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1.
J Appl Lab Med ; 7(2): 409-420, 2022 03 02.
Article in English | MEDLINE | ID: mdl-34999832

ABSTRACT

BACKGROUND: Drug screening by immunoassay is common in pediatric populations. However, false-positive and -negative results due to antibody cross-reactivity and dilute urine are frequent and underappreciated. Accurate ascertainment of drug exposure in children has significant clinical and medico-legal consequences. DESIGN AND METHODS: We developed and characterized an LC-MS/MS drug screening assay to supplant immunoassay and detect 38 compounds at the lowest concentrations distinguishable from analytic noise. Once implemented, we conducted a retrospective analysis of 3985 pediatric urine drug screens performed a year before (n = 1663) and after (n = 2322) implementation to examine the frequency and breadth of drug detection in our pediatric population. RESULTS: Using immunoassay, 23% (293/1269) of samples from the general pediatric and 37% (147/394) of nursery populations had presumptively positive results. Of the presumptive positive compounds, 85% (288/338) from the general pediatric population and 40% (65/162) from the nursery cohort were confirmed by mass spectrometry. After LC-MS/MS implementation, 31% (628/2052) of general pediatric, and 18% (48/270) of the nursery samples were positive for 1 or more compounds. In the nursery population, immunoassays over-detected the presence of THC but under-detected exposure to cocaine. CONCLUSION: A broadly targeted, analytically sensitive LC-MS/MS drug screening assay detects a larger number and variety of compounds in a single step compared to a screen-then-confirm approach initiated by immunoassay in our pediatric population. Rapid delivery of accurate results enables timely, appropriate disposition of patients in a variety of settings including the emergency department and labor/delivery.


Subject(s)
Substance Abuse Detection , Tandem Mass Spectrometry , Child , Chromatography, Liquid/methods , Drug Evaluation, Preclinical , Humans , Retrospective Studies , Substance Abuse Detection/methods , Tandem Mass Spectrometry/methods
2.
J Inherit Metab Dis ; 40(4): 555-567, 2017 07.
Article in English | MEDLINE | ID: mdl-28643139

ABSTRACT

Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides "proof of principle" that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH, and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since, in general, Arg to Cys changes comprise about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.


Subject(s)
Arginine/chemistry , Cysteamine/chemistry , Cysteine/chemistry , Cystinosis/therapy , Mutation , Animals , Apolipoprotein E3/metabolism , Argininosuccinate Lyase/metabolism , Cystathionine beta-Synthase/metabolism , Cystinosis/genetics , Cystinosis/metabolism , Homeostasis , Humans , Hydrogen-Ion Concentration , Molecular Conformation , Mutation, Missense , Oxidation-Reduction , Sulfhydryl Compounds/chemistry , Thromboplastin/metabolism
3.
Psychiatriki ; 27(3): 169-181, 2016.
Article in English | MEDLINE | ID: mdl-27837571

ABSTRACT

Research has highlighted the wide impact of maternal mental health problems during and beyond the postpartum period and the public health role of community health professionals in early detection of women who may be at risk. This paper aims to describe, explore and test an a priori hypothesised conceptual model of postnatal experience, identifying the relationships between postnatal mental vulnerability and postnatal adjustment to maternal roles and attitudes, marital/partner-relationship and sense of coherence. Three validated self-report questionnaires (WAST, MAMA, SOC) measuring the variables of the encompassing framework and EPDS were administered in random order. The conceptual models were tested using the software IBM SPSS Statistics and LISREL and the tests performed were: Student's ttest, chi-square tests, Explanatory factor analysis using a Varimax rotation Principal Components Method, Confirmatory analysis -known as structural equation modelling- of principal components. Psychometric scores indicate high correlation between WAST, MAMA, SOC and EPDS. An exploratory factor analysis confirmed the role of SOC, specific MAMA subscales (maternal roles and attitudes, body image, sex, breasts, nausea) and WAST (relationship tension and emotional and physical abuse) subscales (KMO measure of sampling adequacy=0.735 and Bartlett's test of sphericity=184,786, df=36, p<0.0005). The latent variables confirmed with SEM were marital relationship, maternity experience and self-efficacy (Chi-square=28.45, df=24, P-value=0.24, RMSEA=0.046 p<0.05). Marital Relationship (Factor I: Eigenvalue=3.066) concerning lack of or disappointment with partner support, poor marital relationship and emotional/physical abuse has been associated with high levels of postpartum anxiety and depression. Maternity Experience (Factor II: Eigenvalue=1.280) representing postnatal roles and attitudes towards their infant can be as useful as mood changes for evaluation of mothers. Self-Efficacy (Factor III: Eigen- value=3.144) and especially attitudes regarding body image, sex and coping resources and options of dealing with the stressor, has been demonstrated that serve as a mediator or buffer for psychological distress. The results of this study have implications for the prevention and intervention of postnatal adjustment difficulties both of which need to be intensified in order to minimise perinatal mental vulnerability.


Subject(s)
Depression, Postpartum/diagnosis , Depression, Postpartum/epidemiology , Early Diagnosis , Early Medical Intervention , Mass Screening , Cross-Sectional Studies , Female , Greece , Humans , Psychometrics/statistics & numerical data , Reproducibility of Results , Risk Factors , Self Efficacy , Self Report , Social Support , Statistics as Topic , Surveys and Questionnaires
4.
Mol Genet Metab ; 104(4): 476-9, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21908220

ABSTRACT

BACKGROUND: The number of newborns and the number of disorders detected by large-scale screening programs has increased dramatically in the last decade. Newborn screening is a multi-step process requiring confirmatory testing to establish and refine a diagnosis. Whereas screening cutoffs are established to detect all cases of a specific disease, confirmatory testing is performed against a backdrop of many co-morbid conditions and interpretation of results is often not straightforward. The goal of the current study was to define the range of amino acid concentrations encountered in normal, premature, and acutely ill newborns as an aid to the interpretation of follow-up testing for suspicious newborn screens. MATERIALS AND METHODS: Residual plasma samples from 354 neonates (age 1-10 days) were utilized. 206 samples were from neonates with uncomplicated birth histories and prompt hospital discharge. 98 specimens were derived from a population of children receiving intensive care with diagnoses that included sepsis, respiratory insufficiency, cardiac malfunction/malformation and gastrointestinal complications. 50 samples were from infants born after 32 but before 37 full weeks gestation that were discharged following uneventful hospital courses. 25 amino acids were quantitated by LC-MS/MS and reference intervals determined by non-parametric statistical methods. Distributions were compared using Kruskal-Wallis analyses for independent samples. RESULTS: The distributions of multiple amino acids in premature and critically ill infants were significantly different than those observed in healthy newborns. Differing distributions were found for phenylalanine, the branched chain amino acids, methionine, glutamine, glutamate, arginine, lysine, α-aminoadipic acid, and ß-aminoisobutyric acid. In most cases median values were increased and distributions more positively skewed in premature or ill newborns compared to healthy newborns. In addition, we report neonatal homocitrulline reference intervals for these newborn populations determined by an LC-MS/MS technique that is not confounded by methionine interference. CONCLUSION: These data provide a basis for improved detection of genetic metabolic disorders in newborns, particularly those born prematurely or with a variety of critical co-morbid conditions.


Subject(s)
Amino Acids/blood , Infant, Premature/blood , Neonatal Screening , Case-Control Studies , Chromatography, Reverse-Phase , Critical Illness , Female , Gastrointestinal Diseases/blood , Gastrointestinal Diseases/diagnosis , Heart Defects, Congenital/blood , Heart Defects, Congenital/diagnosis , Humans , Infant, Newborn , Male , Reference Values , Respiratory Distress Syndrome, Newborn/blood , Respiratory Distress Syndrome, Newborn/diagnosis , Sepsis/blood , Sepsis/diagnosis , Tandem Mass Spectrometry
5.
Clin Chem ; 52(4): 743-6, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16455869

ABSTRACT

BACKGROUND: Immunoassay-based screening for amphetamines has a variable positive predictive value (PPV) for detecting amphetamine abuse. The lack of immunoassay specificity necessitates confirmatory testing by gas chromatography-mass spectrometry (GC/MS), but the technical complexity and expense of GC/MS limit its availability. Physicians may make decisions regarding patient disposition based on unverified results. In this study we assessed the utility of using dose-response properties to distinguish urine samples containing amphetamines from samples containing cross-immunoreactive species. METHODS: Urine was supplemented with known concentrations of amphetamine, methamphetamine, methylenedioxymethamphetamine (MDMA), or pseudoephedrine. Using a series of dilutions, we determined the maximum change in rate over the fractional change in concentration for each compound in the Emit II amphetamine/methamphetamine immunoassay. Patient urine samples that screened positive for amphetamines were diluted 1:1, 1:10, and 1:20, and maximum slope estimates within the dynamic assay range were determined. An optimal slope cutoff that differentiated samples containing (meth)amphetamine from those containing cross-reacting species was determined by ROC analysis. RESULTS: The slope of the dose response was largest for amphetamine and methamphetamine, followed by MDMA and pseudoephedrine. The optimum slope cutoff for identifying patient specimens containing (meth)amphetamine was 320 (sensitivity, 96%; specificity, 90%; PPV, 92%). High concentrations of less reactive compounds may mask low concentrations of amphetamines. CONCLUSIONS: Use of the slope of the dose-response relationship in patient urine specimens can enhance the PPV of presumptive positive immunoassay results but does not exclude the presence of low amphetamine concentrations in samples containing high concentrations of cross-reactive species.


Subject(s)
Amphetamine/urine , Ephedrine/urine , Methamphetamine/urine , N-Methyl-3,4-methylenedioxyamphetamine/urine , Substance Abuse Detection/methods , Sympathomimetics/urine , Cross Reactions , Humans , Immunoassay , ROC Curve
6.
Clin Chem ; 50(4): 717-22, 2004 Apr.
Article in English | MEDLINE | ID: mdl-14764642

ABSTRACT

BACKGROUND: The analytic performance and accuracy of drug detection below Substance Abuse and Mental Health Services Administration (SAMHSA) cutoffs is not well known. In some patient populations, clinically significant concentrations of abused drugs in urine may not be detected when current SAMHSA cutoffs are used. Our objectives were to define the precision profiles of three immunoassay systems for drugs of abuse and to evaluate the accuracy of testing at concentrations at which the CV was <20%. METHODS: Drug-free urine was supplemented with analytes to assess the precision in three commercial drugs-of-abuse immunoassay systems below the SAMHSA-dictated cutoffs for amphetamines, opiates, benzoylecgonine, phencyclidine, and cannabinoids. Consecutive urine samples with signals associated with a CV <20% by Emit immunoassay and below SAMHSA cutoffs were then subjected to confirmatory analysis. RESULTS: The CV of all immunoassay systems tested remained <20% to drug concentrations well below SAMHSA cutoffs. The accuracy of urine drug-screening results between the SAMHSA-specified cutoffs and the precision-based cutoffs was less than accuracy for specimens above the SAMHSA cutoffs, but the use of the precision-based cutoff produced a 15.6% increase in the number of screen-positive specimens and a 7.8% increase in the detection of specimens that yielded positive results on confirmatory testing. CONCLUSION: The precision of three commercial immunoassay systems for drugs-of-abuse screening is adequate to detect drugs below SAMHSA cutoffs. Knowledge of the positive predictive values of screening immunoassays at lower cutoff concentrations could enable efficient use of confirmatory testing resources and improved detection of illicit drug use.


Subject(s)
Cocaine/analogs & derivatives , Dronabinol/analogs & derivatives , Substance Abuse Detection/methods , Cocaine/urine , Dextroamphetamine/urine , Dronabinol/urine , Gas Chromatography-Mass Spectrometry , Humans , Immunoassay , Morphine/urine , Narcotics/urine , Phencyclidine/urine , Predictive Value of Tests , Sensitivity and Specificity
7.
J Vasc Surg ; 32(1): 32-6, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10876204

ABSTRACT

PURPOSE: Noninvasive measurements of limb systolic pressures are used routinely in the assessment of the severity of peripheral arterial disease, including the evaluation for critical limb ischemia. However, ankle pressures cannot be measured reliably in patients with medial calcification, which is especially common among patients with diabetes. Skin lesions on the toes or previous digital amputations may preclude the measurement of toe pressures. Measurements of skin perfusion pressure (SPP) are not subject to such limitations and were shown to be useful in the assessment of the severity of peripheral arterial disease. Because toe pressure is often used in the evaluation of severity of arterial disease and in the assessment for critical ischemia, we undertook to study whether there is a sufficient correlation between toe pressure and foot SPP that would allow the use of SPP measurements when toe pressures cannot be measured. METHODS: Measurements were carried out in 85 limbs of 71 patients referred to the vascular laboratory for evaluation for peripheral arterial disease. Diabetes mellitus was present in 43 patients. Each patient had foot SPP and toe pressure measurements. Toe pressures measured with photoplethysmography were correlated with foot SPP measured with laser Doppler scanning. RESULTS: There was a strong linear correlation between SPP and toe pressure (r = 0.87; P <.01). Also, significant correlation was found in both the patients with diabetes and the patients without diabetes (r = 0.85 and 0.93, respectively; P <.01 in both cases). CONCLUSIONS: We concluded that SPP measured in the foot correlates well with toe pressure and can be substituted for toe pressure measurement in patients in whom toe pressures cannot be measured.


Subject(s)
Foot/blood supply , Ischemia/diagnosis , Leg/blood supply , Adult , Aged , Aged, 80 and over , Diabetic Angiopathies/diagnosis , Diabetic Angiopathies/physiopathology , Female , Humans , Ischemia/physiopathology , Male , Middle Aged , Regional Blood Flow , Skin/blood supply , Toes/blood supply
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