117 results on '"Holmes DT"'
Search Results
2. Aluminum toxicity due to intravenous injection of boiled methadone.
- Author
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Yong RL, Holmes DT, and Sreenivasan GM
- Published
- 2006
3. Effects of COVID-19 mRNA vaccination on HIV viremia and reservoir size.
- Author
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Duncan MC, Omondi FH, Kinloch NN, Lapointe HR, Speckmaier S, Moran-Garcia N, Lawson T, DeMarco ML, Simons J, Holmes DT, Lowe CF, Bacani N, Sereda P, Barrios R, Harris M, Romney MG, Montaner JSG, Brumme CJ, Brockman MA, and Brumme ZL
- Subjects
- Humans, Male, Female, Middle Aged, Adult, Longitudinal Studies, Antibodies, Viral blood, British Columbia, Vaccination, Disease Reservoirs virology, HIV Infections drug therapy, HIV Infections prevention & control, Viral Load, COVID-19 Vaccines immunology, COVID-19 Vaccines administration & dosage, COVID-19 prevention & control, Viremia, SARS-CoV-2 immunology
- Abstract
Objective: The immunogenic nature of coronavirus disease 2019 (COVID-19) mRNA vaccines led to some initial concern that these could stimulate the HIV reservoir. We analyzed changes in plasma HIV loads (pVL) and reservoir size following COVID-19 mRNA vaccination in 62 people with HIV (PWH) receiving antiretroviral therapy (ART), and analyzed province-wide trends in pVL before and after the mass vaccination campaign., Design: Longitudinal observational cohort and province-wide analysis., Methods: Sixty-two participants were sampled prevaccination, and one month after their first and second COVID-19 immunizations. Vaccine-induced anti-SARS-CoV-2-Spike antibodies in serum were measured using the Roche Elecsys Anti-S assay. HIV reservoirs were quantified using the intact proviral DNA assay; pVL were measured using the cobas 6800 (lower limit of quantification: 20 copies/ml). The province-wide analysis included all 290 401 pVL performed in British Columbia, Canada between 2012 and 2022., Results: Prevaccination, the median intact reservoir size was 77 [interquartile range (IQR): 20-204] HIV copies/million CD4 + T-cells, compared to 74 (IQR: 27-212) and 65 (IQR: 22-174) postfirst and -second dose, respectively (all comparisons P > 0.07). Prevaccination, 82% of participants had pVL <20 copies/ml (max: 110 copies/ml), compared to 79% postfirst dose (max: 183 copies/ml) and 85% postsecond dose (max: 79 copies/ml) ( P > 0.4). There was no evidence that the magnitude of the vaccine-elicited anti-SARS-CoV-2-Spike immune response influenced pVL nor changes in reservoir size ( P > 0.6). We found no evidence linking the COVID-19 mass vaccination campaign to population-level increases in detectable pVL frequency among all PWH in the province, nor among those who maintained pVL suppression on ART., Conclusion: We found no evidence that COVID-19 mRNA vaccines induced changes in HIV reservoir size nor plasma viremia., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2024
- Full Text
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4. Association of admission serum sodium and outcomes following out-of-hospital cardiac arrest.
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Ye SC, Cheung CC, Lauder E, Grunau B, Moghaddam N, van Diepen S, Holmes DT, Sekhon MS, Christenson J, Tallon JM, and Fordyce CB
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- Adult, Humans, Sodium, Prognosis, Hypernatremia etiology, Hypernatremia complications, Hyponatremia etiology, Hyponatremia complications, Out-of-Hospital Cardiac Arrest etiology, Out-of-Hospital Cardiac Arrest therapy, Cardiopulmonary Resuscitation
- Abstract
Background: The prognostic association between dysnatremia and outcomes in out-of-hospital cardiac arrest (OHCA) is not well understood. Given hypernatremia is associated with poor outcomes in critical illness and hyponatremia may exacerbate cerebral edema, we hypothesized that dysnatremia on OHCA hospital admission would be associated with worse neurological outcomes., Methods: We studied adults (≥19 years) with non-traumatic OHCA between 2009 and 2016 who were enrolled in the British Columbia Cardiac Arrest Registry and survived to hospital admission at 2 quaternary urban hospitals. We stratified cases by admission serum sodium into hyponatremic (<135 mmol/L), normonatremic (135-145 mmol/L), and hypernatremic (>145 mmol/L) groups. We used logistic regression models, adjusted for age, sex, shockable rhythm, admission serum lactate, and witnessed arrest, to estimate the association between admission sodium and favorable neurological outcome (cerebral performance category 1-2 or modified Rankin scale 0-3)., Results: Of 414 included patients, 63 were hyponatremic, 330 normonatremic, and 21 hypernatremic. In each respective group, 21 (33.3%), 159 (48.2%), and 3 (14.3%) experienced good neurological outcomes. In univariable models, hyponatremia (OR 0.53, 95% CI 0.30-0.93) and hypernatremia (OR 0.19, 95% CI 0.05-0.65) were associated with lower odds of good neurological outcomes compared to the normonatremia group. After adjustment, only hypernatremia was associated with lower odds of good neurological outcomes (OR 0.22, 95% CI 0.05-0.98)., Conclusions: Hypernatremia at admission was independently associated with decreased probability of good neurological outcomes at discharge post-OHCA. Future studies should focus on elucidating the pathophysiology of dysnatremia following OHCA., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)
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- 2024
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5. Dynamics of T-cell Responses Following COVID-19 mRNA Vaccination and Breakthrough Infection in Older Adults.
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Datwani S, Kalikawe R, Mwimanzi F, Speckmaier S, Liang R, Sang Y, Waterworth R, Yaseen F, Lapointe HR, Barad E, DeMarco ML, Holmes DT, Simons J, Montaner JSG, Romney MG, Brumme ZL, and Brockman MA
- Abstract
Introduction: While older adults generally mount weaker antibody responses to a primary COVID-19 vaccine series, T-cell responses remain less well characterized in this population. We compared SARS-CoV-2 spike-specific T-cell responses after 2- and 3-dose COVID-19 mRNA vaccination and subsequent breakthrough infection in older and younger adults., Methods: We quantified CD4+ and CD8+ T-cells reactive to overlapping peptides spanning the ancestral SARS-CoV-2 spike protein in 40 older adults (median age 79) and 50 younger health care workers (median age 39), all COVID-19 naive, using an activation-induced marker assay. T-cell responses were further assessed in 24 participants, including 8 older adults, who subsequently experienced their first SARS-CoV-2 breakthrough infection., Results: A third COVID-19 mRNA vaccine dose significantly boosted spike-specific CD4+ and CD8+ T-cell frequencies to above 2-dose levels in older and younger adults. T-cell frequencies did not significantly differ between older and younger adults after either dose. Multivariable analyses adjusting for sociodemographic, health, and vaccine-related variables confirmed that older age was not associated with impaired cellular responses. Instead, the strongest predictors of CD4+ and CD8+ T-cell frequencies post-third-dose were their corresponding post-second-dose frequencies. Breakthrough infection significantly increased both CD4+ and CD8+ T-cell frequencies, to comparable levels in older and younger adults. Exploratory analyses revealed an association between HLA-A*02:03 and higher post-vaccination CD8+ T-cell frequencies, which may be attributable to numerous strong-binding HLA-A*02:03-specific CD8+ T-cell epitopes in the spike protein., Conclusion: Older adults mount robust T-cell responses to 2- and 3-dose COVID-19 mRNA vaccination, which are further boosted following breakthrough infection., Competing Interests: The authors report no conflicts of interest to declare., (Copyright © 2023 Pathogens and Immunity.)
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- 2023
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6. Age specific reference intervals for plasma biomarkers of neurodegeneration and neurotrauma in a Canadian population.
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Cooper JG, Stukas S, Ghodsi M, Ahmed N, Diaz-Arrastia R, Holmes DT, and Wellington CL
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- Humans, Male, Child, Female, Aged, Child, Preschool, Adolescent, Young Adult, Adult, Middle Aged, Canada, tau Proteins, Biomarkers, Amyloid beta-Peptides, Alzheimer Disease
- Abstract
Introduction: In this study, we aimed to create reference intervals (RI) using a large Canadian population-based cohort, for plasma protein biomarkers with potential utility to screen, diagnosis, prognosticate and manage a variety of neurological diseases and disorders. RIs were generated for: the ratio of amyloid beta 42 over 40 (Aβ42/40), phosphorylated tau-181 (p-tau-181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)., Methods: 900 plasma specimens from male and female participants aged 3-79 years old were obtained from the Statistics Canada Biobank, which holds specimens from the Canadian Health Measures Survey. Analysis of Aβ42/40, p-tau-181, NfL and GFAP was performed on the Quanterix Simoa HD-X analyzer using the Neurology 4-plex E and p-tau-181 assays. Discrete RIs were produced according to Clinical Laboratory Standards Institute guidelines (EP28-A3c). Continuous RIs were created using quantile regression., Results: For discrete RIs, significant age partitions were determined for each biomarker. No significant sex partitions were found. The following ranges and age partitions were determined: Aβ42/40: 3-<55y = 0.053-0.098, 55-<80y = 0.040-0.090; p-tau-181: 3-<12y = 1.4-5.6 pg/ml, 12-<60y = 0.8-3.1 pg/ml, 60-<80y = 0.9-4.0 pg/ml; NfL: 3-<40y = 2.6-11.3 pg/ml, 40-<60y = 4.6-17.7 pg/ml, 60-<80y = 8.1-47.1 pg/ml; GFAP; 3-<10y = 47.0-226 pg/ml, 10-<60y = 21.2-91.9 pg/ml, 60-<80y = 40.7-228 pg/ml. Continuous RIs produced smooth centile curves across the age range, from which point estimates for each year of age were calculated., Conclusions: Discrete and continuous RIs for neurological plasma biomarkers will help refine normative cut-offs across the lifespan and improve the precision of interpretating biomarker levels. Continuous RIs are recommended for use in age groups, such as pediatrics and older adults, that experience rapid concentration changes by age., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)
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- 2023
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7. Lithium related thyroid and parathyroid disease: Updated clinical practice guidelines are needed.
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Bann S, Nguyen A, Gill S, Raudzus J, Holmes DT, and Wiseman SM
- Abstract
Objective: This study aims to estimate the prevalence of and determine physician approaches to the screening and management of lithium-associated thyroid and parathyroid disorders in British Columbia, Canada., Methods: Serum lithium and thyroid/parathyroid laboratory data were collected retrospectively for patients with lithium levels measured at seven BC hospitals between 2012 and 2021. A mail-out survey about screening and management of thyroid/parathyroid disorders in patients on lithium was sent to the ordering physicians of patients with abnormal results. Three months after, a follow-up questionnaire was sent to respondents, and the original survey was re-sent to non-responders., Results: Of 4917 patients, 1.9 % had PTH (mean 22.33 ± 23.00 pmol/L) and 77.1 % had TSH (mean 3.61 ± 6.69 pmol/L) measured. Of 222 hypercalcemic patients (defined as any serum calcium or ionized calcium above the laboratory reference), 17.6 % had a PTH level measured. From 294 surveys sent to 214 physicians, the overall response rate was 31.6 % (n = 93) with twelve fully completed surveys. All twelve respondents monitored TSH levels every 6-12 months, and eight physicians monitored PTH and/or calcium at variable intervals. Two physicians routinely ordered both thyroid and parathyroid screening laboratory tests. Of the 80 non-respondents, limited patient contact was the most common reason for opting out (n = 27)., Conclusions: Our results suggest biochemical screening for lithium-associated parathyroid disorders is less common than for thyroid disorders. There is insufficient data to determine the true prevalence of lithium-associated thyroid and parathyroid disorders. This highlights the need for updated clinical guidelines for management of lithium-associated thyroid and parathyroid disorders., Competing Interests: Declaration of competing interest The authors do not declare any conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
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8. Effects of COVID-19 mRNA vaccination on HIV viremia and reservoir size.
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Duncan MC, Omondi FH, Kinloch NN, Lapointe HR, Speckmaier S, Moran-Garcia N, Lawson T, DeMarco ML, Simons J, Holmes DT, Lowe CF, Bacani N, Sereda P, Barrios R, Harris M, Romney MG, Montaner JSG, Brumme CJ, Brockman MA, and Brumme ZL
- Abstract
Objective: The immunogenic nature of COVID-19 mRNA vaccines led to some initial concern that these could stimulate the HIV reservoir. We analyzed changes in plasma HIV loads (pVL) and reservoir size following COVID-19 mRNA vaccination in 62 people with HIV (PWH) receiving antiretroviral therapy (ART), and analyzed province-wide trends in pVL before and after the mass vaccination campaign., Design: Longitudinal observational cohort and province-wide analysis., Methods: 62 participants were sampled pre-vaccination, and one month after their first and second COVID-19 immunizations. Vaccine-induced anti-SARS-CoV-2-Spike antibodies in serum were measured using the Roche Elecsys Anti-S assay. HIV reservoirs were quantified using the Intact Proviral DNA Assay; pVL were measured using the cobas 6800 (LLOQ:20 copies/mL). The province-wide analysis included all 290,401 pVL performed in British Columbia, Canada between 2012-2022., Results: Pre-vaccination, the median intact reservoir size was 77 (IQR:20-204) HIV copies/million CD4+ T-cells, compared to 74 (IQR:27-212) and 65 (IQR:22-174) post-first and -second dose, respectively (all comparisons p>0.07). Pre-vaccination, 82% of participants had pVL<20 copies/mL (max:110 copies/mL), compared to 79% post-first dose (max:183 copies/mL) and 85% post-second dose (max:79 copies/mL) (p>0.4). The magnitude of the vaccine-elicited anti-SARS-CoV-2-Spike antibody response did not correlate with changes in reservoir size nor detectable pVL frequency (p>0.6). We found no evidence linking the COVID-19 mass vaccination campaign to population-level increases in detectable pVL frequency among all PWH in the province, nor among those who maintained pVL suppression on ART., Conclusion: We found no evidence that COVID-19 mRNA vaccines induced changes in HIV reservoir size nor plasma viremia.
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- 2023
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9. Bone turnover markers for assessment of anti-resorptive effect in clinical practice: A good idea meets the problem of measurement uncertainty.
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Kline GA and Holmes DT
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- Humans, Female, Uncertainty, Diphosphonates pharmacology, Diphosphonates therapeutic use, Bone Remodeling, Biomarkers, Collagen Type I pharmacology, Bone Density physiology, Peptides therapeutic use
- Abstract
Objectives: Bone turnover markers (BTM) are measures for understanding the effect of anti-resorptives upon osteoclast activity. Post-hoc trial data suggests reduction in BTM of 40% may represent a target for defining appropriate response to therapy. We modeled clinical application of this target threshold in an individual patient setting where assay measurement uncertainty and biological variation are included., Design: Using serum C-telo-peptide (ß-CTX), we constructed hypothetical scenarios of ß-CTX measurement pre and post bisphosphonate therapy. Using typical ß-CTX assay characteristics (analytical coefficient of variation, CV 5.0%) and published intra-individual ß-CTX data for post-menopausal women (CV 18.0%), we calculated the post-therapy ß-CTX that must be seen on single repeat measure for 95% confidence that the observed result was ≥40% below baseline. Sensitivity analyses considered greater and lesser variations in the combined sources of variation., Results: The one-tailed 95% reference change value for any detectable therapeutic decrease in ß-CTX was 22%. However, to have 95% confidence of having achieved a reduction ≥40%, an observed ß-CTX decrease of ≥56% is required. Larger decreases are needed for scenarios of greater analytical or intra-individual variation., Conclusions: Although population data suggest a ß-CTX decrease of 40% is commensurate with adequate therapeutic response to anti-resorptives, application to an individual patient where measurement and natural variation are present is problematic. ß-CTX decreases much >40% are required to be confident of having achieved the optimal treatment response. It is uncertain whether this is a legitimate change to be expected in all individual patients and therefore clinical application of this threshold is uncertain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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10. People With Human Immunodeficiency Virus Receiving Suppressive Antiretroviral Therapy Show Typical Antibody Durability After Dual Coronavirus Disease 2019 Vaccination and Strong Third Dose Responses.
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Lapointe HR, Mwimanzi F, Cheung PK, Sang Y, Yaseen F, Umviligihozo G, Kalikawe R, Speckmaier S, Moran-Garcia N, Datwani S, Duncan MC, Agafitei O, Ennis S, Young L, Ali H, Ganase B, Omondi FH, Dong W, Toy J, Sereda P, Burns L, Costiniuk CT, Cooper C, Anis AH, Leung V, Holmes DT, DeMarco ML, Simons J, Hedgcock M, Prystajecky N, Lowe CF, Pantophlet R, Romney MG, Barrios R, Guillemi S, Brumme CJ, Montaner JSG, Hull M, Harris M, Niikura M, Brockman MA, and Brumme ZL
- Subjects
- Humans, HIV, COVID-19 Vaccines, SARS-CoV-2, Antibodies, Vaccination, Antibodies, Viral, COVID-19 prevention & control, HIV Infections drug therapy
- Abstract
Background: Longer-term humoral responses to 2-dose coronavirus disease 2019 (COVID-19) vaccines remain incompletely characterized in people living with human immunodeficiency virus (HIV) (PLWH), as do initial responses to a third dose., Methods: We measured antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain, angiotensin-converting enzyme 2 (ACE2) displacement, and viral neutralization against wild-type and Omicron strains up to 6 months after 2-dose vaccination, and 1 month after the third dose, in 99 PLWH receiving suppressive antiretroviral therapy and 152 controls., Results: Although humoral responses naturally decline after 2-dose vaccination, we found no evidence of lower antibody concentrations or faster rates of antibody decline in PLWH compared with controls after accounting for sociodemographic, health, and vaccine-related factors. We also found no evidence of poorer viral neutralization in PLWH after 2 doses, nor evidence that a low nadir CD4+ T-cell count compromised responses. Post-third-dose humoral responses substantially exceeded post-second-dose levels, though Omicron-specific responses were consistently weaker than responses against wild-type virus. Nevertheless, post-third-dose responses in PLWH were comparable to or higher than controls. An mRNA-1273 third dose was the strongest consistent correlate of higher post-third-dose responses., Conclusion: PLWH receiving suppressive antiretroviral therapy mount strong antibody responses after 2- and 3-dose COVID-19 vaccination. Results underscore the immune benefits of third doses in light of Omicron., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2023
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11. Impact of Age and Severe Acute Respiratory Syndrome Coronavirus 2 Breakthrough Infection on Humoral Immune Responses After Three Doses of Coronavirus Disease 2019 mRNA Vaccine.
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Mwimanzi F, Lapointe HR, Cheung PK, Sang Y, Yaseen F, Kalikawe R, Datwani S, Burns L, Young L, Leung V, Ennis S, Brumme CJ, Montaner JSG, Dong W, Prystajecky N, Lowe CF, DeMarco ML, Holmes DT, Simons J, Niikura M, Romney MG, Brumme ZL, and Brockman MA
- Abstract
Background: Longer-term immune response data after 3 doses of coronavirus disease 2019 (COVID-19) mRNA vaccine remain limited, particularly among older adults and after Omicron breakthrough infection., Methods: We quantified wild-type- and Omicron-specific serum immunoglobulin (Ig)G levels, angiotensin-converting enzyme 2 displacement activities, and live virus neutralization up to 6 months after third dose in 116 adults aged 24-98 years who remained COVID-19 naive or experienced their first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during this time., Results: Among the 78 participants who remained COVID-19 naive throughout follow up, wild-type- and Omicron-BA.1-specific IgG concentrations were comparable between younger and older adults, although BA.1-specific responses were consistently significantly lower than wild-type-specific responses in both groups. Wild-type- and BA.1-specific IgG concentrations declined at similar rates in COVID-19-naive younger and older adults, with median half-lives ranging from 69 to 78 days. Antiviral antibody functions declined substantially over time in COVID-19-naive individuals, particularly in older adults: by 6 months, BA.1-specific neutralization was undetectable in 96% of older adults, versus 56% of younger adults. Severe acute respiratory syndrome coronavirus 2 infection, experienced by 38 participants, boosted IgG levels and neutralization above those induced by vaccination alone. Nevertheless, BA.1-specific neutralization remained significantly lower than wild-type, with BA.5-specific neutralization lower still. Higher Omicron BA.1-specific neutralization 1 month after third dose was an independent correlate of lower SARS-CoV-2 infection risk., Conclusions: Results underscore the immune benefits of the third COVID-19 mRNA vaccine dose in adults of all ages and identify vaccine-induced Omicron-specific neutralization as a correlate of protective immunity. Systemic antibody responses and functions however, particularly Omicron-specific neutralization, decline rapidly in COVID-19-naive individuals, particularly in older adults, supporting the need for additional booster doses., Competing Interests: Potential conflicts of interest. The authors have no conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2023
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12. End-to-End Data Automation for Pooled Sample SARS-CoV-2 Using R and Other Open-Source Tools.
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Mobini M, Matic N, Gugten JGV, Ritchie G, Lowe CF, and Holmes DT
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- Humans, COVID-19 Testing, Real-Time Polymerase Chain Reaction, SARS-CoV-2 genetics, COVID-19 diagnosis, COVID-19 epidemiology
- Abstract
Background: Due to supply chain shortages of reagents for real-time (RT)-PCR for SARS-CoV-2 and increasing demand on technical staff, an end-to-end data automation strategy for SARS-CoV-2 sample pooling and singleton analysis became necessary in the summer of 2020., Methods: Using entirely open source software tools-Linux, bash, R, RShiny, ShinyProxy, and Docker-we developed a modular software application stack to manage the preanalytical, analytical, and postanalytical processes for singleton and pooled testing in a 5-week time frame., Results: Pooling was operationalized for 81 days, during which time 64 pooled runs were performed for a total of 5320 sample pools and approximately 21 280 patient samples in 4:1 format. A total of 17 580 negative pooled results were released in bulk. After pooling was discontinued, the application stack was used for singleton analysis and modified to release all viral RT-PCR results from our laboratory. To date, 236 109 samples have been processed avoiding over 610 000 transcriptions., Conclusions: We present an end-to-end data automation strategy connecting 11 devices, one network attached storage, 2 Linux servers, and the laboratory information system., (© American Association for Clinical Chemistry 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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13. Corrigendum to "Migration from RIA to LC-MS/MS for aldosterone determination: Implications for clinical practice and determination of plasma and urine reference range intervals in a cohort of healthy Belgian subjects" [Clin. Mass Spectrom. 9 (2018) 7-17].
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Le Goff CM, Gonzalez-Antuña A, Peeters SD, Fabregat-Cabello N, Van Der Gugten JG, Vroonen L, Pottel H, Holmes DT, and Cavalier E
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[This corrects the article DOI: 10.1016/j.clinms.2018.06.002.]., (© 2022 THE AUTHORS. Publishing services by ELSEVIER B.V. on behalf of MSACL.)
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- 2022
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14. Older Adults Mount Less Durable Humoral Responses to Two Doses of COVID-19 mRNA Vaccine but Strong Initial Responses to a Third Dose.
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Mwimanzi F, Lapointe HR, Cheung PK, Sang Y, Yaseen F, Umviligihozo G, Kalikawe R, Datwani S, Omondi FH, Burns L, Young L, Leung V, Agafitei O, Ennis S, Dong W, Basra S, Lim LY, Ng K, Pantophlet R, Brumme CJ, Montaner JSG, Prystajecky N, Lowe CF, DeMarco ML, Holmes DT, Simons J, Niikura M, Romney MG, Brumme ZL, and Brockman MA
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- Aged, Angiotensin-Converting Enzyme 2, Antibodies, Neutralizing, Antibodies, Viral, Humans, RNA, Messenger, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Vaccines, Synthetic, mRNA Vaccines, COVID-19 prevention & control, COVID-19 Vaccines
- Abstract
Background: Third coronavirus disease 2019 (COVID-19) vaccine doses are broadly recommended, but immunogenicity data remain limited, particularly in older adults., Methods: We measured circulating antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain, ACE2 displacement, and virus neutralization against ancestral and omicron (BA.1) strains from prevaccine up to 1 month following the third dose, in 151 adults aged 24-98 years who received COVID-19 mRNA vaccines., Results: Following 2 vaccine doses, humoral immunity was weaker, less functional, and less durable in older adults, where a higher number of chronic health conditions was a key correlate of weaker responses and poorer durability. One month after the third dose, antibody concentrations and function exceeded post-second-dose levels, and responses in older adults were comparable in magnitude to those in younger adults at this time. Humoral responses against omicron were universally weaker than against the ancestral strain after both the second and third doses. Nevertheless, after 3 doses, anti-omicron responses in older adults reached equivalence to those in younger adults. One month after 3 vaccine doses, the number of chronic health conditions, but not age, was the strongest consistent correlate of weaker humoral responses., Conclusions: Results underscore the immune benefits of third COVID-19 vaccine doses, particularly in older adults., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2022
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15. Serial infection with SARS-CoV-2 Omicron BA.1 and BA.2 following three-dose COVID-19 vaccination.
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Lapointe HR, Mwimanzi F, Cheung PK, Sang Y, Yaseen F, Kalikawe R, Datwani S, Waterworth R, Umviligihozo G, Ennis S, Young L, Dong W, Kirkby D, Burns L, Leung V, Holmes DT, DeMarco ML, Simons J, Matic N, Montaner JSG, Brumme CJ, Prystajecky N, Niikura M, Lowe CF, Romney MG, Brockman MA, and Brumme ZL
- Subjects
- Angiotensin-Converting Enzyme 2, Antibodies, Viral, BNT162 Vaccine, COVID-19 Vaccines, Humans, Immunoglobulin G, SARS-CoV-2, Vaccination, COVID-19 prevention & control, Viral Vaccines
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SARS-CoV-2 Omicron infections are common among individuals who are vaccinated or have recovered from prior variant infection, but few reports have immunologically assessed serial Omicron infections. We characterized SARS-CoV-2 humoral responses in an individual who acquired laboratory-confirmed Omicron BA.1.15 ten weeks after a third dose of BNT162b2, and BA.2 thirteen weeks later. Responses were compared to 124 COVID-19-naive vaccinees. One month post-second and -third vaccine doses, the participant's wild-type and BA.1-specific IgG, ACE2-displacement and virus neutralization activities were average for a COVID-19-naive triple-vaccinated individual. BA.1 infection boosted the participant's responses to the cohort ≥95th percentile, but even this strong "hybrid" immunity failed to protect against BA.2. Reinfection increased BA.1 and BA.2-specific responses only modestly. Though vaccines clearly protect against severe disease, results highlight the continued importance of maintaining additional protective measures to counteract the immune-evasive Omicron variant, particularly as vaccine-induced immune responses naturally decline over time., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lapointe, Mwimanzi, Cheung, Sang, Yaseen, Kalikawe, Datwani, Waterworth, Umviligihozo, Ennis, Young, Dong, Kirkby, Burns, Leung, Holmes, DeMarco, Simons, Matic, Montaner, Brumme, Prystajecky, Niikura, Lowe, Romney, Brockman and Brumme.)
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- 2022
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16. Automated Library Construction and Analysis for High-Throughput Nanopore Sequencing of SARS-CoV-2.
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Coope RJN, Matic N, Pandoh PK, Corbett RD, Smailus DE, Pleasance S, Lowe CF, Ritchie G, Chorlton SD, Young M, Ally AA, Asano JK, Carlsen RE, Chahal SS, Zhao Y, Holmes DT, Romney MG, Jones SJM, and Marra MA
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- Humans, Reproducibility of Results, SARS-CoV-2 genetics, COVID-19 diagnosis, COVID-19 epidemiology, Nanopore Sequencing, Nanopores
- Abstract
Background: To support the implementation of high-throughput pipelines suitable for SARS-CoV-2 sequencing and analysis in a clinical laboratory, we developed an automated sample preparation and analysis workflow., Methods: We used the established ARTIC protocol with approximately 400 bp amplicons sequenced on Oxford Nanopore's MinION. Sequences were analyzed using Nextclade, assigning both a clade and quality score to each sample., Results: A total of 2179 samples on twenty-five 96-well plates were sequenced. Plates of purified RNA were processed within 12 h, sequencing required up to 24 h, and analysis of each pooled plate required 1 h. The use of samples with known threshold cycle (Ct) values enabled normalization, acted as a quality control check, and revealed a strong correlation between sample Ct values and successful analysis, with 85% of samples with Ct < 30 achieving a "good" Nextclade score. Less abundant samples responded to enrichment with the fraction of Ct > 30 samples achieving a "good" classification rising by 60% after addition of a post-ARTIC PCR normalization. Serial dilutions of 3 variant of concern samples, diluted from approximately Ct = 16 to approximately Ct = 50, demonstrated successful sequencing to Ct = 37. The sample set contained a median of 24 mutations per sample and a total of 1281 unique mutations with reduced sequence read coverage noted in some regions of some samples. A total of 10 separate strains were observed in the sample set, including 3 variants of concern prevalent in British Columbia in the spring of 2021., Conclusions: We demonstrated a robust automated sequencing pipeline that takes advantage of input Ct values to improve reliability., Competing Interests: Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: None declared. Consultant or Advisory Role: None declared. Stock Ownership: S.D. Chorlton, PathoGene Inc., BugSeq Bioinformatics Inc. Honoraria: None declared. Research Funding: Researchers from the St. Paul’s Hospital Department of Pathology and Laboratory Medicine have received institutional support from the Public Health Agency of Canada’s COVID-19 Immunity Task Force Hot Spots Competitive Grant, 2021-HQ-000120 (M.G. Romney, N. Matic, G. Ritchie, C.F. Lowe, M. Young), Genome BC COVID-19 rapid response grant (M.G. Romney, N. Matic, G. Ritchie, C.F. Lowe, M. Young), Genome BC Rapid SARS-CoV-2 Vaccine Research Initiative in BC (M.G. Romney and C.F. Lowe), Providence Health Care Research Institute (N. Matic), and Canada Foundation for Innovation Exceptional Opportunities Fund–COVID-19 (C.F. Lowe). M.A. Marra, S. Jones, D.E. Smailus, R. Corbett, S. Pleasance, S. Chahal, R.E. Carlsen, R.J.N. Coope, P.K. Pandoh, J. Asano, A. Ally, Y. Zhao, and Canada’s Michael Smith Genome Sciences Centre, have also received institutional support from Genome BC (COV-088), Genome Canada (262SEQ), and the Canada Foundation for Innovation and BC Knowledge Development Fund (#40991). S.D. Chorlton has received funding from the Open Philanthropy Project. Expert Testimony: None declared. Patents: None declared. Other Remuneration: D. Holmes has received travel reimbursements from AACC and MSACL., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2022
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17. Clinical Pathology and the Data Science revolution.
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Bunch DR and Holmes DT
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- 2022
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18. Older Adults Mount Less Durable Humoral Responses to a Two-dose COVID-19 mRNA Vaccine Regimen, but Strong Initial Responses to a Third Dose.
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Mwimanzi F, Lapointe HR, Cheung PK, Sang Y, Yaseen F, Umviligihozo G, Kalikawe R, Datwani S, Omondi FH, Burns L, Young L, Leung V, Agafitei O, Ennis S, Dong W, Basra S, Lim LY, Ng K, Pantophlet R, Brumme CJ, Montaner JSG, Prystajecky N, Lowe CF, DeMarco ML, Holmes DT, Simons J, Niikura M, Romney MG, Brumme ZL, and Brockman MA
- Abstract
Background: Third COVID-19 vaccine doses are broadly recommended, but immunogenicity data remain limited, particularly in older adults., Methods: We measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement, and virus neutralization against ancestral and Omicron (BA.1) strains from pre-vaccine up to one month following the third dose, in 151 adults aged 24-98 years who received COVID-19 mRNA vaccines., Results: Following two vaccine doses, humoral immunity was weaker, less functional and less durable in older adults, where a higher number of chronic health conditions was a key correlate of weaker responses and poorer durability. Third doses boosted antibody binding and function to higher levels than second-doses, and induced responses in older adults that were comparable in magnitude to those in younger adults. Humoral responses against Omicron were universally weaker than against the ancestral strain after both second and third doses; nevertheless, after three doses, anti-Omicron responses in older adults reached equivalence to those in younger adults. After three vaccine doses, the number of chronic health conditions, but not age per se, was the strongest consistent correlate of weaker humoral responses., Conclusion: Results underscore the immune benefits of third COVID-19 vaccine doses, particularly in older adults.
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- 2022
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19. Subcutaneous transplantation of human thyroid tissue into a pre-vascularized Cell Pouch™ device in a Mus musculus model: Evidence of viability and function for thyroid transplantation.
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Wiseman SM, Memarnejadian A, Boyce GK, Nguyen A, Walker BA, Holmes DT, Welch ID, Mazzuca DM, and Toleikis PM
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- Animals, Humans, Mice, Mice, Nude, Transplantation, Heterologous, Graft Survival physiology, Organ Transplantation methods, Thyroid Gland transplantation
- Abstract
This study aimed to investigate the survival and efficacy indicators of human thyroid tissue transplantation into a retrievable, prevascularized implanted Sernova Corp Cell Pouch™ (CP) device. Thyroid tissue from human donors was transplanted subcutaneously into the pre-implanted CP device or into the subcutaneous (SC) space alone as a control in a nude Mus musculus model. Transplanted M. musculus were monitored for human serum thyroglobulin (TG) levels for 3 months until the transplants were removed for histological assessment. Human thyroid tissue survived and continued to produce TG in transplanted nude M. musculus in the CP, with no adverse events. CP transplants exhibited more persistent and robust production of human TG than tissue placed in the SC space alone from 3 to 13 weeks post transplantation. Fresh thyroid transplants had better survival and function compared to cryopreserved transplants. Thyroid transplant viability correlated with TG levels at 3 months post-transplant (p = 0.03). Immunofluorescence staining of transplants for TG and TPO localized in thyroid follicles. Human thyroid tissue transplanted into the subcutaneously implanted pre-vascularized CP in nude M. musculus survived and continued to produce robust and persistent human TG and warrants further investigation as a treatment for postoperative hypothyroidism., Competing Interests: I have read the journal’s policy and the following authors of this manuscript have the following competing interests. Some of the authors of this study have a commercial affiliation with Sernova Corp as described here: SMW serves on the scientific advisory board of Sernova Corp and received an honorarium from Sernova Corp for drafting and delivery of a KOL online lecture. AM is employed as a Research Scientist at Sernova Corp and receives salary & benefits. DMM was employed as the Senior Director of R&D and Clinical Programs of Sernova Corp and received salary & benefits when this work was carried out. PMT is the President and CEO of Sernova Corp and receives salary & benefits. All other co-authors listed have declared that no competing interests exist.
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- 2022
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20. Quantitation of Thyroglobulin in Serum Using SISCAPA and Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).
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van der Gugten JG, Razavi M, and Holmes DT
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- Antibodies, Monoclonal, Autoantibodies, Chromatography, Liquid methods, Humans, Trypsin, Tandem Mass Spectrometry methods, Thyroglobulin
- Abstract
Accurate measurement of thyrogloblulin (Tg) at low concentrations is essential for recurrence-monitoring in patients who have been treated for papillary and follicular thyroid cancers. The immunoassays commonly employed by clinical laboratories to measure Tg are known to suffer interferences from thyroglobulin autoantibodies (TgAb).We describe a semiautomated stable isotope standards and capture by antipeptide antibodies (SISCAPA®) LC-MS/MS method for the accurate and precise measurement of Tg using 400 uL of serum. Following trypsin digestion of serum proteins in a 96-well plate format, a Tg-specific peptide is captured and concentrated using a monoclonal antibody bound to protein G-coated paramagnetic beads. Eighteen microliters of concentrate are injected into the LC-MS/MS system. Quantitation is performed against a 6-point linear calibration curve prepared in a blank matrix. The assay calibration range is 0.1-10 ng/mL, the range of clinical interest for recurrence detection. Total imprecision in clinical production has been observed to be 13.8% and 6.54% for in-house prepared control materials having Tg concentrations of 0.24 ng/mL and 0.94 ng/mL, respectively. Limit of quantitation was determined to be 0.1 ng/mL., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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21. Quantitation of Renin Activity in Plasma Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).
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van der Gugten JG and Holmes DT
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- Angiotensin I, Chromatography, Liquid methods, Methanol, Mineralocorticoids, Renin, Tandem Mass Spectrometry methods
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Accurate determination of plasma renin activity (PRA) is essential for the development and maintenance of an effective screening program for primary aldosteronism (PA). PRA measurement can also be useful in the investigation of renal artery stenosis, syndrome of mineralocorticoid excess, Addison's disease, congenital adrenal hyperplasia, Bartters and Gitelman syndromes, and for inherited defects in the renin angiotensin aldosterone system (RAAS). We describe a semiautomated and simple method for the accurate and precise measurement of PRA from 500 μL of plasma (250 μL if blank subtraction is omitted, as discussed) using a liquid chromatography and tandem mass spectrometry (LC-MS/MS) method for angiotensin I (AngI) in 96-well format. After a 3 h AngI generation step at 37 °C in buffering conditions at pH 6, the reaction is quenched with 10% formic acid containing AngI internal standard. Sample preparation then proceeds with offline solid phase extraction, two wash steps, and methanol elution followed by injection into the LC-MS/MS system. Quantitation is performed against a 7-point calibration linear curve prepared in buffer. The assay calibration range is 0.34-30.0 ng/mL, which corresponds to PRA values of 0.11-10.0 ng/mL/h: much wider than was possible using traditional competitive antibody-based methods. Total precision in clinical production has been observed to be 5.8-5.0% for BioRad Hypertension Control materials having nominal PRA values ranging from 1.73 to 12.43 ng/mL/h. At AngI concentrations of 0.06 ng/L (corresponding to a PRA of 0.02 ng/mL/h), signal-to-noise ratio is 50:1, indicating that the limit of quantitation is well below the level required for clinical use., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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22. Quantitation of Aldosterone in Serum or Plasma Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).
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van der Gugten JG and Holmes DT
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- Chromatography, Liquid methods, Tandem Mass Spectrometry methods, Aldosterone, Methyl Ethers
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Accurate determination of serum and plasma aldosterone is essential for screening, diagnosis, and subtype classification of primary aldosteronism (PA). Its measurement is also used in the investigation of adrenal incidentaloma, adrenal carcinoma, Addison's disease, congenital adrenal hyperplasia, renal artery stenosis, and renal tubular channelopathies. We describe a simple and robust method for the accurate and precise measurement of aldosterone in serum or plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). After addition of internal standard, aldosterone is extracted from serum samples using supported liquid extraction (SLE) with methyl tert-butyl ether (MtBE). The MtBE is evaporated to dryness, and the sample is reconstituted with mobile phase before injection onto the LC-MS/MS and quantitation using an eight-point calibration curve. The assay calibration range is approximately 50-6500 pM (0.16-234 ng/dL) with total imprecision between 6.8% and 4.1% for concentrations between about 50 and 1000 pM, respectively., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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23. Quantitation of IgG Subclasses in Serum Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).
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van der Gugten JG, Holmes DT, and Mattman A
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- Calibration, Chromatography, Liquid methods, Nephelometry and Turbidimetry, Immunoglobulin G, Tandem Mass Spectrometry methods
- Abstract
Serum IgG subclasses (IgGSC) are measured for a number of indications, but the most common are the identification of selective immunodeficiency disease and the diagnosis of IgG4-related disease (IgG4RD). Traditional nephelometric (IN) assays can suffer from two issues impacting the accuracy of the results: (1) hook effect and (2) antibody cross-reactivity between the subclasses. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is not vulnerable to these modes of interference and therefore serves as an excellent and relatively inexpensive means of diagnosing and/or monitoring the relevant clinical conditions.We describe a semiautomated and simple method for the accurate and precise measurement of IgGSC from 20 μL of serum using a liquid chromatography and tandem mass spectrometry (LC-MS/MS) method following digestion of serum proteins in 96-well plate format. Due to the high abundance of the target proteins, no specialized sample preparation (such as solid phase extraction) is required. Twenty microliters are injected to the LC-MS/MS system. Quantitation is performed against a five-point duplicate linear calibration curve prepared in blank matrix. The assay calibration range is 0.38-7.74 g/L for IgG1, 0.24-4.46 g/L for IgG2, 0.038-0.752 g/L for IgG3, 0.025-0.435 g/L for IgG4, and 0.62-15.5 g/L for total IgG. Total IgG is used as an internal quality control marker and is compared to the sum of the four subclass results. Total imprecision in clinical production has been observed to be 5.1-10.6% for in-house prepared control materials having IgGSC mean values in the range of 0.38-8.43 g/L for IgG1, 0.22-3.76 g/L for IgG2, 0.0387-0.721 g/L for Ig3, and 0.0279-1.46 g/L for IgG4. Limit of quantitation (LoQ) was determined to be 0.29 g/L for IgG1, 0.22 g/L for IgG2, 0.019 g/L for IgG3, and 0.0067 g/L for IgG4., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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24. Continuous reference intervals for pediatric testosterone, sex hormone binding globulin and free testosterone using quantile regression.
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Holmes DT, van der Gugten JG, Jung B, and McCudden CR
- Abstract
Testosterone (T), sex hormone binding globulin (SHBG), free testosterone (FT) and bioavailable testosterone (BAT) are commonly employed tests in pediatric endocrinology and all require age-dependent reference intervals for interpretation. The common methods used to derive these reference intervals require decisions about data shape and/or age partition thresholds, which can result in sharp differences between age groups, particularly for pubescent children. Partitioning also results in a form of data loss, where data from one age-bin is completed disconnected from the adjacent age-bins. Non-parametric continuous reference intervals methods have previously been developed to avoid some of these drawbacks. These strategies use all the available data and smooth transitions between ages avoiding partitioning. However, the fitting process involves selection and adjustment of many parameters and it can be difficult to maintain a reproducible approach. Here we provide a workflow for non-parametric continuous reference intervals applied to T, FT, BAT, and SHBG using the R language quantregGrowth package. T measurements were determined by LC-MS/MS, FT and BAT were calculated, and SHBG was measured on the Roche Cobas e601. The continuous interval methodology is described in detail with code examples and illustrations for reproducibility., (©2021THEAUTHORS.PublishingservicesbyELSEVIERB.V.)
- Published
- 2021
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25. Clinical Trials, Potential Mechanisms, and Adverse Effects of Arnica as an Adjunct Medication for Pain Management.
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Smith AG, Miles VN, Holmes DT, Chen X, and Lei W
- Abstract
Arnica has traditionally been used in treating numerous medical conditions, including inflammation and pain. This review aims to summarize the results of studies testing Arnica products for pain management under different conditions, including post-operation, arthritis, low back pain, and other types of musculoskeletal pain. Based on data from clinical trials, Arnica extract or gel/cream containing Arnica extract shows promising effects for pain relief. These medical benefits of Arnica may be attributed to its chemical components, with demonstrated anti-inflammatory, antioxidant, anti-microbial, and other biological activities. In conclusion, Arnica could be an adjunct therapeutical approach for acute and chronic pain management.
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- 2021
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26. Reproducible manuscript preparation with RMarkdown application to JMSACL and other Elsevier Journals.
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Holmes DT, Mobini M, and McCudden CR
- Abstract
Introduction: With the rising complexity of modern multimarker analytical techniques and notable scientific publication retractions required for erroneous statistical analysis, there is increasing awareness of the importance of research transparency and reproducibility. The development of mature open-source tools for literate programming in multiple langauge paradigms has made fully-reproducible authorship possible., Objectives: We describe the procedure for manuscript preparation using RMarkdown and the R statistical programming language with application to JMSACL or any other Elsevier journal., Methods: An instructional manuscript has been prepared in the RMarkdown markup language with stepwise directions on preparing sections, subsections, lists, tables, figures and reference management in an entirely reproducible format., Results: From RMarkdown code, a submission-ready PDF is generated and JMSACL-compatible LaTeX code is generated. These can be uploaded to the Editorial Manager., Conclusion: A completely reproducible manuscript preparation pipeline using the R and RMarkdown is described., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 THE AUTHORS.)
- Published
- 2021
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27. Data Mining Approaches to Reference Interval Studies.
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Obstfeld AE, Patel K, Boyd JC, Drees J, Holmes DT, Ioannidis JPA, and Manrai AK
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- Humans, Reference Values, Data Mining
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- 2021
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28. Canadian Urological Association guideline on testosterone deficiency in men: Evidence-based Q&A.
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Grober ED, Krakowsky Y, Khera M, Holmes DT, Lee JC, Grantmyre JE, Patel P, Bebb RA, Fitzpatrick R, Campbell JD, Carrier S, and Morgentaler A
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- 2021
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29. Systemic absorption of intranasal corticosteroids may occur and can potentially affect the hypothalamic-pituitary-adrenal axis.
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Kline GA, Symonds CJ, and Holmes DT
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- Absorption, Physiological, Administration, Intranasal, Adrenal Cortex Hormones, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2021
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30. Method Limitations in LC-MS/MS and Immunonephelometric Measurement of IgG Subclasses.
- Author
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van der Gugten G, Mattman A, Ritchie G, Chen LYC, Chin A, Holmes DT, Mills JR, and Rao LV
- Subjects
- Amino Acid Sequence, False Positive Reactions, Humans, Immunoglobulin G classification, Immunoglobulin G genetics, Paraproteinemias blood, Polymorphism, Single Nucleotide, Chromatography, Liquid methods, Immunoglobulin G blood, Immunoturbidimetry methods, Tandem Mass Spectrometry methods
- Published
- 2021
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31. Proteomic applications in pathology and laboratory medicine: Present state and future prospects.
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Holmes DT, Romney MG, Angel P, and DeMarco ML
- Subjects
- Chemistry, Clinical methods, Chromatography, Liquid methods, Drug Monitoring methods, Forecasting, Humans, Immunoprecipitation methods, Microbiological Techniques, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization methods, Tandem Mass Spectrometry methods, Diagnostic Tests, Routine methods, Diagnostic Tests, Routine trends, Pathology methods, Proteomics methods, Proteomics trends
- Abstract
Clinical mass spectrometry applications have traditionally focused on small molecules, particularly in the areas of therapeutic drug monitoring, toxicology, and measurement of endogenous and exogenous steroids. More recently, the use of matrix assisted laser desorption/ionization time of flight mass spectrometry for the identification of microbial pathogens has been widely implemented. Following this evolution, there has been an expanding role for the measurement of peptides and proteins in pathology and laboratory medicine. This review explores the current state of protein measurement by clinical mass spectrometry and the analytical strategies employed, as well as emerging applications in clinical chemistry, clinical microbiology and anatomical pathology., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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32. In IgG4 related disease, elevated IgG2 is an artifact not a biomarker.
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Mattman A, Chen LYC, van der Gugten G, Chin A, Carruthers M, DeMarco ML, and Holmes DT
- Subjects
- Artifacts, Biomarkers, Humans, Immunoglobulin G, Immunoglobulin G4-Related Disease
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- 2020
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33. Self-Ordering Laboratory Testing: Limitations When a Physician Is not Part of the Model.
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Holmes DT
- Subjects
- Genetic Testing standards, Genomics standards, Humans, United States, United States Food and Drug Administration, Direct-To-Consumer Screening and Testing standards
- Abstract
This review discusses considerations related to laboratory diagnostic testing purchased directly by consumers without the care and oversight of a medical doctor. There are necessary tensions between the patient, physician, laboratory medical professional (physician or scientist), laboratory as a corporate entity (where applicable), and manufacturers of diagnostic equipment. When the physician, in particular, the primary care physician, is removed from this relationship, there is a significant opportunity of exploitation of the patient. All downstream investigations following direct-to-consumer testing, including attendant risk, are offloaded onto the traditional medical system, caring physician(s), and patients themselves. This process places patients at risk of iatrogenic harm., Competing Interests: Disclosure Dr D.T. Holmes provides clinical mass spectrometry consultation to Dian Diagnostics in Hangzhou, China., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2020
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34. Your results may vary: the imprecision of medical measurements.
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McCormack JP and Holmes DT
- Subjects
- Adaptor Proteins, Vesicular Transport blood, Bone Density drug effects, Bone Density Conservation Agents pharmacology, Clinical Laboratory Techniques standards, Diabetes Mellitus, Type 2 diagnosis, Diagnostic Errors, Diphosphonates pharmacology, Drug Monitoring methods, Glycated Hemoglobin metabolism, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Reproducibility of Results, Uncertainty, Biomarkers metabolism, Diagnostic Tests, Routine standards
- Abstract
Competing Interests: Competing interests: We have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare.
- Published
- 2020
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35. Reproducible Research and Reports with R.
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Simons JE and Holmes DT
- Subjects
- Data Analysis, Humans, Reproducibility of Results, Research standards, Research Report standards, Software
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- 2019
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36. Correct implementation of the Hoffmann method.
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Holmes DT
- Subjects
- Laboratories, Reference Values, Clinical Laboratory Services
- Published
- 2019
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37. Widespread Implementation of the Hoffmann Method: A Second Opinion.
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Katayev A, Fleming JK, Holmes DT, and Buhr KA
- Subjects
- Humans, Referral and Consultation, Research Design
- Published
- 2019
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38. A brief update on mass spectrometry applications to routine clinical endocrinology.
- Author
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Holmes DT
- Abstract
Mass spectrometry in clinical laboratories has traditionally focussed on small molecule analysis making endocrinology applications a natural choice given the numerous diagnostic targets in the steroid family, many of which could be multiplexed. Over time, methods for lower abundance steroids were successfully translated meaning that almost all small molecule targets in clinical endocrinology could be performed using mass spectrometry. This has paved the way for standardization efforts which have ultimately forced the improvements in the immunoassay industry. More recently, however improvements in quantitative mass spectrometric protein workflows have permitted the translation of a number of specific protein targets into routine analysis. In addition to the benefits in analytical specificity, judicious selection of peptide targets has permitted simultaneous quantitation and phenotyping in some cases. Mass spectrometry continues to clarify previously unnoticed but significant analytical problems with commercial immunoassays and permits the investigation of interferences in individual patient cases on an ad hoc basis., (© 2019 The Association for Mass Spectrometry: Applications to the Clinical Lab (MSACL). Published by Elsevier B.V.)
- Published
- 2019
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39. Surprisingly low aldosterone levels in peripheral veins following intravenous sedation during adrenal vein sampling: implications for the concept of nonsuppressibility in primary aldosteronism.
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Kline GA, Darras P, Leung AA, So B, Chin A, and Holmes DT
- Subjects
- Administration, Intravenous, Adrenal Glands blood supply, Blood Specimen Collection, Humans, Aldosterone blood, Hyperaldosteronism blood, Hyperaldosteronism physiopathology, Hypnotics and Sedatives administration & dosage, Hypnotics and Sedatives adverse effects
- Abstract
Background: Constituitively high and nonsuppressible aldosterone levels are considered to be the hallmark of primary aldosteronism. We observed a high proportion of primary aldosteronism patients with surprisingly low aldosterone levels in peripheral veins during adrenal vein sampling (AVS) and sought to further characterize the phenomenon., Methods: Database analysis of patients with primary aldosteronism at the University of Calgary who underwent AVS under intravenous sedation. Aldosterone levels following sedation were compared with aldosterone measured at diagnosis in the free-living state. A validation analysis was performed on a similar database from the University of British Columbia., Results: Seventy-two percent of 127 patients had AVS aldosterone levels more than 30% lower than their outpatient aldosterone measure (468 vs. 278 pmol/l, P < 0.001). Thirty-nine percent of patients had aldosterone levels less than 200 pmol/l and 13% had levels less than 140 pmol/l during AVS. Repeat analysis on the UBC cohort produced similar results with 88% having an aldosterone more than 30% lower than the outpatient measure (median aldosterone 568 vs. 201 pmol/l, P < 0.001)., Conclusion: A majority of primary aldosteronism patients have markedly lower aldosterone levels during sedated AVS compared with those found during outpatient diagnosis. In the absence of confounding medications, hypokalemia, circadian timing, postural variation and with low correlation to measures of hypothalamic-pituitary-adrenal activity, this suggests that many primary aldosteronism patients may, at times, have aldosterone levels that are surprisingly low-normal. This finding challenges the concept that a persistently high and nonsuppressible aldosterone level is a sine qua non of primary aldosteronism.
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- 2019
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40. Widespread Incorrect Implementation of the Hoffmann Method, the Correct Approach, and Modern Alternatives.
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Holmes DT and Buhr KA
- Subjects
- Computer Simulation, Humans, Likelihood Functions, Male, Probability, Reference Values, Statistics as Topic, Models, Statistical, Research Design
- Abstract
Objectives: The Hoffmann method is a procedure for reference interval estimation using routine clinical results. Many authors incorrectly prepare Hoffmann plots on a linear rather than normal probability scale. We explore the consequences., Methods: This was investigated algebraically, by random number simulations (45 simulations, n = 100,000 each) and using clinical data sets. Strategies compared were: Hoffmann's method as originally and incorrectly implemented, Bhattacharya's method, and maximum likelihood (ML). All R source code and data sets are provided., Results: As the proportion of healthy individuals approaches 1, the incorrect approach generates reference interval estimates of approximately μH ± 1.19 σH delineating the central 77% of the healthy subpopulation, not the central 95%. Inappropriately narrow reference interval estimates were seen on random simulations and clinical data sets. ML methods performed best., Conclusions: The erroneous variant Hoffmann method should not be used. ML methods outperform others and are not restricted by Gaussian assumptions.
- Published
- 2019
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41. Comparison of four clinically validated testosterone LC-MS/MS assays: Harmonization is an attainable goal.
- Author
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French D, Drees J, Stone JA, Holmes DT, and van der Gugten JG
- Abstract
Introduction: Immunoassays and liquid chromatography-tandem mass spectrometry assays are commonly employed in clinical laboratories for measurement of total testosterone in serum. Results obtained from either of these methodologies compare poorly due to differences in calibration and/or inadvertent detection of interfering substances by the immunoassays. Standardization efforts are underway, but recent studies indicate that accuracy remains an issue., Methods: This study compares the results from four independently developed and validated LC-MS/MS assays for total testosterone. The calibration for each assay was verified using National Institute of Standards and Technology Standard Reference Material 971., Results: Initially, one of the four assays had a mean percent difference of +11.44%, compared to the All Method Mean, but following re-verification of all five non-zero calibrator concentrations with the NIST SRM 971, the mean percent difference decreased to -4.88%. Subsequently, the agreement between all four assays showed a mean bias of <5% across the range of all testosterone concentrations (0.13-38.10 nmol/L; 3.7-1098 ng/dL), including at low concentrations of <1 nmol/L (<29 ng/dL)., Conclusions: Excellent agreement between four independently developed LC-MS/MS assays demonstrates that harmonization using standard reference material is attainable. However, as we found in this study, to ensure accurate calibration it is critical to validate the concentrations of new lots of calibrators., (© 2019 The Association for Mass Spectrometry: Applications to the Clinical Lab (MSACL). Published by Elsevier B.V.)
- Published
- 2018
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42. Thyrotoxicosis due to 1000-fold error in compounded liothyronine: A case elucidated by mass spectrometry.
- Author
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Khan W, Van Der Gugten G, and Holmes DT
- Abstract
Background: Thyrotoxicosis attributable exclusively to triiodothyronine (T3) is, by necessity, caused by accidental or intentional ingestion of pharmaceutical preparations. The clinical presentation of T3 overdose appears to differ from classic thyroid storm., Case: A 30-year-old female patient presented serially to the emergency department with headache, nausea and vomiting. Neurological work-up was negative and she was treated for presumed viral gastroenteritis. Eventually she developed confusion and was admitted. Laboratory investigations showed a suppressed TSH and a free T3 above the linear range (>30 pmol/L), estimated by dilution in normal serum to be 330 pmol/L. She was diagnosed with thyrotoxicosis secondary to recently prescribed compounded liothyronine and was treated with seven rounds of plasmapheresis. Using a rapidly developed mass spectrometric method for T3, it was determined that compounding pharmacy had dispensed liothyronine at a concentration ≃ 1000 -times the prescribed dosage., Conclusion: The clinical and mass spectrometry laboratories played an essential role in the diagnosis of thyroid storm in this case of T3 overdose as the expected clinical features of hyperpyrexia, tachycardia and hypertension were initially absent., (© 2018 The Association for Mass Spectrometry: Applications to the Clinical Lab (MSACL). Published by Elsevier B.V.)
- Published
- 2018
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43. Sex Differences in Cardiac Troponin Testing in Patients Presenting to the Emergency Department with Chest Pain.
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Humphries KH, Gao M, Lee MK, Izadnegahdar M, Holmes DT, Scheuermeyer FX, Mackay M, Mattman A, and Grafstein E
- Subjects
- Adult, Angina Pectoris epidemiology, Canada epidemiology, Cardiac Catheterization methods, Cardiac Catheterization statistics & numerical data, Electrocardiography methods, Electrocardiography statistics & numerical data, Emergency Service, Hospital statistics & numerical data, Female, Humans, Male, Middle Aged, Myocardial Infarction epidemiology, Sex Factors, Triage methods, Triage statistics & numerical data, Angina Pectoris diagnosis, Chest Pain blood, Chest Pain diagnosis, Chest Pain epidemiology, Myocardial Infarction diagnosis, Troponin blood
- Abstract
Background: Elevated cardiac troponin (cTn), with signs/symptoms of ischemia, is a key element in a diagnosis of myocardial infarction (MI). Underdiagnosis of MI in women has been attributed to atypical symptoms, inconsistent ECG findings, and less diagnostic testing. We sought to determine if there are sex differences in cTn testing following presentation to the emergency department (ED) with a chief complaint of ischemic chest pain (CP) and if presentation affects diagnostic assessment., Methods: All adults presenting to six hospital EDs in the Vancouver, Canada with a chief complaint of ischemic CP from 2009 to 2013 were included. The highest cTn level within 24 hours of ED presentation was used. CP was classified into cardiac- or respiratory dominant based on standard Canadian Emergency Department Triage and Acuity Scale coding. Chi-square testing was used to test for sex differences in CP categories and cTn testing within 24 hours. Logistic regression models were used to examine the association between sex, cTn testing, and CP categories., Results: Of 27,063 patients with ischemic CP, cardiac presentation was more common in men than women, irrespective of age. Among cardiac CP, 24.7% of men were <50 years compared to 18.2% of women; however, more women (19.9%) than men (11.6%) were >80 years. Overall, women were 1.8% less likely to have cTn testing; in patients <50 years, testing was markedly lower in women compared to men [odds ratio, OR (95% confidence intervals, CI) 0.78 (0.70-0.87)]. The odds of cardiac catheterization within 90 days of ED presentation were lower in women [OR, (95% CI) 0.52 (0.44-0.63)]. Even with cardiac CP, 17.7% of women versus 32.7% of men had cardiac catheterization., Conclusions: In men and women presenting to the ED with ischemic CP, cTn testing overall is similar except among young women under 50 years old, where it is markedly lower. Women undergo less cardiac catheterization, irrespective of CP type.
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- 2018
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44. Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity.
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Carter RLR, Talbot K, Hur WS, Meixner SC, Van Der Gugten JG, Holmes DT, Côté HCF, Kastrup CJ, Smith TW, Lee AYY, and Pryzdial ELG
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- Administration, Oral, Anticoagulants chemistry, Blood Coagulation drug effects, Catalytic Domain, Cross-Linking Reagents chemistry, Factor Xa Inhibitors pharmacology, Fibrin chemistry, Fibrinolysin chemistry, Fibrinolysis, Humans, Phospholipids chemistry, Thrombin chemistry, Thrombolytic Therapy, Thrombosis, Tissue Plasminogen Activator chemistry, Factor Xa chemistry, Pyrazoles pharmacology, Pyridones pharmacology, Rivaroxaban pharmacology
- Abstract
Essentials Activated clotting factor X (FXa) acquires fibrinolytic cofactor function after cleavage by plasmin. FXa-mediated plasma fibrinolysis is enabled by active site modification blocking a second cleavage. FXa-directed oral anticoagulants (DOACs) alter FXa cleavage by plasmin. DOACs enhance FX-dependent fibrinolysis and plasmin generation by tissue plasminogen activator., Background: When bound to an anionic phospholipid-containing membrane, activated clotting factor X (FXa) is sequentially cleaved by plasmin from the intact form, FXaα, to FXaβ and then to Xa33/13. Tissue-type plasminogen activator (t-PA) produces plasmin and is the initiator of fibrinolysis. Both FXaβ and Xa33/13 enhance t-PA-mediated plasminogen activation. Although stable in experiments using purified proteins, Xa33/13 rapidly loses t-PA cofactor function in plasma. Bypassing this inhibition, covalent modification of the FXaα active site prevents Xa33/13 formation by plasmin, and the persistent FXaβ enhances plasma fibrinolysis. As the direct oral anticoagulants (DOACs) rivaroxaban and apixaban bind to the FXa active site, we hypothesized that they similarly modulate FXa fibrinolytic function., Methods: DOAC effects on fibrinolysis and the t-PA cofactor function of FXa were studied in patient plasma, normal pooled plasma and purified protein experiments by the use of light scattering, chromogenic assays, and immunoblots., Results: The plasma of patients taking rivaroxaban showed enhanced fibrinolysis correlating with FXaβ. In normal pooled plasma, the addition of rivaroxaban or apixaban also shortened fibrinolysis times. This was related to the cleavage product, FXaβ, which increased plasmin production by t-PA. It was confirmed that these results were not caused by DOACs affecting activated FXIII-mediated fibrin crosslinking, clot ultrastructure and thrombin-activatable fibrinolysis inhibitor activation in plasma., Conclusion: The current study suggests a previously unknown effect of DOACs on FXa in addition to their well-documented anticoagulant role. By enabling the t-PA cofactor function of FXaβ in plasma, DOACs also enhance fibrinolysis. This effect may broaden their therapeutic indications., (© 2018 International Society on Thrombosis and Haemostasis.)
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- 2018
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45. Migration from RIA to LC-MS/MS for aldosterone determination: Implications for clinical practice and determination of plasma and urine reference range intervals in a cohort of healthy Belgian subjects.
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Le Goff CM, Gonzalez-Antuña A, Peeters SD, Fabregat-Cabello N, Van Der Gugten JG, Vroonen L, Pottel H, Holmes DT, and Cavalier E
- Abstract
Background: Aldosterone measurement is critical for diagnosis of primary aldosteronism and disorders of the renin-angiotensin system. We developed an LC-MS/MS method for plasma and urinary aldosterone and compared it to our RIA method. We present a reference interval study for a Belgian population., Methods: 68 plasma and 23 urine samples were assayed for as part of a method comparison. For the reference interval study, we enrolled 282 healthy Caucasian volunteers (114 Male: mean age 35 ± 11 y and 168 Female: mean age 42 ± 13 y). A subset of 139 healthy volunteers agreed to a 24-h urine collection. For the method validation, 5 plasma and 8 urine pools were run in triplicate and quadruplicate, respectively, on 3 different days., Results: Between-run imprecision (CV) was 2.8-5.1% for plasma and 4.5-8.6% for urine, except at the low urine concentration of 2.99 nmol/L where a CV of 15.4% was observed. The limit of quantitation was 0.04 nmol/L for plasma and 6.65 nmol/L for urine. Recoveries, based on spiking experiments into natural matrix, did not differ significantly from 100%. Regression comparisons showed that, on average, RIA generated results were 59% and 11% higher than LC-MS/MS for plasma and urine, respectively. The MS reference interval we propose for plasma aldosterone is 0.07 nmol/L-0.73 nmol/L for women and 0.04 nmol/L-0.41 nmol/L for men. No gender difference was observed for urine aldosterone. The reference interval was determined to be <60.94 nmol/day., Conclusions: The LC-MS/MS method was validated and reference intervals for plasma and urine were established. A significant bias between RIA and LC-MS/MS was noted., (© 2018 Published by Elsevier B.V. on behalf of The Association for Mass Spectrometry: Applications to the Clinical Lab (MSACL).)
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- 2018
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46. Concentrations of Trace Elements and Clinical Outcomes in Hemodialysis Patients: A Prospective Cohort Study.
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Tonelli M, Wiebe N, Bello A, Field CJ, Gill JS, Hemmelgarn BR, Holmes DT, Jindal K, Klarenbach SW, Manns BJ, Thadhani R, and Kinniburgh D
- Subjects
- Humans, Logistic Models, Prospective Studies, Renal Dialysis adverse effects, Trace Elements analysis
- Abstract
Background and Objectives: Deficiency of essential trace elements and excess of potentially toxic trace elements are common in patients on hemodialysis. Whether these abnormalities are associated with poor outcomes is unknown but worth investigating, because they are potentially treatable., Design, Setting, Participants, & Measurements: We did a prospective longitudinal study of 1278 patients on incident hemodialysis, assessing blood concentrations of 25 trace elements at baseline. We used adjusted logistic regression to evaluate the association between trace element status and four outcomes (death, cardiovascular events, systemic infection, and hospitalization). A priori hypotheses concerned ( 1 ) deficiency of zinc, selenium, and manganese and ( 2 ) excess of lead, arsenic, and mercury. Concentrations of the other 19 elements were tested in hypothesis-generating analyses., Results: Over 2 years of follow-up, 260 (20%) patients died, 285 (24%) experienced a cardiovascular event, 117 (10%) were hospitalized for systemic infection, and 928 (77%) were hospitalized for any cause. Lower concentrations of zinc or manganese and higher concentrations of lead, arsenic, or mercury were not independently associated with higher risk of clinical outcomes. Lower concentrations of selenium were strongly and independently associated with death (odds ratio, 0.86 per decile; 99.2% confidence interval, 0.80 to 0.93) and all-cause hospitalization (odds ratio, 0.92 per decile; 99.2% confidence interval, 0.86 to 0.98). In exploratory analyses, higher copper concentrations were significantly associated with higher risk of death (odds ratio, 1.07 per decile; 99.2% confidence interval, 1.00 to 1.15), and cadmium levels in the highest decile were associated with higher risk of death (odds ratio, 1.89; 99.2% confidence interval, 1.06 to 3.38)., Conclusions: Lower levels of zinc or manganese and higher concentrations of lead, arsenic, or mercury were not associated with higher risk of clinical outcomes, but lower concentrations of selenium were strongly and independently associated with the risks of death and hospitalization., (Copyright © 2018 by the American Society of Nephrology.)
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- 2018
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47. Comment on: IgG4-related disease presenting with raised serum IgG2-real timeline of IgG4-RD?
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Mattman A, Chen LYC, van der Gugten G, Chin A, Carruthers M, DeMarco ML, and Holmes DT
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- Humans, Autoimmune Diseases, Immunoglobulin G
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- 2018
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48. Resolution of Spurious Immunonephelometric IgG Subclass Measurement Discrepancies by LC-MS/MS.
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van der Gugten G, DeMarco ML, Chen LYC, Chin A, Carruthers M, Holmes DT, and Mattman A
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- Female, Humans, Limit of Detection, Male, Chromatography, Liquid methods, Immunoglobulin G blood, Immunoglobulin G classification, Immunoturbidimetry methods, Tandem Mass Spectrometry methods
- Abstract
Background: The Binding Site immunonephelometric (IN) IgG subclass reagents (IgG1, IgG2, IgG3, IgG, BSIN) are used for assessment of both immunodeficiency and IgG4-related disease (IgG4-RD). In our laboratory, suspected analytic errors were noted in patients with increases in IgG4: The sum of the individual IgG subclasses was substantially greater than the measured total IgG concentrations (unlike samples with normal IgG4), and the IgG4 concentration was always less than the IgG2 concentration., Methods: We developed a tryptic digest LC-MS/MS method to quantify IgG1, IgG2, IgG3, and IgG4 in serum. Samples with IgG4 concentrations ranging from <0.03 g/L to 32 g/L were reanalyzed by LC-MS/MS, and a subset was also reanalyzed by Siemens IN (SIN) subclass measurements., Results: Multivariate linear regression identified 3 subclass tests with multiple predictors of the measured subclass concentration. For these 3 subclasses, the predominant predictors were (in terms of LC-MS/MS IgG subclass measurement coefficients) BSIN IgG1 = 0.89·IgG1 + 0.4·IgG4; BSIN IgG2 = 0.94·IgG4 + 0.89·IgG2; and SIN IgG2 = 0.72·IgG2 + 0.24·IgG4., Conclusions: There is apparent IgG4 cross-reactivity with select IN subclass measurements affecting tests from both vendors tested. These findings can be explained either by direct cross-reactivity of the IN reagents with the IgG4 subclass or unique physicochemical properties of IgG4 that permit nonspecific binding of IgG4 heavy chain to other IgG immunoglobulin heavy chains. Irrespective of the mechanism, the observed intermethod discrepancies support the use of LC-MS/MS as the preferred method for measurement of IgG subclasses when testing patients with suspected IgG4-RD., (© 2018 American Association for Clinical Chemistry.)
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- 2018
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49. Sex Differences in Diagnoses, Treatment, and Outcomes for Emergency Department Patients With Chest Pain and Elevated Cardiac Troponin.
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Humphries KH, Lee MK, Izadnegahdar M, Gao M, Holmes DT, Scheuermeyer FX, Mackay M, Mattman A, and Grafstein E
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- Adult, Age Factors, Aged, Canada epidemiology, Cardiovascular Diseases epidemiology, Chest Pain epidemiology, Chest Pain therapy, Female, Hospitalization, Humans, Male, Middle Aged, Myocardial Infarction epidemiology, Myocardial Infarction therapy, Proportional Hazards Models, Sex Factors, Chest Pain diagnosis, Emergency Service, Hospital statistics & numerical data, Myocardial Infarction diagnosis, Troponin I blood
- Abstract
Objective: While sex differences in the treatment and outcomes of subjects with acute coronary syndromes are well documented, little is known about the impact of cardiac troponin (cTn) levels obtained in the emergency department (ED) on the observed sex differences. We sought to determine whether cTn levels by chest pain features modify sex differences in diagnosis, treatment, and outcomes in patients presenting with chest pain suggestive of ischemia., Methods: All adults presenting to two hospitals in Vancouver, Canada, between May 2008 and March 2013 with ischemic chest pain and with cTn testing were included in the study. Outcomes were obtained through data linkage with population-based administrative data sets, including Vital Statistics (death), Discharge Abstract Database (hospitalizations), and PharmaNet (medications). Cumulative event rates for the composite major adverse cardiac event (MACE) endpoint (death, myocardial infarction [MI], incident admission for heart failure or for angina requiring diagnostic catheterization or revascularization) were estimated for each sex and cTn level using the Kaplan-Meier method; Cox models were used to estimate hazard ratios and 95% confidence interval (CIs) for 1-year MACE and 7-day catheterization. Logistic models were used to estimate odds ratios (ORs) and 95% CI for 90-day medication use., Results: Over the 5-year study period, 25,539 patients presented to the ED with chest pain of which 7,272 (2,933 females and 4,339 males) met the inclusion criteria. Among patients with chest pain with cardiac features/history and cTn > 99th percentile, females were less likely to be diagnosed with MI (46.4% vs. 57.5%). Females in the cTnI > 99th percentile group had the worst outcomes with a 1-year MACE rate of 22.7% (95% CI = 18.5-27.7) versus 18.8% (95% CI = 16.2-21.6), although this difference was attenuated and not statistically significant after adjustment for baseline differences. Overall, females underwent fewer diagnostic catheterizations than males within 7 days of admission to the ED. Even when cTn was above the 99th percentile and the chest pain was cardiac in nature, 48.4% of females underwent a diagnostic catheterization compared to 64.3% of males (p < 0.001). Within 90 days of discharge, females were less likely to use the evidence-based cardiac medications. The most striking sex differences were noted when cTnI levels were > 99th percentile and when the chest pain was cardiac in nature; males filled 25% more prescriptions for statins than their female counterparts. Adjustment for baseline differences did not attenuate this difference., Conclusions: Sex differences in diagnosis and treatment after presentation to the ED with chest pain are not explained by differences in chest pain features or levels of cTn. Even when females have cardiac chest pain and cTn levels > 99th percentile, they are less likely to be diagnosed with MI, less likely to undergo diagnostic cardiac catheterization within 7 days, and less likely to use evidence-based cardiac medications, but they have the highest 1-year MACE rate. The higher MACE rate appears to be driven by the higher burden of comorbid conditions., (© 2017 by the Society for Academic Emergency Medicine.)
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- 2018
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50. Performance characteristics of the Beckman Coulter UniCel DxI 800 TSH (3rd IS) assay.
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Winston-McPherson GN, Samraj AN, Poster K, Yamaguchi D, Dickerson JA, Drees JC, Holmes DT, and Greene DN
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- Bias, Calibration, Clinical Laboratory Techniques standards, Humans, Quality Control, Reproducibility of Results, Clinical Laboratory Techniques instrumentation, Thyrotropin analysis
- Abstract
Introduction: Beckman Coulter recently reformulated their commercial TSH assay with primary calibration to the World Health Organization 3rd TSH international standard. An extensive evaluation of the performance characteristics for this assay was completed., Methods: Intra-day and inter-day precision was evaluated using 3 concentrations of commercial quality control material. Linearity, reportable range, stability, sensitivity and susceptibility to common inferences were determined using pooled patient specimens. Inter-assay variability was assessed across 5 different platforms (n=47 patient specimens)., Results: Intra-day and inter-day CVs were <10% at all concentrations evaluated. The LOQ, LOD and LOB were 0.0047μIU/ml (10% CV), 0.0012μIU/ml and 0.0005μIU/ml, respectively. Variable bias was observed for the TSH3 assay when evaluated against the previous generation assay and other platforms, but overall TSH3 gave comparable results., Conclusions: The TSH3 assay for UniCel DxI 800, is precise, highly sensitive and comparable to the previous generation assay. The assay is acceptable for clinical testing., (Copyright © 2018 Elsevier B.V. All rights reserved.)
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- 2018
- Full Text
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