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1.  Pharmacy study of natural health product adverse reactions (SONAR): a cross-sectional study using active surveillance in community pharmacies to detect adverse events associated with natural health products and assess causality 
BMJ Open  2014;4(3):e003431.
Objectives
To investigate the rates and causality of adverse event(s) (AE) associated with natural health product (NHP) use, prescription drug use and concurrent NHP-drug use through active surveillance in community pharmacies.
Design
Cross-sectional study of screened patients.
Setting
10 community pharmacies across Alberta and British Columbia, Canada from 14 January to 30 July 2011.
Participants
The participating pharmacy staff screened consecutive patients, or agents of patients, who were dropping or picking up prescription medications.
Primary outcome measures
Patients were screened to determine the proportions of them using prescription drugs and/or NHPs, as well as their respective AE rates. All AEs reported by the screened patients who took a NHP, consented to, and were available for, a detailed telephone interview (14%) were adjudicated fully to assess for causality.
Results
Over a total of 105 pharmacy weeks and 1118 patients screened, 410 patients reported taking prescription drugs only (36.7%; 95% CI 33.9% to 39.5%), 37 reported taking NHPs only (3.3%; 95% CI 2.4% to 4.5%) and 657 reported taking prescription drugs and NHPs concurrently (58.8%; 95% CI 55.9% to 61.6%). In total, 54 patients reported an AE, representing 1.2% (95% CI 0.51% to 2.9%), 2.7% (95% CI 0.4% to 16.9%) and 7.3% (95% CI 5.6% to 9.6%) of each population, respectively. Compared with patients who reported using prescription drugs, the patients who reported using prescription drugs and NHPs concurrently were 6.4 times more likely to experience an AE (OR; 95% CI 2.52 to 16.17; p<0.001). Combined with data from Ontario, Canada, a national proportion was calculated, which found that 45.4% (95% CI 43.8% to 47.0%) of Canadians who visit community pharmacies take NHPs and prescription drugs concurrently, and of those, 7.4% (95% CI 6.3% to 8.8%) report an AE.
Conclusions
A substantial proportion of community pharmacy patients use prescription drugs and NHPs concurrently; these patients are at a greater risk of experiencing an AE. Active surveillance provides a means of detecting such AEs and collecting high-quality data on which causality assessment can be based.
doi:10.1136/bmjopen-2013-003431
PMCID: PMC3975764  PMID: 24682573
Complementary Medicine; Toxicology
2.  Within-Individual Hematocrit Variations and Self-Monitoring of Blood Glucose 
Many self-monitoring of blood glucose (SMBG) systems have generated artefactually increased glucose results in low-hematocrit patients (e.g., intensive care unit and renal failure patients); conversely, these devices could produce artefactually decreased glucose results in high-hematocrit patients (e.g., neonates). The introduction of hematocrit-independent SMBG systems permits more accurate testing in anemic or polycythemic individuals. In this issue of Journal of Diabetes Science and Technology, Ramljak and coauthors have created glucose bias graphs for 19 common SMBG devices and declared certain systems to be optimally accurate because of insensitivity to hematocrit variation over a broad hematocrit range. Luckily, the average within-individual variation of hematocrit is low (between 2.9 and 3.3%). As such, a larger spectrum of SMBG devices can be regarded as optimally hematocrit independent.
PMCID: PMC3692233  PMID: 23439177
biologic variation; glucose; hemoglobin; intraindividual variation; self-monitoring of blood glucose; SMBG
3.  Consensus Report: The Current Role of Self-Monitoring of Blood Glucose in Non-Insulin-Treated Type 2 Diabetes 
The Coalition for Clinical Research—Self-Monitoring of Blood Glucose Scientific Board convened a meeting in San Francisco, CA, July 20–21, 2011, to discuss the current practice of self-monitoring of blood glucose (SMBG) in non-insulin-treated (NIT) type 2 diabetes mellitus (T2DM). Twelve physician panel members from academia, practice, and government attended this meeting. These experts came from the United States, Brazil, Canada, France, Germany, Italy, and the United Kingdom. In addition, three consultants from Australia, Germany, and the United States contributed to the group’s final report. This coalition was organized by Diabetes Technology Society. Self-monitoring of blood glucose was studied from eight perspectives related to patients with NIT T2DM: (1) epidemiological studies; (2) randomized controlled trials (RCT)s and meta-analyses; (3) targets, timing, and frequency of SMBG use; (4) incidence and role of SMBG in preventing hypoglycemia with single-drug regimens and combination regimens consisting of antihyperglycemic agents other than secretagogues and insulin; (5) comparison of SMBG with continuous glucose monitoring; (6) technological capabilities and limitations of SMBG; (7) barriers to appropriate use of SMBG; and (8) methods and end points for appropriate future clinical trials. The panel emphasized recent studies, which reflect the current approach for applying this intervention. Among the participants there was consensus that:
SMBG is an established practice for patients with NIT T2DM, and to be most effective, it should be performed in a structured format where information obtained from this measurement is used to guide treatment;New, high-quality efficacy data from RCTs have demonstrated efficacy of SMBG in NIT T2DM in trials reported since 2008;Both patients and health care professionals require education on how to respond to the data for SMBG to be effective; andAdditional well-defined studies are needed to assess the benefits and costs of SMBG with end points not limited to hemoglobin A1c.
PMCID: PMC3262725  PMID: 22226276
hemoglobin A1c; non-insulin treated; self-monitored blood glucose; type 2 diabetes
4.  Study of Natural Health Product Adverse Reactions (SONAR): Active Surveillance of Adverse Events Following Concurrent Natural Health Product and Prescription Drug Use in Community Pharmacies 
PLoS ONE  2012;7(9):e45196.
Background
Many consumers use natural health products (NHPs) concurrently with prescription medications. As NHP-related harms are under-reported through passive surveillance, the safety of concurrent NHP-drug use remains unknown. To conduct active surveillance in participating community pharmacies to identify adverse events related to concurrent NHP-prescription drug use.
Methodology/Principal Findings
Participating pharmacists asked individuals collecting prescription medications about (i) concurrent NHP/drug use in the previous three months and (ii) experiences of adverse events. If an adverse event was identified and if the patient provided written consent, a research pharmacist conducted a guided telephone interview to gather additional information after obtaining additional verbal consent and documenting so within the interview form. Over a total of 112 pharmacy weeks, 2615 patients were screened, of which 1037 (39.7%; 95% CI: 37.8% to 41.5%) reported concurrent NHP and prescription medication use. A total of 77 patients reported a possible AE (2.94%; 95% CI: 2.4% to 3.7%), which represents 7.4% of those using NHPs and prescription medications concurrently (95%CI: 6.0% to 9.2%). Of 15 patients available for an interview, 4 (26.7%: 95% CI: 4.3% to 49.0%) reported an AE that was determined to be “probably” due to NHP use.
Conclusions/Significance
Active surveillance markedly improves identification and reporting of adverse events associated with concurrent NHP-drug use. Although not without challenges, active surveillance is feasible and can generate adverse event data of sufficient quality to allow for meaningful adjudication to assess potential harms.
doi:10.1371/journal.pone.0045196
PMCID: PMC3461007  PMID: 23028841
5.  Preanalytic and Analytic Accuracy: Toward More Realistic and Meaningful Self-Monitoring of Blood Glucose Submissions for Regulatory Approval 
Dr. Cembrowski provides an analysis of an article by Harrison and colleagues in this issue of Journal of Diabetes Science and Technology in which the authors describe the evaluation of a new device for self-monitoring of blood glucose, the Bayer CONTOUR® blood glucose monitoring system.
PMCID: PMC3192610  PMID: 21880246
accuracy; blood glucose; evaluations; hyperglycemia; hypoglycemia; regulatory approval
6.  Design and implementation of the canadian kidney disease cohort study (CKDCS): A prospective observational study of incident hemodialysis patients 
BMC Nephrology  2011;12:10.
Background
Many nephrology observational studies use renal registries, which have well known limitations. The Canadian Kidney Disease Cohort Study (CKDCS) is a large prospective observational study of patients commencing hemodialysis in five Canadian centers. This study focuses on delineating potentially reversible determinants of adverse outcomes that occur in patients receiving dialysis for end-stage renal disease (ESRD).
Methods/Design
The CKDCS collects information on risk factors and outcomes, and stores specimens (blood, dialysate, hair and fingernails) at baseline and in long-term follow-up. Such specimens will permit measurements of biochemical markers, proteomic and genetic parameters (proteins and DNA) not measured in routine care. To avoid selection bias, all consenting incident hemodialysis patients at participating centers are enrolled, the large sample size (target of 1500 patients), large number of exposures, and high event rates will permit the exploration of multiple potential research questions.
Preliminary Results
Data on the baseline characteristics from the first 1074 subjects showed that the average age of patients was 62 (range; 50-73) years. The leading cause of ESRD was diabetic nephropathy (41.9%), and the majority of the patients were white (80.0%). Only 18.7% of the subjects received dialysis in a satellite unit, and over 80% lived within a 50 km radius of the nearest nephrologist's practice.
Discussion
The prospective design, detailed clinical information, and stored biological specimens provide a wealth of information with potential to greatly enhance our understanding of risk factors for adverse outcomes in dialysis patients. The scientific value of the stored patient tissue will grow as new genetic and biochemical markers are discovered in the future.
doi:10.1186/1471-2369-12-10
PMCID: PMC3050805  PMID: 21324196
7.  A Review of Standards and Statistics Used to Describe Blood Glucose Monitor Performance 
Glucose performance is reviewed in the context of total error, which includes error from all sources, not just analytical. Many standards require less than 100% of results to be within specific tolerance limits. Analytical error represents the difference between tested glucose and reference method glucose. Medical errors include analytical errors whose magnitude is great enough to likely result in patient harm. The 95% requirements of International Organization for Standardization 15197 and others make little sense, as up to 5% of results can be medically unacceptable. The current American Diabetes Association standard lacks a specification for user error. Error grids can meaningfully specify allowable glucose error. Infrequently, glucose meters do not provide a glucose result; such an occurrence can be devastating when associated with a life-threatening event. Nonreporting failures are ignored by standards. Estimates of analytical error can be classified into the four following categories: imprecision, random patient interferences, protocol-independent bias, and protocol-dependent bias. Methods to estimate total error are parametric, nonparametric, modeling, or direct. The Westgard method underestimates total error by failing to account for random patient interferences. Lawton's method is a more complete model. Bland–Altman, mountain plots, and error grids are direct methods and are easier to use as they do not require modeling. Three types of protocols can be used to estimate glucose errors: method comparison, special studies and risk management, and monitoring performance of meters in the field. Current standards for glucose meter performance are inadequate. The level of performance required in regulatory standards should be based on clinical needs but can only deal with currently achievable performance. Clinical standards state what is needed, whether it can be achieved or not. Rational regulatory decisions about glucose monitors should be based on robust statistical analyses of performance.
PMCID: PMC2825627  PMID: 20167170
error grid; glucose specification; ISO 15197; mountain plot; total error
8.  Increases in Whole Blood Glucose Measurements Using Optically Based Self-Monitoring of Blood Glucose Analyzers Due to Extreme Canadian Winters 
Background
Temperature and humidity have been reported to influence the results of whole blood glucose (WBG) measurements.
Methods
To determine whether patient WBG values were affected by seasonal variation, we conducted a retrospective analysis of 3 years' worth of weekly averages of patient WBG in five Edmonton hospitals.
Results
In all five hospitals, the winter WBG averages were consistently higher than the summer WBG averages, with the differences varying between 5% and 9%. Whole blood glucose averages were negatively correlated with the outside temperature. This seasonal variation was not observed in weekly patient averages of specimens run in a central hospital laboratory.
Interpretation
It is probable that the seasonal variation of WBG arises from the very low indoor humidities that are associated with external subzero temperatures. These increases in WBG in cold weather may be due to limitations in the WBG measuring systems when operated in decreased humidities and/or increased evaporation of the blood sample during the blood glucose measurement process. The implications of this seasonal variation are significant in that it (1) introduces increased variability in patient WBG, (2) may result in increased glucose-lowering therapy during periods of external cold and low indoor humidity, and (3) confounds evaluations of WBG meter technology in geographic regions of subzero temperature and low indoor humidity. To mitigate the risk of diagnosing and treating factitious hyperglycemia, the humidity of patient care areas must be strictly controlled.
PMCID: PMC2769945  PMID: 20144309
diabetes; environmental effects; humidity; whole blood glucose monitoring
9.  Seasonal Variation in Hemoglobin A1c: Is It the Same in Both Hemispheres? 
Introduction
There are several reports from locations in the northern hemisphere of seasonal variation in hemoglobin A1c (HbA1c) levels with higher values noted in the cooler months. The variation has been attributed to holiday seasons, temperature differences, and changes in diet. This article describes the seasonal variation in both hemispheres and in a country on the equator with minimal temperature variation.
Methods
The mean and median HbA1c by month was calculated for a maximum of 2 years for HbA1c data from the different locations: Edmonton and Calgary, Canada; Singapore; Melbourne, Australia; and Marshfield, Wisconsin. The mean monthly temperature for each location was found from available meteorological information.
Results
In both northern and southern hemispheres, the HbA1c was higher in cooler months and lower in the warmer months. In Singapore, where there is minimal temperature variation, there is also minimal variation in HbA1c values over the year. The difference in HbA1c over a year appears to be related to the difference in temperature.
Conclusion
Hemoglobin A1c is higher in cooler months and lower in the warmer months in both hemispheres. In a country with minimal monthly temperature variation, there is only minimal variation in HbA1c values through the year. In all locations, the mean and median HbA1c declined over the study period, possibly due to better glycemic control of patients with diabetes or an increase in use of HbA1c as a screening test for diabetes or a combination of both.
PMCID: PMC2769947  PMID: 20144310
hemoglobin A1c; seasonal; variation
10.  Influence of Variables on Hemoglobin A1c Values and Nonheterogeneity of Hemoglobin A1c Reference Ranges 
Introduction
Hemoglobin A1c (HbA1c) values are influenced by analytical interferences such as HbF and hemoglobin variants and clinical factors such as increased red cell turnover. Although less well-known, demographic factors such as race, age, and sex also influence HbA1c values.
The HbA1c reference range should be homogenous in the United States based on the use of National Glycohemoglobin Standardization Program certified methods and the recommendations in the National Academy of Clinical Biochemistry guidelines.
Methods
Data on age, race, sex, HbA1c, and glucose values were extracted from the National Health and Nutrition Examination study for a 3 year period. A search for reference range data for laboratories in the United States was performed using the Google search engine.
Results
Extracted data agree with published data on the influence of age, sex, and smoking status on HbA1c values. There is substantial heterogeneity in HbA1c reference ranges in laboratories in the United States.
Conclusion
Age, sex, and smoking status influence HbA1c values. Despite standardization of HbA1c methods and published recommendations, there is wide heterogeneity in HbA1c reference ranges in the United States.
PMCID: PMC2769978  PMID: 20144306
age; HbA1c; race; reference range; smoking status; variables
11.  Use of Serial Patient Hemoglobin A1c Differences to Determine Long-Term Imprecision of Immunoassay and High-Performance Liquid Chromatography Analyzers 
Background
The quality of the HbA1c assay is inversely proportional to the variation of the assay. Most published measures of HbA1c variation are limited by the data collection period, the statistical treatment of outliers, and even the noncommutability of the products used to generate the variation measurements. We have used an alternate approach to derive HbA1c variation, using serial patient data.
Methods
HbA1c measurements of outpatient blood sample pairs drawn within 30 days of each other were made on three different immunoassay systems: the Roche INTEGRA® 700, the Roche INTEGRA® 400, and the Dade Dimension® RxL; and two high-performance liquid chromatography assays: the Tosoh G7 and the Tosoh 2.2+. The standard deviation of duplicates was calculated for the following time intervals: 1 to 3 days, 4 to 6 days, 7 to 9 days,…, 28 to 30 days. These intra-individual variations were then plotted; extrapolation to time zero yields the long term total random error which consists of both analytic and pre-analytic error. Data collection periods were usually 2 years.
Results
At the mean HbA1cs of 7.08%, 7.14%, 7.20%, 6.96%, and 7.51% for populations tested on the Roche INTEGRA 700, Roche INTEGRA 400, Dade Dimension RxL, Tosoh 2.2+, and Tosoh G7, respectively, the total analytic imprecisions (coefficient of variation) were 2.56%, 2.29%, 2.25%, 1.66%, and 1.14%, respectively.
Conclusion
Assessment of the HbA1c long term total imprecisions shows that while the three immunoassay systems are acceptable, the Tosoh HbA1c analyzers demonstrate superior analytic performance.
PMCID: PMC2769869  PMID: 20144278
hemoglobin A1c; long-term analytic variation
12.  Variation in the Frequency of Hemoglobin A1c (HbA1c) Testing: Population Studies Used to Assess Compliance with Clinical Practice Guidelines and Use of HbA1c to Screen for Diabetes 
Background
The volume of hemoglobin A1c (HbA1c) testing has increased dramatically over the past decade and few studies have attempted to determine how the test is used. The goals of this study were to evaluate the frequency of HbA1c testing in regional populations to assess the extent of screening for diabetes and to determine if the HbA1c testing intervals of known diabetic patients were consistent with clinical practice guidelines.
Methods
Two years of HbA1c results were extracted from laboratory information systems in four regions of the province of Alberta that represent urban, mixed urban–rural, and rural populations. HbA1c testing frequencies and the proportions of nondiabetic patients undergoing HbA1c tests were derived.
Results
Approximately 60% of HbA1c tests in each region were done on patients who had only a single test during the 2-year interval. Testing of nondiabetic patients accounted for 24% of HbA1c tests and varied by region. While the cumulative frequency distributions of HbA1c test intervals resembled each other, detailed analyses of the frequency distributions depicted broad multimodal peaks and regional variations that suggest a great deal of heterogeneity among practices. The most common HbA1c testing interval was 3 months ± 3 weeks in each region and is consistent with the 3-month test interval target in a clinical practice guideline.
Conclusions
HbA1c testing is being performed on a substantial proportion of nondiabetic patients. On average, patients with diabetes in Alberta receive 1.5 HbA1c tests per year. However, we observed regional differences in the frequency of testing and variation in compliance with clinical practice guidelines.
PMCID: PMC2769871  PMID: 20144276
diabetes mellitus–blood; diabetes mellitus–diagnosis; glycated hemoglobins; screening; utilization
13.  Falsely elevated point-of-care lactate measurement after ingestion of ethylene glycol 
Background
A patient presented with severe acidosis and a point-of-care lactate measurement of 42 mmol/L. Mesenteric ischemia was suspected, with a potential need for laparotomy; however, plasma lactate measurements were below 4 mmol/L. Ethylene glycol ingestion was subsequently diagnosed. We therefore wished to determine why discrepancies in lactate measurements occur and whether this “lactate gap” could be clinically useful.
Methods
We phlebotomized blood, added various concentrations of metabolites of ethylene glycol, and tested the resulting samples with the 5 most common lactate analyzers.
Results
With the Radiometer 700 point-of-care analyzer, glycolate addition resulted in an artifactual, massive lactate elevation, even at low glycolate concentrations. Another major ethylene glycol metabolite, glyoxylate (but not oxalate or formate), caused similar elevations. The i-STAT and Bayer point-of-care analyzers and the Beckman and Vitros laboratory analyzers reported minimal lactate elevations. Lactate gap was determined by comparing the Radiometer result with the corresponding result from any of the other analyzers.
Interpretation
We demonstrated how inappropriate laparotomy or delayed therapy might occur if clinicians are unaware of this phenomenon or have access to only a single analyzer. We also showed that lactate gap can be exploited to expedite treatment, diagnose late ethylene-glycol ingestion and terminate dialysis. By comparing lactate results from the iSTAT or Bayer devices with that from the Radiometer, ethylene-glycol ingestion can be diagnosed at the point of care. This can expedite diagnosis and treatment by hours, compared with waiting for laboratory results for plasma ethylene glycol.
doi:10.1503/cmaj.061288
PMCID: PMC1839775  PMID: 17420492

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