Publications by authors named "Hans Schneider"

74 Publications

Misclassification of calcium status in end-stage kidney disease using albumin-adjusted calcium levels.

Nephrology (Carlton) 2021 Sep 22;26(9):725-732. Epub 2021 Jun 22.

Department of Renal Medicine, Alfred Health, Melbourne, Victoria, Australia.

Background: Albumin-adjusted calcium remains widely used in clinical practice with guidelines for chronic kidney disease (CKD) mineral bone disorder recommending the use of serum calcium for monitoring. This is despite ionized calcium being the biologically active fraction. This study aimed to investigate the ability of total calcium and albumin-adjusted calcium to correctly assign calcium status in stage 5/5D CKD across non-dialysis, haemodialysis and peritoneal dialysis patients.

Methods: Over a 6-months, 352 paired serum and ionized calcium samples were collected from stage 5 (n = 58) and 5D (n = 294, 196 haemodialysis, 98 peritoneal dialysis) CKD patients in a tertiary-hospital setting. Albumin-adjusted calcium was calculated using the modified-Payne formula. Ionized calcium was the reference standard. The agreement between the two methods in assigning calcium status was assessed using Cohen's weighted kappa (κ) statistic.

Results: Albumin-adjusted calcium was a poor predictor of calcium status compared to ionized calcium in stage 5/5D CKD (observed agreement 0.42, weighted κ 0.20, 95% CI 0.15-0.26). Dialysis dependence was associated with worse agreement (observed agreement 0.38, weighted κ 0.14, 95% CI 0.09-0.19). Total calcium was more reliable, however, remained inaccurate. Calcium status was not more accurately classified in those with higher albumin levels ≥30 g/L (observed agreement 0.47, weighted κ 0.23, 95% CI 0.10-0.36).

Conclusion: Total calcium provides better approximation of calcium status than albumin-adjusted calcium in stage 5/5D CKD. Albumin-adjusted calcium tends to 'overcorrect' serum calcium upward. Clinicians should use ionized calcium where accurate measure of calcium is indicated, with total calcium used as the next best option where resources are limited.
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http://dx.doi.org/10.1111/nep.13910DOI Listing
September 2021

Urine toxicology screening by liquid chromatography time-of-flight mass spectrometry in a quaternary hospital setting.

Clin Biochem 2021 Sep 12;95:66-72. Epub 2021 May 12.

Clinical Biochemistry, Alfred Health, 55 Commercial Rd, Melbourne 3004, Australia; School of Public Health and Preventative Medicine, Commercial Rd, Melbourne 3004, Monash University, Australia.

Objective: Validation of a non-targeted method for urine drug screening (UDS) by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF), and comparison to an established GC-MS method in a hospital setting.

Methods: 217 UDS specimens sent to a quaternary hospital pathology department, were analysed by a CEDIA® immunoassay screen (six drug panels; amphetamines, barbiturates, benzodiazepines, cocaine metabolites, cannabinoids and opiates) on an Abbott Architect instrument. Specimens were subsequently analysed by an established non-targeted qualitative GC-MS method and results compared with a general unknown screening method by LC-QTOF that was under evaluation as a replacement method.

Results: 42 selected drugs were evaluated; limits of identification ranged from 2 to 100 µg/L and most drugs (n = 39) were stabile for 24 h after preparation. Matrix effects greater than 25% were observed in seven of the selected drugs. 87% of the specimens tested positive to 1 or more drug panels in a CEDIA® screen. A total of 537 positive drug findings were identified by GC-MS compared to 1,267 positive findings by LC-QTOF. On average, each GC-MS screen identified 2.5 ± 1.8 drugs and the LC-QTOF screen identified 5.8 ± 3.2 drugs. No drugs were identified in 11.3% of the GC-MS screens, whereas drugs were detected in 99% of these by the LC-QTOF. In almost all instances, the LC-QTOF screen could provide mass spectrometric confirmatory results of positive immunoassay screens and was able to identify a wider range of additional drugs and drug metabolites.

Conclusions: The described general unknown screening (non-targeted, qualitative) LC-QTOF method can detect a larger range of drugs encountered in a hospital setting. The method has been shown to be suitable for comprehensive toxicology screening in a clinical toxicology laboratory.
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http://dx.doi.org/10.1016/j.clinbiochem.2021.05.004DOI Listing
September 2021

Technical-scale biophotovoltaics for long-term photo-current generation from Synechocystis sp. PCC6803.

Biotechnol Bioeng 2021 07 5;118(7):2637-2648. Epub 2021 May 5.

Systems Biotechnology group, Department of Solar Materials, Helmholtz Centre for Environmental Research - UFZ, Leipzig, 04318, Germany.

A carbon-free energy supply is essential to sustain our future. Biophotovoltaics (BPV) provides a promising solution for hydrogen supply by directly coupling light-driven water splitting to hydrogen formation using oxygenic photoautotrophic cyanobacteria. However, BPV is currently limited by its low photon-to-current efficiency, and current experimental setups at a miniaturized scale hinder the rational investigation of the process and thus system optimization. In this article, we developed and optimized a new technical-scale (~250 ml working volume) BPV platform with defined and controllable operating parameters. Factors that interfered with reproducible and stable current output signals were identified and adapted. We found that the classical BG11 medium, used for the cultivation of cyanobacteria and also in many BPV studies, caused severe interferences in the bioelectrochemical experiments. An optimized nBG11 medium guaranteed a low and stable background current in the BPV reactor, regardless of the presence of light and/or mediators. As proof-of-principle, a very high long-term light-dependent current output (peak current of over 20 µA) was demonstrated in the new set-up over 12 days with living Synechocystis sp. PCC6803 cells and validated with appropriate controls. These results report the first reliable BPV platform generating reproducible photocurrent while still allowing quantitative investigation, rational optimization, and scale-up of BPV processes.
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http://dx.doi.org/10.1002/bit.27784DOI Listing
July 2021

Aetiologies and factors associated with poor clinical outcomes in rhabdomyolysis: a retrospective cohort study in an Australian trauma centre.

Intern Med J 2021 Feb;51(2):264-267

Department of General Medicine, The Alfred Hospital, Melbourne, Victoria, Australia.

Rhabdomyolysis is a clinical syndrome with significant morbidity and mortality that occurs as a result of traumatic and non-traumatic aetiologies. Acute kidney injury, the need for dialysis, and death, can occur due to rhabdomyolysis. This study explores the aetiologies, clinical outcomes and associated factors for poor outcomes in a cohort of patients with rhabdomyolysis in a tertiary trauma centre in Australia.
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http://dx.doi.org/10.1111/imj.15183DOI Listing
February 2021

Association of Lesion Location and Depressive Symptoms Poststroke.

Stroke 2021 03 28;52(3):830-837. Epub 2021 Jan 28.

Department of Neurology, University of Leipzig Medical Center, Germany.

Background And Purpose: Poststroke depression is a common stroke sequel, yet its neurobiological substrates are still unclear. We sought to determine whether specific lesion locations are associated with depressive symptoms after stroke.

Methods: In a prospective study, 270 patients with first ever stroke were repeatedly tested with the depression subscale of the Hospital Anxiety and Depression Scale within the first 4 weeks and 6 months after stroke. Voxel-based lesion behavior mapping based on clinical imaging was performed to test for associations between symptoms of depression and lesion locations.

Results: Frequency of poststroke depression (Hospital Anxiety and Depression Scale-D score >7) after 6 months was 19.6%. Higher Hospital Anxiety and Depression Scale-D scores for depression within the first 4 weeks were the only independent predictor for poststroke depression after 6 months in a multiple logistic regression also including age, sex, lesion volume, stroke severity, Barthel-Index, and the anxiety subscale of the Hospital Anxiety and Depression Scale. Nonparametric permutation-test based voxel-based lesion behavior mapping identified a cluster of voxels mostly within the left ventrolateral prefrontal cortex where lesions were significantly associated with more depressive symptoms after 6 months. No such association was observed within the right hemisphere despite better lesion coverage.

Conclusions: Lesions in the left ventrolateral prefrontal cortex increase the risk of depressive symptoms 6 months poststroke. Lesions within the right hemisphere are unrelated to depressive symptoms. Recognition of left frontal lesions as a risk factor should help in the early diagnosis of poststroke depression through better risk stratification. The results are in line with evidence from functional imaging and noninvasive brain stimulation in patients without focal brain damage indicating that dysfunction in the left lateral prefrontal cortex contributes to depressive disorders.
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http://dx.doi.org/10.1161/STROKEAHA.120.031889DOI Listing
March 2021

[Uretero-iliac artery fistula as a urological emergency].

Aktuelle Urol 2020 Nov 19. Epub 2020 Nov 19.

Sozialstiftung Bamberg, Klinik für Urologie, Kinderurologie und roboterassistierte minimalinvasive Urologie, Bamberg.

Uretero-iliac artery fistulae represent a urological emergency with considerable mortality. We present 2 cases of a uretero-iliac artery fistula. Nowadays, minimally-invasive endovascular therapy seems to be the treatment of choice. For an optimal outcome, a multidisciplinary team with imminent availability of radiology, vascular surgery, urology and anaesthesia is required.
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http://dx.doi.org/10.1055/a-1180-0191DOI Listing
November 2020

Arterio-VENouS Intra Subject agreement for blood gases within intensive care: The AVENSIS study.

J Intensive Care Soc 2020 Feb 7;21(1):64-71. Epub 2019 May 7.

The Alfred Hospital, Melbourne, Australia.

Background: In critically ill patients, who require multiple blood gas assessments, agreement between arterial and venous blood gas values for pH and partial pressure of carbon dioxide, is not clear. Good agreement would mean that venous values could be used to assess ventilation and metabolic status of patients in intensive care unit.

Methods: All adult patients admitted to Alfred intensive care unit, Melbourne, from February 2013 to January 2014, who were likely to have arterial and central venous lines for three days, were enrolled. Patients on extra-corporeal life support and pregnant women were excluded. After enrolment, near simultaneous arterial and central venous sampling and analysis were performed at least once per nursing shift till the lines were removed or the patient died. Bland-Altman analysis for repeated measures was performed to assess the agreement between arterio-venous pH and partial pressure of carbon dioxide.

Results: A total of 394 paired blood gas analyses were performed from 59 participants. The median (IQR) number of samples per patient was 6 (5-9) with the median (IQR) sampling interval 9.4 (5.2-18.5) h. The mean bias for pH was  + 0.036 with 95% limits of agreement ranging from - 0.005 to + 0.078. For partial pressure of carbon dioxide, the values were -2.58 and -10.43 to + 5.27 mmHg, respectively.

Conclusions: The arterio-venous agreement for pH in intensive care unit patients appears to be acceptable. However, the agreement for partial pressure of carbon dioxide was poor.
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http://dx.doi.org/10.1177/1751143719840259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137164PMC
February 2020

A practical guide to laboratory investigations at diagnosis and follow up in Waldenström macroglobulinaemia: recommendations from the Medical and Scientific Advisory Group, Myeloma Australia, the Pathology Sub-committee of the Lymphoma and Related Diseases Registry and the Australasian Association of Clinical Biochemists Monoclonal Gammopathy Working Group.

Pathology 2020 Feb 3;52(2):167-178. Epub 2020 Jan 3.

Department of Haematology, ACT Pathology, Canberra Hospital, ACT, Australia; ANU Medical School, College of Medicine and Health, Australian National University, Canberra, ACT, Australia; Medical and Scientific Advisory Group, Myeloma Australia; Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia. Electronic address:

Waldenström macroglobulinaemia (WM) is an indolent non-Hodgkin lymphoma which usually presents with symptoms related to infiltration of bone marrow or other tissues like lymph nodes, liver or spleen and has certain unusual clinical manifestations, e.g., renal and central nervous system (CNS) involvement. It also has an array of laboratory features including hypersecretion of IgM, cryoglobulinaemia, increased plasma viscosity and identification of mutated MYD88 in more than 90% of cases. In this review, we aim to provide a guide to the laboratory investigations recommended for WM at initial diagnosis and at follow-up. A discussion on the nuances of diagnosis and differential diagnoses is followed by bone marrow (BM) assessment, measurement of paraprotein and other ancillary investigations. Recommendations are provided on laboratory work-up at diagnosis, in the asymptomatic follow-up phase, and during and post-treatment. Finally, we briefly discuss the implications of laboratory diagnosis in regard to recruitment and monitoring on clinical trials.
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http://dx.doi.org/10.1016/j.pathol.2019.11.002DOI Listing
February 2020

Preoperative biomarker evaluation for the prediction of cardiovascular events after major vascular surgery.

J Vasc Surg 2019 11;70(5):1564-1575

Department of Cardiovascular Medicine, Alfred Hospital, Melbourne, Victoria, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia. Electronic address:

Objective: The cause of perioperative myocardial infarction (PMI) is postulated to involve hemodynamic stress or coronary plaque destabilization. We aimed to evaluate perioperative factors in patients with peripheral artery disease (PAD) undergoing major vascular surgery to determine the likely mechanisms and predictors of PMI.

Methods: This was a prospective cohort study of 133 patients undergoing major vascular surgery including open abdominal aortic aneurysm (AAA) repair (n = 40) and major suprainguinal or infrainguinal arterial bypasses (non-AAA; n = 93). Preoperative assessment with history, physical examination, and peripheral artery tonometry was performed in addition to plasma sampling of biomarkers associated with inflammation and coronary plaque instability. The primary outcome was occurrence of a 30-day cardiovascular event (CVE; composite of PMI [troponin I elevation >99th percentile reference of ≥0.1 μg/L], stroke, or death).

Results: Of 133 patients, 36 patients (27%) developed a 30-day CVE after vascular surgery, and all were PMI. Patients with 30-day CVE were older (75 ± 8 years vs 69 ± 10 years, mean ± standard deviation; P = .001), had higher prevalence of hypertension (94% vs 79%; P = .01) and preoperative beta-blocker therapy (50% vs 29%; P = .02), and had longer duration of surgery (5.1 ± 1.8 hours vs 4.0 ± 1.1 hours; P < .0001). Significant elevations in cystatin C, N-terminal pro-B-type natriuretic peptide (NT-proBNP), troponin I, high-sensitivity troponin T, matrix metalloproteinase 3, and osteoprotegerin occurred in those who developed 30-day CVE (all P < .05). Multivariate binary logistic regression identified AAA surgery and log-transformed NT-proBNP to be independent preoperative predictors of 30-day CVE (area under the receiver operating characteristic curve = 0.81).

Conclusions: In patients with peripheral artery disease undergoing major vascular surgery, the likely mechanism of PMI appears to be the hemodynamic stress related to the type and duration of surgery. NT-proBNP was a useful independent predictor of CVE and thus may serve as an important biomarker of cardiovascular fitness for surgery.
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http://dx.doi.org/10.1016/j.jvs.2019.02.041DOI Listing
November 2019

Modification of spintronic terahertz emitter performance through defect engineering.

Sci Rep 2019 Sep 16;9(1):13348. Epub 2019 Sep 16.

Fachbereich Physik and Landesforschungszentrum OPTIMAS, Technische Universität Kaiserslautern, Erwin-Schrödinger-Str. 56, 67663, Kaiserslautern, Germany.

Spintronic ferromagnetic/non-magnetic heterostructures are novel sources for the generation of THz radiation based on spin-to-charge conversion in the layers. The key technological and scientific challenge of THz spintronic emitters is to increase their intensity and frequency bandwidth. Our work reveals the factors to engineer spintronic Terahertz generation by introducing the scattering lifetime and the interface transmission for spin polarized, non-equilibrium electrons. We clarify the influence of the electron-defect scattering lifetime on the spectral shape and the interface transmission on the THz amplitude, and how this is linked to structural defects of bilayer emitters. The results of our study define a roadmap of the properties of emitted as well as detected THz-pulse shapes and spectra that is essential for future applications of metallic spintronic THz emitters.
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http://dx.doi.org/10.1038/s41598-019-49963-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746872PMC
September 2019

Turmeric Induced Liver Injury: A Report of Two Cases.

Case Reports Hepatol 2019 28;2019:6741213. Epub 2019 Apr 28.

Department of Gastroenterology, The Alfred Hospital, 55 Commercial Road, Melbourne, Victoria, Australia.

Turmeric is a commonly used oral herbal supplement with purported anti-inflammatory and antineoplastic properties. It is promoted as safe, with limited reports of severe adverse effects directly related to oral turmeric thus far in the literature. Herein we report two cases of turmeric supplement induced severe hepatitis. These cases highlight the need for physicians to be aware of patients taking this common supplement and the potential risks that exist.
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http://dx.doi.org/10.1155/2019/6741213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535872PMC
April 2019

SuhB is an integral part of the ribosomal antitermination complex and interacts with NusA.

Nucleic Acids Res 2019 07;47(12):6504-6518

Biopolymers, University of Bayreuth, Universitätsstraße 30, 95447 Bayreuth, Germany.

The synthesis of ribosomal RNA (rRNA) is a tightly regulated central process in all cells. In bacteria efficient expression of all seven rRNA operons relies on the suppression of termination signals (antitermination) and the proper maturation of the synthesized rRNA. These processes depend on N-utilization substance (Nus) factors A, B, E and G, as well as ribosomal protein S4 and inositol monophosphatase SuhB, but their structural basis is only poorly understood. Combining nuclear magnetic resonance spectroscopy and biochemical approaches we show that Escherichia coli SuhB can be integrated into a Nus factor-, and optionally S4-, containing antitermination complex halted at a ribosomal antitermination signal. We further demonstrate that SuhB specifically binds to the acidic repeat 2 (AR2) domain of the multi-domain protein NusA, an interaction that may be involved in antitermination or posttranscriptional processes. Moreover, we show that SuhB interacts with RNA and weakly associates with RNA polymerase (RNAP). We finally present evidence that SuhB, the C-terminal domain of the RNAP α-subunit, and the N-terminal domain of NusG share binding sites on NusA-AR2 and that all three can release autoinhibition of NusA, indicating that NusA-AR2 serves as versatile recruitment platform for various factors in transcription regulation.
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http://dx.doi.org/10.1093/nar/gkz442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614797PMC
July 2019

In Reply.

Clin Chem 2019 05 25;65(5):706-707. Epub 2019 Mar 25.

Clinical Biochemistry Unit Alfred Pathology Service Alfred Health Melbourne, Victoria, Australia

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http://dx.doi.org/10.1373/clinchem.2019.302216DOI Listing
May 2019

Harmala Alkaloids Identify Ayahausca Intoxication in a Urine Drug Screen.

J Anal Toxicol 2019 May;43(4):e23-e27

Clinical Biochemistry, Alfred Pathology Service, Alfred Health, Commercial Road, Melbourne VIC, Australia.

Background: Ayahausca is an ethnobotanical drink of South America and the compound dimethyltryptamine (DMT) is primarily responsible for the hallucinogenic effects. DMT has a short half-life and its detection in urinary drug screens is challenging. We investigate a simple alternate approach to detect ayahuasca consumption by relying on other constituents of the drink, the β-carboline harmala alkaloids.

Methods: Three commercially sourced harmala alkaloids were characterized and added to a non-targeted high-resolution mass spectrometry urine drug screening method. All analyses were performed on a Waters Xevo G2-XS LC-QTof, in positive electrospray ionization mode. The mass detector was operated in MSE mode and data processed with UNIFI™ software. A urine specimen from a patient suspected to have consumed ayahuasca was analyzed by a non-targeted drug screen.

Results: The harmala alkaloids: harmine, harmaline and tetrohydroharmaline (THH) were characterized and their detection data added to the toxicology screening library. Harmaline and THH were detected in the patient's urine specimen.

Conclusion: The inclusion of the harmala alkaloids into the drug screen method library may enable the detection of ayahuasca use in patients that undergo non-targeted drug screen.
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http://dx.doi.org/10.1093/jat/bky105DOI Listing
May 2019

Pirfenidone causes false-positive urine benzodiazepine results: Implications for patients with pulmonary fibrosis.

J Heart Lung Transplant 2018 12 25;37(12):1475-1477. Epub 2018 Sep 25.

Clinical Biochemistry, Alfred Pathology Service, Alfred Health, Melbourne, Victoria, Australia; School of Public Health and Preventative Medicine, Monash University, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1016/j.healun.2018.09.014DOI Listing
December 2018

Misclassification of Calcium Status Based on Albumin-Adjusted Calcium: Studies in a Tertiary Hospital Setting.

Clin Chem 2018 12 23;64(12):1713-1722. Epub 2018 Oct 23.

Clinical Biochemistry Unit, Alfred Pathology Service, Alfred Health, Melbourne, Australia;

Background: Clinical laboratories measure total calcium and adjust for albumin concentrations to predict calcium status. We compared total and adjusted calcium (Adj-Ca) with ionized calcium (Ca) for correct assignment of calcium status. The effect of restriction of Adj-Ca reporting in patients with hypoalbuminemia was determined on the basis of frequency of misclassifications.

Methods: Extraction of laboratory results was performed for 24 months. Adj-Ca was calculated from a modified Payne formula. A further prospective data set for 6 months was collected after stopping reporting of Adj-Ca for patients with an albumin <3.0 g/dL. The agreement between Ca and Adj-Ca or total Ca was assessed with Cohen's kappa statistic.

Results: In 5553 hospitalized patients, 13604 paired Ca results were analyzed retrospectively. Prospective collection in 1113 paired samples was from 450 patients. Adj-Ca was a poor predictor of calcium status compared to the Ca reference standard in both data sets (agreement 56.9% in the first, 65.6% in the second data set). Renal failure and low albumin concentrations were associated with worse agreement between Adj-Ca and Ca. Restriction of reporting of Adj-Ca to albumin concentrations >3.0g/dL improved correct classification of calcium status from 65.6% to 77.6% ( < 0.0001). Total Ca performed better than Adj-Ca for low albumin (<3.0g/dL) and performed similarly in samples with albumin >3.0g/dL.

Conclusions: Adj-Ca is unreliable for the classification of calcium status in hospital patients when compared to Ca. Adj-Ca overestimates calcium for patients with renal impairment and albumin concentrations <3.0g/dL. Restriction of reporting Adj-Ca for albumin below 3.0 g/dL reduces the number of misclassified patients.
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http://dx.doi.org/10.1373/clinchem.2018.291377DOI Listing
December 2018

Crystallographic searches for weak interactions - the limitations of data mining.

Acta Crystallogr B Struct Sci Cryst Eng Mater 2018 Aug 22;74(Pt 4):322-324. Epub 2018 Jun 22.

FR Organische Chemie, Universität des Saarlandes, Stadtwald, Saarbrücken, D-66041, Germany.

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http://dx.doi.org/10.1107/S2052520618007783DOI Listing
August 2018

Novel Benzodiazepines (Clonazolam and Flubromazolam) Identified in Candy-Like Pills.

J Appl Lab Med 2018 Jul;3(1):48-55

Clinical Biochemistry, Alfred Health, Commercial Road, Melbourne, Australia.

Objectives: To identify the contents of pills found on an intoxicated patient by ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTof).5 To highlight the potential ability that this technique can add to the clinical laboratory.

Methods: Illicit PEZ-like pills purchased from an online vendor, containing unknown substances, were investigated by UHPLC-QTof. Accurate mass and experimental data were obtained. Tentative identifications were subsequently confirmed with commercial standards.

Results: Accurate mass data, high-energy mass spectra, elucidation software, and a review of the scientific literature enabled the tentative identification of clonazolam and flubromazolam in the PEZ-like pills. On the basis of these tentative identifications, commercial standards were purchased to confirm the initial findings. On subsequent reinterrogation of the data, flubromazolam was identified in the urine specimen of the patient.

Conclusions: Utilizing high-resolution mass data, 2 novel benzodiazepines were tentatively identified by reinterrogation of a routine analysis for drugs of abuse. Use of UHPLC-QTof in a clinical toxicology laboratory provides additional capabilities to explain and potentially improve treatment of patients presenting to the emergency department with symptoms possibly due to toxic substance ingestion.
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http://dx.doi.org/10.1373/jalm.2017.025387DOI Listing
July 2018

The cocaine cutting agent levamisole is frequently detected in cocaine users.

Pathology 2018 Aug 21;50(5):536-539. Epub 2018 Jun 21.

Clinical Biochemistry, Alfred Pathology Service, Alfred Health, Melbourne, Vic, Australia; Central Clinical School, Monash University, Melbourne, Vic, Australia.

Cocaine use in Australia is increasing, with approximately 2.5% of the surveyed population having used cocaine. In the USA, levamisole, a widely used anti-helminthic veterinary drug has been increasingly detected as a cutting agent in cocaine seizures. Levamisole is known to cause agranulocytosis in humans. We ascertained the prevalence of levamisole-adulterated cocaine, detectable in the urine from patients that had undergone a pathology request for a urine drug screen. We assayed routinely requested urines that were positive for cocaine on immunoassay with liquid chromatography high resolution quadrupole time of flight mass spectrometry (LC-QToF). We investigated available urine samples from a period of 2 years that had a positive result for cocaine. In addition, we examined samples that were below the cut-off for cocaine on immunoassay. Specimens were analysed for the presence of levamisole and other 'unknown' drugs. In the period under investigation the laboratory examined 3665 urine samples for cocaine: 1.4% (n = 51) of the samples were positive for cocaine by immunoassay and half of these (n = 26, 51%) were further examined by LC-QToF. In addition, we examined 10 samples that were negative by immunoassay (as defined by AS/NZS 4308:2008). Levamisole was detected in the urine of cocaine users in approximately 75% of cases. Other illicit drugs were also frequently found in this cohort. The most common illicit drugs detected were methamphetamine, ecstasy and cannabis. Australian cocaine is widely adulterated with levamisole. Cocaine users are at risk of levamisole related health problems in addition to the problems related to cocaine.
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http://dx.doi.org/10.1016/j.pathol.2018.03.006DOI Listing
August 2018

Simultaneous determination of voriconazole, posaconazole, itraconazole and hydroxy-itraconazole in human plasma using LCMS/MS.

Clin Biochem 2018 Mar 9;53:110-115. Epub 2018 Jan 9.

Clinical Biochemistry Unit, Alfred Pathology Service, Melbourne, Australia; Monash University, Melbourne, Australia.

Introduction: Invasive fungal infections are an increasing cause of mortality and morbidity in high risk patient populations such as those on immunosuppressive therapy. Triazole antifungals are recommended for the prevention and treatment of such infections. The aim of this study was to develop and validate a simple, sensitive and robust LCMS/MS method for the simultaneous analysis in human plasma of three frequently used antifungal drugs: voriconazole, posaconazole, and itraconazole.

Methods: Precipitation reagent, containing deuterated internal standards, is added to 50μL of plasma. The vials are vortexed before centrifugation. The organic supernatant is transferred to a polypropylene vial and 1μL is injected into the Waters Acquity® Ultra Performance Liquid Chromatography system coupled with a Waters Acquity® TQ Detector system. Chromatographic separation is achieved on a BEH C column using gradient elution with mobile phases consisting of 2mM ammonium acetate with 0.1% formic acid in water and methanol. Run time is <5min between injections.

Results: The evaluation of the LCMS/MS triazole method showed good precision (intra-assay CVs<6.7%, inter-assay CVs<8.3%). The lower limit of quantitation for all antifungal triazoles tested was 0.10mg/L. Passing Bablok comparisons of voriconazole (n=50) and posaconazole (n=50) showed good correlation with the current HPLC method (Voriconazole LCMS=0.94(HPLC)+0.03, r=0.99; Posaconazole LCMS=1.18(HPLC)-0.04, r=0.95). Passing Bablok comparisons of itraconazole and hydroxy-itraconazole (n=18) showed good agreement with an external referral laboratory's antifungal LCMS/MS method (Itraconazole LCMS=1.00(referral lab)+0.01, r=0.99; Hydroxy-Itraconazole LCMS=1.05(referral lab)+0.04, r=0.99). External quality assurance samples for posaconazole and voriconazole (n=12, UK NEQAS Antifungal Pilot Panel) were assayed 'blind' and results were in good agreement with consensus mean values (both r=0.99).

Conclusion: The rapid pre-analytical sample preparation procedure, short chromatographic time, limit of quantitation and linear range make this LCMS/MS method suitable for determination of plasma voriconazole, posaconazole, itraconazole and hydroxy-itraconazole levels in a high throughput laboratory.
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http://dx.doi.org/10.1016/j.clinbiochem.2018.01.004DOI Listing
March 2018

Rapid and safe discharge from the emergency department: A single troponin to exclude acute myocardial infarction.

Emerg Med Australas 2018 08 8;30(4):486-493. Epub 2018 Jan 8.

Emergency and Trauma Centre, The Alfred Hospital, Melbourne, Victoria, Australia.

Objective: To determine variables that could facilitate safe discharge from the ED following a single high-sensitivity troponin I (HsTnI) result to exclude acute myocardial infarction (AMI).

Methods: A retrospective cohort study was performed at a tertiary hospital of all patients that had serial HsTnI performed within 12 h of arrival to the ED over a 3 year period. The primary exposure variable of interest was a very low troponin initial result (HsTnI <5 ng/L). Medical record review and risk stratification score calculations were undertaken for all patients with the exposure variable of interest and an abnormal second troponin measurement (HsTnI ≥16 ng/L in women and HsTnI ≥26 ng/L in men).

Results: There were 11 970 patients who presented between 1 July 2013 and 30 June 2016 that had serial HsTnI measurements performed. Of these, 4172 (34.9%) patients had an initial HsTnI measurement <5 ng/L. Of the patients with an initial HsTnI <5 ng/L that met inclusion criteria, 56 (1.3%) had a second troponin result above the 99th percentile and 32 (0.8%) cases of non-ST elevation myocardial infarction were diagnosed as well as 15 (0.4%) cases of ST elevation myocardial infarction. There were 44 (93.6%) of all AMI cases that met criteria for high-risk presentations under the National Heart Foundation of Australia guidelines. The negative predictive value of an initial HsTnI <5 ng/L to exclude AMI was 98.9% (95% confidence interval 98.5-99.1).

Conclusions: This supports the utilisation of a rapid rule out strategy to exclude AMI for patients that have an initial HsTnI measurement <5 ng/L in conjunction with a robust risk assessment.
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http://dx.doi.org/10.1111/1742-6723.12919DOI Listing
August 2018

Near-infrared autofluorescence induced by intraplaque hemorrhage and heme degradation as marker for high-risk atherosclerotic plaques.

Nat Commun 2017 07 13;8(1):75. Epub 2017 Jul 13.

Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia.

Atherosclerosis is a major cause of mortality and morbidity, which is mainly driven by complications such as myocardial infarction and stroke. These complications are caused by thrombotic arterial occlusion localized at the site of high-risk atherosclerotic plaques, of which early detection and therapeutic stabilization are urgently needed. Here we show that near-infrared autofluorescence is associated with the presence of intraplaque hemorrhage and heme degradation products, particularly bilirubin by using our recently created mouse model, which uniquely reflects plaque instability as seen in humans, and human carotid endarterectomy samples. Fluorescence emission computed tomography detecting near-infrared autofluorescence allows in vivo monitoring of intraplaque hemorrhage, establishing a preclinical technology to assess and monitor plaque instability and thereby test potential plaque-stabilizing drugs. We suggest that near-infrared autofluorescence imaging is a novel technology that allows identification of atherosclerotic plaques with intraplaque hemorrhage and ultimately holds promise for detection of high-risk plaques in patients.Atherosclerosis diagnosis relies primarily on imaging and early detection of high-risk atherosclerotic plaques is important for risk stratification of patients and stabilization therapies. Here Htun et al. demonstrate that vulnerable atherosclerotic plaques generate near-infrared autofluorescence that can be detected via emission computed tomography.
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http://dx.doi.org/10.1038/s41467-017-00138-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509677PMC
July 2017

Challenges for Detecting Valproic Acid in a Nontargeted Urine Drug Screening Method.

Ther Drug Monit 2017 08;39(4):457-460

*Clinical Biochemistry, Alfred Pathology Service, Alfred Health; †Department of Forensic Medicine, Monash University; ‡Victorian Institute of Forensic Medicine; and §Central Clinical School, Monash University, Melbourne, Australia.

Background: Valproic acid (VPA) is a widely prescribed medicine, and acute toxicity is possible. As such, it should be included in any nontargeted urine drug screening method. In many published liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) methods, VPA is usually measured using a pseudo-multiple reaction monitoring (MRM) transition. We investigate a simple ultra-high-performance liquid chromatography-quadrupole time-of-flight (QTof) approach to detect the presence of VPA with more confidence.

Methods: Three commercially sourced VPA metabolites were characterized and added to a nontargeted high-resolution MS urine drug screening method. All analyses were performed on a Waters Xevo G2-XS LC-QTof in negative electrospray ionization mode. The mass detector was operated in MS mode, and data were processed with UNIFI software. Sixty-eight patient urine samples, which were previously identified by a well-established gas chromatography-MS method as containing VPA, were analyzed on the Waters Xevo G2-XS LC-QTof, to validate this approach.

Results: VPA metabolite standards were characterized, and their detection data were added to the broad drug screening library. VPA metabolites were readily detectable in the urine of patients taking VPA.

Conclusions: The inclusion of characterized VPA metabolites provides a simple and reliable method enabling the detection of VPA in nontargeted urine drug screening.
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http://dx.doi.org/10.1097/FTD.0000000000000417DOI Listing
August 2017

Predictive performance of different kidney function estimation equations in lung transplant patients.

Clin Biochem 2017 May 17;50(7-8):385-393. Epub 2017 Jan 17.

Department of Nephrology, Alfred Health, Melbourne, Australia; Central Clinical School, Monash University, Melbourne, Australia.

Background: There has been limited examination of the performance of glomerular filtration rate estimation (eGFR) equations in lung transplant populations. This study aimed to compare the performance of serum creatinine and cystatin C based eGFR equations with Tc-99m diethylenetriaminepentaacetic acid (DTPA) GFR measurements in individuals with end-stage lung disease, either prior to, or following, lung transplantation.

Methods: In this prospective observational study, participants underwent GFR measurements with Tc-99m Pentetate. Measured results were compared with GFR estimates derived from estimation equations [4-variable Modification of Diet in Renal Disease, Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine, cystatin C and creatinine-cystatin C combined equations].

Results: Ninety-seven individuals were studied (77 post- and 20 wait-listed for transplantation). Median (range) radionucleotide GFR was 56.7ml/min/1.73m (22.8-109.2ml/min/1.73m). In the study cohort as a whole, the CKD-EPI creatinine-cystatin C combined equation showed the highest performance, but was only slightly superior to the CKD-EPI creatinine equation. However, in individuals with cystic fibrosis, low arm muscle mass and/or low body mass index, all of the creatinine-based equations showed unacceptable performance. In these subgroups, improved GFR estimation was seen with the CKD-EPI cystatin C equation, and predictions were better still using the CKD-EPI creatinine-cystatin C combined equation.

Conclusions: This study shows adequate predictive ability of CKD-EPI creatinine in the cohort as a whole, but unacceptable performance in patients with cystic fibrosis, low arm muscle mass and/or low body mass index. Our findings demonstrate that cystatin C may be a preferable filtration marker in these subgroups.
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http://dx.doi.org/10.1016/j.clinbiochem.2017.01.008DOI Listing
May 2017

Plasma Macrophage Migration Inhibitor Factor Is Elevated in Response to Myocardial Ischemia.

J Am Heart Assoc 2016 06 30;5(7). Epub 2016 Jun 30.

Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Department of Cardiovascular Medicine, The Alfred Hospital, Melbourne, Victoria, Australia

Background: Macrophage migration inhibitory factor (MIF) is a key regulator of inflammatory responses, including in the heart. Plasma MIF is elevated early in the course of acute myocardial infarction. In this study, we hypothesized that plasma MIF may also be increased in acute myocardial ischemia.

Methods And Results: Patients undergoing cardiac stress test (stress nuclear myocardial perfusion scan or stress echocardiography) were recruited. Twenty-two patients had a stress test indicative of myocardial ischemia and were compared with 62 patients who had a negative stress test. Plasma MIF was measured by ELISA before and after the stress test. MIF was also measured in patients with peripheral arterial occlusive disease before and after exercise causing claudication. Gene and protein expression of MIF was measured in mouse cardiac and skeletal muscle tissue by real-time polymerase chain reaction and western blot, respectively. Plasma MIF was elevated at 5 and 15 minutes after stress (relative to before stress) in patients with a positive test, compared with those with a negative test. In contrast, high-sensitivity troponin T and C-reactive protein were not altered after stress in either group. MIF was not altered after exercise in PAOD patients, despite the occurrence of claudication, suggesting that plasma MIF is not a marker for skeletal muscle ischemia. This may be explained by a lower gene and protein expression of MIF in skeletal muscle than the heart.

Conclusions: Our results suggest that plasma MIF is an early marker for acute myocardial ischemia.
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http://dx.doi.org/10.1161/JAHA.115.003128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015363PMC
June 2016

Impact of High-Sensitivity Troponin I Testing with Sex-Specific Cutoffs on the Diagnosis of Acute Myocardial Infarction.

Clin Chem 2016 06 26;62(6):831-8. Epub 2016 Apr 26.

Clinical Biochemistry Unit, Alfred Pathology Service, Alfred Health, Melbourne, Australia; Central Clinical School, Monash University, Melbourne, Australia.

Background: High-sensitivity cardiac troponin I (hs-cTnI) assays show sex-dependent differences in the 99th percentile of healthy populations, with concentrations in women approximately 50% lower. The adoption of sex-specific cutoffs seems appropriate, although it is not yet clear what effect these will have on acute myocardial infarction (AMI) diagnosis and management.

Methods: We conducted a retrospective pre- and postchangeover analysis of troponin I testing in the 6 months before and after moving from the contemporary Abbott Architect TnI assay (cTnI) to hs-cTnI at 2 tertiary centers in Australia and New Zealand. The cTnI cutoff was 30 ng/L for both sexes, whereas a female-specific cutoff of 16 ng/L was adopted upon changeover to hsTnI.

Results: Changeover from the cTnI assay to the hs-cTnI assay increased the number of female patients with increased troponin I concentrations at both sites (from 29.7% to 34.9% and from 22.4% to 30.8%; P < 0.001). There was no statistically significant change in the number of men with increased concentrations in the same time period (P = 0.09). The increased percentage of women with increased troponin I was not associated with an increase in the number of women with AMI diagnoses at either center. Angiographic data available from 1 center showed no change in the percentage of angiograms performed in women.

Conclusions: Although increasing the proportion of women with increased troponin I, adopting sex-specific cutoffs with the hs-cTnI assay did not lead to an increase in AMI diagnoses in females, or in the number of women undergoing angiography.
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http://dx.doi.org/10.1373/clinchem.2015.252569DOI Listing
June 2016

Consensus Statement for the Management and Communication of High Risk Laboratory Results.

Clin Biochem Rev 2015 Aug;36(3):97-105

Alfred Pathology Services, Vic., Australia.

Ineffective test follow-up is a major source of harm for patients around the world. Unreliable communication from medical laboratories (henceforth termed 'laboratories') to clinicians of results that represent critical or significant risk to patients (collectively termed 'high risk results') is a contributing factor to this problem. Throughout Australasia, management practices for such results vary considerably. The recommendations presented in this document are based on best practice derived from the published literature and follow consultation with a wide range of stakeholders. These recommendations were created to harmonise Australasian practices by guiding laboratories in the design and implementation of safe and effective communication procedures for managing high risk results which require timely notification.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745612PMC
August 2015

Should routine laboratories stop doing screening serum protein electrophoresis and replace it with screening immune-fixation electrophoresis? No quick fixes: Counterpoint.

Clin Chem Lab Med 2016 Jun;54(6):967-71

Monoclonal gammopathies are characterised by the production of a monoclonal immunoglobulin or free light chains by an abnormal plasma cell or B-cell clone and may indicate malignancy or a precursor (MGUS). There is currently no consensus on the initial test or combination of tests to be performed in suspected monoclonal gammopathies but serum protein electrophoresis and urine protein electrophoresis are commonly requested as initial investigations. If abnormal, immunofixation electrophoresis is then performed to confirm the presence of paraprotein and to determine its heavy and light chain type. Recently, some groups have developed simplified "screening" IFE methods for use in parallel to SPEP for the detection monoclonal gammopathies. We argue here that screening IFE may be of benefit in clinical laboratories using SPEP with poor resolution in the β-region, assisting in the detection of mainly IgA paraprotein, but may be of less benefit in laboratories utilising higher resolution gels. Further it may increase the detection of trace bands of questionable clinical significance, representing transient phenomena in infectious and auto-immune conditions or very low risk MGUS. The increased detection of these bands using screening IFE would require further patient follow up, possibly causing unnecessary patient anxiety and additional follow up healthcare costs.
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http://dx.doi.org/10.1515/cclm-2015-0806DOI Listing
June 2016
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