Plasmalemmal vesicle associated protein (Plvap/PV1) is a structural protein required for the formation of the stomatal diaphragms of caveolae. Caveolae are plasma membrane invaginations that were implicated in SV40 virus entry in primate cells. Here we show that de novo Plvap/PV1 expression in CV-1 green monkey epithelial cells significantly reduces the ability of SV40 virus to establish productive infection, when cells are incubated with low concentrations of the virus. However, in presence of high viral titers PV1 has no effect on SV40 virus infectivity. Mechanistically, PV1 expression does not reduce the cell surface expression of known SV40 receptors such as GM1 ganglioside and MHC class I proteins. Furthermore, PV1 does not reduce the binding of virus-like particles made by SV40 VP1 protein to the CV-1 cell surface and does not impact their internalization when cells are incubated with either high or low VLP concentrations. These results suggest that PV1 protein is able to block SV40 infectivity at low but not at high viral concentration either by interfering with the infective internalization pathway at the cell surface or at a post internalization step.
Objective. Asymmetric plantar temperature differences secondary to inflammation is a hallmark for the diagnosis and treatment response of Charcot foot syndrome. However, little attention has been given to temperature response to activity. We examined dynamic changes in plantar temperature (PT) as a function of graduated walking activity to quantify thermal responses during the first 200 steps.
Methods. Fifteen individuals with Acute Charcot neuroarthropathy (CN) and 17 non-CN participants with type 2 diabetes and peripheral neuropathy were recruited. All participants walked for two predefined paths of 50 and 150 steps. A thermal image was acquired at baseline after acclimatization and immediately after each walking trial. The PT response as a function of number of steps was examined using a validated wearable sensor technology. The hot spot temperature was identified by the 95th percentile of measured temperature at each anatomical region (hind/mid/forefoot). Results. During initial activity, the PT was reduced in all participants, but the temperature drop for the nonaffected foot was 1.9 times greater than the affected side in CN group (P = 0.04). Interestingly, the PT in CN was sharply increased after 50 steps for both feet, while no difference was observed in non-CN between 50 and 200 steps. Conclusions. The variability in thermal response to the graduated walking activity between Charcot and non-Charcot feet warrants future investigation to provide further insight into the correlation between thermal response and ulcer/Charcot development. This stress test may be helpful to differentiate CN and its response to treatment earlier in its course.
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).
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.
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.
Antigliadin antibodies; Antitissue transglutaminase; Celiac disease; Diagnosis; Gluten intolerance; Serology
Adventitious bursae typically develop in areas of chronic frictional irritation, usually under bony prominences. Although adventitious bursae are generally well understood, there is a paucity of data on effects of bursae underlying chronic wounds in neuropathic patients. This manuscripts reviews 4 clinical cases, each with a neuropathic patient with adventitious bursae underlying chronic nonhealing wound and strategies for treatment.
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.
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.
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.
‘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.
Point-of-care practice audits allow documentation of procedural outcomes to support quality improvement in endoscopic practice.
To evaluate a colonoscopists’ practice audit tool that provides point-of-care data collection and peer-comparator feedback.
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.
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).
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.
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.
Colonoscopy; Health care; Practice audit; Quality assurance; Quality indicators
Peripheral arterial disease (PAD) is a major risk factor for adverse cardiovascular events. There has been a definite push for wider use of the ankle-brachial index (ABI) as a simple screening tool for PAD. Perhaps this has occurred to the detriment of a thorough physical examination.
To assess the accuracy of the physical examination to detect clinically significant PAD compared with the ABI.
PADfile, the PAD module of CARDIOfile (the Kingston Heart Clinic’s cardiology database [Kingston, Ontario]), was searched for all patients who underwent peripheral arterial testing. Of 1619 patients, 1236 had all of the necessary data entered. Patients’ lower limbs were divided into two groups: those with a normal ABI between 0.91 and 1.30, and those with an abnormal ABI of 0.90 or lower. Peripheral pulses were graded as either absent or present. Absent was graded as 0/3, present but reduced (1/3), normal (2/3) or bounding (3/3). Femoral bruits were graded as either present (1) or absent (0). Using the ABI as the gold standard, the sensitivity, specificity, negative predictive value (NPV), positive predictive value and overall accuracy were calculated for the dorsalis pedis pulse, the posterior tibial pulse, both pedal pulses, the presence or absence of a femoral bruit and, finally, for a combination of both pedal pulses and the presence or absence of a femoral bruit.
In 1236 patients who underwent PAD testing and who underwent a complete peripheral vascular physical examination (all dorsalis pedis and posterior tibial pulses palpated and auscultation for a femoral bruit), the sensitivity, specificity, NPV, positive predictive value and accuracy for PAD were 58.2%, 98.3%, 94.9%, 81.1% and 93.8%, respectively.
The clinical examination of the peripheral arterial foot pulses and the auscultation for a femoral bruit had a high degree of accuracy (93.8%) for the detection or exclusion of PAD compared with the ABI using the cut-off of 0.90 or lower. If both peripheral foot pulses are present in both lower limbs and there are no femoral bruits, the specificity and NPV of 98.3% and 94.9%, respectively, make the measurement of the ABI seem redundant. The emphasis in PAD detection should be redirected toward encouraging a thorough physical examination.
Ankle-brachial index; Peripheral arterial disease; Physical examination
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.
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.
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.
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.
sleep; validation; GHQ-12; JSQ; single-item; multi-item
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.
diabetic foot ulcers; sugar; wound healing
Autologous platelet-rich plasma (PRP) may enhance wound healing through the formation of a platelet plug that provides both hemostasis and the secretion of biologically active proteins, including growth factors such as platelet-derived growth factor, transforming growth factor (TGF)-β, TGF-β2, and epidermal growth factor. The release of these growth factors into the wound may create an environment more conducive to tissue repair and could accelerate postoperative wound healing. To our knowledge, there are no reports of combining the use of PRP with curative diabetic foot surgery. This article provides a summary of the literature regarding PRP and wound healing and presents a case of a 49-year-old man with diabetes and a three-month history of a deep, nonhealing plantar hallux wound in which PRP was combined with a first metatarsophalangeal joint arthroplasty. Through the use of the PRP and bioengineered tissue to supplement curative diabetic foot surgery, the patient healed uneventfully at seven weeks.
diabetic; foot surgery; platelet rich plasma; wound
The cost-effectiveness of initial strategies in managing Canadian patients with uninvestigated upper gastrointestinal symptoms remains controversial.
To assess the cost-effectiveness of six management approaches to uninvestigated upper gastrointestinal symptoms in the Canadian setting.
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.
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.
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.
Antisecretory therapy; Cost-effectiveness; Dyspepsia; Economic modelling; Endoscopy; Helicobacter pylori
Diabetes around the globe results in one major limb amputation every 30 seconds, over 2500 limbs lost per day. The underlying pathophysiology sometimes leads to a chronic inflammatory stage, which may prevent appropriate healing, and therefore, the need for a clear strategy for assessing and classifying wounds and wound healing cannot be overstated. Temperature is a surrogate marker for inflammation. Quantitative thermography using a numerical index provides a useful way to assess wound healing. Advances in technology have afforded the availability of low-cost, high-resolution thermal imaging systems, which can be used to quantify sensitive changes on the skin surface and may be particularly useful to develop monitoring strategies for wounds. This article provides a standardized technique for calculating a thermal index (TI) supported with a case report from assessment of a diabetic foot ulcer. In this single case study, the TI/wound inflammatory index indicates a shift from negative to positive (p < .05) before it reaches zero.
diabetic foot ulcers; thermal index; thermography; thermometry; wound healing
Cutaneous wound measurements are important to track the healing of a wound and direct appropriate therapy. The most commonly used method to calculate wound area is an estimation by multiplying the longest length by the widest width. Other devices can provide an accurate and precise measurement of the true area (TA). This study aim was to compare wound areas calculated by computerized planimetry with standard area estimation by multiplying the longest length by the widest width (l × w).
We reviewed the wound records of 10 patients with circular or oval wounds and estimated the area with the l × w method. We compared this with the TA obtained by a specialized planimetric camera.
Average wound size was 4.3 cm2 by l × w estimation and 3 cm2 by TA calculation. We found the l × w method overestimated wound area an average of 41%.
Standard, manual (l × w) measurement of cutaneous wounds inaccurately overestimates wound area by roughly 40%.
planimetry; Silhouette; ulcer; wound measurement
The standard of care for wound coverage is to use an autologous skin graft. However, large or chronic wounds become an exceptionally challenging problem especially when donor sites are limited. It is important that the clinician be aware of various treatment modalities for wound care and incorporate those methods appropriately in the proper clinical context. This report reviews an alternative to traditional meshed skin grafting for wound coverage: micrografting. The physiological concept of micrografting, along with historical context, and the evolution of the technique are discussed, as well as studies needed for micrograft characterization and future applications of the technique.
diabetic foot ulcers; micrografting; wound healing
Negative pressure wound therapy (NPWT) is frequently employed in the treatment of complex wounds. A variety of wound chemotherapeutic agents such as insulin, which acts as a growth factor, may prove helpful in treatment as well. We present a case report in which insulin was used as a chemotherapeutic agent in continuous-instillation NPWT. To our knowledge, this is the first report in the literature describing this method of delivery.
diabetic foot ulcers; insulin; negative pressure wound therapy; wound chemotherapy
Disruption of the body’s plantar fat pad can occur as a result of one of three mechanisms: simple fat pad atrophy associated with age-related degeneration, steroid use, or collagen vascular disease. Actual or relative displacement in to the underlying osseous prominences may be seen in association with structural deformity of the foot. Disease states such as diabetes may alter the normal structural integrity of soft tissues through nonenzymatic glycation leading to increased stiffness and thus reduced attenuating capacity. Fat pad atrophy, regardless of the cause, is often associated with substantial emotional, physical, productivity, and financial losses. In situations where the patient is sensate, the resultant skin on bone situation is extremely painful, especially when walking.
atrophy; augmentation; pressure; silicone
Objective/Background: Telemedicine has, even in its infancy, had an impact on the provision of healthcare, particularly in rural communities. However, this often relies on an expensive and ponderous infrastructure that reduces the rapid use and spontaneity for consultations. Methods: Using postoperative and intraoperative examples, we describe the use of one rapid and widely available technology (iPhone FaceTime, Cupertino, California). Results: The device, in allowing “one button connection” similar to making a phone call, reduced the need for preplanning that is generally required for real-time telemedicine consultation. Conclusions: The ability to communicate quickly with something that is an afterthought has the potential to alter how we work with our colleagues and patients. Just as with the iPod in music and the laptop in computing, it is not the change in technology, but the change in form factor and ubiquity that alters this landscape.
Amyloid β (Aβ) is thought to promote neuronal cell loss in Alzheimer’s disease (AD), in part through the generation of reactive oxygen species (ROS) and subsequent activation of mitogen-activated protein kinase (MAPK) pathways. Protein phosphatase 5 (PP5) is a ubiquitously expressed serine/threonine phosphatase which has been implicated in several cell stress response pathways and shown to inactivate MAPK pathways through key dephosphorylation events. Therefore we examined whether PP5 protects dissociated embryonic rat cortical neurons in vitro from cell death evoked by Aβ. As predicted, neurons in which PP5 expression was decreased by siRNA treatment were more susceptible to Aβ toxicity. In contrast, overexpression of PP5, but not the inactive PP5 mutant, H304Q, prevented MAPK phosphorylation and neurotoxicity induced by Aβ. PP5 also prevented cell death caused by direct treatment with H2O2, but did not prevent Aβ-induced production of ROS. Thus, the neuroprotective effect of PP5 requires its phosphatase activity and lies downstream of Aβ-induced generation of ROS. In summary, our data indicate that PP5 plays a pivotal neuroprotective role against cell death induced by Aβ and oxidative stress. Consequently, PP5 might be an effective therapeutic target in AD and other neurodegenerative disorders in which oxidative stress is implicated.
PP5; protein phosphatase 5; amyloid β; Alzheimer’s disease; neuroprotection; oxidative stress
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.
A postal survey of all consultant neurologists in the UK registered with the
Association of British Neurologists.
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.
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.
To determine the normal range of estimated right ventricular systolic pressure (RVSP) at peak exercise during exercise stress echocardiography (ExECHO) in a series of consecutive patients referred for the investigation of coronary artery disease.
Of 1057 ExECHO examinations over a span of 11 months, 807 met the study criteria. A total of 250 patients were excluded, 188 for missing rest or peak RVSP measurements, 16 for a resting RVSP above 50 mmHg, 16 for nondiagnostic echocardiographic images and the remaining 30 for missing data. The maximal tricuspid regurgitant jet was recorded at rest and following acquisition of the stress images (mean [± SD] time 103.1±35.2 s). A mean right atrial pressure of 10 mmHg was used in the calculation of RVSP. All data were entered into a cardiology database (CARDIOfile; Registered trademark, Kingston Heart Clinic) for later retrieval and analysis.
There were 206 male (58.9±12.0 years of age) and 601 female patients (57.4±12.0 years of age). Patient age ranged from 18 to 90 years. The mean resting and peak exercise RVSP was 27.8±7.8 mmHg and 34.8±11.3 mmHg in men, and 27.8±7.7 mmHg and 34.6±11.7 mmHg in women, respectively. The mean increase in RVSP was 7.0±8.8 mmHg in men and 6.7±8.9 mmHg in women. The 95% CI for peak RVSP was 12.2 mmHg to 57.4 mmHg in men, and 11.2 mmHg to 58.0 mmHg in women. There was no significant difference in peak RVSP for a normal ExECHO compared with an abnormal ExECHO. RVSP at rest and at peak exercise increased with both age and left atrial size.
In individual patients, the RVSP should not increase above the resting value by more than 24.6 mmHg in men and 24.5 mmHg in women. This value was calculated as the increase in RVSP plus 2×SD of the RVSP. Peak RVSP should not exceed 57.4 mmHg in men and 58.0 mmHg in women. If either of these criteria is exceeded, the response of RVSP to exercise should be considered abnormal.
Coronary artery disease; Right ventricular systolic pressure; Stress echocardiography
Previous studies have shown that in the absence of underlying cardiac pathology, the echocardiographic estimate of right ventricular systolic pressure (RVSP) increases progressively and normally with age. There are limited data in patients older than 60 years of age.
To define the ranges of RVSP according to age and to include more elderly patients than have previously been reported.
All patients undergoing echocardiography since May 26, 1999, at the Kingston Heart Clinic (Kingston, Ontario) have had their data entered into a locally designed cardiology database (CARDIOfile; Registered trademark, Kingston Heart Clinic). RVSP was calculated from the peak tricuspid regurgitant jet velocity (V) using the modified Bernoulli equation (RVSP = 4V2 + RAP), with the mean right atrial pressure (RAP) estimated to be 10 mmHg. Of the 22,628 patients who had undergone echocardiography, 10,905 had RVSP measured. All abnormal echocardiograms were excluded, leaving 1559 echocardiograms for analysis.
Patient age ranged from 15 to 93 years. The mean age was 49 years. RVSP increased significantly only after the age of 50 years. The mean (± SD) RVSP for those younger than 50 years, 50 to 75 years, and older than 75 years of age was 27.3±5.7 mmHg, 30.2±7.6 mmHg and 34.8±8.7 mmHg, respectively (P<0.0001 among all age groups). The normal range (95% CI) of RVSP in those younger than 50 years, 50 to 75 years, and older than 75 years of age was 16 mmHg to 39 mmHg, 15 mmHg to 45 mmHg, and 17 mmHg to 52 mmHg, respectively. Multivariate analysis indicated that age, mitral diastolic early-to-late filling velocity ratio, ejection fraction, aortic size and early mitral filling velocity/early diastolic mitral annular velocity were the only significant independent variables. There were significant changes in diastolic function with increasing age, which may have been responsible for the changes in RVSP.
RVSP remains stable in both men and women until the age of 50 years. Thereafter, RVSP increases progressively in a linear manner with age and is significantly higher in patients older than 75 years of age. The changes may relate to changes in diastolic function. These ranges should be taken into account when using echocardiogram-derived RVSP for the diagnosis of pulmonary hypertension in the absence of cardiovascular disease.
Echocardiography; Pulmonary hypertension
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.
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.
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.
Management of acute coronary syndrome (ACS) patients with non-obstructive epicardial coronary artery disease (CAD) remains poorly understood.
ACS patients with non-obstructive CAD are less likely to receive effective cardiac medications upon discharge from the hospital.
We identified patients hospitalized with ACS that underwent coronary angiography and had 6-month follow-up. Patients were grouped by CAD severity: non-obstructive CAD (<50% blockage in all vessels) or obstructive CAD (≥50% blockage in ≥1 vessels). Data were collected on demographics, medications at discharge, and adverse outcomes at 6 months, for all patients.
Of the 2,264 ACS patients included in the study: 123 patients had non-obstructive CAD and 2,141 had obstructive CAD. Cardiac risk factors including hypertension and diabetes were common among patients with non-obstructive CAD. Men and women with non-obstructive CAD were less likely to receive cardiac medications compared to patients with obstructive CAD including aspirin (87.8% vs. 95.0%, p=0.001), beta-blockers (74.0% vs. 89.2%, p<0.001), or statins (69.1% vs. 81.2%, p=0.001). No gender-related differences in discharge medications were observed for patients with nonobstructive CAD. However women with non-obstructive CAD had similar rates of cardiac-related rehospitalization as men with obstructive CAD (23.3% and 25.9%, respectively).
Patients with non-obstructive CAD are less likely to receive evidence-based medications compared to patients with obstructive CAD, despite the presence of CAD risk factors and occurrence of an ACS event. Further research is warranted to determine if receipt of effective cardiac medications among patients with non-obstructive CAD would reduce cardiac related events.
Non-obstructive coronary artery disease; Acute Coronary Syndrome; Prevention
The behavioural impact of pharmacogenomics is untested; informing smokers of genetic test results for responsiveness to smoking cessation medication may increase adherence to this medication. The objective of this trial is to estimate the impact upon adherence to nicotine replacement therapy (NRT) of informing smokers that their oral dose of NRT has been tailored to a DNA analysis. Hypotheses to be tested are as follows:
I Adherence to NRT is greater among smokers informed that their oral dose of NRT is tailored to an analysis of DNA (genotype), compared to one tailored to nicotine dependence questionnaire score (phenotype).
II Amongst smokers who fail to quit at six months, motivation to make another quit attempt is lower when informed that their oral dose of NRT was tailored to genotype rather than phenotype.
An open label, parallel groups randomised trial in which 630 adult smokers (smoking 10 or more cigarettes daily) using National Health Service (NHS) stop smoking services in primary care are randomly allocated to one of two groups:
i. NRT oral dose tailored by DNA analysis (OPRM1 gene) (genotype), or
ii. NRT oral dose tailored by nicotine dependence questionnaire score (phenotype)
The primary outcome is proportion of prescribed NRT consumed in the first 28 days following an initial quit attempt, with the secondary outcome being motivation to make another quit attempt, amongst smokers not abstinent at six months. Other outcomes include adherence to NRT in the first seven days and biochemically validated smoking abstinence at six months. The primary outcome will be collected on 630 smokers allowing sufficient power to detect a 7.5% difference in mean proportion of NRT consumed using a two-tailed test at the 5% level of significance between groups. The proportion of all NRT consumed in the first four weeks of quitting will be compared between arms using an independent samples t-test and by estimating the 95% confidence interval for observed between-arm difference in mean NRT consumption (Hypothesis I). Motivation to make another quit attempt will be compared between arms in those failing to quit by six months (Hypothesis II).
This is the first clinical trial evaluating the behavioural impact on adherence of prescribing medication using genetic rather than phenotypic information. Specific issues regarding the choice of design for trials of interventions of this kind are discussed.
Funder: Medical Research Council (MRC)
Grant number: G0500274
Date trial stated: June 2007
Expected end date: December 2009
Expected reporting date: December 2010