Establishment of CA19-9 reference intervals in an apparently healthy adult population in Singapore.

BACKGROUND: CA19-9 is elevated in pancreatic cancer and other malignancies, and commonly used in clinical practice. Unfortunately, CA19-9 immunoassays are not harmonized, and reference intervals may differ between assays. The aim of this study was to establish the reference interval of the ADVIA Centaur/Atellica IM CA19-9 assay in an apparently healthy Singapore adult population. METHODS: This is a retrospective cross-sectional study. De-identified data from Health Screening participants were extracted from our database. Subjects with biochemical results suggesting anaemia, diabetes mellitus, viral hepatitis or abnormal liver, and renal and tumour markers were excluded. Outlier and subclass analyses by age and sex were performed. CA19-9 reference limits and 90% confidence intervals were then determined for candidate subclasses. RESULTS: Data from 12,174 subjects (5846 males and 6328 females) were available after exclusion criteria were applied. CA19-9 results did not follow a normal distribution and were higher in females compared to males (P < .001). Although CA19-9 means were statistically different between certain age groups, the evaluable 99th percentile reference limits were not statistically different. The overall 99th percentile reference limits for the Centaur/Atellica CA19-9 assay was 37 U/mL for males 21-80 years, and 60 U/mL for females 21-80 years. CONCLUSIONS: Our results suggest that separate CA19-9 reference intervals should be applied for males and females.

Commutability assessment of human urine certified reference materials for albumin and creatinine on multiple clinical analyzers using different statistical models.

Urine albumin concentration and albumin-creatinine ratio are important for the screening of early-stage kidney damage. Commutable urine certified reference materials (CRMs) for albumin and creatinine are necessary for standardization of urine albumin and accurate measurement of albumin-urine ratio. Two urine CRMs for albumin and creatinine with certified values determined using higher-order reference measurement procedures were evaluated for their commutability on five brands/models of clinical analyzers where different reagent kits were used, including Roche Cobas c702, Roche Cobas c311, Siemens Atellica CH, Beckman Coulter AU5800, and Abbott Architect c16000. The commutability study was conducted by measuring at least 26 authentic patient urine samples and the human urine CRMs using both reference measurement procedures and the routine methods. Both the linear regression model suggested by the Clinical and Laboratory Standard Institute (CLSI) guidelines and log-transformed model recommended by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Commutability Working Group were used to evaluate the commutability of the human urine CRMs. The commutability of the human urine CRMs was found to be generally satisfactory on all five clinical analyzers for both albumin and creatinine, suggesting that they are suitable to be used routinely by clinical laboratories as quality control or for method validation of urine albumin and creatinine measurements.

Pharmacological Characterization of a Novel Neuroactive Steroid Prodrug, NTS-104, and Its Neuroprotective Activity in Experimental Stroke Models.

BACKGROUND: Ischemic stroke affects about 700 000 patients per year in the United States, and to date, there are no effective pharmacological agents that promote recovery. Here, we studied the pharmacokinetics, pharmacodynamics, and efficacy of NTS-105, a novel neuroactive steroid, and NTS-104, a prodrug of NTS-105, in 2 models of ischemic stroke. METHODS: The pharmacodynamics and pharmacokinetics of NTS-104/105 were investigated in naive and stroke rats, and models of embolic and transient middle cerebral artery occlusion were used to investigate the dose-related effects of NTS-104. All rats were randomly assigned into the experimental groups, and all outcome measurements were performed blindly. RESULTS: Blood plasma and brain pharmacokinetic analysis revealed that NTS-104 rapidly converted to NTS-105, which reached peak concentration at ≈1 hour after dosing and distributed similarly to normal and ischemic brains. NTS-104 administration 4 hours after embolic middle cerebral artery occlusion led to a dose-dependent improvement of neurological outcomes and a dose-dependent reduction of infarct volumes relative to vehicle-treated animals. A single dose level study confirmed that NTS-104 administered 4 hours after transient middle cerebral artery occlusion was also neuroprotective. Quantitative ELISA revealed that NTS-104 treatment resulted in time- and dose-dependent changes in AKT activation and cytokine levels within the ischemic brain, which included reductions of IL-6, VEGF, ICAM-1, IL-1ß, MCP-1, RAGE, and GM-CSF. Time- and dose-dependent reductions in IL-6 and GM-CSF were also observed in the plasma along with an elevation of galectin-1. CONCLUSIONS: NTS-104 is a novel prodrug that converts to a novel neuroactive steroid, NTS-105, which improves functional outcomes in experimental ischemic stroke models.

Clinical and neurocognitive outcomes after transcatheter aortic valve implantation (TAVI) with cerebral protection: initial experience with a novel dual-filter device in Southeast Asia.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) is increasingly performed in patients with severe aortic stenosis. A novel dual-filter system to reduce cerebral embolism during TAVI recently became available. We aimed to assess the feasibility, safety, and clinical and neurocognitive outcomes of TAVI with cerebral protection in Asian patients. METHODS: 40 consecutive patients undergoing TAVI with cerebral protection were enrolled. All procedures were performed via femoral access using the self-expanding Evolut R/PRO or Portico, or the balloon-expandable SAPIEN 3 bioprostheses. Baseline characteristics, procedural and clinical outcomes were recorded. Cognition was assessed at baseline and 30 days using the abbreviated mental test (AMT). RESULTS: The mean age of the patients (75% male) was 76.4 ± 8.4 years. TAVI was uncomplicated in all patients. The filter device was successfully deployed in 38 (95.0%) patients without safety issues. There was no stroke or death at 30 days, and the survival rate at nine months was 95.0%. There was no overall cognitive change (baseline vs. 30-day AMT: 9.2 ± 1.1 vs. 9.0 ± 1.5, p = 0.12), and only 1 (2.5%) patient developed impaired cognition at 30 days. Patients with a decreased AMT score at 30 days were significantly older than those without (82.1 ± 4.5 vs. 74.4 ± 7.7 years, p = 0.019). All patients with decreased AMT scores were aged ≥ 76 years. CONCLUSION: In this early Asian experience of TAVI under cerebral protection, the filter device was successfully deployed in 95% of patients, with 100% procedural success. There were no filter-related complications and no stroke or mortality at 30 days. Overall cognition was preserved, although increased age was associated with a decline in AMT score.

Use of a fluorescence imaging device to detect elevated bacterial loads, enhance antimicrobial stewardship, and increase communication across inpatient complex wound care teams.

INTRODUCTION: Wounds are increasing in number and complexity within the hospital inpatient system, and coordinated and dedicated wound care along with the use of emerging technologies can result in improved patient outcomes. OBJECTIVE: This prospective implementation study at 2 hospital inpatient sites examines the effect of bedside fluorescence imaging of wounds in the detection of elevated bacterial loads and its location in/around the wound on the inpatient wound population. MATERIALS AND METHODS: Clinical assessment and fluorescence imaging assessments were performed on 26 wounds in 21 patients. Treatment plans were recorded after the clinical assessment and again after fluorescence imaging, and any alterations made to the treatment plans after imaging were noted. RESULTS: Prior to fluorescence imaging, antimicrobial use in this patient population was common. An antimicrobial dressing, a topical antibiotic, or an oral antibiotic was prescribed in 23 wounds (88% of assessments), with antimicrobial dressings prescribed 73% of the time. Based on clinical assessment, more than half of the treated wounds were deemed negative for suspected infection. In 12 of 26 wounds, the fluorescence imaging information on bacterial presence had the potential to prompt a change in whether an antimicrobial dressing was prescribed. Five of these 12 wounds were fluorescence imaging-positive and an antimicrobial drug was not prescribed, whereas 7 of the 12 wounds were negative upon fluorescence imaging and clinical assessment but antimicrobial dressing was prescribed. Overall, fluorescence imaging detected 70% more wounds, with bacterial fluorescence indicating elevated bacterial loads, compared with clinical assessment alone, and use of imaging resulted in altered treatment plans in 35% of cases. CONCLUSIONS: Fluorescence imaging can aid in antimicrobial stewardship goals by supporting evidence-based decision-making at the point of care. In addition, use of such imaging resulted in increased communication, enhanced efficiency, and improved continuity of care between wound care providers and hospital sites.

Evaluation of the Impact of Esterases and Lipases from the Circulatory System against Substrates of Different Lipophilicity.

Esterases and lipases can process amphiphilic esters used as drugs and prodrugs and impact their pharmacokinetics and biodistribution. These hydrolases can also process ester components of drug delivery systems (DDSs), thus triggering DDSs destabilization with premature cargo release. In this study we tested and optimized assays that allowed us to quantify and compare individual esterase contributions to the degradation of substrates of increased lipophilicity and to establish limitations in terms of substrates that can be processed by a specific esterase/lipase. We have studied the impact of carbonic anhydrase; phospholipases A1, A2, C and D; lipoprotein lipase; and standard lipase on the hydrolysis of 4-nitrophenyl acetate, 4-nitrophenyl palmitate, DGGR and POPC liposomes, drawing structure-property relationships. We found that the enzymatic activity of these proteins was highly dependent on the lipophilicity of the substrate used to assess them, as expected. The activity observed for classical esterases was diminished when lipophilicity of the substrate increased, while activity observed for lipases generally increased, following the interfacial activation model, and was highly dependent on the type of lipase and its structure. The assays developed allowed us to determine the most sensitive methods for quantifying enzymatic activity against substrates of particular types and lipophilicity.

Thyroid Function During the Fetal and Neonatal Periods.

Thyroid hormones are essential during infancy and childhood for growth and brain development. The formation and maturation of the newborn's hypothalamic-pituitary-thyroid axis begin in utero with fetal dependence on maternal thyroid hormones early in the pregnancy. As the fetal thyroid gland begins to produce thyroid hormones in the second trimester, the reliance decreases and remains at lower levels until birth. After birth, the detachment from the placenta and the change in thermal environment lead to a rapid increase in circulating thyroid-stimulating hormone in the neonate within hours, resulting in subsequent increases in thyroxine and triiodothyronine concentrations. Preterm infants may have lower thyroxine concentrations because of an immature hypothalamic-pituitary-thyroid axis at the time of birth and premature discontinuation of transference of maternal thyroid hormones. Similarly, infants with critical illness unrelated to the thyroid gland may have lower thyroxine levels. Infants born to mothers with Graves' disease are at risk for hypothyroidism and hyperthyroidism, which is related to the placental transfer of maternal autoantibodies, as well as antithyroid medications. An understanding of the normal embryology and physiology of the fetal and neonatal thyroid will help in evaluating a newborn for thyroid disorders.

Anion gap reference intervals show instrument dependence and weak correlation with albumin levels.

BACKGROUND: Anion gap (AG) aids the differential diagnosis of acid-base disorders. Its value has decreased, because of new analytical methods. Our goal was to compare AG reference intervals for different instruments and Southeast Asian populations. METHODS: We studied AG at three hospitals. One used the cobas 8000; two others, the Architect c16000. We included consecutive adults ≥18 years whose samples were sent for electrolytes and creatinine. We assessed AG for all patients and patients with normal electrolytes. RESULTS: AG means differed significantly (P < 0.001) between the three hospitals for all patients and the normal electrolyte subgroup. AG reference intervals from all patients were 9-19, 5-15, and 5-15 mmol/L, and for the normal electrolyte subgroup, 10-17, 6-14, and 5-12 mmol/L, respectively. Compared to the normal albumin group, hypoalbuminemia patients showed lower AG in two hospitals (P < 0.001, P = 0.03), whereas patients with hyperalbuminemia demonstrated higher AG in all three hospitals (P < 0.001). CONCLUSIONS: Different instruments produce different AGs. There is a weak correlation between albumin levels and AG. Laboratorians should verify reference intervals used when detecting laboratory errors and assisting clinicians in the differential diagnosis of acid base disorders and other medical conditions.

Intrathyroidal Thymic Tissue in an Adolescent with Graves' Disease: Case Report and Review of Current Literature.

Intrathyroidal thymic tissue (ITT) is a benign entity found in children and young adolescents that often mimics a concerning thyroid nodule with microcalcifications on ultrasound. It is challenging for the clinician to distinguish between these two entities, which may lead to unnecessary invasive procedures. We report an adolescent female patient with Graves' disease who underwent total thyroidectomy for a thyroid nodule concerning for malignancy for which the surgical pathology ultimately revealed ITT. As ITT is rarely found beyond childhood, the concurrent Graves' disease may have led to persistence of thymic tissue in this patient. Several sonographic features can help in differentiating ITT from a concerning thyroid nodule. Once identified, ITT should be followed by serial imaging with anticipation of decreasing size or complete resolution over time.

Thyroid Function Testing in Neonates With Maternal History of Disease.

Maternal history of thyroid disease can cause congenital hypothyroidism due to thyroid-stimulatng hormone (TSH) blocking antibodies. No guidelines exist regarding testing beyond the newborn screen. TSH and T4 levels exhibit significant fluctuations after birth which complicates testing. A total of 561 newborns with thyroid function testing done for maternal history of thyroid disease in the newborn nursery were identified retrospectively via chart review, and thyroid disease status was assessed in 352. Newborn screening data were also obtained. Of these infants, 7 had hypothyroidism with 3 having negative newborn screens. No cases of neonatal graves were identified. The 3 infants with negative newborn screens had TSH levels ranging from 6.58 to 28.4 prior to treatment with levothyroxine. All required treatment beyond age 3 years, despite trial off levothyroxine. Infants with maternal history of thyroid disease may require additional testing beyond the newborn screen. However, providers can consider delaying test until after thyroid levels are more stable.

A Case of Thyroid Storm Associated with Cardiomyopathy and Poststreptococcal Glomerulonephritis.

Thyroid storm has a high mortality rate and is often associated with a precipitating factor such as intercurrent illness or infection. It is rare in pediatric patients. Cardiac disease in hyperthyroidism mostly manifests itself as tachycardia but more serious cardiac findings have also been described. A 5-year-old male with recent strep throat infection presented with dilated cardiomyopathy, hematuria, and symptoms and lab findings consistent with severe hyperthyroidism. He was diagnosed with thyroid storm secondary to concurrent Graves' disease and poststreptococcal glomerulonephritis (PSGN). After starting the treatment with methimazole and a beta-blocker, his cardiac disease gradually improved and the PSGN resolved over time. There are no specific pediatric criteria for thyroid storm. Adult criteria can be difficult to apply to pediatric cases. Criteria for diagnosis of thyroid storm are less clear for pediatric patients. Dilated cardiomyopathy is a rare cardiac manifestation of hyperthyroidism. PSGN is due to glomerular immune complexes and can complicate group A strep infection. Providers should be aware of cardiac disease as a complication of hyperthyroidism. PSGN should not mechanistically be related to hyperthyroidism but can precipitate the signs of thyroid storm such as hypertension. This association has not been previously reported in the literature.

Evaluation of puberty by verifying spontaneous and stimulated gonadotropin values in girls.

BACKGROUND: Changes in pharmacological agents and advancements in laboratory assays have changed the gonadotropin-releasing hormone analog stimulation test. OBJECTIVE: To determine the best predictive model for detecting puberty in girls. SUBJECTS: Thirty-five girls, aged 2 years 7 months to 9 years 3 months, with central precocious puberty (CPP) (n=20) or premature thelarche/premature adrenarche (n=15). METHODS: Diagnoses were based on clinical information, baseline hormones, bone age, and pelvic sonogram. Gonadotropins and E2 were analyzed using immunochemiluminometric assay. Logistic regression for CPP was performed. RESULTS: The best predictor of CPP is the E2-change model based on 3- to 24-h values, providing 80% sensitivity and 87% specificity. Three-hour luteinizing hormone (LH) provided 75% sensitivity and 87% specificity. Basal LH lowered sensitivity to 65% and specificity to 53%. CONCLUSIONS: The E2-change model provided the best predictive power; however, 3-h LH was more practical and convenient when evaluating puberty in girls.

Improved long-term glucose control in neonatal diabetes mellitus after early sulfonylurea allergy.

BACKGROUND: Activating mutations of the ABCC8 gene can lead to permanent neonatal diabetes mellitus (PNDM). Glucose variability in infants with NDM treated with insulin can be extreme. We report long-term glycemic control in a patient with PNDM on sulfonylurea therapy, despite initial allergic reaction. METHODS: A Chinese girl presented on the first day of life with persistent hyperglycemia. Despite treatment with various insulin regimens, hemoglobin (Hb)A1c (normal 4.8%-6.3%) increased from 5.0% at 14 days of age to a peak of 9.7% at 15 months of age. Her average insulin dose was 0.5 units/kg/day. Genetic analysis revealed two novel ABCC8 gene activating mutations encoding the beta-cell sulfonylurea-1 receptor of the ATP-sensitive potassium channel. At age 3 years 2 months, transition from insulin to the oral sulfonylurea glyburide was initiated. After 8 days, she developed urticaria, palmar erythema, and a diffuse maculopapular rash, which resolved when medication was discontinued. At age 3 years 11 months, glyburide was reintroduced at a very low dose and was increased with concomitant weaning of insulin over the following 6 months. RESULTS: Normoglycemia (HbA1c 5.6%) was achieved on glyburide without any further allergic reaction at the age of 4 years 5 months with improved metabolic control. For the next 3 years, HbA1c measurements, and glucose means and variability were significantly lower compared with values during insulin therapy. CONCLUSIONS: As compared with subcutaneous insulin, oral sulfonylureas improved long-term metabolic control in a patient with NDM caused by novel activating mutations in the ABCC8 gene. Desensitization permitted safe oral sulfonylurea therapy in our patient with NDM despite initial allergic reaction. Fewer episodes of hypoglycemia occurred on sulfonylurea than on insulin therapy, which is an advantage in a very young child.

Outcomes of children and adolescents with well-differentiated thyroid carcinoma and pulmonary metastases following ¹³¹I treatment: a systematic review.

BACKGROUND: The optimal dose and efficacy of ¹³¹I treatment of children and adolescents with well-differentiated thyroid carcinoma (WDTC) and pulmonary metastases are not well established. A therapeutic challenge is to achieve the maximum benefit of ¹³¹I to decrease disease-related morbidity and obtain disease-free survival while avoiding the potential complications of ¹³¹I therapy. SUMMARY: We systematically reviewed the published literature on children and adolescents with WDTC and pulmonary metastases treated with ¹³¹I to examine outcomes after ¹³¹I administration and the risks and benefits of therapy. After reviewing 14 published articles, 9 articles met our inclusion criteria encompassing 112 pediatric and adolescent patients with WDTC and pulmonary metastases 21 years of age or younger at diagnosis spanning a follow-up period of 0.6­45 years. ¹³¹I therapy after surgery and thyrotropin suppression resulted in complete, partial, and no disease response in 47.32%, 38.39%, and 14.29% of patients, respectively. Five studies provided data on disease response in relation to ¹³¹I dose. In general, nonresponders received the highest ¹³¹I doses and complete responders received a higher dose than partial responders. The disease-specific mortality rate was 2.68%. Survival was 97.32%. A second primary malignancy occurred in one patient. One out of 11 patients studied experienced radiation fibrosis. CONCLUSIONS: This review confirms that the majority of pediatric and adolescent patients with WDTC and pulmonary metastases treated with ¹³¹I do not achieve complete response to therapy, yet disease-specific morbidity and mortality appear to remain low. It is therefore prudent to use caution in the repeated administration of ¹³¹I to such patients to ensure that adverse effects of therapy do not cause more harm than good in a disease that has an overall favorable natural course. Long-term prospective studies are needed to analyze disease-specific morbidity and mortality, recurrence rate, dose-specific response, and dose-related adverse effects of ¹³¹I in this patient population.

A somatic gain-of-function mutation in the thyrotropin receptor gene producing a toxic adenoma in an infant.

BACKGROUND: Activating mutations of the thyroid stimulating hormone receptor gene (TSHR) are rare in the neonate and in the pediatric population. They are usually present in the germline, and are either inherited or occur de novo. Somatic mutations in TSHR are unusual in the pediatric population. METHODS: We describe a nine-month-old infant with thyrotoxicosis who harbored an activating somatic mutation in TSHR that was not present in the germline. RESULTS: As genomic DNA analysis failed to show a TSHR gene mutation, a radioiodide scan was performed to reveal a unilateral localization of uptake suppressing the remaining thyroid tissue. Genomic and complementary DNA analyses of the active thyroid tissue, removed surgically, identified a missense mutation (D633Y) located in the sixth transmembrane domain of the TSHR. The absence of this TSHR mutation in circulating mononuclear cells and in unaffected thyroid tissue confirmed the somatic nature of this genetic alteration. CONCLUSIONS: To the authors' knowledge, this is the youngest patient to receive definitive treatment for hyperthyroidism due to an activating mutation of TSHR.

Antenatal treatment of fetal goiter: a therapeutic challenge.

OBJECTIVE: Pre-natal ultrasonography presents an opportunity for in-utero therapy of a fetal goiter. Because of the morbidity associated with a large goiter and the risks of repeated intra-amniotic injections, controversy arose about the precise indications of this mode of treatment. We describe our observations in treating a 22-week-old fetus with a large goiter because of dyshormogenesis, monitored with serial 3D high frequency, high resolution ultrasonography and amniotic hormonal measurements. Fetal hypothyroidism was confirmed by cordocentesis and amniotic hormone levels. After assessment of relevant risk factors and the criteria for in-utero intervention, including goiter volume, amniotic fluid index, polyhydramnios and tracheal compression, we determined that hormonal therapy was warranted. Levothyroxine was injected every 7-10 days, and its efficacy monitored by ultrasound changes and amniotic hormone sampling. RESULTS: Reduction in goiter volume restored normal neck flexion relieving the pressure on the trachea, polyhydramnios was prevented and amniotic hormone levels were normalised. The infant was euthyroid at birth, however, by age 4 days hypothyroidism was diagnosed, and treatment with l-thyroxine started. CONCLUSION: Advances in fetal ultrasonography permit judicious therapy of an enlarging goiter in a hypothyroid fetus, which may contribute to enhancing cognitive development. We discuss the value of amniotic hormone sampling, the objectives and risks of in-utero intervention in the light of recent literature and our own observations.

Enhanced external counterpulsation.

Enhanced external counterpulsation is a noninvasive technique designed to increase myocardial perfusion and reduce cardiac workload in patients with coronary artery disease. Recent trials have documented beneficial hemodynamic effects. Stress testing and radionuclide imaging have demonstrated improvements in functional capacity and myocardial perfusion. This procedure may be the therapeutic choice for patients with severe diffuse disease or in whom repeat revascularization is not possible. The relatively low cost of the technique makes it feasible for patients in developing countries.