A retrospective review of the short Synacthen test in Queensland hospitals.

BACKGROUND: The short Synacthen test (SST) is widely used to investigate adrenal insufficiency, but it can be time-consuming, costly and labour-intensive to perform and is not without risk of adverse events. AIM: To review SST requesting patterns and practices across public hospitals in Queensland. METHODS: The electronic medical records of patients who underwent a SST with Pathology Queensland between January 2020 and December 2020 were reviewed to collect data regarding the indication for the test, the requesting speciality, SST results and any adverse events. RESULTS: Six hundred and fifty-two SSTs were identified, of which 363 individual patients were included in the analysis. The majority of the tests (n = 198, 54.5%) were performed in the inpatient setting. Endocrinology most commonly ordered SSTs (n = 188, 51.8%). The suspected aetiology of adrenal insufficiency was unclear in a large proportion of requests (n = 167, 46.0%). Static testing of morning cortisol prior to SST was performed in only 249 (68.6%) patients. Of 140 inpatients data, 17.9% (n = 25) showed a robust static cortisol of ≥400 nmol/L and were treated as having normal adrenal function, suggesting SST was unnecessary in these patients. Twenty-two (6.1%) patients had a documented adverse event occurring during or after the SST. CONCLUSIONS: There was wide variability in requesting patterns and practices for SSTs across Queensland. More than one in six SSTs could have been avoided if a static morning cortisol had been performed prior. Clinician education and the adoption of a structured referral form may improve testing practices.

Feasibility of Targeted Next-Generation DNA Sequencing for Expanding Population Newborn Screening.

BACKGROUND: Newborn screening (NBS) is an effective public health intervention that reduces death and disability from treatable genetic diseases, but many conditions are not screened due to a lack of a suitable assay. Whole genome and whole exome sequencing can potentially expand NBS but there remain many technical challenges preventing their use in population NBS. We investigated if targeted gene sequencing (TGS) is a feasible methodology for expanding NBS. METHODS: We constructed a TGS panel of 164 genes which screens for a broad range of inherited conditions. We designed a high-volume, low-turnaround laboratory and bioinformatics workflow that avoids the technical and data interpretation challenges associated with whole genome and whole exome sequencing. A methods-based analytical validation of the assay was completed and test performance in 2552 newborns examined. We calculated annual birth estimates for each condition to assess cost-effectiveness. RESULTS: Assay analytical sensitivity was >99% and specificity was 100%. Of the newborns screened, 1.3% tested positive for a condition. On average, each individual had 225 variants to interpret and 1.8% were variants of uncertain significance (VUS). The turnaround time was 7 to 10 days. Maximum batch size was 1536 samples. CONCLUSIONS: We demonstrate that a TGS assay could be incorporated into an NBS program soon to increase the number of conditions screened. Additionally, we conclude that NBS using TGS may be cost-effective.

Elevated insulin-like growth factor-1 in patients without clinical evidence of acromegaly.

OBJECTIVES: To (1) identify the frequency of IGF-1 elevation in a cohort of patients without clinically suspected GH excess, in a state-based reference laboratory over a 24-month period, and (2) to examine potential differences in comorbidities and relevant medications between people with an elevated IGF-1 compared to a matched control group. DESIGN: All IGF-1 measurements at Pathology Queensland between 1/12/2018-1/12/2020 were identified. The medical records of those with IGF-1 ≥1.1x the upper limit of the reference range were appraised to determine: (1) documentation of acromegalic features, (2) relevant comorbidities and medication use, and (3) further investigations to exclude pathological GH excess. PATIENTS AND MEASUREMENTS: There were 2759 IGF-1 samples measured in 1963 people ≥18 years, over the specified period. Of these, 204 had IGF-1 ≥1.1x the upper limit of the age-matched reference range; 102 cases (61M, 41F) met inclusion criteria, and were matched to 102 controls with a normal IGF-1 based on age, sex, gonadal status and pituitary anatomy on MRI. RESULTS: There were significant differences in the frequency of dopamine agonist use (19/102 cases vs. 6/102 controls, OR = 3.66, 95% confidence interval [CI]: 1.45-9.29, p = .009) and chronic kidney disease (CKD) (14/102 cases vs. 4/102 controls, OR = 3.90, 95% CI: 1.28-11.14, p = .024). CONCLUSIONS: Out of 1963 patients having IGF-1 measured, 102 (5.2%) had an elevated IGF-1 where there was no known acromegaly, GH replacement or endogenous glucocorticoid excess. Intraindividual biological variability, assay imprecision and physiological factors are known contributors to falsely elevated IGF-1, dopamine agonist therapy and CKD should also be considered.

Comparison between free ß subunit of human chorionic gonadotropin (hCG) and total hCG assays in adults with testicular cancer.

OBJECTIVES: We tested the hypothesis that the free-ß subunit (ßhCG) is diagnostically more sensitive with total hCG assays (hCGt) not detecting all tumours secreting ßhCG. The effects of sex, age, and renal failure were investigated as secondary objectives. METHODS: We compared ßhCG with hCGt in 204 testicular cancer patients (99 seminomas, 105 non-seminonatous germ cell tumours). The effects of sex and age were determined in 125 male and 138 female controls and that of renal failure was investigated in 119 haemodialysis patients. Biochemical assessment of gonadal status was performed with LH, FSH, oestradiol and testosterone. RESULTS: Discordant results were common with isolated increases of hCGt observed in 32 (15.7 %) and ßhCG in 14 (6.9 %) patients. Primary hypogonadism was the most common cause of isolated hCGt increases. After therapeutic interventions ßhCG decreased below its upper reference more rapidly than hCGt. We observed unequivocal false negative results in two patients with non-seminomatous germ cell tumours. Both occurred in patients with clinical tumour recurrences; in one instance we observed a false negative hCGt while in the second false negative ßhCG's were documented in serial samples. CONCLUSIONS: The similar false negative rates did not support the hypothesis that ßhCG will detect more patients with testicular cancer than hCGt. In contrast to hCGt, ßhCG was unaffected by primary hypogonadism which is a predictably frequent complication in testicular cancer patients. We therefore recommend ßhCG as the preferred biomarker in testicular cancer.

The inequity of targeted cystic fibrosis reproductive carrier screening tests in Australia.

OBJECTIVE: European and Australian guidelines for cystic fibrosis (CF) reproductive carrier screening recommend testing a small number of high frequency CF causing variants, rather than comprehensive CFTR sequencing. The study objective was to determine variant detection rates of commercially available targeted reproductive carrier screening tests in Australia. METHODS: Next-generation DNA sequencing of the CFTR gene was performed on 2552 individuals from a whole population sample to identify CF causing variants. The variant detection rates of two commercially available Australian reproductive carrier screening tests, which target 50 or 175 CF causing variants, in this population were calculated. The ethnicity of individuals was determined using principal component analysis. RESULTS: Variant detection rates of the tests for 50 and 175 CF causing variants were 88.2% and 90.8%, respectively. No CF causing variants in individuals of East Asian ethnicity (n = 3) were detected by either test, while >86.6% (n = 69) of CF causing variants in Europeans would be identified by either test. CONCLUSIONS: Reproductive carrier screening tests for a targeted set of high frequency CF variants are unable to detect approximately 10% of CF variants in a multiethnic Australian population, and individuals of East Asian ethnicity are disproportionally affected by this test limitation.

Evaluation of the Atellica TnIH cardiac troponin I assay and assessment of biological equivalence.

OBJECTIVES: We evaluated the analytical performance characteristics and the biological equivalence of the Atellica TnIH assay. METHODS: Precision, detection capability, linearity, and sex specific 99th percentiles were determined de novo. Classification of patients relative to the 99th percentiles was used to assess biological equivalence. RESULTS: Analytical precision and detection capability of the Atellica TnIH assay is excellent with a limit of blank <1 ng/L and 62.5% of women and 93% of men had results above the limit of detection. The 99th percentiles (90% CI) in women were 49 ng/L (31-67) and 70 ng/L (48-121) in men. An asymmetrical distribution involving 5% of results was notable. Agreement was moderate (Kappa 0.58, 95% CI 0.53-0.63) with 20% of patients discordantly classified with Atellica TnIH below and Access hsTnI above the 99th percentiles. Serial results in 195 patients demonstrated good agreement (Kappa 0.84, 95% CI 0.77-0.90). Differences greater than the assay specific reference change values (z≥±1.96) occurred in 65% (95% CI 53-76%) of 99th percentile discordant patients compared to 2.7% (p<0.001) and 76% (p=0.17) of the concordant low and high cTnI groups respectively. CONCLUSIONS: The 99th percentile discordant and the concordantly elevated groups are more alike with respect to their z≥±1.96 rates. This favours an overestimated Atellica TnIH 99th percentile as more likely, and we hypothesize that antibody interference resulting in asymmetric scatter of nearly 5% samples may be the underlying mechanism. Analytical accuracy and interferences in cardiac troponin assays should be investigated and resolved with high priority.

Copeptin is increased by nausea and vomiting during hypertonic saline infusion in healthy individuals.

OBJECTIVE: Measurement of hypertonic saline-stimulated copeptin has recently been described for the differentiation of polyuria-polydipsia syndrome. This study aims to determine the copeptin response to intravenous 3% hypertonic saline, including evaluation of adverse effects, in a local cohort of healthy adults >18 years in Australia. DESIGN: Prospective clinical study. METHODS: Twenty healthy volunteers (10 males and 10 females) were recruited. Participants underwent infusion of 3% hypertonic saline via a previously described standardized protocol, until the plasma sodium was ≥150 mmol/L, with measurement of plasma copeptin. RESULTS: Mean peak sodium was 152 mmol/L ± SD 1.4 with osmolality 315 mmol/kg ± SD 3.9. Median volume of hypertonic saline infused to reach target sodium ≥ 150 mmol/L was 1536 mL (IQR 1362, 1992). Mean rate of plasma sodium rise was 5.9 mmol/L/hour ± SD 1.5. Hypertonic saline-stimulated copeptin had non-parametrical distribution with median of 33.8 pmol/L (IQR 27.6, 63.6). Overall median symptom burden was 6/10 (range 3/10-9/10). Copeptin was significantly higher for those who experienced nausea and/or vomiting (n = 13) (median 39.0 pmol/L; IQR 32.5, 90), compared to those participants who did not experience either (median 20.0 pmol/L; IQR 13.0, 31.0) (P = 0.003). There were no serious adverse events. CONCLUSION: Hypertonic saline-stimulated copeptin measurements were similar in our population compared with previously reported reference intervals in healthy volunteers. There is a wide range of stimulated copeptin measurements in the healthy population. Nausea and vomiting are common adverse effects which enhance the copeptin response.

Plasma Cortisol, Aldosterone, and Ascorbic Acid Concentrations in Patients with Septic Shock Do Not Predict Treatment Effect of Hydrocortisone on Mortality. A Nested Cohort Study.

Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogeneity in effect for hydrocortisone on mortality, shock resolution, and other clinical outcomes based on baseline cortisol, aldosterone, and ascorbic acid concentrations.Methods: From May 2014 to April 2017, we obtained serum samples from 529 patients with septic shock from 22 ICUs in Australia and New Zealand.Measurements and Main Results: There were no significant interactions between the association with 90-day mortality and treatment with either hydrocortisone or placebo for total cortisol (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.16 vs. OR, 1.07; 95% CI, 1.00-1.13; P = 0.70), free cortisol (OR, 1.20; 95% CI, 1.04-1.38 vs. OR, 1.16; 95% CI, 1.02-1.32; P = 0.75), aldosterone (OR, 1.01; 95% CI, 0.97-1.05 vs. OR, 1.01; 95% CI, 0.98-1.04; P = 0.99), or ascorbic acid (OR, 1.11; 95% CI, 0.89-1.39 vs. OR, 1.05; 95% CI, 0.91-1.22; P = 0.70), respectively. Similar results were observed for the association with shock resolution. Elevated free cortisol was significantly associated with 90-day mortality (OR, 1.13; 95% CI, 1.00-1.27; P = 0.04), but total cortisol, aldosterone, and ascorbic acid were not.Conclusions: In patients with septic shock, there was no heterogeneity in effect of adjunctive hydrocortisone on mortality, shock resolution, or other clinical outcomes based on cortisol, aldosterone, and ascorbic acid concentrations. Plasma aldosterone and ascorbic acid concentrations are not associated with outcome.

How comparable are total human chorionic gonadotropin (hCGt) tumour markers assays?

Background Total human chorionic gonadotropin (hCGt) tumour marker testing is regarded as an "off label" application for most commercial methods. We compared four assays in patients with a hCGt tumour marker request. We hypothesised that regression slopes would be altered and that outliers would be more common with tumour marker than with pregnancy samples if the detection of malignancy associated hCG molecular forms differed amongst assays. Further such systematic differences would be obvious and large enough to change clinical management decisions. Results We measured hCGt in 390 samples from 137 females and 253 males with a tumour marker request and 208 pregnancy controls with the following methods: Access Total ßhCG, Architect Total-ßhCG, Cobas hCG + ß and Immulite HCG. The between method regressions determined on tumour marker and pregnancy samples were not significantly different. The outlier rates were similar for male and female tumour marker and the pregnancy groups: 1.6% (95% confidence interval [CI] 0%-3.1%), 2.2% (95% CI 0%-4.7%) and 2.9% (95% CI 0.6%-5.2%). The outliers were randomly distributed amongst the methods and we were confident that they would not adversely influence clinical decisions. Conclusions The hCGt results were clinically equivalent with no systematic difference amongst the four assays.

Evaluating Rapid Rule-out of Acute Myocardial Infarction Using a High-Sensitivity Cardiac Troponin I Assay at Presentation.

BACKGROUND: Low concentrations of cardiac troponin (cTn) have been recommended for rapid rule-out of acute myocardial infarction (AMI). We examined the Beckman Coulter Access high-sensitivity cardiac troponin I (hs-cTnI) assay to identify a single test threshold that can safely rule out AMI. METHODS: This analysis used stored samples collected in 2 prospective observational studies. In all, 1871 patients presenting to a tertiary emergency department with symptoms of acute coronary syndrome had blood taken for measurement of cTnI on presentation. The endpoint was type 1 myocardial infarction (T1MI). Sensitivity and negative predictive value (NPV) were calculated for hs-cTnI values below the 99th percentile. RESULTS: Ninety-eight patients had T1MI (5.2%), and 638 (34.1%) patients had an hs-cTnI <2 ng/L (limit of detection), with sensitivity of 99.0% (95% CI, 94.4%-100%) and NPV of 99.8% (95% CI, 99.1%-100%). No hs-cTnI value above a concentration of 2 ng/L achieved sensitivity of 99%. However, an NPV of 99.5% was achieved at values <6 ng/L. A cutoff <6 ng/L enabled 1475 (78.8%) patients to be ruled out on presentation with sensitivity of 93.9% (95% CI, 87.1%-97.7%). CONCLUSIONS: A single baseline cTn <2 ng/L measured with the Access hs-cTnI assay performed well for rule-out of AMI. This cutoff concentration identified 99% of patients with AMI and could reduce the number of patients requiring lengthy assessment. A cutoff of <6 ng/L yielded a high NPV but missed more cases of AMI than would be acceptable to clinicians.

Therapeutic plasma exchange normalizes insulin-mediated response in a child with type 1 diabetes and insulin autoimmune syndrome.

BACKGROUND: Insulin autoimmune syndrome (IAS), characterized by glycemic dysregulation and life-threatening hypoglycemia, can occur in patients with type 1 diabetes (T1D). Diagnostic confirmation is complex but important in order to ensure timely initiation of definitive therapy. AIMS: We aimed to quantitate the degree of immunoglobulin-insulin complex (IIC) formation and its effects on glycemic control in a patient with T1D and IAS compared with T1D and non-T1D controls and before and after therapeutic plasma exchange (TPE). MATERIALS & METHODS: The prospective descriptive study was conducted between June 2015 and December 2015 in a quaternary children's hospital in Brisbane, Australia. Percent Free "Immunoreactive" Insulin (%FII) as assessed by polyethylene glycol precipitation studies and its relationship to plasma glucose and serum insulin concentration. RESULTS: Samples from the patient with T1D and IAS demonstrated lower mean %FII compared to T1D (23.8 ± 2.0 vs 52.0 ± 6.7; P < .0001) and non-T1D (23.8 ± 2.0 vs 102.9 ± 2.7; P < .0001) controls. This was associated with loss of glycemic predictability and frequent severe hypoglycemia. TPE increased %FII (23.8 ± 2.0 before TPE vs 83.6 ± 2.5 after TPE, P < .0001) and reestablished plasma glucose responsiveness to exogenous insulin. DISCUSSION: IAS should be considered in T1D patients with unexplained glycemic instability and hypoglycemia. The laboratory plays an integral diagnostic role. CONCLUSION: TPE is an effective method for removing IICs and normalizing insulin-mediated glucose responses.

Investigating the impact of TB case-detection strategies and the consequences of false positive diagnosis through mathematical modelling.

BACKGROUND: Increasing case notifications is one of the top programmatic priorities of National TB Control Programmes (NTPs). To find more cases, NTPs often need to consider expanding TB case-detection activities to populations with increasingly low prevalence of disease. Together with low-specificity diagnostic algorithms, these strategies can lead to an increasingly high number of false positive diagnoses, which has important adverse consequences. METHODS: We apply TIME, a widely-used country-level model, to quantify the expected impact of different case-finding strategies under two scenarios. In the first scenario, we compare the impact of implementing two different diagnostic algorithms (higher sensitivity only versus higher sensitivity and specificity) to reach programmatic screening targets. In the second scenario, we examine the impact of expanding coverage to a population with a lower prevalence of disease. Finally, we explore the implications of modelling without taking into consideration the screening of healthy individuals. Outcomes considered were changes in notifications, the ratio of additional false positive to true positive diagnoses, the positive predictive value (PPV), and incidence. RESULTS: In scenario 1, algorithm A of prolonged cough and GeneXpert yielded fewer additional notifications compared to algorithm B of any symptom and smear microscopy (n = 4.0 K vs 13.8 K), relative to baseline between 2017 and 2025. However, algorithm A resulted in an increase in PPV, averting 2.4 K false positive notifications thus resulting in a more efficient impact on incidence. Scenario 2 demonstrated an absolute decrease of 11% in the PPV as intensified case finding activities expanded into low-prevalence populations without improving diagnostic accuracy, yielding an additional 23 K false positive diagnoses for an additional 1.3 K true positive diagnoses between 2017 and 2025. Modelling the second scenario without taking into account screening amongst healthy individuals overestimated the impact on cases averted by a factor of 6. CONCLUSION: Our findings show that total notifications can be a misleading indicator for TB programme performance, and should be interpreted carefully. When evaluating potential case-finding strategies, NTPs should consider the specificity of diagnostic algorithms and the risk of increasing false-positive diagnoses. Similarly, modelling the impact of case-finding strategies without taking into account potential adverse consequences can overestimate impact and lead to poor strategic decision-making.

Cost-effective interventions for breast cancer, cervical cancer, and colorectal cancer: new results from WHO-CHOICE.

BACKGROUND: Following the adoption of the Global Action Plan for the Prevention and Control of NCDs 2013-2020, an update to the Appendix 3 of the action plan was requested by Member States in 2016, endorsed by the Seventieth World Health Assembly in May 2017 and provides a list of recommended NCD interventions. The main contribution of this paper is to present results of analyses identifying how decision makers can achieve maximum health gain using the cancer interventions listed in the Appendix 3. We also present methods used to calculate new WHO-CHOICE cost-effectiveness results for breast cancer, cervical cancer, and colorectal cancer in Southeast Asia and eastern sub-Saharan Africa. METHODS: We used "Generalized Cost-Effectiveness Analysis" for our analysis which uses a hypothetical null reference case, where the impacts of all current interventions are removed, in order to identify the optimal package of interventions. All health system costs, regardless of payer, were included. Health outcomes are reported as the gain in healthy life years due to a specific intervention scenario and were estimated using a deterministic state-transition cohort simulation (Markov model). RESULTS: Vaccination against human papillomavirus (two doses) for 9-13-year-old girls (in eastern sub-Saharan Africa) and HPV vaccination combined with prevention of cervical cancer by screening of women aged 30-49 years through visual inspection with acetic acid linked with timely treatment of pre-cancerous lesions (in Southeast Asia) were found to be the most cost effective interventions. For breast cancer, in both regions the treatment of breast cancer, stages I and II, with surgery ± systemic therapy, at 95% coverage, was found to be the most cost-effective intervention. For colorectal cancer, treatment of colorectal cancer, stages I and II, with surgery ± chemotherapy and radiotherapy, at 95% coverage, was found to be the most cost-effective intervention. CONCLUSION: The results demonstrate that cancer prevention and control interventions are cost-effective and can be implemented through a step-wise approach to achieve maximum health benefits. As the global community moves toward universal health coverage, this analysis can support decision makers in identifying a core package of cancer services, ensuring treatment and palliative care for all.

Estimating prevalence trends in adult gonorrhoea and syphilis in low- and middle-income countries with the Spectrum-STI model: results for Zimbabwe and Morocco from 1995 to 2016.

OBJECTIVE: To develop a tool for estimating national trends in adult prevalence of sexually transmitted infections by low- and middle-income countries, using standardised, routinely collected programme indicator data. METHODS: The Spectrum-STI model fits time trends in the prevalence of active syphilis through logistic regression on prevalence data from antenatal clinic-based surveys, routine antenatal screening and general population surveys where available, weighting data by their national coverage and representativeness. Gonorrhoea prevalence was fitted as a moving average on population surveys (from the country, neighbouring countries and historic regional estimates), with trends informed additionally by urethral discharge case reports, where these were considered to have reasonably stable completeness. Prevalence data were adjusted for diagnostic test performance, high-risk populations not sampled, urban/rural and male/female prevalence ratios, using WHO's assumptions from latest global and regional-level estimations. Uncertainty intervals were obtained by bootstrap resampling. RESULTS: Estimated syphilis prevalence (in men and women) declined from 1.9% (95% CI 1.1% to 3.4%) in 2000 to 1.5% (1.3% to 1.8%) in 2016 in Zimbabwe, and from 1.5% (0.76% to 1.9%) to 0.55% (0.30% to 0.93%) in Morocco. At these time points, gonorrhoea estimates for women aged 15-49 years were 2.5% (95% CI 1.1% to 4.6%) and 3.8% (1.8% to 6.7%) in Zimbabwe; and 0.6% (0.3% to 1.1%) and 0.36% (0.1% to 1.0%) in Morocco, with male gonorrhoea prevalences 14% lower than female prevalence. CONCLUSIONS: This epidemiological framework facilitates data review, validation and strategic analysis, prioritisation of data collection needs and surveillance strengthening by national experts. We estimated ongoing syphilis declines in both Zimbabwe and Morocco. For gonorrhoea, time trends were less certain, lacking recent population-based surveys.

Spectrum-Malaria: a user-friendly projection tool for health impact assessment and strategic planning by malaria control programmes in sub-Saharan Africa.

BACKGROUND: Scale-up of malaria prevention and treatment needs to continue but national strategies and budget allocations are not always evidence-based. This article presents a new modelling tool projecting malaria infection, cases and deaths to support impact evaluation, target setting and strategic planning. METHODS: Nested in the Spectrum suite of programme planning tools, the model includes historic estimates of case incidence and deaths in groups aged up to 4, 5-14, and 15+ years, and prevalence of Plasmodium falciparum infection (PfPR) among children 2-9 years, for 43 sub-Saharan African countries and their 602 provinces, from the WHO and malaria atlas project. Impacts over 2016-2030 are projected for insecticide-treated nets (ITNs), indoor residual spraying (IRS), seasonal malaria chemoprevention (SMC), and effective management of uncomplicated cases (CMU) and severe cases (CMS), using statistical functions fitted to proportional burden reductions simulated in the P. falciparum dynamic transmission model OpenMalaria. RESULTS: In projections for Nigeria, ITNs, IRS, CMU, and CMS scale-up reduced health burdens in all age groups, with largest proportional and especially absolute reductions in children up to 4 years old. Impacts increased from 8 to 10 years following scale-up, reflecting dynamic effects. For scale-up of each intervention to 80% effective coverage, CMU had the largest impacts across all health outcomes, followed by ITNs and IRS; CMS and SMC conferred additional small but rapid mortality impacts. DISCUSSION: Spectrum-Malaria's user-friendly interface and intuitive display of baseline data and scenario projections holds promise to facilitate capacity building and policy dialogue in malaria programme prioritization. The module's linking to the OneHealth Tool for costing will support use of the software for strategic budget allocation. In settings with moderately low coverage levels, such as Nigeria, improving case management and achieving universal coverage with ITNs could achieve considerable burden reductions. Projections remain to be refined and validated with local expert input data and actual policy scenarios.

High-sensitivity cardiac troponin: do think twice, it's not all right.

A questionable scientific approach to measuring at low concentrations and inappropriate censoring of results below certain cut-offs have resulted in the dichotomous classification of troponin assays based on their so-called analytical sensitivity. The definition of "high-sensitivity" cardiac troponin is flawed. Evidence suggests that its apparent diagnostic superiority may be explained by the censoring of data. In the evaluation of the detection and quantification capabilities of analytical methods we recommend alignment with International Union of Pure and Applied Chemistry (IUPAC) guidelines, including reporting of all results. This will allow the objective evaluation of the diagnostic performance of troponin assays and will render the current troponin assay classification and nomenclature obsolete.

Glucocorticoid Sensitivity Is Highly Variable in Critically Ill Patients With Septic Shock and Is Associated With Disease Severity.

OBJECTIVES: To measure tissue glucocorticoid sensitivity in patients with septic shock and determine its relationship to standard measurements of adrenal function and of outcome. DESIGN: Prospective observational trial. SETTING: Teaching hospital ICU. SUBJECTS: Forty-one patients and 20 controls were studied. INTERVENTIONS: Glucocorticoid sensitivity was measured by in vitro suppression of cytokine production from lipopolysaccharide-stimulated leukocytes. MEASUREMENTS AND MAIN RESULTS: There was no significant difference between the groups in the relative suppression of cytokine production, although there was a greater range and variance in the patient data. Patients in the lowest quartile of glucocorticoid sensitivity had higher Acute Physiology and Chronic Health Evaluation II scores (25 [24-28] vs 20 [14-23]; p = 0.02) and a trend toward higher mortality (30% vs 0%; p = 0.2) compared to those in the highest. The mRNA expression of the ß variant of the glucocorticoid receptor and the 11-ß hydroxysteroid dehydrogenase 2 isozyme were significantly higher in patients compared to controls (8.6-fold, p = 0.002 and 10.1-fold, p = 0.0002, respectively). Changes in mRNA expression of these genes did not correlate with measurements of glucocorticoid sensitivity. CONCLUSIONS: Patients with septic shock and controls do not differ in their median glucocorticoid sensitivity. However, patients exhibited a greater variability in glucocorticoid responsiveness and had evidence of association between increased sickness sensitivity and reduced glucocorticoid sensitivity. Sensitivity to glucocorticoids did not appear to be mediated by changes in the expression of the ß variant of the glucocorticoid receptor or the 11-ß hydroxysteroid dehydrogenase 2 isozyme.

Discordance with 3 Cardiac Troponin I and T Assays: Implications for the 99th Percentile Cutoff.

BACKGROUND: We compared the 99th percentile reference intervals with 3 modern cardiac troponin assays in a single cohort and tested the hypothesis that the same individuals will be identified as above the cutoff and that differences will be explained by analytical imprecision. METHODS: Blood was collected from 2005 apparently healthy blood donors. Cardiac troponin was measured with Abbott Architect STAT high sensitive troponin I, Beckman Coulter Access AccuTnI+3, and Roche Elecsys troponin T highly sensitive assays. RESULTS: The 99th percentile cutoff limits were as follows: Abbott cardiac troponin I (cTnI) 28.9 ng/L; Beckman Coulter cTnI 31.3 ng/L; and Roche cardiac troponin T (cTnT) 15.9 ng/L. Correlation among the assays was poor: Abbott cTnI vs Beckman Coulter cTnI, R(2) = 0.18; Abbott cTnI vs Roche cTnT, R(2) = 0.04; and Beckman Coulter cTnI vs Roche cTnT R(2) = 0.01. Of the results above the cutoff 50% to 70% were unique to individual assays, with only 4 out of 20 individuals above the cutoff for all 3 assays. The observed differences among assays were larger than predicted from analytical imprecision. CONCLUSIONS: The 99th percentile cutoff values were in agreement with those reported elsewhere. The poor correlation and concordance amongst the assays were notable. The differences found could not be explained by analytical imprecision and indicate the presence of inaccuracy (bias) that is unique to sample and assay combinations. Based on these findings we recommend less emphasis on the cutoff value and greater emphasis on δ values in the diagnosis of myocardial infarction.

Improved Diagnostic Performance of High-Sensitivity Cardiac Troponin Assays Is an Artifact of Censored Data.

BACKGROUND: High-sensitivity cardiac troponin assays with improved analytical performance at low concentrations are credited with increased diagnostic sensitivity in acute coronary syndrome patients. We investigated the relationship between analytical sensitivity (detection capability) and diagnostic accuracy and tested the effect of censoring data with a software model. METHOD: We generated 4 sets of results with decreasing detection capability and compared the ROC curves with and without censored data. RESULTS: There was no relationship between diagnostic performance and detection capability. When data were censored the diagnostic accuracy decreased progressively with an increase in the threshold concentration for censoring. The ROC curves constructed with censored data have a characteristic appearance with a straight line between the censoring point and the top right hand corner. CONCLUSIONS: There is not a direct relationship between the diagnostic accuracy and the detection capability of cardiac troponin assays. The artifactual decrease in diagnostic accuracy can be added to the list of reasons why data should not be censored and this practice should be disclosed in studies on diagnostic accuracy.

The Enhanced liver fibrosis score is associated with clinical outcomes and disease progression in patients with chronic liver disease.

BACKGROUND AND AIMS: Current tools for risk stratification of chronic liver disease subjects are limited. We aimed to determine whether the serum-based ELF (Enhanced Liver Fibrosis) test predicted liver-related clinical outcomes, or progression to advanced liver disease, and to compare the performance of ELF to liver biopsy and non-invasive algorithms. METHODS: Three hundred patients with ELF scores assayed at the time of liver biopsy were followed up (median 6.1 years) for liver-related clinical outcomes (n = 16) and clear evidence of progression to advanced fibrosis (n = 18), by review of medical records and clinical data. RESULTS: Fourteen of 73 (19.2%) patients with ELF score indicative of advanced fibrosis (≥9.8, the manufacturer's cut-off) had a liver-related clinical outcome, compared to only two of 227 (<1%) patients with ELF score <9.8. In contrast, the simple scores APRI and FIB-4 would only have predicted subsequent decompensation in six and four patients respectively. A unit increase in ELF score was associated with a 2.53-fold increased risk of a liver-related event (adjusted for age and stage of fibrosis). In patients without advanced fibrosis on biopsy at recruitment, 55% (10/18) with an ELF score ≥9.8 showed clear evidence of progression to advanced fibrosis (after an average 6 years), whereas only 3.5% of those with an ELF score <9.8 (8/207) progressed (average 14 years). In these subjects, a unit increase in ELF score was associated with a 4.34-fold increased risk of progression. CONCLUSIONS: The ELF score is a valuable tool for risk stratification of patients with chronic liver disease.