Pediatric reference interval verification for 17 specialized immunoassays and cancer markers on the Abbott Alinity i system in the CALIPER cohort of healthy children and adolescents.

OBJECTIVES: Clinical laboratory investigation of autoimmune, metabolic, and oncologic disorders in children and adolescents relies on appropriateness of reference intervals (RIs). The Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) previously established comprehensive pediatric RIs for specialized immunoassays on the Abbott ARCHITECT system. Herein, we aim to verify performance on new Alinity i assays by evaluating sera collected from healthy children as per Clinical and Laboratory Standards Institute (CLSI) EP-28A3C guidelines. METHODS: Precision, linearity, and method comparison experiments were completed for 17 specialized Alinity immunoassays, including cancer antigens, autoimmune peptides, and hormones. Sera collected from healthy children and adolescents (birth-18 years, n=100) were evaluated. CLSI-based verification was completed using previously established CALIPER RIs for ARCHITECT assays as the reference. RESULTS: Of 17 specialized immunoassays assays, only anti-cyclic citrullinated peptides (anti-CCP) did not meet acceptable verification criterion (i.e., ≥90% of results within ARCHITECT reference CI). Anti-thyroglobulin, anti-thyroid peroxidase, and carcinoembryonic antigen did not require age-specific consideration beyond one year of age, with 63, 91, and 80% of samples equalling the limit of detection, respectively. Estimates were separated by sex for relevant assays (e.g., sex hormone binding globulin, total and free prostate specific antigen). CONCLUSIONS: Findings support transferability of pediatric RIs on ARCHITECT system to the Alinity system for 16 specialized immunoassays in the CALIPER cohort and will be a useful resource for pediatric clinical laboratories using Alinity assays. Further work is needed to establish evidence-based interpretative recommendations for anti-CCP and continue to evaluate pediatric RI acceptability for newly available assay technologies.

Individual participant data meta-analysis of metabolomics on sustained knee pain in primary osteoarthritis patients.

OBJECTIVES: Knee pain is the major driver for OA patients to seek healthcare, but after pursuing both conservative and surgical pain interventions, ∼20% of patients continue to report long-term pain following total knee arthroplasty (TKA). This study aimed to identify a metabolomic signature for sustained knee pain after TKA to elucidate possible underlying mechanisms. METHODS: Two independent cohorts from St John's, NL, Canada (n = 430), and Toronto, ON, Canada (n = 495) were included in the study. Sustained knee pain was assessed using the WOMAC pain subscale (five questions) at least 1 year after TKA for primary OA. Those reporting any pain on all five questions were considered to have sustained knee pain. Metabolomic profiling was performed on fasted pre-operative plasma samples using the Biocrates Absolute IDQ p180 kit. Associations between metabolites and pair-wise metabolite ratios with sustained knee pain in each individual cohort were assessed using logistic regression with adjustment for age, sex and BMI. Random-effects meta-analysis using inverse variance as weights was performed on summary statistics from both cohorts. RESULTS: One metabolite, phosphatidylcholine (PC) diacyl (aa) C28:1 (odds ratio = 0.66, P = 0.00026), and three metabolite ratios, PC aa C32:0 to PC aa C28:1, PC aa C28:1 to PC aa C32:0, and tetradecadienylcarnitine (C14:2) to sphingomyelin C20:2 (odds ratios = 1.59, 0.60 and 1.59, respectively; all P < 2 × 10-5), were significantly associated with sustained knee pain. CONCLUSIONS: Though further investigations are needed, our results provide potential predictive biomarkers and drug targets that could serve as a marker for poor response and be modified pre-operatively to improve knee pain and surgical response to TKA.

Glutathione, polyamine, and lysophosphatidylcholine synthesis pathways are associated with circulating pro-inflammatory cytokines.

INTRODUCTION: Pro-inflammatory cytokines are responsible for initiating an effective defense against exogenous pathogens, and their regulation has a vital role in maintaining physiological homeostasis. The involvement of pro-inflammatory cytokines in pathological conditions have been explored in great detail, however, studies investigating metabolic pathways associated with these cytokines under normal homeostatic conditions are scarce. OBJECTIVES: The aim of the current study was to identify metabolites and metabolic pathways associated with circulating pro-inflammatory cytokines under homeostatic conditions using a metabolomics approach. METHODS: The study participants (n = 133) were derived from the Newfoundland Osteoarthritis Study (NFOAS) and the Complex Diseases in the Newfoundland population: Environment and Genetics (CODING) study. Plasma concentrations of cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1ß), and macrophage migration inhibitory factor (MIF) were assessed by enzyme-linked immunosorbent assay. Targeted metabolomic profiling on fasting plasma samples was performed using Biocrates MxP® Quant 500 kit which measures a total of 630 metabolites. Associations between natural log-transformed metabolite concentrations and metabolite sums/ratios and cytokine levels were assessed using linear regression with adjustment for age, sex, body mass index (BMI), and osteoarthritis status. RESULTS: Seven metabolites and 11 metabolite sums/ratios were found to be significantly associated with TNF-α, IL-1ß, and MIF (all p ≤ 5.13 × 10- 5) after controlling multiple testing with Bonferroni method, indicating the association between glutathione (GSH), polyamine, and lysophosphatidylcholine (lysoPC) synthesis pathways and these pro-inflammatory cytokines. CONCLUSION: GSH, polyamine, and lysoPC synthesis pathways were positively associated with circulating TNF-α, IL-1ß, and MIF levels under homeostatic conditions.

Restricting Branched-Chain Amino Acids within a High-Fat Diet Prevents Obesity.

Obesity is a global pandemic, but there is yet no effective measure to control it. Recent metabolomics studies have identified a signature of altered amino acid profiles to be associated with obesity, but it is unclear whether these findings have actionable clinical potential. The aims of this study were to reveal the metabolic alterations of obesity and to explore potential strategies to mitigate obesity. We performed targeted metabolomic profiling of the plasma/serum samples collected from six independent cohorts and conducted an individual data meta-analysis of metabolomics for body mass index (BMI) and obesity. Based on the findings, we hypothesized that restriction of branched-chain amino acids (BCAAs), phenylalanine, or tryptophan may prevent obesity and tested our hypothesis in a dietary restriction trial with eight groups of 4-week-old male C57BL/6J mice (n = 5/group) on eight different types of diets, respectively, for 16 weeks. A total of 3397 individuals were included in the meta-analysis. The mean BMI was 30.7 ± 6.1 kg/m2, and 49% of participants were obese. Fifty-eight metabolites were associated with BMI and obesity (all p ≤ 2.58 × 10-4), linked to alterations of the BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways. The restriction of BCAAs within a high-fat diet (HFD) maintained the mice's weight, fat and lean volume, subcutaneous and visceral adipose tissue weight, and serum glucose and insulin at levels similar to those in the standard chow group, and prevented obesity, adipocyte hypertrophy, adipose inflammation, and insulin resistance induced by HFD. Our data suggest that four metabolic pathways, BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways, are altered in obesity and restriction of BCAAs within a HFD can prevent the development of obesity and insulin resistance in mice, providing a promising strategy to potentially mitigate diet-induced obesity.

Metabolomic signatures for the longitudinal reduction of muscle strength over 10 years.

BACKGROUND: Skeletal muscles are essential components of the neuromuscular skeletal system that have an integral role in the structure and function of the synovial joints which are often affected by osteoarthritis (OA). The aim of this study was to identify the baseline metabolomic signatures for the longitudinal reduction of muscle strength over 10 years in the well-established community-based Tasmanian Older Adult Cohort (TASOAC). METHODS: Study participants were 50-79 year old individuals from the TASOAC. Hand grip, knee extension, and leg strength were measured at baseline, 2.6-, 5-, and 10-year follow-up points. Fasting serum samples were collected at 2.6-year follow-up point, and metabolomic profiling was performed using the TMIC Prime Metabolomics Profiling Assay. Generalized linear mixed effects model was used to identify metabolites that were associated with the reduction in muscle strength over 10 years after controlling for age, sex, and BMI. Significance level was defined at α=0.0004 after correction of multiple testing of 129 metabolites with Bonferroni method. Further, a genome-wide association study (GWAS) analysis was performed to explore if genetic factors account for the association between the identified metabolomic markers and the longitudinal reduction of muscle strength over 10 years. RESULTS: A total of 409 older adults (50% of them females) were included. The mean age was 60.93±6.50 years, and mean BMI was 27.12±4.18 kg/m2 at baseline. Muscle strength declined by 0.09 psi, 0.02 kg, and 2.57 kg per year for hand grip, knee extension, and leg strength, respectively. Among the 143 metabolites measured, 129 passed the quality checks and were included in the analysis. We found that the elevated blood level of asymmetric dimethylarginine (ADMA) was associated with the reduction in hand grip (p=0.0003) and knee extension strength (p=0.008) over 10 years. GWAS analysis found that a SNP rs1125718 adjacent to WISP1gene was associated with ADMA levels (p=4.39*10-8). Further, we found that the increased serum concentration of uric acid was significantly associated with the decline in leg strength over 10 years (p=0.0001). CONCLUSION: Our results demonstrated that elevated serum ADMA and uric acid at baseline were associated with age-dependent muscle strength reduction. They might be novel targets to prevent muscle strength loss over time.

Leading POCT Networks: Operating POCT Programs Across Multiple Sites Involving Vast Geographical Areas and Rural Communities.

Few peer-reviewed publications provide laboratory leaders with useful strategies on which to develop and implement point of care testing (POCT) programs to support delivery of acute care services to remote rural communities, with or without trained laboratory staff on site. This mini review discusses common challenges faced by laboratory leaders poised to implement and operate POCT programs at multiple remote and rural sites. It identifies areas for consideration during the initial program planning phases and provides areas for focus during evaluation and for continued improvement of POCT services at remote locations. Finally, it discusses a potential oversight framework for governance and leadership of multisite POCT programs servicing remote and rural communities.

Task-Oriented Circuit Training as an Alternative to Ergometer-Type Aerobic Exercise Training after Stroke.

Moderate-intensity aerobic exercise training is an important treatment strategy to enhance functional recovery and decrease cardiometabolic risk factors after stroke. However, stroke related impairments limit access to ergometer-type exercise. The aims of the current study were (1) to evaluate whether our task-oriented circuit training protocol (intermittent functional training; IFT) could be used to sustain moderate-intensity aerobic workloads over a 10-week intervention period, and (2) to investigate its preliminary effects on cardiorespiratory fitness and metabolic profiles compared to constant-load ergometer-type exercise (CET). Forty chronic hemiparetic stroke survivors were randomized to receive 30 sessions of IFT or CET over ten weeks. Similar proportions of participants were randomized to IFT (7/19) and CET (9/18) sustained workloads associated with moderate-intensity aerobic exercise over the study period (p = 0.515). However, CET was associated with more substantial changes in maximal oxygen uptake (MD = 2.79 mL min-1 kg-1 CI: 0.84 to 4.74) compared to IFT (MD = 0.62 mL min-1 kg-1 CI: -0.38 to 1.62). Pre to post changes in C-reactive protein (-0.9 mg/L; p =0.017), short-term glycemia (+14.7 mol/L; p = 0.026), and resting whole-body carbohydrate oxidation (+24.2 mg min-1; p = 0.046) were observed when considering both groups together. Accordingly, IFT can replicate the aerobic intensities sustained during traditional ergometer-type exercise training. More work is needed to evaluate the dose-response effects of such task-oriented circuit training protocols on secondary prevention targets across the continuum of stroke recovery.

Canadian Society of Clinical Chemists (CSCC) consensus guidance for testing, selection and quality management of SARS-CoV-2 point-of-care tests.

OBJECTIVES: A consensus guidance is provided for testing, utility and verification of SARS-CoV-2 point-of-care test (POCT) performance and implementation of a quality management program, focusing on nucleic acid and antigen targeted technologies. DESIGN AND METHODS: The recommendations are based on current literature and expert opinion from the members of Canadian Society of Clinical Chemists (CSCC), and are intended for use inside or outside of healthcare settings that have varied levels of expertise and experience with POCT. RESULTS AND CONCLUSIONS: Here we discuss sampling requirements, biosafety, SARS-CoV-2 point-of-care testing methodologies (with focus on Health Canada approved tests), test performance and limitations, test selection, testing utility, development and implementation of quality management systems, quality improvement, and medical and scientific oversight.

Phenylalanine Is a Novel Marker for Radiographic Knee Osteoarthritis Progression: The MOST Study.

OBJECTIVE: To identify plasma markers associated with an increased risk of radiographic knee osteoarthritis(OA) progression using a metabolomics approach. METHODS: Study participants were from the Multicenter Osteoarthritis Study (MOST) and were categorized into 2 groups based on the presence of baseline radiographic OA. Subjects in group 1 had unilateral knee OA and subjects in group 2 had bilateral knee OA. Progression was defined as a half-grade or greater worsening in joint space width at 30-month follow-up. For group 1, a participant progressed when their OA knee showed radiographic progression and the contralateral knee developed OA; for group 2, a participant progressed when both knees with OA showed radiographic progression. Metabolomic profiling was performed on plasma samples collected at baseline and logistic regression was performed to test the association between each metabolite and knee OA progression after adjustment for age, sex, BMI, and clinic site. Significance was defined as P ≤ 0.0003 in the combined analysis. RESULTS: There were 234 progressors (57 in group 1 and 177 in group 2) and 322 nonprogressors (206 in group 1 and 116 in group 2) included in the analyses. Among 157 metabolites studied, we found that odds of progression were 1.46 times higher per SD increase of phenylalanine level (95% CI 1.20-1.77, P = 0.0001) in the combined analysis. Sex-specific analysis showed that an association was seen in women (P = 0.0002) but not in men. CONCLUSION: Our data suggest that phenylalanine might be a novel plasma marker for higher risk of bilateral radiographic knee OA progression in women.

Metabolomic analysis coupled with extreme phenotype sampling identified that lysophosphatidylcholines are associated with multisite musculoskeletal pain.

ABSTRACT: Musculoskeletal pain often occurs simultaneously at multiple anatomical sites. The aim of the study was to identify metabolic biomarkers for multisite musculoskeletal pain (MSMP) by metabolomics with an extreme phenotype sampling strategy. The study participants (n = 610) were derived from the Newfoundland Osteoarthritis Study. Musculoskeletal pain was assessed using a self-reported pain questionnaire where painful sites were circled on a manikin by participants and the total number of painful sites were calculated. Targeted metabolomic profiling on fasting plasma samples was performed using the Biocrates AbsoluteIDQ p180 kit. Plasma cytokine concentrations including tumor necrosis factor-α, interleukin-6, interleukin-1ß, and macrophage migration inhibitory factor were assessed by enzyme-linked immunosorbent assay. Data on blood cholesterol profiles were retrieved from participants' medical records. Demographic, anthropological, and clinical information was self-reported. The number of reported painful sites ranged between 0 and 21. Two hundred and five participants were included in the analysis comprising 83 who had ≥7 painful sites and 122 who had ≤1 painful site. Women and younger people were more likely to have MSMP (P ≤ 0.02). Multisite musculoskeletal pain was associated with a higher risk of having incontinence, worse functional status and longer period of pain, and higher levels of low-density lipoprotein and non-high-density lipoprotein cholesterol (all P ≤ 0.03). Among the 186 metabolites measured, 2 lysophosphatidylcholines, 1 with 26 carbons with no double bond and 1 with 28 carbons with 1 double bond, were significantly and positively associated with MSMP after adjusting for multiple testing with the Bonferroni method (P ≤ 0.0001) and could be considered as novel metabolic markers for MSMP.

Sphingomyelin is involved in multisite musculoskeletal pain: evidence from metabolomic analysis in 2 independent cohorts.

ABSTRACT: Metabolic dysfunction has been suggested to be involved in musculoskeletal pain; however, few studies have identified metabolic markers associated with multisite musculoskeletal pain (MSMP). This study sought to identify metabolic marker(s) for MSMP by metabolomic analysis. The Tasmanian Older Adult Cohort Study (TASOAC) provided the discovery cohort with the Newfoundland Osteoarthritis Study (NFOAS) providing the replication cohort. Multisite musculoskeletal pain was assessed by a self-reported pain questionnaire and defined as painful sites ≥4 in both the TASOAC and the NFOAS. Furthermore, MSMP was also defined as painful sites ≥7, whereas non-MSMP was defined as either painful sites <7 or ≤1 in the NFOAS. Serum samples of the TASOAC received metabolic profiling using The Metabolomics Innovation Centre Prime Metabolomics Profiling Assay. The data on the identified metabolites were retrieved from NFOAS metabolomic database for the purpose of replication. A total of 409 participants were included in the TASOAC, 38% of them had MSMP. Among the 143 metabolites assessed, 129 passed quality control and were included in the analysis. Sphingomyelin (SM) C18:1 was significantly associated with MSMP (odds ratio [OR] per log µM increase = 3.96, 95% confidence interval, 1.95-8.22; P = 0.0002). The significance remained in multivariable analysis (OR per log µM increase = 2.70, 95% confidence interval, 1.25-5.95). A total of 610 participants were included in the NFOAS, and the association with SM C18:1 was successfully replicated with 3 MSMP definitions (OR ranging from 1.89 to 2.82; all P < 0.03). Our findings suggest that sphingomyelin metabolism is involved in the pathogenesis of MSMP, and the circulating level of SM C18:1 could serve as a potential marker in the management of MSMP.

Association Between Epidemiological Factors and Nonresponders to Total Joint Replacement Surgery in Primary Osteoarthritis Patients.

BACKGROUND: While total joint replacement (TJR) is the most effective treatment for end-stage osteoarthritis (OA), one-third of patients do not experience clinically important improvement in pain or function following the surgery. Thus, it is important to identify factors for nonresponders and develop strategies to improve TJR outcomes. METHODS: Study participants were patients who underwent TJR (hip/knee) due to OA and completed the WOMAC before and on average 4 years after surgery. Nonresponders (pain nonresponders, function nonresponders, pain and function nonresponders) were determined using the WOMAC change score from baseline to follow-up under two previously reported criteria. Eighty-eight self-reported factors collected by a general health questionnaire were examined for associations with nonresponders. RESULTS: A total of 601 patients (30.8% hip and 69.2% knee replacement) were included; 18% of them were found to be either pain or function nonresponders. Nine factors were identified in the univariable analyses to be associated with nonresponders, and 5 of them (clinical depression, multisite musculoskeletal pain [MSMP], younger age, golfer's elbow, and driving more than 4 hours on average per working day) remained significant in the multivariable analyses in at least one of six categories. Clinical depression, having MSMP, and younger age were the major factors to be independently associated with nonresponders across five categories. In addition, two factors (age at menopause and age at hysterectomy) were significantly associated with female nonresponders. CONCLUSION: Our data suggested potential roles of pain perception, widespread pain sensitization, patient expectations, and early menopause in females in TJR outcomes, warranting further investigation.

Endotypes of primary osteoarthritis identified by plasma metabolomics analysis.

OBJECTIVE: To identify endotypes of osteoarthritis (OA) by a metabolomics analysis. METHODS: Study participants included hip/knee OA patients and controls. Fasting plasma samples were metabolomically profiled. Common factor analysis and K-means clustering were applied to the metabolomics data to identify the endotypes of OA patients. Logistic regression was utilized to identify the most significant metabolites contributing to the endotypes. Clinical and epidemiological factors were examined in relation to the identified OA endotypes. RESULTS: Six hundred and fifteen primary OA patients and 237 controls were included. Among the 186 metabolites measured, 162 passed the quality control analysis. The 615 OA patients were classified in three clusters (A, 66; B, 200; and C, 349). Patients in cluster A had a significantly higher concentration of butyrylcarnitine (C4) than other clusters and controls (all P < 0.0002). Elevated C4 is thought to be related to muscle weakness and wasting. Patients in cluster B had a significantly lower arginine concentration than other clusters and controls (all P < 7.98 × 10-11). Cluster C patients had a significantly lower concentration of lysophosphatidylcholine (with palmitic acid), which is a pro-inflammatory bioactive compound, than other clusters and controls (P < 3.79 × 10-6). Further, cluster A had a higher BMI and prevalence of diabetes than other clusters (all P ≤ 0.0009), and also a higher prevalence of coronary heart disease than cluster C (P = 0.04). Cluster B had a higher prevalence of coronary heart disease than cluster C (P = 0.003) whereas cluster C had a higher prevalence of osteoporosis (P = 0.009). CONCLUSION: Our data suggest three possible clinically actionable endotypes in primary OA: muscle weakness, arginine deficit and low inflammatory OA.

Canadian society of clinical chemists (CSCC) interim consensus guidance for testing and reporting of SARS-CoV-2 serology.

Clinical laboratories across the world are working to validate and perform testing for SARS-CoV-2 antibodies. Herein, we present interim consensus guidance for Canadian clinical laboratories testing and reporting SARS-CoV-2 serology, with emphasis on the capabilities and limitations of these tests and recommendations for interpretative comments in an effort to achieve harmonized laboratory practices. The consensus document provides a broad overview of topics including sample type and contamination risk; kinetics of antibody response to COVID-19 and the impact on serology testing; clinical utility of SARS-CoV-2 serology testing; clinical performance of commercial laboratory-based assays commonly deployed in North America; recommendations for interim reporting; utility of SARS-CoV-2 antibody testing for pediatric patients; and utility of point-of-care testing. The information is based on the current literature and is subject to change as additional information becomes available.

The effect of laboratory requisition modification, audit and feedback with academic detailing or both on utilization of blood urea testing in family practice in Newfoundland, Canada.

OBJECTIVES: Measuring blood urea at the same time as serum creatinine in stable ambulatory patients in family practice is largely unnecessary. The objective was to assess the relative impact of changing the laboratory requisition versus audit and feedback and academic detailing on the volume of orders for blood urea. DESIGN AND METHODS: A natural experiment was observed over the period April 2015 to March 2018 in the Canadian province of Newfoundland where three health regions had different approaches to trying to reduce such urea testing. The Eastern and Western regions removed urea from the standard laboratory requisition but the test could still be ordered by writing it on the requisition. Central region requisitions continued to list urea. Audit and feedback was undertaken with family doctors in Eastern region after the requisition change and that was followed by academic detailing. A nephrologist gave presentations to groups of family doctors on one occasion in Central region. RESULTS: The volume of serum creatinine testing was largely unchanged over time in each region. The volume of urea testing reduced by 73%, 48% and 28% in Eastern, Western and central regions. Interrupted time series analysis showed significant changes in test volume after requisition change in Eastern and Western regions as well as after audit and feedback in Eastern and the presentations in Central region. The incremental impact of academic detailing was not statistically significant. CONCLUSION: We conclude that removing urea from standard test order menus was the most effective in reducing test volumes, but combination with audit and feedback augmented the impact.

Differential correlation network analysis identified novel metabolomics signatures for non-responders to total joint replacement in primary osteoarthritis patients.

INTRODUCTION: Up to one third of total joint replacement patients (TJR) experience poor surgical outcome. OBJECTIVES: To identify metabolomic signatures for non-responders to TJR in primary osteoarthritis (OA) patients. METHODS: A newly developed differential correlation network analysis method was applied to our previously published metabolomic dataset to identify metabolomic network signatures for non-responders to TJR. RESULTS: Differential correlation networks involving 12 metabolites and 23 metabolites were identified for pain non-responders and function non-responders, respectively. CONCLUSION: The differential networks suggest that inflammation, muscle breakdown, wound healing, and metabolic syndrome may all play roles in TJR response, warranting further investigation.

Metabolomics Signature for Non-Responders to Total Joint Replacement Surgery in Primary Osteoarthritis Patients: The Newfoundland Osteoarthritis Study.

Although total joint replacement (TJR) surgery is considered as the most effective treatment for advanced osteoarthritis (OA) patients, up to one-third of patients reported unfavorable long-term post-operative pain outcomes. We aimed to identify metabolic biomarkers to predict non-responders to TJR using a metabolomics approach. TJR patients were recruited and followed-up at least 1-year post-surgery; TJR outcomes were assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function subscales. Targeted metabolomic profiling was performed on plasma samples collected pre-surgery and pairwise metabolite ratios, as proxies for enzymatic reactions, were calculated. Association tests were performed between each metabolite ratio and non-responders. The metabolome-wide significance was defined as p < 2 × 10-5 . A total of 461 TJR patients due to primary OA were included in the analysis. Fifteen percent of patients were classified as pain non-responders; 16% were classified as function non-responders. Lower baseline WOMAC pain and function scores were significantly associated with pain and function non-responders, respectively (both p < 0.03). Two metabolite ratios were significantly associated with pain non-responders; acetylcarnitine (C2) to phosphatidylcholine acyl-alkyl C40:1 (PC ae C40:1) was five times higher in pain non-responders whereas phosphatidylcholine diacyl C36:4 (PC aa C36:4) to isoleucine was twenty one times lower in pain non-responders than responders (all p ≤ 1.93 × 10-5 ). One metabolite ratio, glutamine to isoleucine, was significantly lower in function non-responders than responders (eight times lower; p = 1.08 × 10-5 ). Three metabolite ratios (C2 to PC ae C40:1, PC aa C36:4, and glutamine to isoleucine) related to inflammation and muscle breakdown could be considered as novel plasma markers for predicting non-responders to TJR and warrant further investigation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:793-802, 2020.

Serum lysophosphatidylcholines to phosphatidylcholines ratio is associated with symptomatic responders to symptomatic drugs in knee osteoarthritis patients.

BACKGROUND: Identification of the optimal treatment for a given patient is of paramount importance. This is of particular relevance in osteoarthritis (OA) because of the high prevalence of the disease, extensive heterogeneity of the disease, and need for long-term treatment. The aim of the study was to examine whether serum lysophosphatidylcholines (lysoPCs) to phosphatidylcholines (PCs) ratio can predict clinical response to licofelone and naproxen treatments in symptomatic knee OA patients. METHODS: One hundred fifty-eight OA patients who completed the study according to protocol (ATP) of a previous 24-month clinical trial cohort comparing the effect of licofelone vs. naproxen in symptomatic knee OA patients were included. Symptomatic responses to either treatments were classified according to the OARSI-OMERACT criteria based on the WOMAC scores at 24 months. Total concentrations of PCs and lysoPCs were measured in the serum samples collected before the initiation of the treatments, and the lysoPCs to PCs ratio was calculated. Student's t test was utilized to compare the difference in the ratio of lysoPCs to PCs between the symptomatic responders and non-responders. Logistic regression was utilized to adjust for the potential confounders. Receiver operating characteristic (ROC) analysis was performed to identify the optimal cutoff of the ratio for prediction. RESULTS: Data showed that 61.4% of the patients symptomatically responded to licofelone and naproxen and 38.6% were deemed as therapeutic failures (non-responders). There was no difference in responders between licofelone and naproxen (p = 0.87). Responders had a significantly higher lysoPCs to PCs ratio than non-responders (0.097 ± 0.003 vs. 0.085 ± 0.003; p = 0.006). Patients with a ratio greater than the optimal cutoff of 0.088 had 2.93 times more likely to respond to licofelone and naproxen (p = 0.002). CONCLUSIONS: Serum lysoPCs to PCs ratio is a marker for response to licofelone and naproxen and may aid in the personalized treatment to knee OA.

Autoverification of test results in the core clinical laboratory.

Verification of laboratory test results represents the last opportunity to identify errors before they become part of the electronic medical record. Manual verification of test results places significant reliance on the experience and attentiveness of individual observers to identify errors and is vulnerable to errors through omission and neglect. Peer-reviewed publications have documented gains in process efficiency and quality improvement by use of middleware or laboratory information systems to autoverify test results based on pre-defined acceptability criteria. This review evaluates the acceptability of autoverification (AV) as a safe and reliable alternative to total manual review of laboratory test results. AV schemes developed in accordance with international guidelines and standards are applied throughout the laboratory. Careful design of AV systems involves using multidisciplinary teams to develop test-specific decision algorithms, to assist with programming, to verify programming, and validate programmed algorithms prior to use in evaluation of patient test result profiles. Development of test specific decision algorithms makes use of criteria based on instrument messages and flags, quality control status, result limit checks, delta checks, critical values, consistency checks, and patient-related clinical information. Monitoring of the performance of AV parameters, and regular audits of the AV system integrity is recommended in both the literature and guidelines. The potential for gains to process efficiency, error detection and patient safety, through adoption of AV as part of a laboratories quality assurance tool-case, is well supported in published literature.

Delta Checks in the clinical laboratory.

International standards and practice guidelines recommend the use of delta check alerts for laboratory test result interpretation and quality control. The value of contemporary applications of simple univariate delta checks determined as an absolute change, percentage change, or rate of change to recognize specimen misidentification or other laboratory errors has not received much study. This review addresses these three modes of calculation, but in line with the majority of published work, most attention is focused on the identification of specimen misidentification errors. Investigation of delta check alerts are time-consuming and the yield of identified errors is usually small compared to the number of delta check alerts; however, measured analytes with low indices of individuality frequently perform better. While multivariate approaches to delta checks suggest improved usefulness over simple univariate delta check strategies, some of these are complex and not easily applied in contemporary laboratory information systems and middleware. Nevertheless, a simple application of delta checks may hold value in identifying clinically significant changes in several clinical situations: for acute kidney injury using changes in serum creatinine, for risk of osmotic demyelination syndrome using rapid acute changes in serum sodium levels, or for early triage of chest pain patients using high sensitivity troponin assays. A careful and highly selective approach to identifying delta check analytes, calculation modes, and thresholds before putting them into practice is warranted; then follow-up with careful monitoring of performance and balancing true positives, false negatives, and false positives among delta check alerts is needed.