reasons. And while women reported more sleep problems for almost every reason compared with men, the patterning of reasons by age showed marked variability. Sleep problem symptoms such as difficulty getting to sleep or waking early also showed variability by different reasons as did the association with major correlates such as worry, depression, anxiety and poor health. While prevalence surveys of ‘insomnia’ or ‘poor sleep’ often assume the identification of an underlying homogeneous construct there may be grounds for recognising the existence of different sleep problem types particularly in the context of the patient's perceived reason for the problem.
PMCID: PMC4077805  PMID: 24983754
11.  Summary of guidelines for infection prevention and control for flexible gastrointestinal endoscopy 
High-quality processes to ensure infection prevention and control in the delivery of safe endoscopy services are essential. In 2010, the Public Health Agency of Canada and the Canadian Association of Gastroenterology (CAG) developed a Canadian guideline for the reprocessing of flexible gastrointestinal endoscopy equipment.
The CAG Endoscopy Committee carefully reviewed the 2010 guidelines and prepared an executive summary.
Key elements relevant to infection prevention and control for flexible gastrointestinal endoscopy were highlighted for each of the recommendations included in the 2010 document. The 2010 guidelines consist of seven sections, including administrative recommendations, as well as recommendations for endoscopy and endoscopy decontamination equipment, reprocessing endoscopes and accessories, endoscopy unit design, quality management, outbreak investigation and management, and classic and variant Creutzfeldt-Jakob Disease.
The recommendations for infection prevention and control for flexible gastrointestinal endoscopy are intended for all individuals with responsibility for endoscopes in all settings where endoscopy is performed.
PMCID: PMC3684370  PMID: 23781518
Endoscopy; Gastrointestinal; Guideline; Infection; Prevention
12.  Virtualizing the Assessment: A Novel Pragmatic Paradigm to Evaluate Lower Extremity Joint Perception in Diabetes 
Gerontology  2012;58(5):463-471.
Persons with diabetes have a higher risk of falls and fall related injuries. People with diabetes often develop peripheral neuropathy (DPN) as well as nerve damage throughout the body. In particular, reduced lower extremity proprioception due to DPN may cause a misjudgment of foot position and thus increase the risk of fall.
An innovative virtual obstacle crossing (VOC) paradigm using wearable sensors was developed in attempt to assess lower extremity position perception damage due to DPN.
Sixty-seven participants (Age: 55.4±8.9; BMI: 28.1±5.8) including diabetes with and without DPN as well as aged matched healthy controls were recruited. Severity of neuropathy was quantified using vibratory perception threshold (VPT) test. The ability of perception of lower extremity was quantified by measuring obstacle crossing success rate (OCSR), toe-obstacle clearance (TOC), and reaction time (TR) while crossing a series of virtual obstacles with heights at 10% and 20% of the subject’s leg length.
No significant difference was found between groups for age and BMI. The data revealed that DPN subjects had a significantly lower OCSR compared to diabetes with no neuropathy and controls at obstacle size of 10% (p<0.05). DPN subjects also demonstrated longer TR compared to other groups and for both obstacle sizes. In addition TOC was reduced in neuropathy groups. Interestingly, a significant correlation between TR and VPT (r=0.5, p<10-5) was observed indicating delay in reaction by increasing neuropathy severity. The delay becomes more pronounced by increasing the size of obstacle. Using regression model suggests that the change in reaction time between obstacle sizes of 10% and 20% of leg size is the most sensitive predictors for neuropathy severity with an odds ratio of 2.70 (p=0.02).
The findings demonstrate proof of concept of virtual reality application as a promising method for objective assessment of neuropathy severity, however; a further study is warranted to establish a stronger relationship between the measured parameters and neuropathy.
PMCID: PMC3955209  PMID: 22572476
Virtual Reality; Diabetes Peripheral Neuropathy; Lower Extremity Joint Perception; Body Worn Sensors; Fall Prevention; Obstacle crossing
13.  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.
PMCID: PMC3891706  PMID: 23249482
cystic fibrosis; Pseudomonas aeruginosa; OprF; OprH; OprG; KatA; mucosal and systemic antibody; vaccine
14.  The 2012 SAGE wait times program: Survey of Access to GastroEnterology in Canada 
Periodically surveying wait times for specialist health services in Canada captures current data and enables comparisons with previous surveys to identify changes over time.
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.
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).
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
15.  Patient-identified quality indicators for colonoscopy services 
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.
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.
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.
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.
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
16.  A survey of the practice of after-hours and emergency endoscopy in Canada 
To determine staffing and practice patterns for after-hours endoscopy service in Canada
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.
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.
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
17.  Long-Term Prognosis of Diabetic Foot Patients and Their Limbs 
Diabetes Care  2012;35(10):2021-2027.
There is a dearth of long-term data regarding patient and limb survival in patients with diabetic foot ulcers (DFUs). The purpose of our study was therefore to prospectively investigate the limb and person survival of DFU patients during a follow-up period of more than 10 years.
Two hundred forty-seven patients with DFUs and without previous major amputation consecutively presenting to a single diabetes center between June 1998 and December 1999 were included in this study and followed up until May 2011. Mean patient age was 68.8 ± 10.9 years, 58.7% were male, and 55.5% had peripheral arterial disease (PAD). Times to first major amputation and to death were analyzed with Kaplan-Meier curves and Cox multiple regression.
A first major amputation occurred in 38 patients (15.4%) during follow-up. All but one of these patients had evidence of PAD at inclusion in the study, and 51.4% had severe PAD [ankle-brachial pressure index ≤0.4]). Age (hazard ratio [HR] per year, 1.05 [95% CI, 1.01–1.10]), being on dialysis (3.51 [1.02–12.07]), and PAD (35.34 [4.81–259.79]) were significant predictors for first major amputation. Cumulative mortalities at years 1, 3, 5, and 10 were 15.4, 33.1, 45.8, and 70.4%, respectively. Significant predictors for death were age (HR per year, 1.08 [95% CI, 1.06–1.10]), male sex ([1.18–2.32]), chronic renal insufficiency (1.83 [1.25–2.66]), dialysis (6.43 [3.14–13.16]), and PAD (1.44 [1.05–1.98]).
Although long-term limb salvage in this modern series of diabetic foot patients is favorable, long-term survival remains poor, especially among patients with PAD or renal insufficiency.
PMCID: PMC3447849  PMID: 22815299
18.  Patterning in Placental 11-B Hydroxysteroid Dehydrogenase Methylation According to Prenatal Socioeconomic Adversity 
PLoS ONE  2013;8(9):e74691.
Prenatal socioeconomic adversity as an intrauterine exposure is associated with a range of perinatal outcomes although the explanatory mechanisms are not well understood. The development of the fetus can be shaped by the intrauterine environment through alterations in the function of the placenta. In the placenta, the HSD11B2 gene encodes the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol thereby protecting the developing fetus from this exposure. This gene is regulated by DNA methylation, and this methylation and the expression it controls has been shown to be susceptible to a variety of stressors from the maternal environment. The association of prenatal socioeconomic adversity and placental HSD11B2 methylation has not been examined. Following a developmental origins of disease framework, prenatal socioeconomic adversity may alter fetal response to the postnatal environment through functional epigenetic alterations in the placenta. Therefore, we hypothesized that prenatal socioeconomic adversity would be associated with less HSD11B2 methylation.
Methods and Findings
We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 444 healthy term newborn infants and several markers of prenatal socioeconomic adversity: maternal education, poverty, dwelling crowding, tobacco use and cumulative risk. We also examined whether such associations were sex-specific. We found that infants whose mothers experienced the greatest levels of socioeconomic adversity during pregnancy had the lowest extent of placental HSD11B2 methylation, particularly for males. Associations were maintained for maternal education when adjusting for confounders (p<0.05).
Patterns of HSD11B2 methylation suggest that environmental cues transmitted from the mother during gestation may program the developing fetus’s response to an adverse postnatal environment, potentially via less exposure to cortisol during development. Less methylation of placental HSD11B2 may therefore be adaptive and promote the effective management of stress associated with social adversity in a postnatal environment.
PMCID: PMC3764127  PMID: 24040322
19.  Developing a Hetero-Alkali-Metal Chemistry of 2,2,6,6-Tetramethyl-piperidide (TMP): Stoichiometric and Structural Diversity within a Series of Lithium/Sodium, Lithium/Potassium and Sodium/Potassium TMP Compounds 
Studied extensively in solution and in the solid state, Li(TMP) (TMP=2,2,6,6-tetramethylpiperidide) is an important utility reagent popular as a strongly basic, weakly nucleophilic tool for C–H metallation. Recently, there has been a surge in interest in mixed metal derivatives containing the bulky TMP anion. Herein, we start to develop hetero (alkali metal) TMP chemistry by reporting the N,N,N′,N′-tetramethylethylenediamine (TMEDA)-hemisolvated sodium–lithium cycloheterodimer [(tmeda)Na(μ-tmp)2Li], and its TMEDA-free variant [{Na(μ-tmp)Li(μ-tmp)}∞], which provides a rare example of a crystallographically authenticated polymeric alkali metal amide. Experimental observations suggest that the former is a kinetic intermediate en route to the latter thermodynamic product. Furthermore, a third modification, the mixed potassium–lithium-rich cycloheterotrimer [(tmeda)K(μ-tmp)Li(μ-tmp)Li(μ-tmp)], has also been synthesised and crystallographically characterised. On moving to the bulkier tridentate donor N,N,N′,N′′,N′′-pentamethyldiethylenediamine (PMDETA), the additional ligation forces the sodium–lithium and potassium–dilithium ring species to open giving the acyclic arc-shaped complexes [(pmdeta)Na(μ-tmp)Li(tmp)] and [(pmdeta)K(μ-tmp)Li(μ-tmp)Li(tmp)], respectively. Completing the series, the potassium–lithium and potassium–sodium derivatives [(pmdeta)K(μ-tmp)2M] (M=Li, Na) have also been isolated as closed structures with a distinctly asymmetric central MN2K ring. Collectively, these seven new bimetallic compounds display five distinct structural motifs, four of which have never hitherto been witnessed in TMP chemistry and three of which are unprecedented in the vast structural library of alkali metal amide chemistry.
PMCID: PMC3761191  PMID: 21766365
aggregation; alkali metals; amides; heterometallic complexes; X-ray diffraction
20.  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.
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.
To evaluate the safety of endoscopy in a retrospective cohort of post-MI patients at a Canadian tertiary centre.
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.
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.
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
21.  Effectiveness of disseminating consensus management recommendations for ulcer bleeding: a cluster randomized trial 
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.
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.
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%.
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:, no. MCT-88113).
PMCID: PMC3576461  PMID: 23318399
22.  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.
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.
To identify key indicators of safety compromise in gastrointestinal endoscopy.
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.
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.
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
23.  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.
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.
To identify processes and indicators of quality and safety relevant to high-quality endoscopy service delivery.
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.
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.
The consensus process identified a clear need for high-quality clinical and outcomes research to support quality improvement in the delivery of endoscopy services.
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
24.  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.
PMCID: PMC3531428  PMID: 23300844
25.  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.
PMCID: PMC3480312  PMID: 19455131

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