Diabetes Study of Children of Diverse Ethnicity and Race: Study design.

AIMS: Determining diabetes type in children has become increasingly difficult due to an overlap in typical characteristics between type 1 diabetes (T1D) and type 2 diabetes (T2D). The Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) programme is a National Institutes of Health (NIH)-supported multicenter, prospective, observational study that enrols children and adolescents with non-secondary diabetes. The primary aim of the study was to develop improved models to differentiate between T1D and T2D in diverse youth. MATERIALS AND METHODS: The proposed models will evaluate the utility of three existing T1D genetic risk scores in combination with data on islet autoantibodies and other parameters typically available at the time of diabetes onset. Low non-fasting serum C-peptide (<0.6 nmol/L) between 3 and 10 years after diabetes diagnosis will be considered a biomarker for T1D as it reflects the loss of insulin secretion ability. Participating centres are enrolling youth (<19 years old) either with established diabetes (duration 3-10 years) for a cross-sectional evaluation or with recent onset diabetes (duration 3 weeks-15 months) for the longitudinal observation with annual visits for 3 years. Cross-sectional data will be used to develop models. Longitudinal data will be used to externally validate the best-fitting model. RESULTS: The results are expected to improve the ability to classify diabetes type in a large and growing subset of children who have an unclear form of diabetes at diagnosis. CONCLUSIONS: Accurate and timely classification of diabetes type will help establish the correct clinical management early in the course of the disease.

High Prevalence of A-ß+ Ketosis-Prone Diabetes in Children with Type 2 Diabetes and Diabetic Ketoacidosis at Diagnosis: Evidence from the Rare and Atypical Diabetes Network (RADIANT).

Background: A-ß+ ketosis-prone diabetes (KPD) in adults is characterized by presentation with diabetic ketoacidosis (DKA), negative islet autoantibodies, and preserved ß-cell function in persons with a phenotype of obesity-associated type 2 diabetes (T2D). The prevalence of KPD has not been evaluated in children. We investigated children with DKA at "T2D" onset and determined the prevalence and characteristics of pediatric A-ß+ KPD within this cohort. Methods: We reviewed the records of 716 children with T2D at a large academic hospital and compared clinical characteristics of those with and without DKA at onset. In the latter group, we identified patients with A-ß+ KPD using criteria of the Rare and Atypical Diabetes Network (RADIANT) and defined its prevalence and characteristics. Results: Mean age at diagnosis was 13.7 ± 2.4 years: 63% female; 59% Hispanic, 29% African American, 9% non-Hispanic White, and 3% other. Fifty-six (7.8%) presented with DKA at diagnosis and lacked islet autoantibodies. Children presenting with DKA were older and had lower C-peptide and higher glucose concentrations than those without DKA. Twenty-five children with DKA (45%) met RADIANT A-ß+ KPD criteria. They were predominantly male (64%), African American or Hispanic (96%), with substantial C-peptide (1.3 ± 0.7 ng/mL) at presentation with DKA and excellent long-term glycemic control (HbA1c 6.6% ± 1.9% at follow-up (median 1.3 years postdiagnosis)). Conclusions: In children with a clinical phenotype of T2D and DKA at diagnosis, approximately half meet criteria for A-ß+ KPD. They manifest the key characteristics of obesity, preserved ß-cell function, male predominance, and potential to discontinue insulin therapy, similar to adults with A-ß+ KPD.

Islet Autoantibody Standardization Program: interlaboratory comparison of insulin autoantibody assay performance in 2018 and 2020 workshops.

AIMS/HYPOTHESIS: The Islet Autoantibody Standardization Program (IASP) aims to improve the performance of immunoassays measuring autoantibodies in type 1 diabetes and the concordance of results across laboratories. IASP organises international workshops distributing anonymised serum samples to participating laboratories and centralises the collection and analysis of results. In this report, we describe the results of assays measuring IAA submitted to the IASP 2018 and 2020 workshops. METHODS: The IASP distributed uniquely coded sera from individuals with new-onset type 1 diabetes, multiple islet autoantibody-positive individuals, and diabetes-free blood donors in both 2018 and 2020. Serial dilutions of the anti-insulin mouse monoclonal antibody HUI-018 were also included. Sensitivity, specificity, area under the receiver operating characteristic curve (ROC-AUC), partial ROC-AUC at 95% specificity (pAUC95) and concordance of qualitative/quantitative results were compared across assays. RESULTS: Results from 45 IAA assays of seven different formats and from 37 IAA assays of six different formats were submitted to the IASP in 2018 and 2020, respectively. The median ROC-AUC was 0.736 (IQR 0.617-0.803) and 0.790 (IQR 0.730-0.836), while the median pAUC95 was 0.016 (IQR 0.004-0.021) and 0.023 (IQR 0.014-0.026) in the 2018 and 2020 workshops, respectively. Assays largely differed in AUC (IASP 2018 range 0.232-0.874; IASP 2020 range 0.379-0.924) and pAUC95 (IASP 2018 and IASP 2020 range 0-0.032). CONCLUSIONS/INTERPRETATION: Assay formats submitted to this study showed heterogeneous performance. Despite the high variability across laboratories, the in-house radiobinding assay (RBA) remains the gold standard for IAA measurement. However, novel non-radioactive IAA immunoassays showed a good performance and, if further improved, might be considered valid alternatives to RBAs.

Von Willebrand factor and disease: a review for laboratory professionals.

Given that von Willebrand disease (VWD) is one of the most common bleeding disorders, the diagnosis or the exclusion is essential in the workup of individuals that have unexplained bleeding. For the clinical laboratory, the challenge is highlighted by the variable presentations of this disorder and the multiple assays that are available from different vendors. This review will give a brief overview of primary hemostasis with a detailed explanation of the biosynthesis, structure, and mechanics of von Willebrand factor (VWF). The final sections will focus on the distinguishing characteristics of the different types of VWD and the array of clinical laboratory tests currently available to assist in the diagnosis.

Trastuzumab with carboplatin/paclitaxel for treatment of advanced stage and recurrent uterine papillary serous carcinoma: A cost-effectiveness analysis.

OBJECTIVE: Uterine papillary serous carcinoma (UPSC) is a variant of endometrial cancer that is aggressive and associated with poor outcomes. We sought to evaluate the cost effectiveness of carboplatin/paclitaxel alone versus carboplatin/paclitaxel with trastuzumab among patients with Her2/neu-positive advanced or recurrent UPSC. METHODS: We designed a Markov model in TreeAge Pro 2019 software to simulate management of a theoretical cohort of 4000 patients with Her2/neu-positive advanced or recurrent uterine papillary serous carcinoma (UPSC) followed for four years. In the carboplatin/paclitaxel with trastuzumab strategy, we included the cost of testing for Her2/neu status. We obtained all model inputs from the literature and a societal perspective was assumed. Outcomes included progression-free survival, progression, UPSC-specific mortality, cost, and quality-adjusted life years (QALYs). The intervention was considered cost effective if the incremental cost-effectiveness ratio (ICER) was below the willingness-to-pay threshold of $100,000 per QALY. Sensitivity analyses were used to determine the robustness of the results. RESULTS: In our theoretical cohort of 4000 women, treatment with the addition of trastuzumab resulted in 637 fewer deaths and 627 fewer cases of progression compared with treatment with carboplatin/paclitaxel alone. Treatment with trastuzumab was associated with an additional cost of $144,335,895, but was associated with an increase of 2065 QALYs. The ICER was $69,903 per QALY, which was below our willingness-to-pay threshold. Sensitivity analysis demonstrated that this treatment strategy was cost-effective until the cost of 6 months of treatment surpassed $38,505 (baseline input: $27,562). CONCLUSION: We found that the addition of trastuzumab to carboplatin/paclitaxel was a cost-effective treatment strategy for patients with advanced/recurrent Her2/neu-positive UPSC.

Temporally resolved thermal desorption of volatile organics from nanoporous silica preconcentrator.

Detection and separation of gas-phase volatile organic compounds (VOCs) is of great importance for many applications including air quality monitoring, toxic gas detection and medical diagnostics. A lack of small and low-cost detectors limits the potential applications of VOC gas sensors, especially in the areas of consumer products and the 'Internet of Things'. Most of the commercially available low-cost technologies are either only capable of measuring a single VOC type, or only provide a total VOC concentration, without the ability to provide information on the nature or type of the VOC. We present a new approach for improving the selectivity of VOC detection, based on temporally resolved thermal desorption of VOCs from a nanoporous material, which can be combined with any existing VOC detector. This work uses a nanoporous silica material that adsorbs VOC molecules, which are then thermally desorbed onto a broadband VOC detector. Different VOCs are desorbed at different temperatures depending on their boiling point and affinity to the porous surface. The nanoporous silica is inert; VOC adsorption is proportional to the concentration of VOC in the environment, and is fully reversible. An example of a detection system using a commercial total VOC photoionization detector and a nanoporous silica preconcentrator is demonstrated here for six different VOCs, and shows potential for discrimination between the VOCs.

Islet Autoantibody Standardization Program 2018 Workshop: Interlaboratory Comparison of Glutamic Acid Decarboxylase Autoantibody Assay Performance.

BACKGROUND: The Islet Autoantibody Standardization Program (IASP) aims to improve the performance of immunoassays measuring type 1 diabetes (T1D)-associated autoantibodies and the concordance of results among laboratories. IASP organizes international interlaboratory assay comparison studies in which blinded serum samples are distributed to participating laboratories, followed by centralized collection and analysis of results, providing participants with an unbiased comparative assessment. In this report, we describe the results of glutamic acid decarboxylase autoantibody (GADA) assays presented in the IASP 2018 workshop. METHODS: In May 2018, IASP distributed to participants uniquely coded sera from 43 new-onset T1D patients, 7 multiple autoantibody-positive nondiabetic individuals, and 90 blood donors. Results were analyzed for the following metrics: sensitivity, specificity, accuracy, area under the ROC curve (ROC-AUC), partial ROC-AUC at 95% specificity (pAUC95), and concordance of qualitative and quantitative results. RESULTS: Thirty-seven laboratories submitted results from a total of 48 different GADA assays adopting 9 different formats. The median ROC-AUC and pAUC95 of all assays were 0.87 [interquartile range (IQR), 0.83-0.89] and 0.036 (IQR, 0.032-0.039), respectively. Large differences in pAUC95 (range, 0.001-0.0411) were observed across assays. Of formats widely adopted, bridge ELISAs showed the best median pAUC95 (0.039; range, 0.036-0.041). CONCLUSIONS: Several novel assay formats submitted to this study showed heterogeneous performance. In 2018, the majority of the best performing GADA immunoassays consisted of novel or established nonradioactive tests that proved on a par or superior to the radiobinding assay, the previous gold standard assay format for GADA measurement.

Behavioral evidence suggestive of frontal lobe pathology in the amnesic H.M.

From the earliest published reports, Henry Gustav Molaison-who until his death in 2008 was known simply by his initials H.M.-was characterized as having a profound anterograde amnesia subsequent to mid temporal lobe resection, and that this amnestic condition was uncomplicated by other cognitive or behavioral impairments. Post-mortem neuropathological examination has detected-in addition to the expected temporal lobe lesions-previously unreported frontal lobe and white matter pathology, inviting questions concerning the behavioral and cognitive consequences that might result from such lesions. The purpose of this article is to recount published descriptions of a range of anomalous behaviors by H.M. that can not be explained by the memory impairments typically associated with anterograde amnesia, to counter previous claims that these behaviors are attributable to amygdalar damage, and to advance the interpretation that these behaviors are instead consistent with well-documented effects of frontal lobe pathology. Transcripts of interviews with H.M. which feature disjointed, often contradictory, and arguably confabulatory responses are presented in support of this argument.

Progression of moderate-to-severe carotid disease.

OBJECTIVE: Our goals were to investigate the degree to which patient demographics, risk factors, laboratory data, and medications influence moderate carotid disease progression among patients with asymptomatic moderate carotid disease and whether such associations are solely based on how progression is defined. In addition, we aimed to establish optimal threshold criteria to categorize patients at high risk of progression. METHODS: In this retrospective study, 621 arteries were evaluated for internal carotid artery (ICA) stenosis between January 1997 and January 2014 and were determined to have moderate (50%-79%) stenosis via color duplex ultrasonography. "Moderate stenosis" was defined as an ICA peak systolic velocity (PSV) ≥120 cm/s and a diastolic ICA velocity <140 cm/s. Kaplan-Meier analysis of the time to progression was conducted using three independent end points: PSV ≥230 cm/s (liberal criterion); ICA/common carotid artery (CCA) ratio ≥4.0 (moderate criterion), and diastolic ICA velocity ≥140 cm/s (strict criterion). Kaplan-Meier survival curves were generated, and multivariate analysis was performed using Cox regression models. Risk stratification criteria were based on optimal sensitivity and specificity generated from receiver operating characteristic (ROC) curve analysis. RESULTS: The overall rate of progression was 28.5%, 21.1%, or 5.1% of study-eligible arteries over 5 years using liberal, moderate, or strict criterion, respectively. Using liberal criterion, multivariate analysis suggested that initial PSV ≥200 cm/s, ICA/CCA ratio ≥3, and male gender were significantly associated with progression. Using the moderate criterion, multivariate analysis revealed that initial PSV ≥200 cm/s, ICA/CCA ratio ≥3, age, and male gender were significantly associated with progression. Using the strict criterion, multivariate analysis revealed that initial PSV ≥200 cm/s was the only statistically significant predictor of progression. No additional patient demographics, comorbidities, initial laboratory values, or medications consistently influenced disease progression across any criteria in our study. ROC analysis suggests PSV ≥165 cm/s is an ideal threshold value for the categorization of high risk patients, as this resulted in an optimal screening sensitivity of nearly 91% and a specificity of 59% over 2 years. CONCLUSIONS: The timing and incidence of carotid disease progression depends on the definition of disease progression. Among all three criteria, only severity of disease at initial presentation reliably predicted progression. Based on the results of our ROC curve analysis, we propose that an initial ICA PSV ≥165 cm/s (sensitivity: 90.7%, specificity: 58.7%) represents a reasonable value for defining high progression risk over a 2-year interval.

IgG4 antibodies in autoimmune polyglandular disease and IgG4-related endocrinopathies: pathophysiology and clinical characteristics.

PURPOSE OF REVIEW: This review discusses the IgG4-related disease spectrum (IgG4-RD), the autoimmune polyglandular syndromes (APS), the association of IgG4 with APS, and possible pathobiology. RECENT FINDINGS: IgG4-RD is a multiorgan autoimmune disorder characterized by fibrous inflammation, IgG4-positive plasma cell infiltration in affected tissues, and elevated serum concentrations of IgG4. IgG4-RD can affect any organ and has a heterogeneous presentation. Consensus criteria for diagnosis in specific organs have been established. The recognition and diagnosis of IgG4-RD are crucial because the disease responds favorably to immunosuppression (e.g., glucocorticoids, rituximab). The precise mechanisms leading to disease are unknown, but IgG4 antibodies may undergo a half antibody exchange, which renders them incapable of activating the complement pathway. SUMMARY: Despite significant advances in disease recognition and treatment strategies, the disorder remains poorly understood. The precise role of IgG4, whether it is protective or pathogenic, is still being debated.

The molecular biology of human iron metabolism.

Iron is one of the most important nonorganic substances that make life possible. Iron plays major roles in oxygen transport (eg, hemoglobin; -67% of total body iron [TBI]), short-term oxygen storage (eg, myoglobin; -3.5% of TBI), and energy generation (eg, cytochromes; -3% of TBI). Iron also serves vital roles in various nonheme-containing enzymes (-2% of TBI). Figure 1 lists heme-containing and nonheme iron-containing proteins. TBI is controlled by the rate of iron absorption; there are no physiologic mechanisms to excrete excess iron. Iron deficiency has many adverse consequences, including anemia, and in children, behavioral and learning disorders. Iron excess is toxic to the body, harming the heart, liver, skin, pancreatic islet beta cells, bones, joints, and pituitary gland. Maintaining proper iron balance is essential for maintaining homeostasis and health. TBI in adults normally ranges between 3.5 and 5.0 g. A total of 75% of TBI is functional, and 25% is stored within cells as ferritin or hemosiderin. Ferritin contains 24 subunits of light chains (L chains; 19.7 kDa) and heavy chains (H chains; 21.1 kDa). The L chains are encoded on chromosome 19q13.33 and are 175 amino acids long. The H chains are encoded on chromosome 11q1 and are 183 amino acids long. Each ferritin molecule can contain as many as approximately 4500 ferric ions. Because the major role of iron is in hemoglobin synthesis, this review will focus on iron, iron transport, and hematopoiesis.

An Introduction to the Complete Blood Count for Clinical Chemists: Platelets.

BACKGROUND: The most ordered laboratory test worldwide is the complete blood count (CBC). CONTENT: In this primer, an introduction to platelet testing in the context of the CBC is provided with a discussion of the laboratory evaluation of platelet abnormalities including thrombocytopenia and thrombocytosis. SUMMARY: As clinical chemists continue to be tasked to direct laboratories outside of the traditional clinical chemistry sections such as hematology, expertise must be developed. This primer is dedicated to that effort.

An Introduction to the Complete Blood Count for Clinical Chemists: Red Blood Cells.

BACKGROUND: The most frequently ordered laboratory test worldwide is the complete blood count (CBC). CONTENT: In this primer, the red blood cell test components of the CBC are introduced, followed by a discussion of the laboratory evaluation of anemia and polycythemia. SUMMARY: As clinical chemists are increasingly tasked to direct laboratories outside of the traditional clinical chemistry sections such as hematology, expertise must be developed. This review article is a dedication to that effort.

Continuing routine cardiac surveillance in long-term use of pegylated liposomal doxorubicin: is it necessary?

OBJECTIVE: The objective of this study was to determine the cardiac safety of high cumulative doses of pegylated liposomal doxorubicin (PLD) in patients with gynecologic malignancies and the need for routine evaluation of left ventricular ejection fraction (LVEF). METHODS: Data were collected for all patients treated with PLD with at least one evaluation of LVEF with either Multi-Gated Acquisition (MUGA) scan or echocardiogram from January 2006 to May 2012. Evaluation of LVEF was used to detect PLD-related cardiac toxicity (defined as a decline in LVEF of greater than 10% compared to baseline measurements). RESULTS: A total of 141 patients were included. Twenty-two patients were treated with a cumulative dose of 500 mg/m(2) or more, and five patients with 1000 mg/m(2) or more. Ten patients (7%) had a reduction in LVEF of greater than 10%, 38 had no significant change or increase in LVEF throughout the duration of treatment, and 93 did not require a follow-up evaluation of LVEF. The LVEFs of two patients dropped below 50% at cumulative doses of 1110 mg/m(2) and 1670 mg/m(2); one began with a baseline of 52%. CONCLUSIONS: Only one patient had a clinically significant decrease in LVEF at a cumulative dose of 1670 mg/m(2), suggesting that PLD does not carry a significant risk of cardiotoxicity, as evidenced by the stability of LVEF even after treatment with large cumulative doses. Routine surveillance of LVEF does not seem to be necessary or cost effective in the absence of other risk factors.

Serum from minimal change patients in relapse increases CD80 expression in cultured podocytes.

BACKGROUND: Minimal change disease (MCD) is the most common cause of nephrotic syndrome in children and is associated with the expression of CD80 in podocytes and the increased excretion of CD80 in urine. We hypothesized that serum from patients with MCD might stimulate CD80 expression in cultured podocytes. METHODS: Sera and peripheral blood mononuclear cells (PBMCs) were collected from subjects with MCD in relapse and remission and from normal controls. Immortalized human podocytes were incubated with culture media containing patient sera or supernatants from patient and control PBMC cultures. CD80 expression was measured by quantitative PCR and western blot analysis. RESULTS: Sera collected from patients with MCD in relapse, but not in remission, significantly increased CD80 expression (mean ± standard deviation: 1.8 ± 0.7 vs. 0.8 ± 0.2; p < 0.004) and CD80 protein secretion by podocytes (p < 0.05 between relapse and normal controls). No such CD80 increase was observed when podocytes were incubated with supernatants of PBMC cultures from patients in relapse. CONCLUSIONS: Sera from MCD patients in relapse, but not in remission, stimulated CD80 expression in cultured podocytes. Identifying this factor in sera could provide insights into the pathogenesis of this disorder. No role in CD80 expression by podocytes was found for cytokines released by PBMCs.

Iron Biology - An Overview for Laboratorians.

Iron serves a critical role in many metabolic processes, including oxygen delivery (e.g., hemoglobin) and oxygen utilization for the generation of ATP (e.g., cytochromes). Disorders of iron metabolism are best recognized and evaluated in the context of iron's absorption, transportation, monitoring, cellular uptake, and recycling. This review highlights these processes so that disorders of iron deficiency and iron excess can be better understood. Key players in iron metabolism will be highlighted, such as hepcidin, ferroportin, erythroferrone, transferrin, ferritin, HFE, and the transferrin receptors.

Hematology and coagulation preanalytics for clinical chemists: Factors intrinsic to the sample and extrinsic to the patient.

In hematology and coagulation, diligence in the preanalytical phase of testing is of critical importance to obtaining reliable test results. If the sample used for testing is unsuitable, even outstanding analytical procedures and technology cannot produce a clinically-reliable result. Therefore, the intent of this manuscript is to review preanalytical factors intrinsic to the sample that affect the hematology and coagulation testing. Factors intrinsic to the sample (excluding in vivo anomalies) can be controlled, theoretically, by phlebotomists (including nurses) and laboratorians in the preanalytical phase of testing. Furthermore, the management and prevention of such factors is highlighted. Erroneous control of preanalytical factors can produce laboratory errors.

Spontaneous hemothorax in pregnant patient with pulmonary arteriovenous malformation.

We present a case of a 34-year-old pregnant patient at 26 weeks' gestation by in vitro fertilization with past medical history of hypertension and infertility who presented to the hospital with abdominal pain. The patient stated her pain was in her left upper quadrant. The morning before arriving to the hospital the patient stated she woke up at 0300 with increasingly severe pain in the same area. A computed tomography angiogram of the chest demonstrated a left-sided pulmonary arteriovenous malformation with adjacent complex left effusion on chest suspicious for a hemothorax. The hemothorax was thought to be brought about by rupture of the arteriovenous malformation with likely intermittent small volume hemorrhages into the pleural space. Thoracic Surgery and Interventional radiology (IR) were each consulted for management of the arteriovenous malformation. Due to the patient's stable hemodynamic status and concern that an invasive procedure might enable a larger rupture and more substantial hemorrhage, the decision was made for embolization of the arteriovenous malformation.