Transformation of Sequential Hospital and Outpatient Laboratory Data into Between-Day Reference Change Values.

BACKGROUND: Serial differences between intrapatient consecutive measurements can be transformed into Taylor series of variation vs time with the intersection at time = 0 (y0) equal to the total variation (analytical + biological + preanalytical). With small preanalytical variation, y0, expressed as a percentage of the mean, is equal to the variable component of the reference change value (RCV) calculation: (CVA2 + CVI2)1/2. METHODS: We determined the between-day RCV of patient data for 17 analytes and compared them to healthy participants' RCVs. We analyzed 653 consecutive days of Dartmouth-Hitchcock Roche Modular general chemistry data (4.2 million results: 60% inpatient, 40% outpatient). The serial patient values of 17 analytes were transformed into 95% 2-sided RCV (RCVAlternate), and 3 sets of RCVhealthy were calculated from 3 Roche Modular analyzers' quality control summaries and CVI derived from biological variation (BV) studies using healthy participants. RESULTS: The RCVAlternate values are similar to RCVhealthy derived from known components of variation. For sodium, chloride, bicarbonate calcium, magnesium, phosphate, alanine aminotransferase, albumin, and total protein, the RCVs are equivalent. As expected, increased variation was found for glucose, aspartate aminotransferase, creatinine, and potassium. Direct bilirubin and urea demonstrated lower variation. CONCLUSIONS: Our RCVAlternate values integrate known and unknown components of analytic, biologic, and preanalytic variation, and depict the variations observed by clinical teams that make medical decisions based on the test values. The RCVAlternate values are similar to the RCVhealthy values derived from known components of variation and suggest further studies to better understand the results being generated on actual patients tested in typical laboratory environments.

Cord-Blood Derived Chemistry Reference Values in Preterm Infants for Sodium, Chloride, Potassium, Glucose, and Creatinine.

OBJECTIVES: International guidelines recommend that preterm infants should be supported to maintain their serum electrolytes within "normal" ranges. In term babies, cord blood values differed in pathological pregnancies from healthy ones. STUDY DESIGN: We examined cord blood sodium, chloride, potassium, glucose, and creatinine to derive maturity-related reference intervals. We examined associations with gestational age, delivery mode, singleton versus multiple, and prenatal maternal adverse conditions. We compared preterm cord values to term, and to adult reference ranges. RESULTS: There were 591 infants, 537 preterm and 54 term. Preterm cord glucose levels were steady (3.7 ± 1.1 mmol/L), while sodium, chloride, and creatinine increased over GA by 0.17, 0.14 mmol/L/week, and 1.07 µmol/L/week, respectively (p < 0.003). Average preterm cord potassium and chloride were higher than the term (p < 0.05). Compared with adult reference intervals, cord preterm reference intervals were higher for chloride (100-111 vs. 98-106 mmol/L), lower for creatinine (29-84 vs. 62-115 µmol/L), and more variable for potassium (2.7-7.9 vs. 3.5-5.0 mmol/L) and sodium (130-141 vs. 136-145 mmol/L). Cesarean section was associated with higher potassium and lower glucose, multiple births with higher chloride and creatinine and lower glucose, and SGA with lower glucose. CONCLUSIONS: Cord blood values varied across the GA range with increases in sodium, chloride, and creatinine, while glucose remained steady. Average preterm reference values were higher than term values for potassium and chloride. Preterm reference values differed from published adults' reference values. The changes across GA and by delivery mode, SGA, and being a multiple, which may have direct implications for neonatal care and fluid management. KEY POINTS: · Cord blood electrolyte, creatinine, and glucose values vary across neonatal gestational age.. · Average preterm cord values of potassium and chloride were higher than term values.. · Cord reference values differ by delivery mode, growth, and multiple impacting neonatal care decisions..

High-Sensitivity Cardiac Troponin-Optimizing the Diagnosis of Acute Myocardial Infarction/Injury in Women (CODE-MI): Rationale and design for a multicenter, stepped-wedge, cluster-randomized trial.

Despite evidence that high-sensitivity cardiac troponin (hs-cTn) levels in women are lower than in men, a single threshold based on the 99th percentile upper reference limit of the overall reference population is commonly used to diagnose myocardial infarction in clinical practice. This trial aims to determine whether the use of a lower female-specific hs-cTn threshold would improve the diagnosis, treatment, and outcomes of women presenting to the emergency department with symptoms suggestive of myocardial ischemia. METHODS/DESIGN: CODE-MI (hs-cTn-Optimizing the Diagnosis of Acute Myocardial Infarction/Injury in Women) is a multicenter, stepped-wedge, cluster-randomized trial of 30 secondary and tertiary care hospitals across 8 Canadian provinces, with the unit of randomization being the hospital. All adults (≥20 years of age) presenting to the emergency department with symptoms suggestive of myocardial ischemia and at least 1 hs-cTn test are eligible for inclusion. Over five, 5-month intervals, hospitals will be randomized to implement lower female hs-cTn thresholds according to the assay being used at each site. Men will continue to be assessed using the overall thresholds throughout. Women with a peak hs-cTn value between the female-specific and the overall thresholds will form our primary cohort. The primary outcome, a 1-year composite of all-cause mortality or readmission for nonfatal myocardial infarction, incident heart failure, or emergent/urgent coronary revascularization, will be compared before and after the implementation of female thresholds using mixed-effects logistic regression models. The cohort and outcomes will be obtained from routinely collected administrative data. The trial is designed to detect a 20% relative risk difference in the primary outcome, or a 2.2% absolute difference, with 82% power. CONCLUSIONS: This pragmatic trial will assess whether adopting lower female hs-cTn thresholds leads to appropriate assessment of women with symptoms suggestive of myocardial infarction, thereby improving treatment and outcomes.

Hypophosphatemia is Prevalent among Preterm Infants Less than 1,500 Grams.

OBJECTIVE: This article identifies the prevalence and associated factors of hypophosphatemia (HP) in very low birth weight (VLBW) infants in the first week of life. STUDY DESIGN: Prospective exploratory cohort study of 106 consecutive VLBW infants admitted to neonatal intensive care at Foothills Hospital, Calgary, Canada. HP was defined as at least one measurement of serum phosphate < 1.5 mmol/L (4.5 mg/dL). RESULTS: Seventy-seven percent (82/106) of the VLBW infants had HP, with significantly higher prevalence in infants < 1,000 g (94%) compared to infants ≥ 1,000 g (61%) (p < 0.001). Hypophosphatemic infants had lower birth weight (p < 0.001), gestational age (p < 0.001), and their increase in phosphate intake was slower (p = 0.003). Respiratory distress syndrome (RDS) (p = 0.002), intraventricular hemorrhage (IVH) ≥ grade III (p = 0.020), and hyperglycemia (p = 0.013) were more frequent among hypophosphatemic infants, especially among those < 1,000 g. Mortality, seizures, arrhythmias, and need for transfusion were not different between groups. Birth weight modified the association between RDS, IVH, hyperglycemia, and HP. CONCLUSION: HP was ubiquitous among infants < 1,000 g and highly prevalent among those weighing 1,000 to 1,500 g. While the direction of effect was not clear, RDS, IVH, and hyperglycemia were associated with HP. Prevention of HP in these physiologically immature neonates might improve neonatal outcomes.

The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study.

BACKGROUND: Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctance to recommend Cannabis extracts given the lack of high quality safety data especially regarding the potential for harm caused by other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC). The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life. METHODS: Twenty-eight children with treatment resistant epileptic encephalopathy ranging in age from 1 to 10 years will be recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal extract on the frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between dose escalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state trough levels of bioactive cannabinoids. (iv) To determine the relation between dose escalation and incidence of adverse effects. DISCUSSION: This paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids. TRIAL REGISTRATION: http://clinicaltrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited 2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827.

Simulation Models of Misclassification Error for Single Thresholds of High-Sensitivity Cardiac Troponin I Due to Assay Bias and Imprecision.

BACKGROUND: Clinical outcome studies for cardiac troponins (cTn) are expensive and difficult to design owing to variation in patients, in the assays, and in the incidence of different types of myocardial infarction (MI). To overcome these difficulties, simulation models were used to estimate the rate of misclassification error for MI and risk prediction resulting from assay bias and imprecision. METHODS: Finite mixture analysis of Abbott high-sensitivity cTnI (hs-cTnI) results at time 0 h in patients presenting early with acute coronary syndrome (ACS) symptoms to the emergency department (ED) [n = 145, Reducing the Time Interval for Identifying New Guideline (RING) study] allowed derivation of a simulation data set (n = 10000). hs-cTnI concentrations were modified by addition of bias or imprecision error. The percentage of all 10000 modified hs-cTnI results that were misclassified for MI at thresholds of 2, 5, 26.2, and 52 ng/L was determined by Monte Carlo simulation. Analyses were replicated with an all-comer emergency department (ED) population (n = 1137) ROMI (Optimum Troponin Cutoffs for ACS in the ED) study. RESULTS: In the RING study, simulation at 26.2-ng/L (99th percentile) and 52-ng/L thresholds were affected by both bias ±2 ng/L and imprecision (10%-20%) and had misclassification rates of 0.4% to 0.6%. Simulations at the 2-ng/L and 5-ng/L thresholds were only affected by bias. Misclassification rates at bias of ±1 ng/L were 10% for the 2-ng/L threshold, and 5% for the 5-ng/L threshold. CONCLUSIONS: Simulation models predicted that hs-cTnI results are seldom misclassified (<1% of patients) when interpretative thresholds are near or exceed the overall 99th percentile. However, simulation models also predicted that low hs-cTnI results, as recommended in guidelines, are prone to misclassification of 5%-10% of patients.

Imprecision of high-sensitivity cardiac troponin assays at the female 99th-percentile.

BACKGROUND: An analytical benchmark for high-sensitivity cardiac troponin (hs-cTn) assays is to achieve a coefficient of variation (CV) of ≤ 10.0 % at the 99th percentile upper reference limit (URL) used for the diagnosis of myocardial infarction. Few prospective multicenter studies have evaluated assay imprecision and none have determined precision at the female URL which is lower than the male URL for all cardiac troponin assays. METHODS: Human serum and plasma matrix samples were constructed to yield hs-cTn concentrations near the female URLs for the Abbott, Beckman, Roche, and Siemens hs-cTn assays. These materials were sent (on dry ice) to 35 Canadian hospital laboratories (n = 64 instruments evaluated) participating in a larger clinical trial, with instructions for storage, handling, and monthly testing over one year. The mean concentration, standard deviation, and CV for each instrument type and an overall pooled CV for each manufacturer were calculated. RESULTS: The CVs for all individual instruments and overall were ≤ 10.0 % for two manufacturers (Abbott CVpooled = 6.3 % and Beckman CVpooled = 7.0 %). One of four Siemens Atellica instruments yielded a CV > 10.0 % (CVpooled = 7.7 %), whereas 15 of 41 Roche instruments yielded CVs > 10.0 % at the female URL of 9 ng/L used worldwide (6 cobas e411, 1 cobas e601, 4 cobas e602, and 4 cobas e801) (CVpooled = 11.7 %). Four Roche instruments also yielded CVs > 10.0 % near the female URL of 14 ng/L used in the United States (CVpooled = 8.5 %). CONCLUSIONS: The number of instruments achieving a CV ≤ 10.0 % at the female 99th-percentile URL varies by manufacturer and by instrument. Monitoring assay precision at the female URL is necessary for some assays to ensure optimal use of this threshold in clinical practice.

Impact of observed versus hypothesized service utilization on the incremental cost of first trimester screening and prenatal diagnosis for trisomy 21 in a Canadian province.

OBJECTIVE: The aim of this research was to determine the impact of observed versus hypothesized service utilization on the cost of first trimester screening (FTS) and prenatal diagnosis for trisomy 21 in a Canadian province. METHODS: A population-based pregnancy cohort was created by linking 12 clinical and administrative databases. Care trajectories were derived to examine utilization patterns for FTS, prenatal diagnosis, and pregnancy termination. A literature review was conducted to determine what utilization parameters were used in economic evaluations of FTS. Local cost data was applied to observed and hypothesized care trajectories. RESULTS: The observed mean cost per fetus with trisomy 21 detected prenatally using FTS was $129,606.04 compared with $27,021.45 for women who did not access FTS. Observed utilization of FTS and prenatal diagnosis among screen positive women and termination of pregnancy following prenatal diagnosis of trisomy 21 were substantially lower than hypothesized in existing cost effectiveness studies. Cost estimates were sensitive to hypothetical changes in utilization of prenatal screening, prenatal diagnosis, and pregnancy termination. CONCLUSION: Literature-based estimates of the cost-effectiveness of prenatal screening may not accurately represent current local practice due to potentially unrealistic assumptions about what proportion of women will proceed to invasive testing and ultimately terminate an affected pregnancy.

The All Our Babies pregnancy cohort: design, methods, and participant characteristics.

BACKGROUND: The prospective cohort study design is ideal for examining diseases of public health importance, as its inherent temporal nature renders it advantageous for studying early life influences on health outcomes and research questions of aetiological significance. This paper will describe the development and characteristics of the All Our Babies (AOB) study, a prospective pregnancy cohort in Calgary, Alberta, Canada designed to examine determinants of maternal, infant, and child outcomes and identify barriers and facilitators in health care utilization. METHODS: Women were recruited from health care offices, communities, and through Calgary Laboratory Services before 25 weeks gestation from May 2008 to December 2010. Participants completed two questionnaires during pregnancy, a third at 4 months postpartum, and are currently being followed-up with questionnaires at 12, 24, and 36 months. Data was collected on pregnancy history, demographics, lifestyle, health care utilization, physical and mental health, parenting, and child developmental outcomes and milestones. In addition, biological/serological and genetic markers can be extracted from collected maternal and cord blood samples. RESULTS: A total of 4011 pregnant women were eligible for recruitment into the AOB study. Of this, 3388 women completed at least one survey. The majority of participants were less than 35 years of age, Caucasian, Canadian born, married or in a common-law relationship, well-educated, and reported household incomes above the Calgary median. Women who discontinued after the first survey (n=123) were typically younger, non-Caucasian, foreign-born, had lower education and household income levels, were less likely to be married or in a common-law relationship, and had poor psychosocial health in early pregnancy. In general, AOB participants reflect the pregnant and parenting population at local and provincial levels, and perinatal indicators from the study are comparable to perinatal surveillance data. CONCLUSIONS: The extensive and rich data collected in the AOB cohort provides the opportunity to answer complex questions about the relationships between biology, early experiences, and developmental outcomes. This cohort will contribute to the understanding of the biologic mechanisms and social/environmental pathways underlying associations between early and later life outcomes, gene-environment interactions, and developmental trajectories among children.

Assessing the impact of the SOGC recommendations to increase access to prenatal screening on overall use of health resources in pregnancy.

OBJECTIVES: The recommendation by the Society of Obstetricians and Gynaecologists of Canada that prenatal screening for fetal aneuploidy be offered to all pregnant women is an important change in clinical obstetrics. However, it is unknown how this recommendation might affect the use of other health resources during pregnancy. METHODS: Twelve clinical and administrative databases were linked, and care paths outlining typical service use in pregnancy were created based on the type of prenatal screening accessed (first trimester screening [FTS], maternal serum screening [MSS], invasive testing only, or no screening and/or diagnosis). Logistic, Poisson, and negative binomial models were applied to the data to examine the association between use of prenatal screening/diagnosis and other health services during pregnancy. RESULTS: Women who accessed prenatal screening/diagnosis were significantly more likely to have a consultation with a medical geneticist (FTS OR 2.42; 95% CI 1.75 to 3.33; MSS OR 4.84; 95% CI 2.92 to 8.03; and invasive testing OR 8.58; 95% CI 5.28 to 13.94), and women who accessed FTS had more prenatal visits (FTS incidence rate ratio 1.03; 95% CI 1.01 to 1.05) than women who did not access prenatal screening/diagnosis. Uptake of invasive tests did not differ between women who accessed FTS and those who accessed MSS. Use of prenatal screening/diagnosis was not significantly associated with use of most other health resources CONCLUSION: In a publicly funded health care system, understanding the impact of recommendations to increase access to a specific service on other services is important. Recommendations to increase access to prenatal screening services may have some unanticipated downstream effects on the use of other services during pregnancy. However, most aspects of health resource use in pregnancy do not appear to be influenced by the use of prenatal screening services.

Objectifs : La recommandation de la Société des obstétriciens et gynécologues du Canada voulant que le dépistage prénatal de l'aneuploïdie fœtale soit offert à toutes les femmes enceintes constitue un changement important dans le domaine de l'obstétrique clinique. Toutefois, nous ne savons pas comment cette recommandation pourrait affecter l'utilisation d'autres ressources de santé au cours de la grossesse. Méthodes : Douze bases de données cliniques et administratives ont été liées, et des cheminements cliniques décrivant l'utilisation typique de services pendant la grossesse ont été créés en fonction du type de dépistage prénatal utilisé (dépistage au cours du premier trimestre [DPT], dépistage sérique maternel [DSM], dépistage effractif seulement ou aucun dépistage et/ou diagnostic). Des modèles logistique, de Poisson et binomial négatif ont été appliqués aux données pour examiner l'association entre l'utilisation du dépistage / diagnostic prénatal et celle d'autres services de santé pendant la grossesse. Résultats : Les femmes qui ont eu recours au dépistage / diagnostic prénatal étaient considérablement plus susceptibles de consulter un généticien médical (DPT, RC, 2,42; IC à 95 %, 1,75 - 3,33; DSM, RC, 4,84; IC à 95 %, 2,92 - 8,03; et dépistage effractif, RC, 8,58; IC à 95 %, 5,28 - 13,94); de plus, les femmes qui ont eu recours au DPT comptaient plus de consultations prénatales (DPT, ratio des taux d'incidence, 1,03; IC à 95 %, 1,01 - 1,05) que les femmes qui n'ont pas eu recours au dépistage / diagnostic prénatal. La mesure dans laquelle les tests effractifs ont été utilisés ne présentait pas de différence chez les femmes qui ont eu recours au DPT et chez celles qui ont eu recours au DSM. L'utilisation du dépistage / diagnostic prénatal n'a pas été associée de façon significative à l'utilisation de la plupart des autres ressources de santé. Conclusion : Dans le cadre d'un système de santé bénéficiant d'un financement public, il est important de comprendre les effets qu'exercent, sur d'autres services, les recommandations voulant augmenter l'accès à un service particulier. Les recommandations voulant augmenter l'accès aux services de dépistage prénatal pourraient exercer des effets en aval non prévus sur l'utilisation d'autres services pendant la grossesse. Toutefois, la plupart des aspects de l'utilisation des ressources de santé pendant la grossesse ne semblent pas être influencés par l'utilisation des services de dépistage prénatal.

Pharmacokinetic analysis of topical tobramycin in equine tears by automated immunoassay.

BACKGROUND: Ophthalmic antibiotic therapy in large animals is often used empirically because of the lack of pharmacokinetics studies. The purpose of the study was to determine the pharmacokinetics of topical tobramycin 0.3% ophthalmic solution in the tears of normal horses using an automated immunoassay analysis. RESULTS: The mean tobramycin concentrations in the tears at 5, 10, 15, 30 minutes and 1, 2, 4, 6 hours after administration were 759 (±414), 489 (±237), 346 (±227), 147 (±264), 27.6 (±28.4), 14.8 (±66.6), 6.7 (±18.6), and 23.4 (±73.4) mg/L. Mean tobramycin concentration was maintained above the MIC90 for commonly isolated bacteria for 68.5 min. CONCLUSION: A single dose of topical tobramycin resulted in therapeutic concentrations of tobramycin in the tears for 1 h after administration. Therapeutic levels of tobramycin remained in equine tears 6 times longer than was reported in rabbit tears.

Basophil activation test compared to skin prick test and fluorescence enzyme immunoassay for aeroallergen-specific Immunoglobulin-E.

BACKGROUND: Skin prick test (SPT) and fluorescence enzyme immunoassay (FEIA) are widely used for the diagnosis of Immunoglobulin-E (IgE)-mediated allergic disease. Basophil activation test (BAT) could obviate disadvantages of SPT and FEIA. However, it is not known whether BAT gives similar results as SPT or FEIA for aeroallergens. OBJECTIVES: In this study, we compared the results of SPT, BAT and FEIA for different aeroallergens. METHODS: We performed BAT, SPT and FEIA in 41 atopic subjects (symptomatic and with positive SPT for at least 1 of 9 common aeroallergens) and 31 non-atopic subjects (asymptomatic and with negative SPT). RESULTS: Correlations between SPT and BAT, SPT and FEIA, and BAT and FEIA results were statistically significant but imperfect. Using SPT as the "gold standard", BAT and FEIA were similar in sensitivity. However, BAT had lower specificity than FEIA. False positive (BATposSPTneg) results were frequent in those atopic subjects who were allergic by SPT to a different allergen and rare in non-atopic subjects. The false positivity in atopic subjects was due in part to high levels of serum Total-IgE (T-IgE) levels in atopic individuals that lead to basophil activation upon staining with fluorochrome-labeled anti-IgE. CONCLUSION: As an alternative to SPT in persons allergic to aeroallergens, BAT in its present form is useful for distinguishing atopic from non-atopic persons. However, BAT in its present form is less specific than FEIA when determining the allergen which a patient is allergic to. This is due to IgE staining-induced activation of atopic person's basophils and/or nonspecific hyperreactivity of atopic person's basophils.

N-Acetylcysteine Interference with a Glucose Dehydrogenase Linked Glucose Meter.

BACKGROUND: Our objective was to determine the effect of therapeutic concentrations of N-acetylcysteine, following intravenous infusion, on the measurement of blood glucose using a Roche Diagnostics glucose dehydrogenase-linked glucose meter compared to hospital laboratory methods. METHODS: N-acetylcysteine was added to aliquots of blood, with glucose promptly measured by the glucose meter, blood gas analyzer (glucose oxidase comparative method) and following centrifugation, plasma glucose measured with a hexokinase spectrophotometric comparative method. Glucose results were evaluated with linear regression and Bland Altman plots. RESULTS: In the presence of NAC, at concentrations greater than 5 mg/dL (0.31 mmol/L), positively biased glucose meter results were compared to the clinical laboratory results. Multivariate linear regression revealed that NAC-mediated meter results are influenced by NAC and glucose concentrations. CONCLUSIONS: The addition of therapeutic concentrations of NAC to blood produces statistically significant positive biases when measured with the glucose dehydrogenase linked glucose meter device.

Maternal and child biomonitoring strategies and levels of exposure in western Canada during the past seventeen years: The Alberta Biomonitoring Program: 2005-2021.

The Alberta Biomonitoring Program (ABP) was created in 2005 with the initial goal of establishing baseline levels of exposure to environmental chemicals in specific populations in the province of Alberta, Canada, and was later expanded to include multiple phases. The first two phases focused on evaluating exposure in pregnant women (Phase One, 2005) and children (Phase Two, 2004-2006) by analyzing residual serum specimens. Phase Three (2013-2016) employed active recruitment techniques to evaluate environmental exposures using a revised list of chemicals in paired serum pools from pregnant women and umbilical cord blood. These three phases of the program monitored a total of 226 chemicals in 285 pooled serum samples representing 31,529 individuals. Phase Four (2017-2020) of the ABP has taken a more targeted approach, focusing on the impact of the federal legalization of cannabis on the exposure of pregnant women in Alberta to cannabis, as well as tobacco and alcohol using residual prenatal screening serum specimens. Chemicals monitored in the first three phases include herbicides, neutral pesticides, metals, metalloids, and micronutrients, methylmercury, organochlorine pesticides, organophosphate pesticides, parabens, phthalate metabolites, perfluoroalkyl substances (PFAS), phenols, phytoestrogens, polybrominated compounds, polychlorinated biphenyls (PCBs), dioxins and furans, polycyclic aromatic hydrocarbons (PAHs), and tobacco biomarkers. Phase Four monitored six biomarkers of tobacco, alcohol, and cannabis. All serum samples were pooled. Mean concentrations and 95% confidence intervals (CIs) were calculated for the chemicals detected in ≥25% of the sample pools. cross the first three phases, the data from the ABP has provided baseline exposure levels for the chemicals in pregnant women, children, and newborns across the province. Comparison within and among the phases has highlighted differences in exposure levels with age, geography, seasonality, sample type, and time. The strategies employed throughout the program phases have been demonstrated to provide effective models for population biomonitoring.

Investigating interferences of a whole-blood point-of-care creatinine analyzer: comparison to plasma enzymatic and definitive creatinine methods in an acute-care setting.

BACKGROUND: Although measurement of whole-blood creatinine at the point of care offers rapid assessment of renal function, agreement of point-of-care (POC) results with central laboratory methods continues to be a concern. We assessed the influence of several potential interferents on POC whole-blood creatinine measurements. METHODS: We compared POC creatinine (Nova StatSensor) measurements with plasma enzymatic (Roche Modular) and isotope dilution mass spectrometry (IDMS) assays in 119 hospital inpatients. We assessed assay interference by hematocrit, pH, pO(2), total and direct bilirubin, creatine, prescribed drugs, diagnosis, red blood cell water fraction, and plasma water fraction. RESULTS: CVs for POC creatinine were 1.5- to 6-fold greater than those for plasma methods, in part due to meter-to-meter variation. Regressioncomparison of POC creatinine to IDMS results gave a standard error (S(y|x)) of 0.61 mg/dL (54 µmol/L), whereas regression of plasma enzymatic creatinine to IDMS was S(y|x) 0.16 mg/dL (14 µmol/L). By univariate analysis, bilirubin, creatine, drugs, pO(2), pH,plasma water fraction, and hematocrit were not found to contribute to method differences. However, multivariate analysis revealed that IDMS creatinine, red blood cell and plasma water fractions, and hematocrit explained 91.8% of variance in POC creatinine results. CONCLUSIONS: These data suggest that whole-blood POC creatinine measurements should be used with caution. Negative interferences observed with these measurements could erroneously suggest adequate renal function near the decision threshold, particularly if estimated glomerular filtration rate is determined. Disparity between whole-blood and plasma matrices partially explains the discordance between whole-blood and plasma creatinine methods.

Milk and acid-base balance: proposed hypothesis versus scientific evidence.

Recently the lay press has claimed a hypothetical association among dairy product consumption, generation of dietary acid, and harm to human health. This theoretical association is based on the idea that the protein and phosphate in milk and dairy products make them acid-producing foods, which cause our bodies to become acidified, promoting diseases of modern civilization. Some authors have suggested that dairy products are not helpful and perhaps detrimental to bone health because higher osteoporotic fracture incidence is observed in countries with higher dairy product consumption. However, scientific evidence does not support any of these claims. Milk and dairy products neither produce acid upon metabolism nor cause metabolic acidosis, and systemic pH is not influenced by diet. Observations of higher dairy product intake in countries with prevalent osteoporosis do not hold when urban environments are compared, likely due to physical labor in rural locations. Milk and other dairy products continue to be a good source of dietary protein and other nutrients. Key teaching points: Measurement of an acidic pH urine does not reflect metabolic acidosis or an adverse health condition. The modern diet, and dairy product consumption, does not make the body acidic. Alkaline diets alter urine pH but do not change systemic pH. Net acid excretion is not an important influence of calcium metabolism. Milk is not acid producing. Dietary phosphate does not have a negative impact on calcium metabolism, which is contrary to the acid-ash hypothesis.

Causal assessment of dietary acid load and bone disease: a systematic review & meta-analysis applying Hill's epidemiologic criteria for causality.

BACKGROUND: Modern diets have been suggested to increase systemic acid load and net acid excretion. In response, alkaline diets and products are marketed to avoid or counteract this acid, help the body regulate its pH to prevent and cure disease. The objective of this systematic review was to evaluate causal relationships between dietary acid load and osteoporosis using Hill's criteria. METHODS: Systematic review and meta-analysis. We systematically searched published literature for randomized intervention trials, prospective cohort studies, and meta-analyses of the acid-ash or acid-base diet hypothesis with bone-related outcomes, in which the diet acid load was altered, or an alkaline diet or alkaline salts were provided, to healthy human adults. Cellular mechanism studies were also systematically examined. RESULTS: Fifty-five of 238 studies met the inclusion criteria: 22 randomized interventions, 2 meta-analyses, and 11 prospective observational studies of bone health outcomes including: urine calcium excretion, calcium balance or retention, changes of bone mineral density, or fractures, among healthy adults in which acid and/or alkaline intakes were manipulated or observed through foods or supplements; and 19 in vitro cell studies which examined the hypothesized mechanism. Urine calcium excretion rates were consistent with osteoporosis development; however calcium balance studies did not demonstrate loss of whole body calcium with higher net acid excretion. Several weaknesses regarding the acid-ash hypothesis were uncovered: No intervention studies provided direct evidence of osteoporosis progression (fragility fractures, or bone strength as measured using biopsy). The supporting prospective cohort studies were not controlled regarding important osteoporosis risk factors including: weight loss during follow-up, family history of osteoporosis, baseline bone mineral density, and estrogen status. No study revealed a biologic mechanism functioning at physiological pH. Finally, randomized studies did not provide evidence for an adverse role of phosphate, milk, and grain foods in osteoporosis. CONCLUSIONS: A causal association between dietary acid load and osteoporotic bone disease is not supported by evidence and there is no evidence that an alkaline diet is protective of bone health.

Cord blood calcium, phosphate, magnesium, and alkaline phosphatase gestational age-specific reference intervals for preterm infants.

BACKGROUND: The objective was to determine the influence of gestational age, maternal, and neonatal variables on reference intervals for cord blood bone minerals (calcium, phosphate, magnesium) and related laboratory tests (alkaline phosphatase, and albumin-adjusted calcium), and to develop gestational age specific reference intervals based on infants without influential pathological conditions. METHODS: Cross-sectional study. 702 babies were identified as candidates for this study in a regional referral neonatal unit. After exclusions (for anomalies, asphyxia, maternal magnesium sulfate administration, and death), relationships were examined between cord blood serum laboratory analytes (calcium, phosphate, magnesium, alkaline phosphatase, and albumin-adjusted calcium) with gestation age and also with maternal and neonatal variables using multiple linear regression. Infants with influential pathological conditions were omitted from the development of gestational age specific reference intervals for the following categories: 23-27, 28-31, 32-34, 35-36 and > 36 weeks. RESULTS: Among the 506 preterm and 54 terms infants included in the sample. Phosphate, magnesium, and alkaline phosphatase in cord blood serum decreased with gestational age, calcium increased with gestational age. Those who were triplets, small for gestational age, and those whose mother had pregnancy-induced hypertension were influential for most of the analytes. The reference ranges for the preterm infants ≥ 36 weeks were: phosphate 1.5 to 2.6 mmol/L (4.5 to 8.0 mg/dL), calcium: 2.1 to 3.1 mmol/L (8.3 to 12.4 mg/dL); albumin-adjusted calcium: 2.3 to 3.2 mmol/L (9.1 to 12.9 mg/dL); magnesium 0.6 to 1.0 mmol/L (1.4 to 2.3 mg/dL), and alkaline phosphatase 60 to 301 units/L. CONCLUSIONS: These data suggest that gestational age, as well as potentially pathogenic maternal and neonatal variables should be considered in the development of reference intervals for preterm infants.