Clinical and serological predictors of post COVID-19 condition-findings from a Canadian prospective cohort study.

Introduction: More than 3 years into the pandemic, there is persisting uncertainty as to the etiology, biomarkers, and risk factors of Post COVID-19 Condition (PCC). Serological research data remain a largely untapped resource. Few studies have investigated the potential relationships between post-acute serology and PCC, while accounting for clinical covariates. Methods: We compared clinical and serological predictors among COVID-19 survivors with (n = 102 cases) and without (n = 122 controls) persistent symptoms ≥12 weeks post-infection. We selected four primary serological predictors (anti-nucleocapsid (N), anti-Spike, and anti-receptor binding domain (RBD) IgG titres, and neutralization efficiency), and specified clinical covariates a priori. Results: Similar proportions of PCC-cases (66.7%, n = 68) and infected-controls (71.3%, n = 87) tested positive for anti-N IgG. More cases tested positive for anti-Spike (94.1%, n = 96) and anti-RBD (95.1%, n = 97) IgG, as compared with controls (anti-Spike: 89.3%, n = 109; anti-RBD: 84.4%, n = 103). Similar trends were observed among unvaccinated participants. Effects of IgG titres on PCC status were non-significant in univariate and multivariate analyses. Adjusting for age and sex, PCC-cases were more likely to be efficient neutralizers (OR 2.2, 95% CI 1.11-4.49), and odds was further increased among cases to report deterioration in quality of life (OR 3.4, 95% CI 1.64-7.31). Clinical covariates found to be significantly related to PCC included obesity (OR 2.3, p = 0.02), number of months post COVID-19 (OR 1.1, p < 0.01), allergies (OR 1.8, p = 0.04), and need for medical support (OR 4.1, p < 0.01). Conclusion: Despite past COVID-19 infection, approximately one third of PCC-cases and infected-controls were seronegative for anti-N IgG. Findings suggest higher neutralization efficiency among cases as compared with controls, and that this relationship is stronger among cases with more severe PCC. Cases also required more medical support for COVID-19 symptoms, and described complex, ongoing health sequelae. More data from larger cohorts are needed to substantiate results, permit subgroup analyses of IgG titres, and explore for differences between clusters of PCC symptoms. Future assessment of IgG subtypes may also elucidate new findings.

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

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

Guidance for use of neurofilament light chain as a cerebrospinal fluid and blood biomarker in multiple sclerosis management.

Neurofilament light chain (NfL) is a long-awaited blood biomarker that can provide clinically useful information about prognosis and therapeutic efficacy in multiple sclerosis (MS). There is now substantial evidence for this biomarker to be used alongside magnetic resonance imaging (MRI) and clinical measures of disease progression as a decision-making tool for the management of patients with MS. Serum NfL (sNfL) has certain advantages over traditional measures of MS disease progression such as MRI because it is relatively noninvasive, inexpensive, and can be repeated frequently to monitor activity and treatment efficacy. sNfL levels can be monitored regularly in patients with MS to determine change from baseline and predict subclinical disease activity, relapse risk, and the development of gadolinium-enhancing (Gd+) lesions. sNfL does not replace MRI, which provides information related to spatial localisation and lesion stage. Laboratory platforms are starting to be made available for clinical application of sNfL in several countries. Further work is needed to resolve issues around comparisons across testing platforms (absolute values) and normalisation (reference ranges) in order to guide interpretation of the results.

Applications of Thermochemical Modeling in Molten Salt Reactors.

The extensively evaluated and consistent thermodynamic database, the Molten Salt Thermal Properties Database-Thermochemical (MSTDB-TC), was used along with additional thermodynamic values from other sources as examples of ways to examine molten salt reactor (MSR) fuel behavior. Relative stability with respect to halide potential and temperature for likely fuel and fission product components were mapped in Ellingham diagrams for the chloride and fluoride systems. The Ellingham diagrams provide a rich, visual means for identifying halide-forming components in proposed fuel/solvent salt systems. Thermochemical models and values from MSTDB-TC and ancillary sources were used in global equilibrium calculations to provide compositions for a close analysis of the behavior of a possible Molten Chloride Salt Fast Reactor and a Molten Salt Reactor Experiment-type system at high burnup (100 GWd/t). The results illustrated the oxidative nature of burnup in MSRs and provided information about redox behavior and possible control.

Results of the Stop the Spread Ottawa (SSO) cohort study: a Canadian urban-based prospective evaluation of antibody responses and neutralisation efficiency to SARS-CoV-2 infection and vaccination.

BACKGROUND: Predictors of COVID-19 vaccine immunogenicity and the influence of prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection require elucidation. METHODS: Stop the Spread Ottawa is a prospective cohort of individuals at-risk for or who have been infected with SARS-CoV-2, initially enrolled for 10 months beginning October 2020. This cohort was enriched for public-facing workers. This analysis focuses on safety and immunogenicity of the initial two doses of COVID-19 vaccine. RESULTS: Post-vaccination data with blood specimens were available for 930 participants. 22.8% were SARS-CoV2 infected prior to the first vaccine dose. Cohort characteristics include: median age 44 (IQR: 22-56), 66.6% women, 89.0% white, 83.2% employed. 38.1% reported two or more comorbidities and 30.8% reported immune compromising condition(s). Over 95% had detectable IgG levels against the spike and receptor binding domain (RBD) 3 months post second vaccine dose. By multivariable analysis, increasing age and high-level immune compromise predicted diminishing IgG spike and RBD titres at month 3 post second dose. IgG spike and RBD titres were higher immediately post vaccination in those with SARS-CoV-2 infection prior to first vaccination and spike titres were higher at 6 months in those with wider time intervals between dose 1 and 2. IgG spike and RBD titres and neutralisation were generally similar by sex, weight and whether receiving homogeneous or heterogeneous combinations of vaccines. Common symptoms post dose 1 vaccine included fatigue (64.7%), injection site pain (47.5%), headache (27.2%), fever/chills (26.2%) and body aches (25.3%). These symptoms were similar with subsequent doses. CONCLUSION: The initial two COVID-19 vaccine doses are safe, well-tolerated and highly immunogenic across a broad spectrum of vaccine recipients including those working in public facing environments.

Cross-sectional Characterization of SARS-CoV-2 Antibody Levels and Decay Rates Following Infection of Unvaccinated Elderly Individuals.

Background: SARS-CoV-2 infections have disproportionally burdened elderly populations with excessive mortality. While several contributing factors exists, questions remain about the quality and duration of humoral antibody-mediated responses resulting from infections in unvaccinated elderly individuals. Methods: Residual serum/plasma samples were collected from individuals undergoing routine SARS-CoV-2 polymerase chain reaction testing in a community laboratory in Canada. The samples were collected in 2020, before vaccines became available. IgG, IgA, and IgM antibodies against SARS-CoV-2 nucleocapsid, trimeric spike, and its receptor-binding domain were quantified via a high-throughput chemiluminescent enzyme-linked immunosorbent assay. Neutralization efficiency was also quantified through a surrogate high-throughput protein-based neutralization assay. Results: This study analyzed SARS-CoV-2 antibody levels in a large cross-sectional cohort (N = 739), enriched for elderly individuals (median age, 82 years; 75% >65 years old), where 72% of samples tested positive for SARS-CoV-2 by polymerase chain reaction. The age group ≥90 years had higher levels of antibodies than that <65 years. Neutralization efficiency showed an age-dependent trend, where older persons had higher levels of neutralizing antibodies. Antibodies targeting the nucleocapsid had the fastest decline. IgG antibodies targeting the receptor-binding domain remained stable over time, potentially explaining the lack of neutralization decay observed in this cohort. Conclusions: Despite older individuals having the highest levels of antibodies postinfection, they are the cohort in which antibody decay was the fastest. Until a better understanding of correlates of protection is acquired, along with the protective role of nonneutralizing antibodies, booster vaccinations remain important in this demographic.

Electrothermally Actuated Semitransparent Shape Memory Polymer Composite with Application as a Wearable Touch Sensor.

A semitransparent shape memory polymer (SMP):silver nanowire (AgNW) composite is demonstrated to be capable of low-temperature actuation, thus making it attractive for wearable electronics applications that require intimate contact with the human body. We demonstrate that the SMP:AgNW composite has tunable electrical and optical transparency through variation of the AgNW loading and that the AgNW loading did not significantly change the mechanical behavior of the SMP. The SMP composite is also capable of electrical actuation through Joule heating, where applying a 4 V bias across the AgNWs resulted in full shape recovery. The SMP was found to have high strain sensitivity at both small (<1%) and large (over 10%) applied strain. The SMP could sense strains as low as 0.6% with a gauge factor of 8.2. The SMP composite was then utilized as a touch sensor, able to sense and differentiate tapping and pressing. Finally, the composite was applied as a wearable ring that was thermally actuated to conformably fit onto a finger as a touch sensor. The ring sensor was able to sense finger tapping, pressing, and bending with high signal-to-noise ratios. These results demonstrate that SMP:AgNW composites are a promising design approach for application in wearable electronics.

Presence of Macrotroponin for Over 2 Years in a Young Woman.

We present the case of a 28-year-old woman who presented with nonspecific symptoms with a high-sensitivity troponin I level > 10,000 ng/L, which led to extensive investigations and a hospital stay. Follow-up testing using an alternate troponin assay yielded undetectable levels. Two years later, the patient had a high-sensitivity troponin I level > 1500 ng/L, with experiments confirming the presence of a macrocomplex. We advocate for communication with laboratory professionals to expedite identification of macrotroponin complexes, so that patients and clinicians can reduce the number of unwarranted investigations. Novel teaching points include the importance of identifying macrocomplexes as a source of persistent false elevations and ensuring that a process is instituted to investigate troponin-level elevations when false-positive results are suspected.

Nous décrivons le cas d'une femme de 28 ans qui présentait des symptômes non spécifiques et un taux de troponine I mesuré par dosage ultrasensible s'élevant à plus de 10 000 ng/l, ce qui a mené à des investigations poussées et à une hospitalisation. Lors d'analyses de suivi avec une mesure alternative de la troponine, les taux étaient indétectables. Deux ans plus tard, le taux de troponine I mesuré par dosage ultrasensible était supérieur à 1500 ng/l chez cette patiente, et des analyses ont confirmé la présence d'un macrocomplexe. Nous préconisons une communication avec les professionnels de laboratoire pour accélérer la détection de complexes de macrotroponine, afin de permettre aux cliniciens de diminuer le nombre d'investigations qui ne sont pas nécessaires chez les patients. Les points d'enseignements les plus récents insistent sur l'importance de détecter les macrocomplexes qui pourraient être à l'origine des taux de troponine faussement élevés persistants et de s'assurer qu'un processus soit mis en place pour investiguer les élévations du taux de troponine lorsque des résultats faussement positifs sont suspectés.

Lot verification practices in Ontario clinical chemistry laboratories - Results of a patterns-of-practice survey.

Objectives: Verifying new reagent or calibrator lots is crucial for maintaining consistent test performance. The Institute for Quality Management in Healthcare (IQMH) conducted a patterns-of-practice survey and follow-up case study to collect information on lot verification practices in Ontario. Methods: The survey had 17 multiple-choice questions and was distributed to 183 licensed laboratories. Participants provided information on materials used and approval/rejection criteria for their lot verification procedures for eight classes of testing systems. The case study provided a set of lot comparison data and was distributed to 132 laboratories. Responses were reviewed by IQMH scientific committees. Results: Of the 175 laboratories that responded regarding reagent lot verifications, 74% verified all tests, 11% some, and 15% none. Of the 171 laboratories that responded regarding calibrator lot verifications, 39% verified all calibrators, 4% some, and 57% none. Reasons for not performing verifications ranged from difficulty performing parallel testing to high reagent cost. For automated chemistry assays and immunoassays, 23% of laboratories did not include patient-derived materials in reagent lot verifications and 42% included five to six patient materials; 58% of laboratories did not include patient-derived materials in calibrator lot verifications and 23% included five to six patient materials. Different combinations of test-specific rules were used for acceptance criteria. For a failed lot, 98% of laboratories would investigate further and take corrective actions. Forty-three percent of laboratories would accept the new reagent lot in the case study. Conclusion: Responses to the survey and case study demonstrated variability in lot verification practices among laboratories.

Crystallization of A3Ln(BO3)2 (A = Na, K; Ln = Lanthanide) from a Boric Acid Containing Hydroxide Melt: Synthesis and Investigation of Lanthanide Borates as Potential Nuclear Waste Forms.

A series of alkali metal rare-earth borates were prepared via high-temperature flux crystal growth, and their structures were characterized by single crystal X-ray diffraction (SXRD). Na3Ln(BO3)2 (Ln = La-Lu) crystallize in the monoclinic space group P21/n, the potassium series K3Ln(BO3)2 (Ln = La-Tb) crystallize in the orthorhombic space group Pnma, while the Ln = Dy, Ho, Tm, Yb analogues crystallize in the orthorhombic space group Pnnm. To demonstrate the generality of this synthetic technique, high-entropy oxide (HEO) compositions K3Nd0.15(1)Eu0.20(1)Gd0.20(1)Dy0.22(1)Ho0.23(1)(BO3)2 and K3Nd0.26(1)Eu0.29(1)Ho0.22(1)Tm0.14(1)Yb0.10(1)(BO3)2 were obtained in single crystal form. Radiation damage investigations determined that these borates have a high radiation damage tolerance. To assess whether trivalent actinide analogues of Na3Ln(BO3)2 and K3Ln(BO3)2 would be stable, density functional theory was used to calculate their enthalpies of formation, which are favorable.

High or increasing serum NfL is predictive of impending multiple sclerosis relapses.

BACKGROUND: One-off serum levels of neurofilament light chain (sNfL) is an established predictor of emerging disease activity in multiple sclerosis (MS). However, the importance of longitudinal increases in sNfL is yet to be enumerated, an important consideration as this test is translated for serial monitoring. Glial Fibrillary Acidic Protein (sGFAP) is another biomarker of predictive interest. Our objective was to assess the association between longitudinal changes sNfL and prediction of future relapses, as well as a possible role for sGFAP. METHODS: Participants with active MS were prospectively monitored for one year as part of a clinical trial testing mesenchymal stem cells. Visits every three months or less included clinical assessments, MRI scans and serum draws. sNfL and sGFAP concentrations were quantified with Single Molecule Array immunoassay. We used Kaplan-Meier estimates and Anderson-Gill Cox regression models with and without adjustment for age, sex, disease subtype, disease duration and expanded disability status score (EDSS) to estimate the rate of relapse predicted by baseline and longitudinal changes in biomarker. RESULTS: 58 Canadian and Italian participants with MS were enrolled in this study. Higher baseline sNfL was future relapse (Log-rank p = 0.0068), MRI lesions (p=0.0096), composite-relapse associated worsening (p=0.01) and progression independent of relapse activity (p=0.0096). Conversely, baseline sGFAP was only weakly associated with MRI lesions (0.044). Cross-sectional analyses of baseline sNfL revealed that a two-fold difference in baseline sNfL, e.g. from 10 to 20 pg/mL, was associated with a 2.3-fold increased risk of relapse during follow-up (95% confidence interval 1.65-3.17). Longitudinally, a two-fold increase in sNfL level from the first measurement was associated with an additional 1.46 times increased risk of relapse (1.07-2.00). The impact of longitudinal increases in sNfL on the risk of relapse were most pronounced for patients with lower baseline values of sNfL (<10 pg/mL: HR = 1.54, 1.06-2.24). These associations remained significant after adjustment for potential confounders. CONCLUSION: We enumerate the risk of relapse associated with dynamic changes in sNfL. Both baseline and longitudinal change in sNfL may help identify patients who would benefit from early treatment optimisation. TRIAL REGISTRATIONS: Canada:NCT02239393, Italy:NCT01854957&EudraCT, 2011-001295-19 CLASSIFICATION OF EVIDENCE: This study provides class 1 evidence that high baseline and longitudinal increases in sNfL are predictive of impending relapses in patients with active MS.

Validation of the Ottawa Troponin Pathway.

BACKGROUND: The Ottawa Troponin Pathway (OTP) was developed to improve Non-ST elevation myocardial infarction (NSTEMI) diagnosis accuracy using 3-h serial conventional troponin I (TnI) measurements. We sought to validate the OTP in patients with TnI values >99th percentile upper reference limit (>45 ng/L). METHODS: We conducted a health records review in adult patients with NSTEMI symptoms with at least two serial TnI and at least one >45 ng/L at two emergency departments (EDs). We collected baseline characteristics, ED management and disposition. 30-day outcomes included death due to cardiac ischemia, an unknown cause, or NSTEMI. RESULTS: 635 patients were included, and 107 patients were diagnosed with NSTEMI within 30-days. 217 patients had at least one TnI value >45 ng/L but <100 ng/L, of whom 4 patients were diagnosed with NSTEMI. 418 patients had at least one TnI value ≥100 ng/L, and 103 were diagnosed with NSTEMI. The OTP accurately identified all 107 patients with NSTEMI: sensitivity and specificity was 100% (95% CI 96.6%-100%) and 32.2% (95% CI 28.2%-36.4) respectively. CONCLUSIONS: The OTP is validated among patients with TnI values above the 99th percentile with symptoms concerning for ACS. Using OTP will allow for early referral and discharge home and improve ED crowding. REB NUMBER: 20180393-01H.

Serum neurofilament light in MS: The first true blood-based biomarker?

A simple blood-derived biomarker is desirable in the routine management of multiple sclerosis (MS) patients and serum neurofilament light chain (sNfL) is the most promising candidate. Although its utility was first shown in cerebrospinal fluid (CSF), technological advancements have enabled reliable detection in serum and less frequently plasma, obviating the need for repeated lumbar punctures. In this review, after defining the knowledge gap in MS management that many hope sNfL could fill, we summarize salient studies demonstrating associations of sNfL levels with outcomes of interest. We group these outcomes into inflammatory activity, progression, treatment response, and prediction/prognosis. Where possible we focus on data from real-world perspective observational cohorts. While acknowledging the limitations of sNfL and highlighting key areas for ongoing work, we conclude with our opinion of the role for sNfL as an objective, convenient, and cost-effective adjunct to clinical assessment. Paving the way for other promising biomarkers both blood-derived and otherwise, sNfL is an incremental step toward precision medicine for MS patients.

Cohort profile: Stop the Spread Ottawa (SSO)-a community-based prospective cohort study on antibody responses, antibody neutralisation efficiency and cellular immunity to SARS-CoV-2 infection and vaccination.

PURPOSE: To investigate the robustness and longevity of SARS-CoV-2 immune responses conferred by natural infection and vaccination among priority populations such as immunocompromised individuals and people with post-acute sequelae of COVID-19 in a prospective cohort study (Stop the Spread Ottawa-SSO) in adults living in the Ottawa region. In this paper, we describe the study design, ongoing data collection and baseline characteristics of participants. PARTICIPANTS: Since October 2020, participants who tested positive for COVID-19 (convalescents) or at high risk of exposure to the virus (under surveillance) have provided monthly blood and saliva samples over a 10-month period. As of 2 November 2021, 1026 adults had completed the baseline survey and 976 had attended baseline bloodwork. 300 participants will continue to provide bimonthly blood samples for 24 additional months (ie, total follow-up of 34 months). FINDINGS TO DATE: The median age of the baseline sample was 44 (IQR 23, range: 18-79) and just over two-thirds (n=688; 67.1%) were female. 255 participants (24.9%) had a history of COVID-19 infection confirmed by PCR and/or serology. Over 600 participants (60.0%) work in high-risk occupations (eg, healthcare, teaching and transportation). 108 participants (10.5%) reported immunocompromising conditions or treatments at baseline (eg, cancer, HIV, other immune deficiency, and/or use of immunosuppressants). FUTURE PLANS: SSO continues to yield rich research potential, given the collection of pre-vaccine baseline data and samples from the majority of participants, recruitment of diverse subgroups of interest, and a high level of participant retention and compliance with monthly sampling. The 24-month study extension will maximise opportunities to track SARS-CoV-2 immunity and vaccine efficacy, detect and characterise emerging variants, and compare subgroup humoral and cellular response robustness and persistence.

Relative Ratios of Human Seasonal Coronavirus Antibodies Predict the Efficiency of Cross-Neutralization of SARS-CoV-2 Spike Binding to ACE2.

BACKGROUND: Antibodies raised against human seasonal coronaviruses (sCoVs), which are responsible for the common cold, are known to cross-react with SARS-CoV-2 antigens. This prompts questions about their protective role against SARS-CoV-2 infections and COVID-19 severity. However, the relationship between sCoVs exposure and SARS-CoV-2 correlates of protection are not clearly identified. METHODS: We performed a cross-sectional analysis of cross-reactivity and cross-neutralization to SARS-CoV-2 antigens (S-RBD, S-trimer, N) using pre-pandemic sera from four different groups: pediatrics and adolescents, individuals 21 to 70 years of age, older than 70 years of age, and individuals living with HCV or HIV. Data was then further analysed using machine learning to identify predictive patterns of neutralization based on sCoVs serology. FINDINGS: Antibody cross-reactivity to SARS-CoV-2 antigens varied between 1.6% and 15.3% depending on the cohort and the isotype-antigen pair analyzed. We also show a range of neutralizing activity (0-45%) with median inhibition ranging from 17.6 % to 23.3 % in serum that interferes with SARS-CoV-2 spike attachment to ACE2 independently of age group. While the abundance of sCoV antibodies did not directly correlate with neutralization, we show that neutralizing activity is rather dependent on relative ratios of IgGs in sera directed to all four sCoV spike proteins. More specifically, we identified antibodies to NL63 and OC43 as being the most important predictors of neutralization. INTERPRETATION: Our data support the concept that exposure to sCoVs triggers antibody responses that influence the efficiency of SARS-CoV-2 spike binding to ACE2, which may potentially impact COVID-19 disease severity through other latent variables. FUNDING: This study was supported by a grant by the CIHR (VR2 -172722) and by a grant supplement by the CITF, and by a NRC Collaborative R&D Initiative Grant (PR031-1).

Survey of renin and aldosterone testing practices by Ontario laboratories - Providing insight into best practices.

OBJECTIVES: Testing for renin and aldosterone in clinical laboratories is complicated by pre-analytical considerations such as the posture for blood collection and susceptibility to cryoactivation of renin. From an analytical perspective, there are both renin activity and renin mass or concentration assays available. There can also be variability in result reporting practices and the aldosterone-renin ratio (ARR) cut-off applied to screen for primary aldosteronism (PA). The Institute for Quality Management in Healthcare (IQMH) Centre for Proficiency Testing surveyed laboratories on their handling of renin and aldosterone testing to better understand current practices. DESIGN AND METHODS: An online survey was prepared and sent to 134 Canadian laboratories enrolled in endocrinology proficiency testing with IQMH. RESULTS: One hundred twenty Ontario laboratories submitted responses. While only six (5%) laboratories perform testing for both renin and aldosterone, 108 (90%) collect and process specimens to be tested by reference laboratories. The survey revealed considerable variation in practices including the recommended state of patients prior to sample collection (for example, regarding medications or salt intake), the patient posture specifications for sample collection, the precautions taken against cryoactivation of renin, the choice of renin activity or mass assay, and the ARR cut-off used. The available literature on these factors was then reviewed. CONCLUSIONS: Although there is no standardized procedure for specimen collection, analysis, or result reporting for renin or aldosterone testing, we have attempted to summarize the available literature to develop evidence-based recommendations. Where laboratory practice differs from peers and/or recommended protocols, laboratories should review their practices.

Serum Neurofilament Light Chain Measurement in MS: Hurdles to Clinical Translation.

Measurement of serum neurofilament light chain concentration (sNfL) promises to become a convenient, cost effective and meaningful adjunct for multiple sclerosis (MS) prognostication as well as monitoring disease activity in response to treatment. Despite the remarkable progress and an ever-increasing literature supporting the potential role of sNfL in MS over the last 5 years, a number of hurdles remain before this test can be integrated into routine clinical practice. In this review we highlight these hurdles, broadly classified by concerns relating to clinical validity and analytical validity. After setting out an aspirational roadmap as to how many of these issues can be overcome, we conclude by sharing our vision of the current and future role of sNfL assays in MS clinical practice.