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Abstract: Background: Tacrolimus, a widely used immunosuppressant, inhibits T-lymphocyte signal transduction and cytokine upregulation. We evaluated and compared the performance of a newly developed tacrolimus immunoassay method to LC–MS/MS. Method: Analytical performance was assessed using quality control materials and whole blood patient samples. Interferences studies were performed using pooled whole-blood samples spiked with each interferent, respectively. Comparison studies were conducted using 145 de-identified whole blood samples collected after routine tacrolimus analysis by LC–MS/MS. Results: CVs were between 3.9 and 8.1% and the method was linear (r 2 =0.99) up to 30.0ng/ml. Calibration was stable ≤12days and LOQ was 0.7ng/ml (14.4% CV). Bilirubin (≤48mg/dl), hemoglobin (≤345mg/dl), and triglycerides (<2800mg/dl) showed no significant interference. Comparison (Passing–Bablok regression) for all samples showed a proportional bias of 17%. Comparisons of liver and kidney transplant patients showed slope biases of 22% and 31%, respectively, whereas other remaining transplant patients (stem cell, heart, lung, and islet) showed a slope bias of 0.98. Conclusions: Overall, the QMS Tacrolimus Immunoassay showed good analytical performance. Comparison studies showed a proportional bias of 17%, which can be attributed to the significant number of liver and kidney transplant patients present in this study (121/145). [Copyright &y& Elsevier]

Background: Interleukin-6 (IL-6) is a proinflammatory cytokine that is associated with many inflammatory diseases. This validation study evaluates the automated Roche Elecsys IL-6 electrochemiluminescent immunoassay that has been granted emergency use authorization by the US Food and Drug Administration., Methods: The Elecsys IL-6 assay was evaluated for precision, linearity, interference (by hemoglobin, bilirubin, triglycerides, and biotin) and clinical performance was compared to the V-PLEX Human IL-6 immunoassay (Meso Scale Discovery), performed by a reference laboratory., Results: The Elecsys IL-6 assay is precise (intra-assay <3% coefficient of variation [CV], interassay <5% CV), exhibits an analytical measurable range of 1.5-4790 pg/mL, and is tolerant of significant interferences (H < 2522, I <62, L<2101, biotin <50 ng/mL). Comparison with the V-PLEX assay revealed a 2.95 slope bias in patient samples evaluated for IL-6 concentration (n = 43, range = 1.5-1891 pg/mL, y = 2.95x - 32.7, r2 = 0.84). Bland-Altman analysis revealed an absolute mean bias of 152 pg/mL (SD = 254 pg/mL), or a mean percentage difference of 73%., Conclusion: The Roche IL-6 assay showed good analytical performance. The large systematic bias compared with another reference method precludes using multiple methods to monitor IL-6 response. The random-access nature of an automated IL-6 assay on the Roche platform makes the test available on demand., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: This study evaluated the suitability and accuracy of the automated Roche Elecsys tacrolimus electrochemiluminescence immunoassay (ECLIA) by comparing it with a current laboratory-developed test by liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Methods: The tacrolimus ECLIA was evaluated for precision, linearity, interference, and postextraction stability. Accuracy was compared with LC-MS/MS., Results: The tacrolimus ECLIA assay is precise, exhibits a measuring range of 0.75 to 30 ng/mL, and is tolerant of significant interferences (plasma indices: hemolysis <2306, icterus <55, lipemia <1427, and biotin <1200 ng/mL). Comparison with LC-MS/MS revealed a 26% proportional bias in patient samples evaluated for tacrolimus concentration (y = 1.26x + 0.08; r2 = 0.97; Sy/x = 0.94; n = 43) and an absolute mean (SD) bias of 2.2 (1.7) ng/mL. Postextraction studies confirmed that samples were stable for up to 30 minutes under routine laboratory conditions., Conclusions: The 2 major challenges for implementation of the tacrolimus ECLIA assay are the postextraction sample stability and the significant proportional bias observed compared with the LC-MS/MS reference method. The 30-minute window for analysis of extracted samples is a practical challenge to the routine workflow of the core laboratory. In addition, disagreement between the immunoassay and LC-MS/MS methods can lead to discordant clinical interpretations and ultimately affect patient care., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Substance use trends are complex; they often rapidly evolve and necessitate an intersectional approach in research, service, and policy making. Current and emerging digital tools related to substance use are promising but also create a range of challenges and opportunities., Objective: This paper reports on a backcasting exercise aimed at the development of a roadmap that identifies values, challenges, facilitators, and milestones to achieve optimal use of digital tools in the substance use field by 2030., Methods: A backcasting exercise method was adopted, wherein the core elements are identifying key values, challenges, facilitators, milestones, cornerstones and a current, desired, and future scenario. A structured approach was used by means of (1) an Open Science Framework page as a web-based collaborative working space and (2) key stakeholders' collaborative engagement during the 2022 Lisbon Addiction Conference., Results: The identified key values were digital rights, evidence-based tools, user-friendliness, accessibility and availability, and person-centeredness. The key challenges identified were ethical funding, regulations, commercialization, best practice models, digital literacy, and access or reach. The key facilitators identified were scientific research, interoperable infrastructure and a culture of innovation, expertise, ethical funding, user-friendly designs, and digital rights and regulations. A range of milestones were identified. The overarching identified cornerstones consisted of creating ethical frameworks, increasing access to digital tools, and continuous trend analysis., Conclusions: The use of digital tools in the field of substance use is linked to a range of risks and opportunities that need to be managed. The current trajectories of the use of such tools are heavily influenced by large multinational for-profit companies with relatively little involvement of key stakeholders such as people who use drugs, service providers, and researchers. The current funding models are problematic and lack the necessary flexibility associated with best practice business approaches such as lean and agile principles to design and execute customer discovery methods. Accessibility and availability, digital rights, user-friendly design, and person-focused approaches should be at the forefront in the further development of digital tools. Global legislative and technical infrastructures by means of a global action plan and strategy are necessary and should include ethical frameworks, accessibility of digital tools for substance use, and continuous trend analysis as cornerstones., (©Florian Scheibein, Elsa Caballeria, Md Abu Taher, Sidharth Arya, Angus Bancroft, Lisa Dannatt, Charlotte De Kock, Nazish Idrees Chaudhary, Roberto Perez Gayo, Abhishek Ghosh, Lillian Gelberg, Cees Goos, Rebecca Gordon, Antoni Gual, Penelope Hill, Iga Jeziorska, Eliza Kurcevič, Aleksey Lakhov, Ishwor Maharjan, Silvia Matrai, Nirvana Morgan, Ilias Paraskevopoulos, Zrinka Puharić, Goodman Sibeko, Jan Stola, Marcela Tiburcio, Joseph Tay Wee Teck, Zaza Tsereteli, Hugo López-Pelayo. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 12.12.2023.)

Background: Telemedicine-delivered medication for opioid use disorder (TMOUD) has become more prevalent during the COVID-19 pandemic, particularly in North America. This is considered a positive development as TMOUD has the potential to increase access to evidence-based treatment for a population heavily affected by the opioid crisis and consequent rising mortality and morbidity rates in relation to opioid use disorder. Despite the increase in the use of TMOUD, there are no established service- and process-focused models to guide the implementation of this intervention., Objective: This study aims to develop a process- and service-focused implementation model in collaboration with key stakeholders and bring together peer-reviewed literature, practice-based knowledge, and expert opinions., Methods: The simple rules for evidence translation in complex systems framework was applied to guide the development of a 6-step qualitative study. The steps were definition of the scope and objectives of the model, identification of evidence, stakeholder engagement, draft model development, key informant consultation, and final model specification., Results: The final specification for the TMOUD implementation model incorporated key strategic priorities, service delivery prerequisites, service design elements, stakeholder identification and engagement, key process domains, and iterative cycles of evaluation and improvement., Conclusions: Through stakeholder engagement and key informant consultation, we produced a process- and service-focused TMOUD implementation model. The model is modifiable to different contexts and settings while also in keeping with the current evidence base and national and international standards of high-quality opioid use disorder care., (©Joseph Tay Wee Teck, Rosalind Gittins, Giedre Zlatkute, Alberto Oteo Pérez, Susanna Galea-Singer, Alexander Baldacchino. Originally published in JMIR Mental Health (https://mental.jmir.org), 18.10.2023.)

Introduction: The COVID-19 pandemic has instigated the development of telemedicine-mediated provision of medications for opioid use disorder such as buprenorphine and methadone, referred to as TMOUD in this study. As services start to return to pre-pandemic norms, there is a debate around the role of TMOUD as addition to or replacement of the conventional cascade of care for people with opioid use disorder (PWOUD). This scoping review is designed to characterize existing TMOUD services and provide insights to enable a more nuanced discussion on the role of telemedicine in the care of PWOUD., Methods: The literature search was conducted in OVID Medline, CINAHL, and PsycINFO, from inception up to and including April 2023, using the Joanna Briggs Institute methodology for scoping reviews. The review considered any study design that detailed sufficient descriptive information on a given TMOUD service. A data extraction form was developed to collect and categorize a range of descriptive characteristics of each discrete TMOUD model identified from the obtained articles., Results: A total of 45 articles met the inclusion criteria, and from this, 40 discrete TMOUD services were identified. In total, 33 services were US-based, three from Canada, and one each from India, Ireland, the UK, and Norway. Through a detailed analysis of TMOUD service characteristics, four models of care were identified. These were TMOUD to facilitate inclusion health, to facilitate transitions in care, to meet complex healthcare needs, and to maintain opioid use disorder (OUD) service resilience., Conclusions: Characterizing TMOUD according to its functional benefits to PWOUD and OUD services will help support evidence-based policy and practice. Additionally, particular attention is given to how digital exclusion of PWOUD can be mitigated against.

Purpose of Review: Opioid overdose events are a time sensitive medical emergency, which is often reversible with naloxone administration if detected in time. Many countries are facing rising opioid overdose deaths and have been implementing rapid opioid overdose response Systems (ROORS). We describe how technology is increasingly being used in ROORS design, implementation and delivery., Recent Findings: Technology can contribute in significant ways to ROORS design, implementation, and delivery. Artificial intelligence-based modelling and simulations alongside wastewater-based epidemiology can be used to inform policy decisions around naloxone access laws and effective naloxone distribution strategies. Data linkage and machine learning projects can support service delivery organizations to mobilize and distribute community resources in support of ROORS. Digital phenotyping is an advancement in data linkage and machine learning projects, potentially leading to precision overdose responses. At the coalface, opioid overdose detection devices through fixed location or wearable sensors, improved connectivity, smartphone applications and drone-based emergency naloxone delivery all have a role in improving outcomes from opioid overdose. Data driven technologies also have an important role in empowering community responses to opioid overdose., Summary: This review highlights the importance of technology applied to every aspect of ROORS. Key areas of development include the need to protect marginalized groups from algorithmic bias, a better understanding of individual overdose trajectories and new reversal agents and improved drug delivery methods., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The COVID-19 pandemic has created an unprecedented natural experiment in drug policy, treatment delivery, and harm reduction strategies by exposing wide variation in public health infrastructures and social safety nets around the world. Using qualitative data including ethnographic methods, questionnaires, and semi-structured interviews with people who use drugs (PWUD) and Delphi-method with experts from field sites spanning 13 different countries, this paper compares national responses to substance use during the first wave of the COVID-19 pandemic. Field data was collected by the Substance Use x COVID-19 (SU x COVID) Data Collaborative, an international network of social scientists, public health scientists, and community health practitioners convened to identify and contextualise health service delivery models and social protections that influence the health and wellbeing of PWUD during COVID-19. Findings suggest that countries with stronger social welfare systems pre-COVID introduced durable interventions targeting structural drivers of health. Countries with fragmented social service infrastructures implemented temporary initiatives for PWUD led by non-governmental organisations. The paper summarises the most successful early pandemic responses seen across countries and ends by calling for greater systemic investments in social protections for PWUD, diversion away from criminal-legal systems toward health interventions, and integrated harm reduction, treatment and recovery supports for PWUD.

Diabetes influences other chronic medical conditions and is influenced by each in turn through multifactorial pathways. These comorbid conditions have a direct relationship with diabetes and can increase the severity of diabetes and the risk of various complications. Each of these comorbidities has unique recommendations for pharmaceutical treatment. However, guidelines for all of these comorbidities also include lifestyle interventions as first-line treatment. Recent research has shown that diabetic medications may play a direct role in treating some of these comorbidities. This article focuses on the best-known comorbid diseases associated specifically with type 2 diabetes and their co-management., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Novel angiogenic biomarker profiles have demonstrated emerging evidence for predicting preeclampsia onset, severity, and adverse outcomes. Limited data exist in screening patients with fetal growth restriction for preeclampsia development using angiogenic biomarkers., Objective: The objective of this study was to risk stratify patients with fetal growth restriction using a soluble fms-like tyrosine kinase-1 to placental growth factor ratio. Previously published cutoff of 38 was used to predict preeclampsia development and severity as well as adverse maternal or neonatal outcomes within a 2-week time period., Study Design: This was a prospective observational cohort study performed in a single tertiary hospital. Patients with a singleton fetal growth restriction pregnancy between 24 and 37 weeks' gestation were evaluated using serial 2-week encounters from the time of enrollment to delivery. Pregnancies with proven genetic or infectious etiology of fetal growth restriction or congenital anomalies were excluded. Ultrasound growth and Doppler measurements were obtained at the start of every encounter with routine preeclampsia laboratory tests and blood pressure checks when clinically indicated. Maternal serum was collected for all serial encounters and measured for soluble fms-like tyrosine kinase-1 and placental growth factor after delivery in a double-blinded fashion. Maternal charts were reviewed for baseline demographic characteristics, pregnancy diagnoses and outcomes, and neonatal outcomes., Results: A total of 45 patients were enrolled for a total of 77 encounters, with the median (quartile 1, quartile 3) gestational age of the study enrolled at 31.43 (28.14-33.57) weeks. Patients were divided into low-risk (ratio of <38) and high-risk (ratio of ≥38) groups. Baseline characteristics of patients did not show any marked differences, including preeclampsia labs or ultrasound parameters, between the 2 groups. Systolic and diastolic blood pressures upon enrollment were statistically elevated when soluble fms-like tyrosine kinase-1 to placental growth factor ratio was ≥38 (P=.02 and P=.01, respectively). Compared to patients with a low ratio, patients with a high ratio had a greater proportion of preeclampsia diagnosis, higher rates of preterm delivery under 34 and 37 weeks gestation, smaller neonatal birthweight, and a shorter time to delivery from testing to delivery., Conclusion: Among patients with fetal growth restriction, the soluble fms-like tyrosine kinase-1 to placental growth factor ratio may serve as a potential biomarker for identifying at risk patients for developing preeclampsia and subsequently preterm delivery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Since the initial identification of the novel coronavirus SARS-CoV-2 in December of 2019, researchers have raced to understand its pathogenesis and begun devising vaccine and treatment strategies. An accurate understanding of the body's temporal immune response against SARS-CoV-2 is paramount to successful vaccine development and disease progression monitoring. To provide insight into the antibody response against SARS-CoV-2, plasma samples from 181 PCR-confirmed COVID-19 patients collected at various timepoints post-symptom onset (PSO) were tested for the presence of anti-SARS-CoV-2 IgM and IgG antibodies via lateral flow. Additionally, 21 donors were tracked over time to elucidate patient-specific immune responses. We found sustained levels of anti-SARS-CoV-2 antibodies past 130 days PSO, with 99% positivity observed at 31-60 days PSO. By 61-90 days PSO, the percentage of IgM-/IgG+ results were nearly equal to that of IgM+/IgG+ results, demonstrating a shift in the immune response with a decrease in IgM antibody levels. Results from this study not only provide evidence that the antibody response to COVID-19 can persist for over 4 months, but also demonstrates the ability of Easy Check™ to monitor seroconversion and antibody response of patients. Easy Check was sufficiently sensitive to detect antibodies in patient samples as early as 1-4 days PSO with 86% positivity observed at 5-7 days PSO. Further studies are required to determine the longevity and efficacy of anti-SARS-CoV-2 antibodies, and whether they are protective against re-infection., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Renee Higgins, Florence Lee and Dena Marrinucci are employees of Truvian Sciences, the company that sells Easy Check. Kiang-Teck J. Yeo is a member of the Scientific Advisory Board of Truvian and has received honoraria and equities from Truvian. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: To evaluate the analytical and clinical performance of the Truvian Easy Check coronavirus disease 2019 (COVID-19) IgM/IgG anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody test.Serologic assays have become increasingly available for surveillance through the Food and Drug Administration emergency use authorization in the ongoing COVID-19 global pandemic. However, widespread application of serologic assays has been curbed by reports of faulty or inaccurate tests. Therefore, rapid COVID-19 antibody tests need to be thoroughly validated prior to their implementation., Methods: The Easy Check device was analytically evaluated and its performance was compared with the Roche Elecsys anti-SARS-CoV-2 antibody assay. The test was further characterized for cross-reactivity using sera obtained from patients infected by other viruses. Clinical performance was analyzed with polymerase chain reaction-confirmed samples and a 2015 prepandemic reference sample set., Results: The Easy Check device showed excellent analytical performance and compares well with the Roche Elecsys antibody assay, with an overall concordance of 98.6%. Clinical performance showed a sensitivity of 96.6%, a specificity of 98.2%, and an overall accuracy of 98.1%., Conclusions: The Easy Check device is a simple, reliable, and rapid test for detection of SARS-CoV-2 seropositivity, and its performance compares favorably against the automated Roche Elecsys antibody assay., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

COVID-19 has resulted in deepened states of crisis and vulnerability for people who use drugs throughout Europe and across the world, with social distancing measures having far-reaching implications for everyday life. Prolonged periods of isolation and solitude are acknowledged within much addiction literature as negatively impacting the experiences of those in recovery, while also causing harm to active users - many of whom depend on social contact for the purchasing and taking of substances, as well as myriad forms of support. Solitude, however, is proposed by the authors as inherent within some aspects of substance use, far from particular to the current pandemic. Certain forms of substance use engender solitary experience, even where use is predicated upon the presence of others. Adopting a cross-disciplinary perspective, this paper takes as its focus the urgent changes wrought by the pandemic upon everyday life for people who use drugs, drawing on recent ethnographic fieldwork with substance users in Scotland. Beyond the current crises, the paper proposes solitude, and by extension isolation, as an analytical framework for better apprehending lived experiences of substance use., 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 © 2021 Roe, Proudfoot, Tay Wee Teck, Irvine, Frankland and Baldacchino.)

Background: Many cancer patients who receive chemotherapy experience adverse drug effects. Pharmacogenomics (PGx) has promise to personalize chemotherapy drug dosing to maximize efficacy and safety. Fluoropyrimidines and irinotecan have well-known germline PGx associations. At our institution, we have delivered PGx clinical decision support (CDS) based on preemptively obtained genotyping results for a large number of non-oncology medications since 2012, but have not previously evaluated the utility of this strategy for patients initiating anti-cancer regimens. We hypothesize that providing oncologists with preemptive germline PGx information along with CDS will enable individualized dosing decisions and result in improved patient outcomes., Methods: Patients with oncologic malignancies for whom fluoropyrimidine and/or irinotecan-inclusive therapy is being planned will be enrolled and randomly assigned to PGx and control arms. Patients will be genotyped in a clinical laboratory across panels that include actionable variants in UGT1A1 and DPYD . For PGx arm patients, treating providers will be given access to the patient-specific PGx results with CDS prior to treatment initiation. In the control arm, genotyping will be deferred, and dosing will occur as per usual care. Co-primary endpoints are dose intensity deviation rate (the proportion of patients receiving dose modifications during the first treatment cycle), and grade ⩾3 treatment-related toxicities throughout the treatment course. Additional study endpoints will include cumulative drug dose intensity, progression-free survival, dosing of additional PGx supportive medications, and patient-reported quality of life and understanding of PGx., Discussion: Providing a platform of integrated germline PGx information may promote personalized chemotherapy dosing decisions and establish a new model of care to optimize oncology treatment planning., Competing Interests: Conflict of interest statement: M.J. Ratain is a coinventor holding patents related to pharmacogenetic diagnostics and receives royalties related to UGT1A1 genotyping., (© The Author(s), 2020.)

Objectives: To evaluate the analytical and clinical performance of the automated Elecsys anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody (Elecsys Ab) assay on the Roche cobas e602 analyzer. With the ongoing global coronavirus disease 2019 (COVID-19) pandemic, widespread and routine serologic testing of SARS-CoV-2 remains a pressing need. To better understand its epidemiologic spread and to support policies aimed at curtailing further infections, reliable serologic testing is crucial for providing insight into the dynamics of the spread of COVID-19 on a population level., Methods: The presence of anti-SARS-CoV-2 antibodies in polymerase chain reaction-positive, confirmed COVID-19 patient samples was determined using the Elecsys Ab assay on the Roche cobas e602 analyzer. The precision and cross-reactivity of the Elecsys Ab assay were characterized and its performance was compared against the EuroImmun IgA/IgG antibody (EuroImmun Ab) assay. Calculated sensitivity, specificity, and positive and negative predictive values were assessed., Results: The Elecsys Ab assay demonstrated good precision, had no cross-reactivity with other viral samples, and showed 100% concordance with the EuroImmun Ab assay. Excellent clinical performance with respect to sensitivity, specificity, and positive and negative predictive values was observed., Conclusions: The Elecsys Ab assay is a precise and highly reliable automated platform for clinical detection of seropositivity in SARS-CoV-2 infection., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Poor adherence is associated with worse disease outcomes. Pharmacogenomics provides a possible intervention to address adherence. We hypothesized that pharmacogenomic-informed care could increase adherence. Patients in a prospective case-control study underwent preemptive pharmacogenomic genotyping with results available for provider use at the point of care; controls (not genotyped) were treated by the same providers. Over 6,000 e-prescriptions for 39 medications with actionable pharmacogenomic information were analyzed. Composite adherence, measured by modified proportion of days covered (mPDC), was compared between cases/controls and genomically concordant vs. genomically higher-risk medications. Overall, 536 patients were included. No difference in mean mPDC was observed due to availability of pharmacogenomic guidance. However, case patients prescribed high-risk pharmacogenomic medications were more than twice as likely to have low mPDC for these medications compared with genomically concordant prescriptions (odds ratio = 2.4 (1.03-5.74), P < 0.05). This study is the first to show that composite pharmacogenomic information predicts adherence., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

The importance of genetic ancestry characterization is increasing in genomic implementation efforts, and clinical pharmacogenomic guidelines are being published that include population-specific recommendations. Our aim was to test the ability of focused clinical pharmacogenomic SNP panels to estimate individual genetic ancestry (IGA) and implement population-specific pharmacogenomic clinical decision-support (CDS) tools. Principle components and STRUCTURE were utilized to assess differences in genetic composition and estimate IGA among 1572 individuals from 1000 Genomes, two independent cohorts of Caucasians and African Americans (AAs), plus a real-world validation population of patients undergoing pharmacogenomic genotyping. We found that clinical pharmacogenomic SNP panels accurately estimate IGA compared to genome-wide genotyping and identify AAs with ≥70 African ancestry (sensitivity >82%, specificity >80%, PPV >95%, NPV >47%). We also validated a new AA-specific warfarin dosing algorithm for patients with ≥70% African ancestry and implemented it at our institution as a novel CDS tool. Consideration of IGA to develop an institutional CDS tool was accomplished to enable population-specific pharmacogenomic guidance at the point-of-care. These capabilities were immediately applied for guidance of warfarin dosing in AAs versus Caucasians, but also provide a real-world model that can be extended to other populations and drugs as actionable genomic evidence accumulates.

Objectives: Analysis of platelet functional responses to stimuli is presently quite limited with respect to measurement of dense granule secretion. We sought to develop a nonradioactive assay of stimulated serotonin release using liquid chromatography tandem mass spectrometry (LC-MS/MS)., Methods: Citrated whole blood (200 μL) was incubated with deuterated serotonin (d45-HT). Following uptake by platelets, blood was diluted 10-fold and aliquots were incubated with platelet stimuli. Following stimulation, blood was further diluted, centrifuged, and supernatant was assayed for released d45-HT by micro-LC-MS/MS., Results: This study demonstrated a broad linear range of 50 to 2,000 pg/mL d45-HT, with a total precision of less than 15.0% coefficient of variation at all quality control levels and a limit of quantitation of 50 pg/mL., Conclusions: Quantification of d45-HT by micro-LC-MS/MS assay offers a highly sensitive, nonradioactive methodology for quantitating platelet serotonin uptake and dense granule secretion, requiring only small volumes of patient blood., (© American Society for Clinical Pathology, 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The interest for vitamin D has exponentially increased testing demand for 25-hydroxy vitamin D [25(OH)D]. Consequently, many laboratories are switching from LC-MS/MS methods to automated, high-throughput immunoassays. One of the major potential issues with these assays has been the lack of cross-reactivity with 25(OH)D2., Methods: We have evaluated the Roche Elecsys vitamin D total II assay for accuracy by comparing 79 patient samples with LC-MS/MS. The cross-reactivity for 25(OH)D2 was evaluated by analyzing samples with high 25(OH)D2 separately and estimating 25(OH)D2 recovery, as well as by spiking of 25(OH)D2. The assay was further evaluated for precision, linearity, sample type, and common interferences., Results: There was mostly good agreement between the Elecsys and LC-MS/MS assays (Deming regression: y = 0.95 x + 0.70), with an overall bias of 2.3% (-0.84 ng/mL). However, there were 6 out of 79 (7.6%) discordant samples. The Deming regression for samples with high 25(OH)D2 compared to LC-MS/MS showed similar slope and intercept ( y = 0.97 x - 1.1). The average recovery of 25(OH)D2 for these samples was 90%. The initial precision studies were in general agreement with the package insert, but long-term clinical use showed higher-than-claimed imprecision (11.7%-14.4% at 12 ng/mL and 6.9%-7.6% at 27 ng/mL; claimed: 7.2% and 5.0%, respectively). We observed 1 falsely high result in plasma, an issue previously addressed by Roche in a medical device correction., Conclusions: The analytical performance of the Roche Vitamin D assay was acceptable, and the assay had a good cross-reactivity for 25(OH)D2., (© 2019 American Association for Clinical Chemistry.)

Preeclampsia-related morbidity and mortality is rising predominantly because of delayed identification of patients at risk for preeclampsia with severe features and associated complications. This study explored the association between angiogenic markers (sFlt1 [soluble fms-like tyrosine kinase-1]) and PlGF [placental growth factor]) and preeclampsia-related peripartum complications. Normotensive women or those with hypertensive disorders of pregnancy were enrolled. Blood samples were collected within 96 hours before delivery, and angiogenic markers were measured on an automated platform. Our study included 681 women, 375 of which had hypertensive disorders. Of these, 127 (33.9%) had severe preeclampsia, and 71.4% were black. Compared with normotensive women, women with severe preeclampsia had higher levels of sFlt1 (9372.5 versus 2857.0 pg/mL; P<0.0001), lower PlGF (51.0 versus 212.0 pg/mL; P<0.0001), and a high sFlt1/PlGF (212.0 versus 14.0; all P<0.0001). A similar trend in sFlt1, PlGF, and sFlt1/PlGF was found in those women with complications secondary to preeclampsia (all P<0.001). The highest tertile of sFlt1/PlGF was strongly associated with severe preeclampsia in a multivariable analysis. Among patients with a hypertensive disorder of pregnancy, 340 (90.7%) developed postpartum hypertension, of which 50.4% had mild, and 40.3% had severe postpartum hypertension. The sFlt1/PlGF ratio was significantly higher for severe and mild postpartum hypertension compared with women with normal postpartum blood pressures (73.5, 46.0, and 13.0, respectively; P values<0.0001). Furthermore, the highest tertile of antepartum sFlt1/PlGF was associated with postpartum hypertension ( P=0.004). This study demonstrates a significant association between an abnormal angiogenic profile before delivery and severe preeclampsia and peripartum complications.

Background: We compared the rates of intraoperative parathyroid hormone (PTH) decline using the Siemens Immulite ® Turbo PTH and Roche Elecsys ® short turnaround time PTH assays in 95 consecutive surgical patients to investigate analytical and turnaround time (TAT) differences between the tests performed in the operating room (OR) vs the central clinical chemistry laboratory (CCL)., Methods: Serial blood samples from 95 patients undergoing parathyroidectomy were collected and measured using the 2 immunoassays. Specimens from the first 15 patients were measured simultaneously in the OR and CCL and used for the TAT study. In addition to 2 baseline samples, specimens were collected at 5, 10, and 15 min (for some patients, >15 min) after parathyroidectomy., Results: In the TAT study, a significant difference was observed (OR median 20 min vs CCL median 27 min; P < 0.05). Of the 95 patient series, slower rates of parathyroid hormone decrease were observed in approximately 20% of the patients when comparing the Roche with the Immulite immunoassay., Conclusions: There was a slightly longer TAT in the CCL compared with running the assay directly within the OR (median difference of approximately 7 min). For a majority of the patients, both methods showed equivalent rates of PTH decline; however, for approximately 20% of the patients, there was a slower rate of PTH decline using the Roche assay., (© 2018 American Association for Clinical Chemistry.)

Background: Angiogenic factors have been implicated in the pathogenesis of preeclampsia. This pilot study explored the association between antenatal blood pressure levels and angiogenic biomarkers (sFlt1 and PlGF) among women with chronic hypertension (cHTN)., Methods: Blood samples were collected from women with cHTN (with/without superimposed preeclampsia) within 96 h prior to delivery. Subjects were stratified by mean outpatient BP as controlled (cBP < 140/90) or uncontrolled (uBP ≥ 140/90). Descriptive statistics were generated and assessed as appropriate. Logistic regression was employed to assess for adverse pregnancy outcomes between groups., Results: Data from seventy-eight women were analyzed, of which 58 (74.4%) were African American. Fifty-six (71.8%) had cBP and 22 (28.2%) had uBP. Use of antepartum outpatient antihypertensive medications was more frequent in patients with uBP (46.4% vs. 13.6%, p = 0.01). Compared to women with cBP, women with uBP had higher levels of pre-delivery sFlt1 and sFlt1/PlGF ratio (sFlt: 4218.5 vs. 3056.0 pg/ml, p = 0.046; sFlt/PlGF: 62.5 vs. 25.0, p = 0.04). Additionally, more uBP patients had superimposed preeclampsia with severe features (54.6% vs. 25.0%; p = 0.01) and preterm delivery (defined as a gestational age <35 weeks (40.9% vs. 10.7%; p = 0.002)) than cBP patients. In the multivariable model, women with uBP had greater odds of preterm delivery (OR 6.78; p = 0.01), superimposed preeclampsia (OR 3.20; p = 0.03) and preeclampsia with severe features (OR 3.27; p = 0.04) than women with cBP., Conclusion: In women with cHTN, elevated antepartum BP is associated with worsened outcomes and may be associated with abnormal angiogenic profile at delivery. Larger studies are needed to confirm these findings., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background: Delivery of cytotoxic therapy is a complex multifaceted process that involves harmonized collaboration between all systems involved. Optimizing laboratory turnaround time (TAT) ensures timely delivery of chemotherapy, which potentially translates into improved patient outcomes and satisfaction. In this study, we aimed to reduce the laboratory TAT for key laboratory tests to optimize the timely administration of chemotherapy., Methods: TAT data for complete blood count (CBC) and comprehensive metabolic panel (CMP) included specimen collection to receipt (Col-Rcv), specimen receipt to result release (Rcv-Res), and the overall TAT from specimen collection to result release (Col-Res). Work flows were reconfigured to transport CBC specimens directly to the hematology laboratory after collection and to treat all CMP samples from chemotherapy clinics as urgent [i.e., shortest turnaround time (STAT)]. From the CMP, total bilirubin and creatinine-the 2 key analytes for liver and renal toxicity assessment before chemotherapy drug administration-were analyzed on ABL 800 whole blood analyzers to further improve the laboratory TAT., Results: CBC showed a significant reduction in the median (Col-Res) TAT to 16 min (P < 0.0001). For CMP, by processing all specimens as STAT samples, the median (Col-Res) TAT was reduced from 74 min to 54 min (P < 0.0001), and it was further reduced to 9 min (P < 0.0001) for total bilirubin and creatinine., Conclusion: Careful work flow analysis and reengineering of preanalytical and analytical process for key laboratory tests significantly reduced median overall TAT to <20 min, which helped facilitate more timely delivery of chemotherapy, without necessitating the construction of a satellite laboratory., (© 2018 American Association for Clinical Chemistry.)

Background: The anti-tumor necrosis factor alpha (TNFα) therapeutic monoclonal antibodies (mAbs), such as adalimumab, are widely used in the treatment of rheumatoid arthritis, inflammatory bowel diseases, and other auto-immune diseases. The administration of adalimumab can elicit the immune responses from some patients, resulting in the formation of anti-drug antibodies (ADAbs). The ADAbs can diminish the therapeutic effects of adalimumab by neutralizing the TNFα binding site or increasing its clearance from circulation., Methods: To effectively monitor the therapeutic concentrations of adalimumab, we developed and validated a targeted quantitative proteomic assay to determine the circulating concentrations of adalimumab. Since drug effects can be attenuated by ADAbs, the method adopted an affinity-enrichment step to selectively quantify the bioavailable forms of adalimumab in patient serum samples., Results: The performance of the LC-MS/MS based assay provides the analytical measuring range and precisions applicable for the therapeutic monitoring of adalimumab. It also provides comparable results to a cell-based activity assay when evaluating patient samples with different concentrations of adalimumab., Conclusion: Our assay can quantify both sub-therapeutic and therapeutic concentrations of bioavailable adalimumab in patient serum samples. This assay design provides an alternative to isotope-labeled peptides approach currently adopted in targeted proteomics methods., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Patients with Smith-Lemli-Opitz Syndrome (SLOS) have defective endogenous cholesterol synthesis, and present with decreased cholesterol levels and multiple developmental dysmorphologies., Case Description: A newborn infant with normal XY karyotype and normal microarray was born with multiple developmental defects and ambiguous genitalia. The patient was diagnosed with SLOS, following biochemical genetic analysis of serum 7-DHC concentrations. The clinical course of the patient was further complicated by the comorbidities associated with SLOS and the bacterial infections., Conclusion: We provide a detailed biochemical profile of the SLOS patient. The report can help us further understand the pathological impacts of cholesterol synthesis deficiency and provide relevant clinical management with outcome of this rare genetic disorder., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Preeclampsia is one of the leading hypertensive disorders of pregnancy. Angiogenic biomarkers such as anti-angiogenic factor soluble fms-like tyrosine kinase 1 (sFlt1) and pro-angiogenic factor placental growth factor (PlGF) are involved in the pathophysiology of preeclampsia., Objective: The aim of this study is to validate the analytical performance of sFlt1 and PlGF on the B·R·A·H·M·S KRYPTOR Compact Plus (ThermoFisher Scientific)., Study Design: We examined K 2 -EDTA plasma samples from 50 patients on B·R·A·H·M·S KRYPTOR Compact Plus, an automated immunoassay platform. QC materials were used to assess intra- and inter-precision of the assay. Lower limit of quantitation and interference studies were determined using pooled patient plasma., Results: The sFlt1 and PlGF assays demonstrated an analytical measuring range of 90-69,000 pg/mL and 11-7000 pg/mL, respectively (r 2  > 0.99). Lower limit of quantitation (20% CV) was interpolated to be 35 pg/mL for sFlt1 and 10 pg/mL for PlGF. Total precision for both assay displayed CVs of <10%. Interference studies showed that both assays were not significantly affected by hemolysis up to an H-index of 1100 for sFlt1 and 300 for PlGF; L- and I-index of 800 and 80 respectively for both assays. The Passing-Bablok regression analysis for sFlt1/PlGF yielded an equation of y = 1.05x + 0.02, and the Bland Altman analysis showed an average bias of 0.84., Conclusion: Plasma levels of sFlt1 and PlGF measured on the B·R·A·H·M·S KRYPTOR Compact Plus platform demonstrate excellent analytical performance and are acceptable as clinical grade assays., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

To test our hypothesis that testosterone deficiency plays an important role in chronic pain, a Phase I/II pilot study was initiated with 12 fibromyalgia patients to verify that a daily dose for 28days with transdermal testosterone gel would 1) significantly and safely increase mean serum testosterone concentrations from low baseline levels to mid/high-normal levels, and 2) effectively treat the pain and fatigue symptoms of fibromyalgia. Pharmacokinetic data confirmed that serum free testosterone concentrations were raised significantly above baseline levels, by assessment of maximum hormone concentration (Cmax) and area under the curve (AUC) parameters: free testosterone Cmax was significantly raised from a mean of 2.64pg/mL to 3.91pg/mL (p<0.05), and 24hour free testosterone AUC was significantly raised from a mean of 35.0pg-hr/mL to 53.89pg-hr/mL. Assessment of the typical symptoms of fibromyalgia by patient questionnaire and tender point exam demonstrated significant change in: decreased muscle pain, stiffness, and fatigue, and increased libido during study treatment. These results are consistent with the hypothesized ability of testosterone to relieve the symptoms of fibromyalgia. Symptoms not tightly related to fibromyalgia were not improved., (Copyright © 2015. Published by Elsevier B.V.)