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Iron deficiency is highly prevalent worldwide and is an issue of health inequity. Despite its high prevalence, uncertainty on the clinical applicability and evidence-base of iron-related lab test cut-offs remains. In particular, current ferritin decision limits for the diagnosis of iron deficiency may not be clinically appropriate nor scientifically grounded.A modified Delphi study was conducted with various clinical experts who manage iron deficiency across Canada. Statements about ferritin decision limits were generated by a steering committee, then distributed to the expert panel to vote on agreement with the aim of achieving consensus and acquiring feedback on the presented statements. Consensus was reached after two rounds, which was defined as 70% of experts rating their agreement for a statement as 5 or higher on a Likert scale from 1 to 7.Twenty-six clinical experts across 10 different specialties took part in the study. Consensus was achieved on 28 ferritin decision limit statements in various populations (including patients with multiple comorbid conditions, pediatric patients, and pregnant patients). For example, there was consensus that a ferritin30 μg/L rules in iron deficiency in all adult patients (age ≥ 18 years) and warrants iron replacement therapy.Consensus statements generated through this study corresponded with current evidence-based literature and guidelines. These statements provide clarity to facilitate clinical decisions around the appropriate detection and management of iron deficiency.

Background Thyroid-stimulating hormone receptor (TSHR)-activating autoantibodies stimulate thyroid growth and hormone synthesis/secretion, causing hyperthyroidism of Graves’ disease (GD). TRAb measurement helps diagnose GD and is an important first test in evaluating hyperthyroidism according to the recent American Thyroid Association guidelines. We compared the performance of the BRAHMS TRAK Kryptor (Thermo Scientific) and Roche cobas TRAb immunoassays for use in GD. Method Method comparison (n = 40) and clinical agreement were assessed between the Kryptor, cobas e411, and cobas e601. The analytical performance of Kryptor and cobas e411 were assessed for within- and between-day imprecision across 20 days, linearity, functional assay sensitivity (FAS), dilution recovery, and cut-off verification. Results The Kryptor, e411, and e601 TRAb immunoassays correlated well (r > 0.95, overall percent agreement = 0.95, Cohen’s kappa = 0.90). With a total allowable error of 20%, percent bias was within 13%, which was minimally negative at 20 IU/L. The Kryptor, but not e411, was linear across the claimed analytical measuring range (AMR). The claimed functional assay sensitivity (FAS), which was close to the clinical GD cut-off 1.8 IU/L, was verified for Kryptor and e411. Conclusion Overall, our evaluation demonstrates acceptable comparability between TRAb immunoassays with in-house imprecision up to 13% and 10% on Kryptor and e411, respectively. While Roche has preferable calibration frequency and on-board reagent stability, both platforms demonstrate acceptable imprecision using patient samples at their claimed FAS, which is important for GD diagnosis. Diluted results (using a negative patient pool as diluent) exhibits proportional positive bias on the Kryptor relative to the Roche methods.

Ferritin is a key diagnostic marker of iron deficiency (ID), but the interpretative guidance provided to physicians varies significantly. Clear discrepancies exist between clinical guidelines that recommend evidence-based ferritin cutoffs and clinical laboratories that report highly variable ferritin reference intervals (RIs) derived from apparently healthy populations. In this study, clinical laboratories across North America were surveyed to assess the RIs provided with ferritin results. Although clinical guidelines often recommend ferritin cutoffs of 15 or 30 µg/L to identify uncomplicated ID, the survey showed that 18 of 23 responding laboratories reported female RI lower limits well below 15 µg/L. To understand the clinical impact, we analyzed 52 027 unique patient ferritin values over a 5-year period (2013–2017) from a tertiary care hospital. In this population, the 90th percentile ferritin cutoff to identify ID anemia in adults was 24 µg/L in female patients and 25 µg/L in male patients. Distribution of ferritin results in female patients showed that menopausal status had a significant effect on median values, which increased 2- to 3-fold in the postmenopausal state. Furthermore, sorting the data for female patients by physician specialty showed the highest prevalence of low ferritin values in patients seen in obstetrics and gynecology. This study highlights the discrepancy between clinical guidelines and clinical laboratory practice for ferritin reporting and indicates that ferritin RIs, particularly for female patients, are set to an inappropriately low threshold in most clinical laboratories in North America; this level provides good specificity but poor sensitivity when screening for ID.

Background The increasing incidence of fatal opioid overdose is a public health crisis in Canada. Given growing consensus that this crisis is related to the presence of highly potent opioid adulterants (e.g., fentanyl) in the unregulated drug supply, drug checking services (DCS) have emerged as part of a comprehensive approach to overdose prevention. In Canada’s largest city, Toronto, a network of DCS launched in 2019 to prevent overdose and overdose-related risk behaviors. This network employs mass spectrometry technologies, with intake sites co-located with supervised consumption services (SCS) at three frontline harm reduction agencies. The protocol and rationale for assessing the impact of this multi-site DCS network in Toronto is described herein. The aims of this study are to (1) evaluate the impact of DCS access on changes in and factors influencing overdose and related risk behaviors, (2) investigate the perceived capacity of DCS to prevent overdose, and (3) identify composition (qualitative and quantitative) trends in Toronto’s unregulated drug supply. Methods We will use a parallel-mixed-methods design with complementary data sources (including data from chemical analysis of drug samples, quantitative intake and post-test surveys, SCS, coroners, paramedic services, and qualitative interviews), followed by a meta-inference process wherein results from analyses are synthesized. Results Whereas most DCS globally target “recreational drug users,” in Toronto, this networked DCS will primarily target marginalized people who use drugs accessing frontline services, many of whom use drugs regularly and by injection. This evolution in the application of DCS poses important questions that have not yet been explored, including optimal service delivery models and technologies, as well as unique barriers for this population. Increasing information on the unregulated drug supply may modify the risk environment for this population of people who use drugs. Conclusions This study addresses evidence gaps on the emerging continuum of overdose prevention responses and will generate critical evidence on a novel approach to reducing the ongoing high incidence of drug-related morbidity and mortality in Canada and elsewhere.

Background Guideline recommendations for the management of lipids in patients at risk for cardiovascular disease is largely based on low-density lipoprotein cholesterol (LDL-C) concentration. LDL-C is commonly calculated by the Friedewald equation, which has many limitations. The National Institutes of Health (NIH) equation better estimates LDL-C, particularly in patients with hypertriglyceridemia and/or low LDL-C. We validated the NIH LDL-C equation at the first Canadian clinical laboratory to implement this equation. Methods A total of 3161 lipid ultracentrifugation results from a specialized lipid cohort of 2836 patients were included. LDL-C was calculated using the NIH and Friedewald equations and compared to LDL-C measured by ultracentrifugation. We determined the accuracy of these equations at treatment thresholds and developed NIH equation restriction criteria to ensure only accurate results are reported. Results Ultracentrifugation LDL-C more strongly correlated with NIH-calculated LDL-C (r2 = 0.889) than Friedewald-calculated LDL-C (r2 = 0.807) and resulted in fewer non-sensical negative LDL-C values. The correlation for NIH-calculated LDL-C improved to r2 = 0.975 after applying our restriction criteria. The NIH equation showed equivalent or superior concordance with ultracentrifugation at treatment thresholds. The LDL-C mean absolute difference increased with increasing TG and decreasing LDL-C concentrations, although the NIH equation was more robust under both conditions. Conclusions We validated the NIH equation against ultracentrifugation in a cohort with a wide lipid concentration range, which supported its superiority over the Friedewald equation. We recommend clinical implementing the NIH equation for all patients except those with type III hyperlipoproteinemia or TG > 9.04 mmol/L, with an LDL-C lower reporting limit of

Overutilization of tests and treatments is a widespread problem in contemporary heath care, and laboratory medicine is no exception. It is estimated that 10-70% of laboratory tests may be unnecessary, with estimates in the literature varying depending on the situation and the laboratory test. Inappropriate use of laboratory tests can lead to further unnecessary testing, adverse events, inaccurate diagnoses, and inappropriate treatments. Altogether, this increases the risk of harm to a patient, which can be physical, psychological, or financial in nature. Overutilization in healthcare is driven by complex factors including care delivery models, litigious practice environments, and medical and patient culture. Quality improvement (QI) methods can help to tackle overutilization. In this review, we outline the global healthcare problem of laboratory overutilization, particularly in the developed world, and describe how an understanding of and application of quality improvement principles can help to address this challenge.

Introduction Novel psychoactive substances (NPS) are increasingly being consumed worldwide, with synthetic cannabinoids and synthetic opioids being the second and third most commonly used NPS, respectively. Certain synthetic cannabinoids can produce significant harms, particularly when used with opioids. The objective of this study was to characterise the presence of synthetic cannabinoids in the unregulated drug supply in three Canadian settings METHODS: In the British Columbia setting, all samples were first analysed at point-of-care using combination Fourier-transform infrared (FTIR) spectroscopy and fentanyl immunoassay strips prior to confirmatory testing using quantitative nuclear magnetic resonance spectroscopy, gas chromatography/mass spectrometry (GC/MS) and/or liquid chromatography/mass spectrometry (LC/MS). In the Toronto, Ontario setting, the samples were analysed directly by GC/MS, LC/MS liquid chromatography-high resolution/mass spectrometry. Results Between January 2018 and December 2019, 38 (2.8%) synthetic cannabinoid samples were detected in the unregulated drug supply (25/909 in British Columbia and 13/440 in Ontario). In British Columbia and Ontario, 76% and 85% of samples, respectively, were expected by individuals to be an opioid. Synthetic cannabinoids detected included AMB-FUBINACA, AB-FUBINACA, 5-fluoro-MDMB-PINACA, and 5-fluoro-MDMB-PICA, and largely co-occurred with fentanyl. In the British Columbia context, Fourier-transform infrared spectroscopy failed to detect synthetic cannabinoid compounds in almost half (48%) of the samples at point-of-care. Discussion and conclusions As point-of-care technologies failed to detect these compounds in many occasions, our findings demonstrate the importance of laboratory confirmatory analysis to identify NPS. Given the high risk of harm associated with the consumption of synthetic cannabinoids, further research should investigate the reasons for adulteration.

Objectives Free thyroid hormones (fT4 and fT3) are one of the most commonly ordered laboratory tests and often ordered when not clinically meaningful. Based on this, many studies have sought to identify strategies to reduce inappropriate fT4 and fT3 testing. The goal of the current study was to implement a quality improvement (QI) framework to identify an optimal approach to reducing inappropriate free thyroid hormone testing through multiple change ideas and Plan-Do-Study-Act (PDSA) cycles. The aim was to reduce fT4 and fT3 30% from baseline at a large tertiary hospital within 12 months. Methods The Model for Improvement Framework was used to implement a total of 3 change ideas in the first and second PDSA cycles. Change ideas included implementation and refinement of a free thyroid hormone forced function reflex system, modifications to test requisitions/order-entry interfaces, and a TSH-only option. Process and balancing measures were evaluated to fine-tune the change interventions. Data was continuously monitored pre and post interventions to assess progress, impact and potential errors. Results In the first PDSA cycle, laboratory testing of fT4 was decreased by 24% and fT3 by 18%. Soliciting physician feedback and assessing balancing measures was important in refining the approach. In the second PDSA cycle, fT4 was decreased by an additional 16% and fT3 by 29%. An audit of the process showed that phone calls to the laboratory to add-on free thyroid hormones did not increase after the second PDSA, averaging 2 calls per month. Conclusions To achieve optimal reductions in free thyroid hormone testing, multiple PDSA cycles were required alongside assessing process and balancing measures. Overall, fT4 and fT3 testing was decreased by 39% and 47%, respectively.

Purpose We evaluated the feasibility and impact of PCT-guided antibiotic duration combined with an established antibiotic stewardship program (ASP) in a community hospital intensive care unit (ICU). Methods We implemented daily PCT levels for ICU patients receiving antibiotics. Our protocol recommended stopping antibiotic therapy if PCT met an absolute or relative stopping threshold. We evaluated the adherence to stopping criteria within 48 h, antibiotic use [days of therapy (DOT) per 1000 patient-days (PD)], length of stay and ICU-mortality. We performed interrupted time series analysis to compare 24 months before and 12 months after implementation. Results A total of 297 antibiotic courses were monitored with PCT in 217 patients. Protocol adherence was 34% (absolute threshold: 39%, relative threshold: 12%). Antibiotic use pre-PCT was 935 DOTs/1000 PDs and post-PCT was 817 DOTs/1000 PDs (RRadj 0.73, 95% CI: 0.62 to 0.86). No statistically significant changes in clinical outcomes were noted. Conclusion In the context of an established ASP in a community hospital ICU, PCT monitoring was feasible and associated with an adjusted overall decrease of 27% in antibiotic use with no adverse impact on clinical outcomes. Incorporating PCT testing to guide antibiotic duration can be successful if integrated into workflow and paired with ASP guidance.

Introduction: Essential nutrients such as iron and B12 have been established as vital components required for hematopoiesis. Patients are at risk of significant comorbidity when these are deficient, including hematologic manifestations and neurological deficits. B12 supplementation is relatively easy to use with no direct adverse effects. Current guidelines use a singular serum cobalamin level < 150 pmol that is static in nature and not adjusted based on patients' underlying age, comorbidities or medications. Many studies have shown symptoms related to deficiency can appear prior to reaching current biochemical definition of deficiency . Methylmalonic acid can be used to detect B12 deficiency earlier, with a sensitivity of approximately 95% however it's utility is limited due to lack of confidence in interpreting it's results and lack of availability . Also, little guidance is provided to clinicians in choosing a method and duration of supplementation in guidelines. Objective : The primary objective of this study was to establish an expert based consensus recommendations for the diagnosis of B12 deficiency using different biochemical tests while accounting for various comorbidities in diverse patient populations. The secondary objective was to provide recommendations around appropriate and cost-effective B12 supplementation when indicated. Methods : A detailed literature review was used to generate evidence based statements around diagnostic thresholds for B12 deficiency in various populations as well as guidelines to determine current target doses. A modified Delphi approach was used to evaluate the statements amongst 28 experts in various specialities, including biochemistry, general internal medicine, hematology, nephrology, gastroenterology, geriatrics, obstetrics/gynaecology and paediatrics. Two online survey cycles were performed. Only statements reaching consensus (score >7 by more than 70 % of the experts and a Cronbach's alpha statistic > 0.80) were included in the final iteration . Statements with a score of 5 or greater by Results: After the first cycle consensus was reached for 20 out of 21 of the statements (Table 1). Based on feedback 1 statement was split and one new statement was added. Only one statement, which was around the use of methylmalonic acid as an adjunct to diagnose B12 deficiency, did not meet consensus after the second cycle. A total of 22 statements achieved the pre-determined cut-off for consensus at the end of round two. An opt out rate of 28- 72 % was observed in statements made regarding the obstetric and paediatrics' population compared to less than 25 percent in all other statements. Discussion: This guideline provides a summary of B12 diagnostic and treatment threshold for various population that is both supported by existing literature and expert opinion. The high rate of consensus in our first round appears to be due to comfort around prescribing and overall safety of B12 supplementation. Statements made around methods of supplementation and duration were widely accepted. Most clinicians agreed that oral replacement was sufficient for patients unless there was evidence of neurological symptoms or previous gastric surgery . This is important given recent literature indicating the high cost Ontario faces due to inappropriate intramuscular B12 prescribing . A high opt out rate was noted in statements predominately geared towards the paediatric and obstetrical patient population which may be due to discomfort around prescribing in specific populations by general clinicians. Using a modified Delphi methodology, we were able to obtain consensus around adjusted diagnostics thresholds for identifying B12 deficiency in patients with varying comorbidities and metabolic demands. We devised guidance around treatment modalities and timelines to decrease the risk of supplementations faced by patients and potentially the health care system. We hope that these statements can be used as a framework for clinicians in all specialities to provide individualized, evidence based care. Disclosures Sholzberg: Amgen: Honoraria, Other: Scientific Advisory Board, Research Funding; Octapharma: Honoraria, Other: Scientific Advisory Board, Research Funding; Novartis: Honoraria, Other: Scientific Advisory Board; Takeda: Honoraria, Other: Scientific Advisory Board, Research Funding; NovoNordisk: Honoraria, Other: Scientific Advisory Board.

Revision of laboratory test requisitions is a simple utilisation strategy that can reduce unnecessary testing.1 2 The goal of this study was to improve test utilisation via a collaborative team-based evaluation and revision of a standardised lab requisition used by six large family medicine units. ### Revising the family requisition form A historical laboratory requisition used by the Family Medicine Department at Unity Health, St. Michael’s Hospital site, Unity Health Toronto, Toronto, Canada, was reviewed and modified by a steering committee comprised of family medicine clinicians (physicians and a nurse practitioner), lab medicine specialists and a quality improvement specialist. Decisions were made by consensus, and input was sought from the entire Department of Family Medicine via departmental rounds before changes were finalised. Laboratory tests were removed from the requisition if there was evidence in the literature of overuse (eg, Aspartate Aminotransferase (AST), folate, urea, Erythrocyte Sedimentation Rate (ESR),3 4 if they were outdated (eg, amylase, Creatine Kinase (CK)),3 or if there was consensus that they were infrequently needed in a family practice (eg, rheumatoid factor, direct bilirubin). The requisition was also revised to improve readability, and education was imbedded regarding some special tests such as urine toxicology screening and coagulation testing (changes in online supplemental table 1). Tests that were removed from the requisition remained orderable with longhand. ### Supplementary data [bmjoq-2020-001219supp001.pdf] ### Data analyses The primary outcome was the monthly volume of targeted tests ordered by the family medicine clinic 6 months pre- and 6 months post-requisition changes (September …

Alzheimer disease (AD) is a devastating neurodegenerative disorder characterized by a progressive decline in cognitive function. In 2010, an estimated 36 million people worldwide had AD or a related dementia, with this number projected to double by 2030. The social and economic burden of AD is well documented and will be amplified by this increase in prevalence. The initial pathophysiologic changes of AD are found in the hippocampus region of the brain, disrupting memory and the ability to learn. AD progression is linked to nerve cell dysfunction and cell death due to the accumulation of 2 protein aggregates: β-amyloid (Aβ)5 and tau. In the cerebrospinal fluid (CSF), these proteins are biomarkers for AD. Cleavage of the amyloid precursor protein (APP) generates varying lengths of Aβ peptides (38–43 amino acids) that accumulate in the extracellular space. Of these monomers, Aβ-42 is the major form associated with AD. In addition, tau entanglement is also associated with AD and consists of insoluble hyperphosphorylated tau protein in the intracellular space. Both total tau (t-tau) and phosphorylated tau (p-tau) proteins are measured and associated with AD. Currently, clinical trials are testing therapies that target these proteins in hopes to delay or halt the cognitive decline in AD patients. In this Q&A, we discuss the current state and future direction of biomarkers, assays, and therapies for AD with 3 experts. Established Alzheimer biomarkers include β-amyloid and tau protein in CSF, as well as imaging techniques that involve MRI and positron emission tomography (PET). What are the limitations of these biomarkers that restrict them mostly to research purposes? Erik Portelius: In the recently updated diagnostic criteria for AD (the International Working Group-2 criteria), the CSF AD biomarkers (Aβ-42, t-tau, and p-tau) and neuroimaging with Pittsburgh compound B (PiB)-PET were included. Although MRI may mirror the disease …

Background Procalcitonin (PCT) monitoring has been shown to result in reduced antibiotic use without an impact on patient outcomes. However, the real-world value of this biomarker has yet to be determined, particularly when efforts to optimize antibiotic use are already in place. We evaluated the feasibility and impact of PCT-guided antibiotic duration combined with an established antibiotic stewardship program (ASP) in a community hospital intensive care unit (ICU) in Toronto, Canada. Methods We conducted a quality improvement initiative in our ICU from November 2017 to October 2018 measuring daily PCT levels for immunocompetent patients receiving antibiotic therapy for suspected or proven bacterial infection with an expected duration between 48 hours and 21 days. Our protocol recommended stopping antibiotic therapy if PCT fell below 0.5 μg/L (absolute threshold) or if it dropped more than 80% from its peak value (relative threshold). ASP rounds took place twice weekly since 2013, integrating a regular discussion about PCT levels once this initiative was implemented. We evaluated the adherence to stopping criteria within 48h, antibiotic use (days of therapy per 1,000 patient-days), length of stay, 48h re-admission, and ICU-mortality. Interrupted time series with segmented regression was performed to evaluate pre-post intervention differences compared with the 12-months prior to implementation. Results A total of 297 antibiotic courses were monitored with PCT in 217 patients. Respiratory (62%), unknown infection (11%), and intra-abdominal infection (7%) were the most common reasons for antibiotics. Protocol adherence was 34% (absolute threshold: 39%, relative threshold: 12%). Adherence by ICU physician varied widely between 24% and 52%. Antibiotic use pre-PCT was 1,002 DOTs/1,000 PDs and post-PCT was 817 DOTs/1,000 PDs (adjusted change −15%, 95% CI: −28% to +8%) (Figure 1). No statistically significant changes in clinical outcomes were noted. Conclusion In the context of an active ASP in a community hospital ICU, PCT monitoring was associated with a non-significant decrease in antibiotic use. Further evaluation of reasons for inter-physician variability in adherence and opportunities for improved and sustained overall adherence should be explored. Disclosures All authors: No reported disclosures.

Rationale:Consensus guidelines on the management of methotrexate-induced nephrotoxicity using glucarpidase (Voraxaze) may be relatively unfamiliar to the nephrology community.Presenting concerns of the patient:A 61-year-old man with intravascular large B-cell lymphoma was admitted for cycle #1 of high-dose methotrexate (HDMTX) following 2 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. On admission, he was clinically euvolemic and had a creatinine clearance of 98 mL/min. He received standard HDMTX toxicity prophylaxis with volume expansion, urinary alkalinization, and leucovorin rescue.Diagnoses:Despite prophylactic efforts, he developed a severe acute kidney injury, creatinine 63 to 226 µmol/L (2.56 mg/dL), following HDMTX, impaired methotrexate clearance, and neurotoxicity manifested by status epilepticus.Interventions:He was given glucarpidase to convert extracellular methotrexate into its inactive metabolites, glutamate and DAMPA (4-deoxy-4-amino- N10-methylpteroic acid) at 52 hours post-HDMTX. Cross-reactivity between commercial methotrexate immunoassays with DAMPA led to falsely elevated methotrexate concentrations for much longer than expected based on the current guideline (5 days instead of Outcomes:The patient remained nonoliguric and did not develop acute indications for dialysis. Serum creatinine peaked at 608 µmol/L (6.88 mg/dL) 6 days after HDMTX. He ultimately had a full renal and neurologic recovery.Lessons learned:Glucarpidase is an effective option for nonrenal elimination of methotrexate-induced nephrotoxicity. Timing of methotrexate concentration monitoring to assess for toxicity, how to access the drug, and the need for ongoing monitoring by mass spectrometry beyond the guideline recommendation are highlighted for centers where HDMTX therapy may be used.

Objective: Glycogen synthase kinase (GSK)-3α/β has been implicated in the pathogenesis of diseases including diabetes, cancer, Alzheimer’s and atherosclerosis. The tissue and homolog specific functions of GSK3α and β in atherosclerosis are unknown. This study examines the effect of hepatocyte or myeloid cell specific deletion of GSK3α or GSK3β on atherosclerosis in LDLR-/- mice. Approach and results: We ablated GSK3α or GSK3β expression in hepatic or myeloid cells of LDLR-/- mice and mice were fed a high fat diet for 10 weeks. GSK3α or GSK3β deficiency in hepatic or myeloid cells did not affect metabolic parameters, including plasma lipid levels. Hepatic deletion of GSK3α or GSK3β did not affect the development of atherosclerosis or hepatic lipid content. Myeloid deletion of GSK3α, but not GSK3β, reduced atherosclerotic lesion volume as well as lesion complexity. Mice lacking GSK3α in myeloid cells had a less inflammatory and more anti-inflammatory plasma cytokine profile. Macrophages within atherosclerotic lesions of myeloid GSK3α deficient mice, but not GSK3β deficient mice, displayed reduced expression of markers associated with M1 macrophage polarization and enhanced expression of the M2 markers. Finally, bone marrow derived macrophages were isolated and differentiated into classical M1 macrophages or alternative M2 macrophages in vitro. GSK3α deletion, but not GSK3β deletion, attenuated the expression of genes associated with M1 polarization while promoting the expression of genes associated with M2 polarization. Mechanistically, GSK3α regulated macrophage polarization by modulating the phosphorylation and activation of STAT transcription factors. Conclusions: Our findings suggest that deletion of myeloid GSK3α attenuates the progression of atherosclerosis by regulating STAT activation and promoting an M2 macrophage phenotype.