Safety and efficiency of implementation of high-sensitivity troponin T in the assessment of emergency department patients with cardiac chest pain.

BACKGROUND: For emergency department (ED) patients with cardiac chest pain, introduction of high-sensitivity troponin (hsTnT) pathways has been associated with reductions in length of stay of less than 1 h. METHODS: At two urban Canadian sites, we introduced hsTnT on January 26, 2016. While the prior diagnostic algorithm required troponin testing at 0 and 6 h, serial hsTnT serial testing was conducted at 0 and 3 h. We identified consecutive patients who presented with cardiac chest pain from January 1, 2015, to March 31, 2017, along with 30-day outcomes. The primary outcome was a missed 30-day major adverse cardiac event, (MACE) defined as death, revascularization, or readmission for myocardial infarction occurring in a patient-discharged home with a minimizing diagnosis and without cardiac-specific follow-up. Secondary outcomes included admission rate, ED length of stay, and MACE. We compared pre- and post- implementation periods using descriptive methods and repeated this analysis in patients with noncardiac chest pain. RESULTS: We collected 5585 patients with cardiac chest pain, (2678 pre- and 2907 post-introduction) and 434 had (7.8%, 95% CI 7.1 to 8.5%) MACE, with 1 missed MACE. (0.2%, 95% CI 0.04 to 1.3%). Admission rate was stable at 24.1% pre- and 23.7% while median length of stay decreased from 464 to 285 min, a difference of 179 min. (95% CI 61 to 228 min). For 11,611 patients with noncardiac chest pain, admission rate (9%) and length of stay (191 versus 193 min) remained constant. CONCLUSIONS: Implementation of hsTnT for evaluation of ED chest pain patients was safe and associated with a 3-h decrease in length of stay.

RéSUMé: CONTEXTE: Pour les patients des urgences (DE) souffrant de douleurs cardiaques à la poitrine, l'introduction de voies de troponine à haute sensibilité (hsTnT) a été associée à une réduction de la durée du séjour de moins d'une heure. MéTHODES: Dans deux sites urbains canadiens, nous avons présenté la hsTnT le 26 janvier 2016. Alors que l'algorithme de diagnostic précédent exigeait des essais de troponine à zéro et six heures, les essais en série hsTnT ont été effectués à zéro et trois heures. Nous avons identifié des patients consécutifs qui ont présenté une douleur cardiaque à la poitrine du 1er janvier 2015 au 31 mars 2017, ainsi que des résultats de 30 jours. Le principal résultat était un événement cardiaque indésirable majeur (AAMMA) de 30 jours, défini comme la mort, la revascularisation ou la réadmission pour infarctus du myocarde survenant chez un patient qui avait été libéré avec un diagnostic minimisant et sans suivi spécifique au cœur. Les critères secondaires comprenaient le taux d'admission, la durée du séjour en salle d'opération et le MACE. Nous avons comparé les périodes pré- et post-mise en œuvre à l'aide de méthodes descriptives et répété cette analyse chez des patients souffrant de douleurs thoraciques non cardiaques. RéSULTATS: Nous avons recueilli 5585 patients souffrant de douleurs cardiaques à la poitrine (2678 avant et 2907 après l'introduction) et 434 avec MACE (7.8 %, IC à 95 % 7.1 à 8.5 %), dont un MACE manqué. (0.2 %, IC à 95 % 0.04 à 1.3 %). Le taux d'admission était stable à 24.1 % avant et 23.7 %, tandis que la durée médiane du séjour diminuait de 464 à 285 minutes, soit une différence de 179 minutes (IC 95 % 61 à 228 minutes). Pour 11611 patients souffrant de douleurs thoraciques non cardiaques, le taux d'admission (9 %) et la durée du séjour (191 contre 193 minutes) sont restés constants. CONCLUSION: La mise en œuvre de la TTS pour l'évaluation des patients souffrant de douleur thoracique en salle d'opération était sans danger et associée à une diminution de trois heures de séjour.

Iron Deficiency and Sleep/Wake Behaviors: A Scoping Review of Clinical Practice Guidelines-How to Overcome the Current Conundrum?

Current evidence suggests that iron deficiency (ID) plays a key role in the pathogenesis of conditions presenting with restlessness such as attention deficit hyperactivity disorder (ADHD) and restless legs syndrome (RLS). In clinical practice, ID and iron supplementation are not routinely considered in the diagnostic work-up and/or as a treatment option in such conditions. Therefore, we conducted a scoping literature review of ID guidelines. Of the 58 guidelines included, only 9 included RLS, and 3 included ADHD. Ferritin was the most frequently cited biomarker, though cutoff values varied between guidelines and depending on additional factors such as age, sex, and comorbidities. Recommendations surrounding measurable iron biomarkers and cutoff values varied between guidelines; moreover, despite capturing the role of inflammation as a concept, most guidelines often did not include recommendations for how to assess this. This lack of harmonization on the interpretation of iron and inflammation biomarkers raises questions about the applicability of current guidelines in clinical practice. Further, the majority of ID guidelines in this review did not include the ID-associated disorders, ADHD and RLS. As ID can be associated with altered movement patterns, a novel consensus is needed for investigating and interpreting iron status in the context of different clinical phenotypes.

CRP and sCD25 help distinguish between adult-onset Still's disease and HLH.

OBJECTIVE: Adult-onset Still's disease (AOSD) and secondary hemophagocytic lymphohistiocytosis (sHLH) are both hyperferritinemic cytokine storm syndromes that can be difficult to distinguish from each other in hospitalized patients. The objective of this study was to compare the inflammatory markers ferritin, D-dimer, C-reactive protein (CRP), and soluble CD25 (sCD25) in patients with AOSD and sHLH. These four markers were chosen as they are widely available and represent different aspects of inflammatory diseases: macrophage activation (ferritin); endothelialopathy (D-dimer); interleukin-1/interleukin-6/tumour necrosis factor elevation (CRP) and T cell activation (sCD25). METHODS: This was a single-center retrospective study. Patients diagnosed by the Hematology service at Vancouver General Hospital for AOSD or sHLH from 2009 to 2023 were included. RESULTS: There were 16 AOSD and 44 sHLH patients identified. Ferritin was lower in AOSD than HLH (median 11 360 µg/L vs. 29 020 µg/L, p = .01) while D-dimer was not significantly different (median 5310 mg/L FEU vs. 7000 mg/L FEU, p = .3). CRP was higher (median 168 mg/L vs. 71 mg/L, p <.01) and sCD25 was lower (median 2220 vs. 7280 U/mL, p = .004) in AOSD compared to HLH. The combined ROC curve using CRP >130 mg/L and sCD25< 3900 U/mL to distinguish AOSD from HLH had an area under the curve (AUC) of 0.94 (95% confidence interval 0.93-0.97) with sensitivity 91% and specificity 93%. CONCLUSIONS: These findings suggest that simple, widely available laboratory tests such as CRP and sCD25 can help clinicians distinguish AOSD from HLH in acutely ill adults with extreme hyperferritinemia. Larger studies examining a wider range of clinically available inflammatory biomarkers in a more diverse set of cytokine storm syndromes are warranted.

Molecular confirmation of alpha 1-antitrypsin deficiency in liver transplant setting: A province-wide experience.

Background and Aim: Patients suspected of Alpha 1-Antitrypsin (A1AT) abnormality based on low serum concentration are routinely confirmed through polymerase chain reaction (PCR) testing of peripheral blood. Genotyping formalin-fixed paraffin-embedded (FFPE) tissue is a novel approach that could aid in detecting variant A1AT. We performed qPCR on FFPE liver explants with Periodic Acid Schiff after Diastase (PASD)- and A1AT-positive globules to confirm and estimate the frequency of A1AT deficiency in transplant cases. Materials and Methods: Eighteen (12.68%) of 142 patients with end-stage liver disease showed PASD/A1AT positive globules. FFPE of the explants was tested through qPCR to detect S and Z alleles. A second age- and sex-matched control group consisting of five liver transplant patients with negative globules was included in the study. Results: qPCR assay was successful with all the samples meeting QC parameters. All patients included in the study elucidated Z allele variants; 2 homozygous (11.1%) and 16 heterozygous (88.9%). The control group demonstrated normal wild-type MM allele. Conclusion: Screening for A1AT deficiency using serum levels is not sufficiently sensitive to detect deficiency, especially in carriers. If A1AT testing was not performed preoperatively and the risk is high based on the PASD/A1AT-positive globules in the explants, then molecular testing of FFPE tissue can be a viable method for confirming the diagnosis.

Mass spectrometry in IgG4-related disease diagnosis.

We compared liquid chromatography tandem mass spectrometry (LC-MS/MS) against Binding Site immunonephelometry (BSIN) with regards to these methods' abilities to diagnose IgG4-related disease (IgG4-RD). IgG subclasses were gathered from laboratory from December 2011 to December 2020. The IgG4-RD positive and negative patients were diagnosed according to the ACR/EULAR classification criteria by extensive chart review. Both methods' results were compared in terms of test characteristics. For BSIN, there were 43 IgG4-RD positive cases and 174 disease negative cases, while for LC-MS/MS, there were 102 IgG4-RD positive cases and 562 disease negative cases. The majority of IgG4-RD patients by BSIN and LC-MS/MS had an elevated IgG4 level, 81% and 86%, respectively. For BSIN, the ROC curve, cut-off value of 1.25 g/L, had a sensitivity of 81% and a specificity of 84%. For LC-MS/MS, the ROC curve, cut-off value of 1.25 g/L, had a sensitivity of 86% and a specificity of 84%. The responder index score to IgG4 level r-correlation value for BSIN and LC-MS/MS was 0.5 and 0.6, respectively. In our center, LC-MS/MS and BSIN are equivalent test methods in IgG4-RD diagnosis. IgG4 level does correlate with disease activity by the responder index. LC-MS/MS is a valid and equally reliable alternative to BSIN in the diagnosis of IgG4-related disease.

Macrocytosis in Mitochondrial DNA Deletion Syndromes.

Large single mitochondrial DNA (mtDNA) deletion syndrome is a rare inborn error of metabolism with variable heteroplasmy levels and clinical phenotype among affected individuals. Chronic progressive external ophthalmoplegia (CPEO) is the most common phenotype in adults with this form of mitochondrial disease [J Intern Med. 2020;287(6):592-608 and Biomed Rep. 2016;4(3):259-62]. The common CPEO clinical manifestations are ptosis and ophthalmoplegia. More variable phenotypic manifestations of CPEO (CPEO plus) include involvement of the peripheral nervous system and myopathy. Here, we describe a 62-year-old female with CPEO and the major mtDNA deletion present at 40% heteroplasmy, who had a coexistent previously undescribed CPEO phenotypic feature of persistent unexplained macrocytosis without anemia. Building on this case, we reviewed other major mtDNA deletion cases seen in our Adult Metabolic Diseases Clinic (AMDC) at the University of British Columbia, Vancouver, Canada, from 2016 to 2022. The major mtDNA deletion cases (n = 26) were compared with mtDNA missense variants identified in the clinic over the same period who acted as the comparison group (n = 16). Of these, the most frequent diagnosis was maternally inherited diabetes and deafness and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. Ten out of 26 (38%) of mtDNA deletion patients had macrocytosis with elevated mean corpuscular volume (MCV), median (interquartile range) of 108 fL (102-114 fL). Seven of the patients with macrocytosis had no pertinent etiology. None of the comparison group had macrocytosis. There was a significant difference (p = 0.000) between the MCV and MCH in the mtDNA deletion group compared to the comparison group. This communication sheds light on the association of macrocytosis with the mtDNA deletion syndrome. It would be of great interest to determine if the association is found in other mitochondrial disease clinic populations.

Functional Localization of Adult-Onset Idiopathic Nesidioblastosis.

Nesidioblastosis is a rare pancreatic disorder involving enlarged beta cells throughout the pancreas, causing elevated insulin production. We present the case of a 53-year-old woman with the initial symptom of fasting hypoglycemia. No pancreatic lesions were indicated on computed tomography and magnetic resonance imaging scans, and an octreotide scan was negative for insulinoma. Selective arterial calcium stimulation (SACST) showed increased insulin production from the stimulation of 3 out of 5 arteries. The SACST results suggested a diagnosis of nesidioblastosis, which was confirmed by histopathology after a subtotal distal pancreatectomy. The patient has normal glucose tolerance after surgery with no further problems of hypoglycemia, indicating that this is a rare case of nesidioblastosis extending only partially through the pancreas.

Quantitation of IgG Subclasses in Serum Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

Serum IgG subclasses (IgGSC) are measured for a number of indications, but the most common are the identification of selective immunodeficiency disease and the diagnosis of IgG4-related disease (IgG4RD). Traditional nephelometric (IN) assays can suffer from two issues impacting the accuracy of the results: (1) hook effect and (2) antibody cross-reactivity between the subclasses. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is not vulnerable to these modes of interference and therefore serves as an excellent and relatively inexpensive means of diagnosing and/or monitoring the relevant clinical conditions.We describe a semiautomated and simple method for the accurate and precise measurement of IgGSC from 20 µL of serum using a liquid chromatography and tandem mass spectrometry (LC-MS/MS) method following digestion of serum proteins in 96-well plate format. Due to the high abundance of the target proteins, no specialized sample preparation (such as solid phase extraction) is required. Twenty microliters are injected to the LC-MS/MS system. Quantitation is performed against a five-point duplicate linear calibration curve prepared in blank matrix. The assay calibration range is 0.38-7.74 g/L for IgG1, 0.24-4.46 g/L for IgG2, 0.038-0.752 g/L for IgG3, 0.025-0.435 g/L for IgG4, and 0.62-15.5 g/L for total IgG. Total IgG is used as an internal quality control marker and is compared to the sum of the four subclass results. Total imprecision in clinical production has been observed to be 5.1-10.6% for in-house prepared control materials having IgGSC mean values in the range of 0.38-8.43 g/L for IgG1, 0.22-3.76 g/L for IgG2, 0.0387-0.721 g/L for Ig3, and 0.0279-1.46 g/L for IgG4. Limit of quantitation (LoQ) was determined to be 0.29 g/L for IgG1, 0.22 g/L for IgG2, 0.019 g/L for IgG3, and 0.0067 g/L for IgG4.

The impact of IgG subclass deficiency on the risk of mortality in hospitalized patients with COPD.

BACKGROUND: Immunoglobulin G (IgG) deficiency increases the risk of acute exacerbations and mortality in chronic obstructive pulmonary disease (COPD). However, the impact of IgG subclass deficiency on mortality in COPD is unknown. Here, we determined which IgG subclass, if any, is associated with increased risk of mortality in COPD. METHODS: We measured serum IgG subclass concentrations of 489 hospitalized patients with COPD who were enrolled in the Rapid Transition Program (clinicaltrials.gov identifier NCT02050022). To evaluate the impact of IgG subclass deficiency on 1-year mortality, Cox proportional hazards regression analyses were performed with adjustments for potential confounders. RESULTS: Deficiencies in IgG1, IgG2, IgG3, and IgG4 were present in 1.8%, 12.1%, 4.3%, and 11.2% of patients, respectively. One-year mortality was 56% in patients with IgG1 deficiency, 27% in IgG2 deficiency, 24% in IgG3 deficiency, and 31% in IgG4 deficiency. Cox proportional modeling showed that IgG1 and IgG4 deficiencies increased the 1-year mortality risk with an adjusted hazard ratio of 3.92 (95% confidence interval [CI] = 1.55-9.87) and 1.74 (95% CI = 1.02-2.98), respectively. Neither IgG2 nor IgG3 deficiency significantly increased 1-year mortality. Two or more IgG subclass deficiencies were observed in 5.3%. Patients with 2 or more IgG subclass deficiencies had a higher 1-year mortality than those without any deficiencies (46.2% vs. 19.7%, p < 0.001), with an adjusted hazard ratio of 2.22 (95% CI = 1.18-4.17). CONCLUSIONS: IgG1 and IgG4 deficiency was observed in 1.8% and 11.2% of hospitalized patients with COPD, respectively, and these deficiencies were associated with a significantly increased risk of 1-year mortality.

Clinical interpretation of serum hepcidin-25 in inflammation and renal dysfunction.

Introduction: Hepcidin is a hormone that regulates systemic iron homeostasis. Serum hepcidin levels are under the influence of various stimuli, particularly inflammation and renal dysfunction. The measurement of hepcidin in circulation is a potentially useful clinical tool in the diagnosis, monitoring and treatment of iron metabolism disorder, although clinical interpretation of hepcidin level remains difficult. We evaluated he diagnostic potential and limitations of hepcidin-25 by investigating its relationship with iron and hematological indices, inflammation, and renal dysfunction. Methods: This retrospective study included 220 adult patients not requiring dialysis. Variations of biologically active hepcidin-25 were examined using a mass spectrometry-based assay in various inflammatory and renal states. The log[hepcidin]:log[ferritin] ratio was calculated as an hepcidin index. Results: In 220 adult patients not requiring dialysis, variation in hepcidin-25 level was significantly larger once CRP exceeded 10 mg/l (p < 0.001). Inflammation was not a determinant of hepcidin-25 in the setting of renal dysfunction. Hepcidin-25 median (7.37 nM) and variance were significantly higher (p < 0.001), once estimated glomerular filtration rate (eGFR) dropped below 30 ml/min/1.73 m2. The log[hepcidin]:log[ferritin] index normalized hepcidin levels. Patients with iron deficiency have a notably lower index when compared to controls (-0.66 vs 0.3). Conclusion: Severe renal dysfunction (eGFR < 30) affected hepcidin-25 expression and clearance to variable degree between individuals. Although, hepcidin-25 testing is not warranted in patients with infection, inflammatory autoimmune conditions (CRP > 10 mg/l) and/or severe renal dysfunction (eGFR < 30), the hepcidin index may serve as a potential biomarker for iron deficiency in complex cases.

Is the diagnostic rate for the common subtypes of A1AT deficiency consistent across two Canadian Provinces?

BACKGROUND: The diagnosis of alpha-1-antitrypsin (A1AT) deficiency has been hindered by obscurity concerning the testing process and treatment implications. In this study, we aimed to identify regional differences in the diagnostic rates for A1AT deficiency in the western Canadian provinces of British Columbia (BC) and Alberta (AB). METHODS: The number of A1AT deficiency variant genotype (ZZ, SZ, MZ, SS, and MS) diagnoses were reviewed for BC and AB. The regional diagnostic rates for A1AT deficiency variants in these two provinces, normalized for the predicted population prevalence of each variant genotype, was defined as the annual provincial diagnostic rate (APDR) for a given variant genotype. Sex specific variations in the mean age at diagnosis for the five variant genotypes were compared both within and between provinces. RESULTS: The SZ and MZ genotype APDRs were significantly increased in the AB population compared to the BC population. The SS and MS APDRs were similar between AB and BC. There was a significantly decreased mean age of diagnosis for AB males, as compared to BC males (for the SZ, MS, and MZ genotypes) and as compared to AB females (for the MS, MZ, and SS genotypes). There were no significant differences in the mean age of diagnosis between the females and males in BC, or between females in AB and BC, for any genotype. CONCLUSION: The notably higher APDR for more severe A1AT deficiency genotypes, and lower mean age of diagnosis for most variant genotypes in AB males, deserves further investigation to determine the explanation(s) for these differences.

Polyclonal hypergammaglobulinaemia: assessment, clinical interpretation, and management.

This Review outlines a practical approach to assessing and managing polyclonal hypergammaglobulinaemia in adults. Polyclonal hypergammaglobulinaemia is most commonly caused by liver disease, immune dysregulation, or inflammation, but can also provide an important diagnostic clue of rare diseases such as histiocyte disorders, autoimmune lymphoproliferative syndrome, Castleman disease, and IgG4-related disease. Causes of polyclonal hypergammaglobulinaemia can be divided into eight categories: liver disease, autoimmune disease and vasculitis, infection and inflammation, non-haematological malignancy, haematological disorders, IgG4-related disease, immunodeficiency syndromes, and iatrogenic (from immunoglobulin therapy). Measuring serum concentrations of C-reactive protein and IgG subclasses are helpful in diagnosis. IL-6-mediated inflammation, associated with persistently elevated C-reactive protein concentrations (≥30 mg/L), is an important driver of polyclonal hypergammaglobulinaemia in some cases. Although the presence of markedly elevated serum IgG4 concentrations (>5 g/L) is around 90% specific for diagnosing IgG4-related disease, mildly elevated serum IgG4 concentrations are seen in many conditions. In most cases, managing polyclonal hypergammaglobulinaemia simply involves treating the underlying condition. Rarely, however, polyclonal hypergammaglobulinaemia can lead to hyperviscosity, requiring plasmapheresis.

Falsely elevated serum estradiol due to heterophile antibody interference: a case report

SUMMARY Falsely elevated estradiol is rare, may result from heterophile antibody interference, and can result in unnecessary investigation and intervention. We present the case of a 56-year-old female with falsely elevated estradiol levels inconsistent with her overall clinical picture, which ultimately led to an unnecessary surgical procedure. With the use of alternative analytical platforms and a heterophile antibody blocking agent, we determined the false elevation was due to heterophile antibody interference. Clinicians must suspect and investigate for laboratory error when the clinical picture contradicts laboratory results.

Maternal vitamin B12 status in early pregnancy and its association with birth outcomes in Canadian mother-newborn Dyads.

Vitamin B12 (B12) is a co-enzyme essential for fetal growth and development. Lower maternal B12 status has been associated with preterm birth (<37 gestational weeks) and low birth weight (<2500 g), which are linked to morbidity and mortality across the lifespan. In Canada, 17-25 % of women in early pregnancy had a serum total B12 concentration <148 pmol/l and maternal total B12 concentration decreased throughout pregnancy. This study aimed to determine the association between maternal B12 status and birth outcomes in Canadian mother-newborn dyads. A secondary analysis of 709 mother-newborn dyads in British Columbia (BC), Canada, was conducted. Bio-banked first- (n 656) and second-trimester (n 709) maternal serum samples of apparently healthy South Asian (50 %) and European (50 %) women from the BC Prenatal Genetic Screening Program were quantified for B12 biomarkers (total B12, holotranscobalamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy)). Obstetric history and birth outcome data were obtained from the BC Perinatal Data Registry. All associations were determined using multiple linear regression. Maternal serum total B12, holoTC, MMA and tHcy had a mean weekly decrease of 3·64 pmol/l, 1·04 pmol/l, 1·44 nmol/l and 0·104 µmol/l, respectively (P < 0·001). Despite a total B12 concentration <148 pmol/l among 20-25 % of the women, maternal B12 biomarker concentrations were not associated with birth weight z-score, head circumference z-score and gestational age at birth (P > 0·05). Additional research in women at high risk of adverse birth outcomes and the association between maternal B12 status and functional, for example, cognitive, outcomes is needed.