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.

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.

Does N-Terminal Pro-B-Type Natriuretic Peptide Improve the Risk Stratification of Emergency Department Patients With Syncope?

BACKGROUND: Studies have reported that natriuretic peptides provide prognostic information for emergency department (ED) syncope. OBJECTIVE: To evaluate whether adding N-terminal pro-B-type natriuretic peptide (NT-proBNP) to the Canadian Syncope Risk Score (CSRS) improves prediction of 30-day serious adverse events (SAEs). DESIGN: Prospective cohort study. SETTING: 6 EDs in 2 Canadian provinces. PARTICIPANTS: 1452 adult ED patients with syncope. INTERVENTION: Serum NT-proBNP was measured locally at 1 site and batch processed at a central laboratory from other sites. The concentrations were not available to treating physicians or for adjudication of outcomes. MEASUREMENTS: An adjudicated composite outcome of 30-day SAEs, including death and cardiac (arrhythmic and nonarrhythmic) and noncardiac events. RESULTS: Of 1452 patients enrolled, 152 (10.5% [95% CI, 9.0% to 12.1%]) had 30-day SAEs, 57 (3.9%) of which were identified after the index ED disposition. Serum NT-proBNP concentrations were significantly higher among patients with SAEs than those without them (median, 626.5 ng/L vs. 81 ng/L; P < 0.001). Adding NT-proBNP values to the CSRS did not significantly improve prognostication (c-statistic, 0.89 and 0.90; P = 0.12 for difference), regardless of SAE subgroup or whether the SAE was identified after the index ED visit. The net reclassification index shows that NT-proBNP would have correctly reclassified 3% of patients with SAEs at the expense of incorrectly reclassifying 2% of patients without SAEs. LIMITATIONS: Our study was powered to detect a 3% difference in the area under the curve. The heterogeneity of outcomes and robust baseline discrimination by the CSRS will make improvements challenging. CONCLUSION: Although serum NT-proBNP concentrations were generally much higher among ED patients with syncope who had a 30-day SAE, this blood test added little new information to the CSRS. Routine use of NT-proBNP for ED syncope prognostication is not recommended. PRIMARY FUNDING SOURCE: Physicians' Services Incorporated Foundation, Canadian Institutes of Health Research, and The Ottawa Hospital Academic Medical Organization.

An international multi-center serum protein electrophoresis accuracy and M-protein isotyping study. Part II: limit of detection and follow-up of patients with small M-proteins.

Background Electrophoretic methods to detect, characterize and quantify M-proteins play an important role in the management of patients with monoclonal gammopathies (MGs). Significant uncertainty in the quantification and limit of detection (LOD) is documented when M-proteins are <10 g/L. Using spiked sera, we aimed to assess the variability in intact M-protein quantification and LOD across 16 laboratories. Methods Sera with normal, hypo- or hyper-gammaglobulinemia were spiked with daratumumab or elotuzumab, with concentrations from 0.125 to 10 g/L (n = 62) along with a beta-migrating sample (n = 9). Laboratories blindly analyzed samples according to their serum protein electrophoresis (SPEP)/isotyping standard operating procedures. LOD and intra-laboratory percent coefficient of variation (%CV) were calculated and further specified with regard to the method (gel/capillary electrophoresis [CZE]), gating strategy (perpendicular drop [PD]/tangent skimming [TS]), isotyping (immunofixation/immunosubtraction [ISUB]) and manufacturer (Helena/Sebia). Results All M-proteins ≥1 g/L were detected by SPEP. With isotyping the LOD was moderately more sensitive than with SPEP. The intensity of polyclonal background had the biggest negative impact on LOD. Independent of the method used, the intra-laboratory imprecision of M-protein quantification was small (mean CV = 5.0%). Low M-protein concentration and high polyclonal background had the strongest negative impact on intra-laboratory precision. All laboratories were able to follow trend of M-protein concentrations down to 1 g/L. Conclusions In this study, we describe a large variation in the reported LOD for both SPEP and isotyping; overall LOD is most affected by the polyclonal immunoglobulin background. Satisfactory intra-laboratory precision was demonstrated. This indicates that the quantification of small M-proteins to monitor patients over time is appropriate, when subsequent testing is performed within the same laboratory.

An international multi-center serum protein electrophoresis accuracy and M-protein isotyping study. Part I: factors impacting limit of quantitation of serum protein electrophoresis.

Background Serum protein electrophoresis (SPEP) is used to quantify the serum monoclonal component or M-protein, for diagnosis and monitoring of monoclonal gammopathies. Significant imprecision and inaccuracy pose challenges in reporting small M-proteins. Using therapeutic monoclonal antibody-spiked sera and a pooled beta-migrating M-protein, we aimed to assess SPEP limitations and variability across 16 laboratories in three continents. Methods Sera with normal, hypo- or hypergammaglobulinemia were spiked with daratumumab, Dara (cathodal migrating), or elotuzumab, Elo (central-gamma migrating), with concentrations from 0.125 to 10 g/L (n = 62) along with a beta-migrating sample (n = 9). Provided with total protein (reverse biuret, Siemens), laboratories blindly analyzed samples according to their SPEP and immunofixation (IFE) or immunosubtraction (ISUB) standard operating procedures. Sixteen laboratories reported the perpendicular drop (PD) method of gating the M-protein, while 10 used tangent skimming (TS). A mean percent recovery range of 80%-120% was set as acceptable. The inter-laboratory %CV was calculated. Results Gamma globulin background, migration pattern and concentration all affect the precision and accuracy of quantifying M-proteins by SPEP. As the background increases, imprecision increases and accuracy decreases leading to overestimation of M-protein quantitation especially evident in hypergamma samples, and more prominent with PD. Cathodal migrating M-proteins were associated with less imprecision and higher accuracy compared to central-gamma migrating M-proteins, which is attributed to the increased gamma background contribution in M-proteins migrating in the middle of the gamma fraction. There is greater imprecision and loss of accuracy at lower M-protein concentrations. Conclusions This study suggests that quantifying exceedingly low concentrations of M-proteins, although possible, may not yield adequate accuracy and precision between laboratories.

Diagnostic outcome and indications for testing in patients with positive ANCA at a Canadian tertiary care centre.

INTRODUCTION/OBJECTIVE: With widespread availability of anti-neutrophil cytoplasmic antibody (ANCA) testing, interpreting positive results has become increasingly challenging. Here, we conducted a retrospective study to evaluate indications for testing and diagnosis of patients with positive ANCA. METHODS: Positive ANCA tests (immunofluorescence or immunoassay) performed between April 2014 and March 2015 were identified using the Ottawa Hospital (TOH) laboratory information system. TOH electronic records of subjects with positive ANCA were reviewed. RESULTS: 96 patients had first-time positive ANCA in the study year. The indications for testing were suspicion for: AAV in 22 patients (23%), unspecified vasculitis in 24(25%), an inflammatory condition in 46(48%), and unknown in 4(4%). Twenty-eight patients (29% of first-time positives) were diagnosed with AAV, corresponding to 16(72%), 8(33%), 4(9%), and 0 patients tested for these indications, respectively; 49(51%) of patients had other inflammatory or infectious etiologies, and non-inflammatory diagnoses accounted for the remaining 19(20%). One hundred and forty-four repeat ANCAs were performed with life-time mean of 4.4 re-tests per patient (range 0-44). Routine monitoring accounted for 86(72%) of all repeat tests. Management was changed following 34% of all re-tests performed for changed clinical status and 1% of re-tests conducted routinely. CONCLUSION: Few patients who start with low clinical suspicion for AAV and have positive ANCA are subsequently diagnosed with AAV. Serial ANCA testing is common but is not supported by clear evidence, and rarely leads to change in management. Clarification of guidelines on effective ANCA ordering may reduce hospital laboratory costs.

Are Anti-ß2 Glycoprotein 1 Antibodies Associated with Placenta-Mediated Pregnancy Complications? A Nested Case-Control Study.

BACKGROUND: While anti-ß2 glycoprotein 1 (anti-ß2GP1) antibody positivity is included in the diagnostic criteria for antiphospholipid syndrome (APS), the association between anti-ß2GP1 and the obstetrical complications of APS has been inconsistently reported and remains unclear. OBJECTIVE: We completed a case-control study nested within the Canadian Ottawa and Kingston (OaK) Birth Cohort to evaluate the association between anti-ß2GP1 antibody positivity and placenta-mediated pregnancy complications. STUDY DESIGN: Five hundred cases were randomly selected among pregnant women who experienced any of the following independently adjudicated placenta-mediated pregnancy complications: preeclampsia, placental abruption, late pregnancy loss (≥ 12 weeks' gestation), and birth of a small-for-gestational age (SGA) infant < 10th percentile. Five hundred pregnant women without any placenta-mediated pregnancy complications were selected as controls. Stored blood samples were analyzed for the presence of anti-ß2GP1 antibodies by enzyme-linked immunosorbent assay. RESULTS: Anti-ß2GP1 immunoglobulin G (IgG) and/or immunoglobulin M (IgM) antibodies in titers ≥ 20 G/M units (> 99th percentile) were present in 24 of 497 (4.8%) of controls and 33 of 503 (6.6%) of cases. There was no significant difference between cases and controls for the composite outcome of any placenta-mediated pregnancy complications (odds ratio, 1.38, 95% confidence interval [CI], 0.8-2.37, p = 0.25). CONCLUSION: Our results call into question the association between anti-ß2GP1 antibodies and placenta-mediated pregnancy complications, with further research needed.

Incremental value of natriuretic peptide measurement in acute decompensated heart failure (ADHF): a systematic review.

The aim of this systematic review was to determine whether B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) independently add incremental value for predicting mortality and morbidity in patients with acute decompensated heart failure (ADHF). Medline(®), Embase™, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL were searched from 1989 to June 2012. We also searched reference lists of included articles, systematic reviews, and the gray literature. Studies were screened for eligibility criteria and assessed for risk of bias. Data were extracted on study design, population demographics, assay cutpoints, prognostic risk prediction model covariates, statistical methods, outcomes, and results. From 183 citations, only seven studies (5 BNP and 2 NT-proBNP) considered incremental value in ADHF subjects admitted to acute care centers. Admission assay levels and length of follow-up varied for BNP studies (31 days to 12 months) and for NT-proBNP studies (25-82 months). All studies presented at least one estimate of incremental value of BNP/NT-proBNP relative to the base prognostic model. Using discrimination or likelihood statistics, these studies consistently showed that BNP or NT-proBNP increased model performance. Three studies used reclassification and model validation computations to establish incremental value; these studies showed less consistency with respect to added value. In conclusion, the literature assessing incremental value of BNP/NT-proBNP in ADHF populations is limited to seven studies evaluating only mortality outcomes and at moderate risk of bias. Although there were differences in the base risk prediction models, assay cutpoints, and lengths of follow-up, there was consistency in BNP/NT-proBNP adding incremental value in prediction models in ADHF patients.

Prediction of clinical outcomes using B-type natriuretic peptides in the general population: a systematic review.

The use of B-type natriuretic peptides to predict outcomes in general populations has been investigated in a number of primary studies. A previous systematic review considering natriuretic peptides in cardiovascular disease included a subgroup of general population studies, which suggested an association with a number of clinical outcomes. We electronically searched Medline, Embase, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL for English-language articles published between 1989 and mid-2012. We utilized trained reviewers and standardized forms to screen articles for inclusion and extract data from included articles. All included studies (n = 7) were summarized in narrative and tabular form. A general population was defined as one that was randomly selected from a community setting where no specific inclusion or exclusion criteria were specified. The seven included studies all used FDA approved assays for NT-proBNP. The range of clinical outcomes and heterogeneity did not allow for meta-analysis. The hazard ratios for predicting outcomes in the included studies ranged from 1.0 to 4.1 (all p values <0.05). The discrimination statistics reported in four studies all demonstrated statistically significant improvements in predicting outcomes. NT-proBNP is associated with heart failure, all-cause and cardiovascular mortality, and other combined cardiovascular events in a general unselected population. The discrimination statistics suggest modest improvements in risk stratification. No prospective studies exist to demonstrate the clinical utility of using B-type natriuretic peptides to predict clinical outcomes in a general population.

Performance of BNP and NT-proBNP for diagnosis of heart failure in primary care patients: a systematic review.

National and international guidelines have been published recommending the use of natriuretic peptides as an aid to the diagnosis of heart failure (HF) in acute settings; however, few specific recommendations exist for governing the use of these peptides in primary care populations. To summarize the available data relevant to the diagnosis of HF in primary care patient population, we systematically reviewed the literature to identify original articles that investigated the diagnostic accuracy of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) in primary care settings. The search yielded 25,864 articles in total: 12 investigating BNP and 20 investigating NT-proBNP were relevant to our objective and included in the review. QUADAS-2 and GRADE were used to assess the quality of the included articles. Diagnostic data were pooled based on three cutpoints: lowest and optimal, as chosen by study authors, and manufacturers' suggested. The effect of various determinants (e.g., age, gender, BMI, and renal function) on diagnostic performance was also investigated. Pooled sensitivity and specificity of BNP and NT-proBNP using the lowest [0.85 (sensitivity) and 0.54 (specificity)], optimal (0.80 and 0.61), and manufacturers' (0.74 and 0.67) cutpoints showed good performance for diagnosing HF. Similar performance was seen for NT-proBNP: lowest (0.90 and 0.50), optimal (0.86 and 0.58), and manufacturers' (0.82 and 0.58) cutpoints. Overall, we rated the strength of evidence as high because further studies will be unlikely to change the estimates diagnostic performance.

BNP and NT-proBNP as prognostic markers in persons with chronic stable heart failure.

Prognosis permits clinicians to separate persons with heart failure (HF) into subgroups based on likely health outcomes. Treatment is partly guided by these likely outcomes. This systematic review explores whether brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are independent predictors of prognosis in persons with chronic stable HF. We electronically searched Medline, Embase, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL for English-language articles published between 1989 and mid-2012. We utilized trained reviewers and standardized forms to screen articles for inclusion and extracted data from included articles. All included studies were summarized in narrative and tabular form. We used the Hayden criteria to assess the risk of bias. Sixteen BNP publications and 88 NT-proBNP publications were included in the systematic review. BNP was positively associated with all-cause and HF mortality. NT-proBNP was positively associated with all-cause and cardiovascular mortality. BNP and NT-proBNP levels are useful for estimating prognosis in persons with chronic stable HF. Further research is required to establish optimal cutpoints and to assess whether prognostic effects differ by age, sex, or time period.

Use of BNP and NT-proBNP for the diagnosis of heart failure in the emergency department: a systematic review of the evidence.

Our purpose was to determine the test performance characteristics of BNP and NT-proBNP in the diagnosis of heart failure for patients presenting to an emergency department or urgent care center. We searched Medline, Embase, AMED, Cochrane, Cochrane Database of Systematic Reviews, and CINAHL for English-language articles published between 1989 and June 2012. Studies were limited to those using FDA-approved assays. We examined test performance at three pre-specified cutpoints (manufacturers' suggested, researchers' optimal, and lowest) and considered the effect of age, gender, ethnicity and renal function. We used the QUADAS-2 tool to examine risk of bias and applicability, and the AHRQ Methods Guide to assess the strength of evidence. Seventy-six articles met our inclusion criteria, 37 examined BNP, 25 examined NT-proBNP, and 14 examined both. Pooled sensitivity and specificity for BNP at the three pre-specified cutpoints were 95, 91, and 95 % (sensitivity) and 55, 80, and 67 % (specificity), respectively. For NT-proBNP, sensitivity and specificity at the same cutpoints were 91, 90, and 96 % (sensitivity) and 67, 74, and 55 % (specificity). Both BNP and NT-proBNP perform well to rule out, but less well to rule in, the diagnosis of heart failure among persons presenting to emergency departments or urgent care centers. Both BNP and NT-proBNP levels are positively associated with age and negatively associated with renal function. However, the effect of these factors with respect to selecting optimal cutpoints is unclear. For BNP, 100 pg/mL appears to be a consensus cutpoint. No clear consensus has emerged for NT-proBNP, but the age-adjusted cutpoints of 450 pg/mL for <50 years, 900 pg/mL for 50-75 years and 1,800 pg/mL for >75 years appear promising and merit greater scrutiny and validation.

A systematic review of BNP and NT-proBNP in the management of heart failure: overview and methods.

B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) levels are increased in persons with heart failure (HF); low levels of these peptides rule out HF. We systematically reviewed the literature to assess the use of BNP and NT-proBNP in the diagnosis, prognosis, and treatment for HF. We also examined the biological variation of these peptides in persons with and without HF. We searched Medline, Embase, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL for English-language studies published between January 1989 and June 2012. Supplemental searches involved the gray literature and the reference lists of included studies. Trained reviewers used standardized forms to screen articles for inclusion in the review and to extract data from included papers. We examined the risk of bias with QUADAS-2 for diagnosis studies, the Hayden criteria for prognosis studies, and the Jadad scale for treatment studies. We assessed the strength of evidence in four domains (risk of bias, consistency, directness, and precision) for the diagnosis and treatment studies. Results were reported as narrative syntheses. Additional meta-analyses were conducted for the diagnosis studies. Three hundred ten articles passed through screening and were included in the review. One hundred four articles applied to diagnostic accuracy, 190 papers pertained to prognosis, and nine articles addressed BNP- or NT-proBNP-guided treatment. Each individual paper in this series reports, summarizes, and discusses the evidence regarding diagnosis, prognosis, or treatment.

B-type natriuretic peptide-guided therapy: a systematic review.

BNP/NT-proBNP measurement has not gained widespread use for the management of patients with heart failure (HF) despite several randomized controlled trials. A systematic review addressing the question of whether patients with HF benefit from BNP-assisted therapy or intensified therapy compared with usual care was undertaken. Relevant randomized controlled trial (RCTs) were selected by searching Medline, Embase, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL for English-language articles published from 1980 to 2012. Selected studies required patients to be treated for chronic HF with medical therapy based on BNP/NT-proBNP or usual care. There were no restrictions except that BNP/NT-proBNP measurement had to be done by an FDA approved method. Nine RCTs were identified with 2,104 patients with study duration that ranged from 3 to 18 months. Overall, there was a wide variation in study design and how parameters were reported including patient selection, baseline characteristics, therapy goals, BNP/NT-proBNP cutpoint, and outcome types. Meta-analysis was not appropriate given this study heterogeneity. The strength of evidence for the outcome of mortality, reported in seven studies, was found to be low due to inconsistency and imprecision. This systematic review showed that the evidence is of low quality and insufficient to support the use of BNP/NT-proBNP to guide HF therapy. Further trials with improved design are needed.

BNP and NT-proBNP as prognostic markers in persons with acute decompensated heart failure: a systematic review.

A systematic review was undertaken to examine the evidence for B-type natriuretic peptides (BNP and NT-proBNP) as independent predictors of mortality, morbidity, or combined mortality and morbidity outcomes in persons with acute decompensated heart failure (ADHF). Electronic databases (Medline(®), Embase™, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL) were searched from 1989 to June 2012. Reference lists of included articles, systematic reviews, and the gray literature were also searched. English language studies were eligible if they included subjects with ADHF and measured BNP/NT-proBNP using FDA approved assays. Standardized forms were used to select studies, extract data, and assess risk of bias. Seventy-nine studies, ranging over followup intervals from 14 days to 7 years, evaluating levels of BNP (n = 38), NT-proBNP (n = 35), or both (n = 6) were eligible. The majority of studies predicted mortality outcomes for admission BNP/NT-proBNP levels, with fewer studies evaluating serial, change from admission, or discharge levels. In general, higher levels of admission BNP or NT-proBNP predicted greater risk for all outcomes. Decreased levels post-admission predicted decreased risk. Overall, these studies were rated as having moderate risk of bias. This systematic review shows that BNP and NT-proBNP are independent predictors of mortality (all-cause and cardiovascular) in ADHF despite different cutpoints, time intervals, and prognostic models. Findings for morbidity and composite outcomes were less frequently evaluated and showed inconsistency. Further research is required to assess cutpoints for admission, serial measurements, change following admission, and discharge levels to assist clinical decision-making.

Incremental predictive value of natriuretic peptides for prognosis in the chronic stable heart failure population: a systematic review.

The aim of this study was to determine whether measurement of natriuretic peptides independently adds incremental predictive value for mortality and morbidity in patients with chronic stable heart failure (CSHF). We electronically searched Medline®, Embase™, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL from 1989 to June 2012. We also searched reference lists of included articles, systematic reviews, and the gray literature. Studies were screened for eligibility criteria and assessed for methodological quality. Data were extracted on study design, population demographics, assay cutpoints, prognostic risk prediction model covariates, statistical methods, outcomes, and results. One hundred and eighty-three studies were identified as prognostic in the systematic review. From these, 15 studies (all NT-proBNP) considered incremental predictive value in CSHF subjects. Follow-up varied from 12 to 37 months. All studies presented at least one estimate of incremental predictive value of NT-proBNP relative to the base prognostic model. Using discrimination or likelihood statistics, these studies consistently showed that NT-proBNP increased model performance. Three studies used re-classification and model validation computations to establish incremental predictive value; these studies showed less consistency with respect to added value. Although there were differences in the base risk prediction models, assay cutpoints, and lengths of follow-up, there was consistency in NT-proBNP adding incremental predictive value for prognostic models in chronic stable CSHF patients. The limitations in the literature suggest that studies designed to evaluate prognostic models should be undertaken to evaluate the incremental value of natriuretic peptide as a predictor of mortality and morbidity in CSHF.

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.

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.

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.

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.