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ObjectivesIdentifying patients with a possible SARS-CoV-2 infection in the emergency department (ED) is challenging. Symptoms differ, incidence rates vary and test capacity may be limited. As PCR-testing all ED patients is neither feasible nor effective in most centres, a rapid, objective, low-cost early warning score to triage ED patients for a possible infection is developed.DesignCase–control study.SettingSecondary and tertiary hospitals in the Netherlands.ParticipantsThe study included patients presenting to the ED with venous blood sampling from July 2019 to July 2020 (n=10 417, 279 SARS-CoV-2-positive). The temporal validation cohort covered the period from July 2020 to October 2021 (n=14 080, 1093 SARS-CoV-2-positive). The external validation cohort consisted of patients presenting to the ED of three hospitals in the Netherlands (n=12 061, 652 SARS-CoV-2-positive).Primary outcome measuresThe primary outcome was one or more positive SARS-CoV-2 PCR test results within 1 day prior to or 1 week after ED presentation.ResultsThe resulting ‘CoLab-score’ consists of 10 routine laboratory measurements and age. The score showed good discriminative ability (AUC: 0.930, 95% CI 0.909 to 0.945). The lowest CoLab-score had high sensitivity for COVID-19 (0.984, 95% CI 0.970 to 0.991; specificity: 0.411, 95% CI 0.285 to 0.520). Conversely, the highest score had high specificity (0.978, 95% CI 0.973 to 0.983; sensitivity: 0.608, 95% CI 0.522 to 0.685). The results were confirmed in temporal and external validation.ConclusionsThe CoLab-score is based on routine laboratory measurements and is available within 1 hour after presentation. Depending on the prevalence, COVID-19 may be safely ruled out in over one-third of ED presentations. Highly suspect cases can be identified regardless of presenting symptoms. The CoLab-score is continuous, in contrast to the binary outcome of lateral flow testing, and can guide PCR testing and triage ED patients.

Androgen abuse is associated with unfavourable changes in blood pressure, lipid metabolism and erythrocytosis. Most knowledge is based on cross-sectional studies sensitive to bias. We assessed the magnitude of these effects and their recovery in a prospective cohort study which included 100 men (≥18 years) performing an androgen cycle. Clinic visits took place before the cycle, at the end, 3 months after and 1 year after start of the cycle and included measurement of blood pressure, lipid parameters and haematocrit. During androgen use, systolic and diastolic blood pressure increased 6.87 (95% CI 4.34-9.40) and 3.17 mmHg (1.29-5.04) compared to baseline respectively. LDL cholesterol and ApoB increased 0.45 mmol/L (0.29-0.61) and 18.2 mg/dl (13.5-22.8) respectively, whereas HDL cholesterol, ApoA and Lp(a) decreased with 0.40 mmol/L (-0.45 to 0.35), 36.6 mg/dl (30.2-42.9) and 37.6% (13.9-61.3). ANGPTL3 increased 20.3% (7.38-33.2). Mean haematocrit increased 0.03 L/L (0.02-0.03). Three months after the cycle, and 1 year after the start, these parameters returned to baseline. In conclusion, androgen abuse induces small but clinically relevant adverse changes in blood pressure, lipid metabolism and erythrocytosis which are rapidly reversible after cessation. As follow-up was limited to 1 year, the impact of androgen abuse on cardiovascular disease remains uncertain.

An estimated 4-6% of fitness center visitors uses anabolic-androgenic steroids (AAS). Reliable data about adverse reactions of AAS are scarce. The HAARLEM study aimed to provide insight into the positive and negative effects of AAS use. One hundred men (≥18 years) who intended to start an AAS cycle on short notice were included for follow-up. Clinic visits took place before (T0), at the end (T1), and three months after the end of the AAS cycle (T2), and one year after the start of the cycle (T3), and comprised a medical history, physical examination, laboratory analysis, and psychological questionnaires. During the follow-up period, four subjects reported a serious adverse event, that is, congestive heart failure, acute pancreatitis, suicidal ideation, and exacerbation of ulcerative colitis. All subjects reported positive side effects during AAS use, mainly increased strength (100%), and every subject reported at least one negative health effect. Most common were fluid retention (56%) and agitation (36%) during the cycle, and decreased libido (58%) after the cycle. Acne and gynecomastia were observed in 28% and 19%. Mean alanine transaminase (ALT) and creatinine increased 18.7 U/l and 4.7 µmol/L, respectively. AAS dose and cycle duration were not associated with the type and severity of side effects. After one-year follow-up (T3), the prevalence of observed effects had returned to baseline. There was no significant change in total scores of questionnaires investigating wellbeing, quality of life, and depression. In conclusion, all subjects experienced positive effects during AAS use. Four subjects experienced a serious adverse event. Other side effects were mostly anticipated, mild, and transient.

Objective To determine cut-off values for a recently introduced high sensitive cardiac troponin assay (hs-cTnI) which provide similar sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) for acute myocardial infarction (AMI) as known cut-off values for an hs-cTnT assay. Methods A prospective observational study was performed. Hs-cTnT (Roche) and hs-cTnI (Abbott) were measured in consecutive patients with symptoms suggestive of AMI. Representative measurements (obtained at least 3 h after chest pain has started) and serial measurements with a time delay between 2.5 h and 4.5 h were used to determine cut-off levels. Two independent clinicians adjudicated the final diagnosis. Results 1490 patients were included in the study of whom 114 (8%) received a final diagnosis of AMI. Receiver operating characteristics analysis showed no statistically significant differences in the areas under the curve between the two assays. Cut-off values for representative hs-TnI were found to be as follows: rule-out: 10 ng/L (sensitivity: 98.2%; 95% CI 95.7% to 100.0% and NPV: 99.8%; 99.5% to 100.0%); rule-in: 70 ng/L (specificity: 90.8%; 89.3% to 92.4% and PPV: 39.7%; 36.1% to 43.3%). For serial measurements we found a Δ rule-out cut-off value of 20 ng/L (sensitivity: 94.9%; 88.0% to 100.0% and NPV: 98.7%; 96.9% to 100.0%) and Δ rule-in cut-off values of 100 ng/L (specificity: 92.7%; 87.9% to 95.8% and PPV: 57.6%; 39.4% to 74.0%) and 300% (specificity: 93.8%; 90.4% to 97.2% and PPV: 61.3%; 51.1% to 71.5%). Conclusions Cut-off values for hs-cTnI measurements are determined which allow a similar diagnostic classification as compared with hs-cTnT. Importantly, for a rule-out paradigm this cut-off value is unmistakably lower than the upper reference limit.

Importance: High-sensitivity cardiac troponin I testing is widely used to evaluate patients with suspected acute coronary syndrome. A cardiac troponin concentration of less than 5 ng/L identifies patients at presentation as low risk, but the optimal threshold is uncertain.Objective: To evaluate the performance of a cardiac troponin I threshold of 5 ng/L at presentation as a risk stratification tool in patients with suspected acute coronary syndrome.Data Sources: Systematic search of MEDLINE, EMBASE, Cochrane, and Web of Science databases from January 1, 2006, to March 18, 2017.Study Selection: Prospective studies measuring high-sensitivity cardiac troponin I concentrations in patients with suspected acute coronary syndrome in which the diagnosis was adjudicated according to the universal definition of myocardial infarction.Data Extraction and Synthesis: The systematic review identified 19 cohorts. Individual patient-level data were obtained from the corresponding authors of 17 cohorts, with aggregate data from 2 cohorts. Meta-estimates for primary and secondary outcomes were derived using a binomial-normal random-effects model.Main Outcomes and Measures: The primary outcome was myocardial infarction or cardiac death at 30 days. Performance was evaluated in subgroups and across a range of troponin concentrations (2-16 ng/L) using individual patient data.Results: Of 11 845 articles identified, 104 underwent full-text review, and 19 cohorts from 9 countries were included. Among 22 457 patients included in the meta-analysis (mean age, 62 [SD, 15.5] years; n = 9329 women [41.5%]), the primary outcome occurred in 2786 (12.4%). Cardiac troponin I concentrations were less than 5 ng/L at presentation in 11 012 patients (49%), in whom there were 60 missed index or 30-day events (59 index myocardial infarctions, 1 myocardial infarction at 30 days, and no cardiac deaths at 30 days). This resulted in a negative predictive value of 99.5% (95% CI, 99.3%-99.6%) for the primary outcome. There were no cardiac deaths at 30 days and 7 (0.1%) at 1 year, with a negative predictive value of 99.9% (95% CI, 99.7%-99.9%) for cardiac death.Conclusions and Relevance: Among patients with suspected acute coronary syndrome, a high-sensitivity cardiac troponin I concentration of less than 5 ng/L identified those at low risk of myocardial infarction or cardiac death within 30 days. Further research is needed to understand the clinical utility and cost-effectiveness of this approach to risk stratification.

We hypothesized that a high circulating free fatty acid (FFA) concentration is involved in the pathogenesis of hyposomatotropism associated with obesity. To evaluate this hypothesis, 10 healthy premenopausal women (body mass index 33.8 ± 1.0 kg/m2) were studied in the follicular phase of their menstrual cycle at two occasions with a time interval of at least 8 wk, where body weight remained stable. Subjects were randomly assigned to treatment with either acipimox (an inhibitor of lipolysis, 250 mg orally 4 times daily) or placebo in a double-blind crossover design, starting 1 day before admission until the end of the blood sampling period. Blood samples were taken during 24 h with a sampling interval of 10 min for assessment of growth hormone (GH) concentrations, and GH secretion was estimated by deconvolution analysis. Identical methodology was used to study GH secretion in a historical control group of age-matched normal weight women. GH secretion was clearly blunted in obese women (total daily release 66 ± 10 vs. lean controls: 201 ± 23 mU·lVd-1·24 h-1, P = 0.005, where lVd is liter of distribution volume). Acipimox considerably enhanced total (113 ± 50 vs. 66 ± 10 mU·lVd-1·24 h-1, P = 0.02) and pulsatile GH secretion (109 ± 49 vs. 62 ± 30 mU·lVd-1·24 h-1, P = 0.02), but GH output remained lower compared with lean controls. Further analysis did not show any relationship between the effects of acipimox on GH secretion and regional body fat distribution. In conclusion, acipimox unleashes spontaneous GH secretion in obese women. It specifically enhances GH secretory burst mass. This might mean that lowering of systemic FFA concentrations by acipimox modulates neuroendocrine mechanisms that orchestrate the activity of the somatotropic ensemble.

Abdominally obese individuals have reduced 24-h plasma GH concentrations. Their normal plasma IGF-I levels may reflect GH hypersensitivity. Alternatively, obesity-associated hyposomatotropism may cause less biological effect in target tissues. We therefore determined whole-body responsiveness to the anabolic effects of GH in abdominally obese (OB) and normal weight (NW) premenopausal women. A 1-h iv infusion of GH or placebo was randomly administered to six NW (body mass index, 21.1 ± 1.9 kg/m2) and six OB (body mass index, 35.5 ± 1.5 kg/m2) women in a cross-over design. Endogenous insulin, glucagon and GH secretion was suppressed by infusion of somatostatin. Whole-body protein turnover was measured using a 10-h infusion of [13C]-leucine. GH administration induced a similar plasma GH peak in NW and OB women (49.8 ± 10.4 vs. 45.1 ± 5.6 mU/liter). GH, compared with placebo infusion, increased nonoxidative leucine disposal, P < 0.0001) and endogenous leucine appearance (Ra, P = 0.0004) but decreased leucine oxidation (P = 0.0051). All changes were similar in both groups. Accordingly, whole-body GH responsiveness, defined as the maximum response of nonoxidative leucine disposal, leucine Ra, and oxidation per unit of GH, was not different in OB and NW women (0.25 ± 0.18 vs. 0.19 ± 0.17 μmol/kg·h, 0.21 ± 0.23 vs. 0.13 ± 0.17 μmol/kg·h, and −0.10 ± 0.08 vs. −0.08 ± 0.05 μmol/kg·h, respectively). These results indicated that whole-body tissue responsiveness to the net anabolic effect of GH is similar in OB and NW women. Hence, we inferred that hyposomatotropism may promote amino acid oxidation and blunt protein turnover in abdominal obesity. However, hyposomatotropism cannot account for all anomalous features of protein metabolism in abdominally obese humans.

Lipolysis (the breakdown of fat) is generally estimated using stable isotopes, where the rate of appearance (Ra) of glycerol is calculated using Steele's equations. These equations are based on single-compartment differential equations for tracer and tracee where rate of change is approximated by the change in concentration from one time point to the next. We demonstrate an alternative approach to estimate metabolic processes, and to determine relationships between hormones and their actions. Growth hormone (GH) or saline was administered in a double-blind randomized crossover design to eight normal weight (NW) and eight obese (OB) subjects, and differences in the effects of GH on lipolysis were investigated. The relationship between the plasma GH concentration and glycerol Ra (as an index of lipolysis) was described using PK/PD modeling. The model incorporated the plasma GH, glycerol and D5-glycerol concentration profiles, and two sequential effect compartments to account for the delay in response. The estimated time-profile of glycerol Ra was compared with estimates obtained using Steele's equations. NONMEM (Version V) FOCE was used for parameter estimation, four differential equations were used, and glycerol and D5-glycerol were estimated simultaneously. The model adequately described both primary variables (glycerol) and derived variables (glycerol Ra as obtained using Steele's equations). Modeling allowed the assessment of potential differences in GH sensitivity in the two groups, and indicated the importance of GH in lipolysis.

Abdominal obesity is associated with reduced 24-h plasma GH concentrations. It is unclear whether hyposomatotropism in abdominally obese humans is compensated by up-regulation of GH receptor sensitivity or causes less biological effect in target tissues. We, therefore, determined the responsiveness of adipose tissue to the lipolytic action of GH in abdominally obese (OB) and normal weight (NW) postmenopausal women. An iv bolus of recombinant human GH or placebo was randomly administered to eight NW [body mass index (BMI): 22.2 ± 1.6 kg/m2] and eight abdominally OB (BMI: 32.1 ± 2.6 kg/m2) women. Lipolysis was measured by infusion of D5-glycerol and modeled as a function of plasma GH concentrations to describe adipose tissue responsiveness. Similar plasma GH concentration peaks (∼20 mU/liter) were achieved by GH injection in both groups. During placebo conditions, the average plasma GH level was significantly lower in OB compared with NW women (0.74 ± 0.52 vs. 2.08 ± 1.18 mU/liter, P = 0.023). Adipose tissue responsiveness, expressed as glycerol rate of appearance per kilogram of fat mass per unit plasma GH concentration was not different in both groups (NW: 1.06, OB: 0.68, P > 0.05). These results suggest that hyposomatotropism in abdominally obese individuals is not compensated by increased adipose tissue responsiveness to GH bio-action and, therefore, blunts lipolysis in these individuals.

In this article, we discuss possible explanations for the discrepancy in results between urine and blood pregnancy tests. The first patient, a 26-year-old woman, had breast tenderness, was tired and suffered from abdominal pain. A urine pregnancy test was negative, but blood human chorion gonadotropin (hCG) concentration was 455 U/l (reference value6 U/l). It was concluded that the patient was pregnant and she was followed in the outpatient clinic. Three days later she suffered blood loss and her hCG levels returned to normal. The diagnosis was a spontaneous abortion. The second patient, a 45-year-old woman, complained of abdominal pain, nausea and more blood loss than with a normal period. The urine pregnancy test was negative, but the hCG level in her blood was 470.000 U/l. Echography showed a thickened, irregular endometrium. A molar pregnancy was suspected and curettage was performed. The hCG level dropped initially but had increased at follow-up. Persistent trophoblastic disease was suspected and the patient underwent additional treatment.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are commonly used biomarkers for liver damage. As well as in liver tissue, AST is also present in cardiac and skeletal muscle and in erythrocytes, making ALT the most specific marker for liver damage. Here, we describe two patients with sustained increases in ALT and AST levels. The first patient is a 79-year-old woman who developed elevated serum transaminases shortly after having a myocardial infarction. The second patient, an obese 40-year-old woman presented with increased ALT and AST levels in the absence of physical symptoms. Notably, her father died of liver cirrhosis without a history of alcohol abuse. Based upon these case reports we discuss the differential diagnostic work-up of elevated serum transaminase levels. Furthermore, we explain monitoring, test performance, reference values and analytical pitfalls of these biomarkers.

Measurement of serum 25-hydroxyvitamin D [25(OH)D] is generally considered to be a reliable indicator of vitamin D status. High variability in 25(OH)D measurements due to utilized test and assay technologies, non-equimolar detection of 25(OH)D2 and 25(OH)D3, interferences from other hydroxylated vitamin D metabolites, and the lack of a definite reference method often confounds proper assessment of vitamin D status (1, 2). Recently, two reference measurement procedures for 25(OH)D3 and 25(OH)D2 have been described using isotope-dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) (3, 4). The recent increase in diversity of 25(OH)D assays prompted us to evaluate the performance of chromatographic methods (two in-house ID-LC-MS/MS and HPLC (ClinRep, Recipe)), a protein binding method (Cobas-25(OH)D-total, Roche) and immunochemical methods (Liaison and RIA (Diasorin), iSYS (IDS), ADVIA Centaur (Siemens), and Architect i1000 and i2000 (Abbott)). Blood (serum-gel, S-Monovette, Sarstedt, Nümbrecht, Germany) was drawn at one site from random outpatients (N=60) after informed consent. Sample aliquots were prepared, frozen and transported to participating centers. Method comparison was performed according to CLSI-EP9 specifications. The Architect assays as well as the ADVIA Centaur assay evaluated in this study have been adjusted by the supplier relatively quickly after release on the market. All assays were compared to an established LC-MS/MS method (LC-MS/MS-a) (5). The accuracy of the second MS method (LC-MS/MS-b) was established by measuring the standard and a control with a reference measurement procedure (4). Details of the LC-MS/MS-b method have been published recently (6). The relative content of 3-epi-25(OH)D3 was measured by a modification of LC-MS/MS-a using a fluorophenyl column (7). Individual patient samples were measured in duplicate, with exception of HPLC, RIA and the Architect-i1000 where singular measurements were performed. For method comparison studies we applied Deming regression and Bland-Altman bias plots using EP Evaluator Release 9 (D.G. Rhoads Associates Inc., Kennett Square, PA, USA) or Analyse-it software program (Microsoft Corporation). Module CLSI EP9 Method Comparison was used for analysis of duplicate measurements, whereas module Alternate (Quantitative) Method Comparison was used for singular measurements.

To evaluate the possible role of the kidney in the enhanced metabolic clearance rate (MCR) of GH in obesity, we studied the kinetics of GH and renal fractional extraction of GH (RFEGH) in 12 male hypertensive patients over a wide range of body weights (71.7-129 kg) while undergoing contrast angiography on suspicion of renal artery stenosis. A continuous infusion of recombinant human GH was administered during a continuous infusion of somatostatin to suppress endogenous GH secretion. After 2 h of GH infusion, when plasma GH had reached a steady state at concentrations that were still in the physiological range, blood was sampled from the left and right renal arteries and veins for determination of GH levels. Subsequently, the GH infusion was stopped, and GH kinetics were investigated with noncompartmental analysis. In none of the patients was hemodynamically significant renal artery stenosis present. Whole body MCR of GH averaged 375 +/- 142 ml/min. Average GH levels were significantly higher in arterial plasma than in simultaneously sampled renal venous plasma (P < 0.001). RFEGH was 8.6 +/- 6.8%. The MCRs of both GH and RFEGH correlated significantly with body weight, body fat mass, and endogenous creatinine clearance. Renal uptake of GH per 100 g kidney tissue correlated inversely with MCR. These results suggest that RFEGH rises with increasing adiposity, but per unit of renal mass, the capacity of the kidney to remove GH from the circulation falls at high MCR values.

It has been suggested that (abdominally) obese individuals are hypersensitive to growth hormone (GH) action. Because GH affects glucose metabolism, this may impact glucose homeostasis in abdominal obesity. Therefore, we studied the effect of GH on glucose metabolism in abdominally obese (OB) and normal-weight (NW) premenopausal women. A 1-h intravenous infusion of GH or placebo was randomly administered to six NW [body mass index (BMI) 21.1 ± 1.9 kg/m2] and six OB (BMI 35.5 ± 1.5 kg/m2) women in a crossover design. Insulin, glucagon, and GH secretion were suppressed by concomitant infusion of somatostatin. Glucose kinetics were measured using a 10-h infusion of [6,6-2H2]glucose. In both groups, similar physiological GH peaks were reached by infusion of GH. GH strongly stimulated endogenous glucose production (EGP) in both groups. The percent increase was significantly greater in OB than in NW women (29.8 ± 11.3 vs. 13.3 ± 7.4%, P = 0.014). Accordingly, GH responsiveness, defined as the maximum response of EGP per unit GH, was increased in OB vs. NW subjects (6.0 ± 2.1 vs. 2.2 ± 1.5 μmol·min−1·mU−1·l−1, P = 0.006). These results suggest that the liver is hyperresponsive to GH action in abdominally obese women. The role of the somatotropic ensemble in the control of glucose homeostasis in abdominal obesity is discussed.

Background: Abdominal obesity is associated with a blunted lipolytic response to fasting that may contribute to the preservation of adipose tissue mass. Objective: To further explore the pathophysiology of blunted lipolysis during fasting in obesity, we simultaneously measured lipolysis and distinct neuroendocrine regulatory hormones in abdominally obese and normal-weight (NW) women. Design: Eight abdominally obese [(x) over bar +/- SD body mass index (BMI; in kg/m(2)): 32.1 +/- 2.6] and 6 NW (BMI: 22.7 +/- 1.5) women were studied during the last 8 It of a 20-h fast. The glycerol appearance rate and the serum and plasma concentrations of insulin, leptin, cortisol, and growth hormone were measured regularly. Results: At 13 h of fasting, the mean ( SD) glycerol appearance rate corrected for fat mass was greater in NW women than in obese women (7.2 +/- 1.0 and 5.1 +/- 0.6 mumol . kg(-1) . min(-1), respectively; P = 0.001). After a 20-h fast, lipolysis increased to 8.9 +/- 1.5 mmol . kg(-1) . min(-1) in NW women (23%), whereas it did not change significantly in obese women (-2%). Fasting decreased insulin concentrations by approximate to 30% in both groups, but it did not induce significant changes in leptin concentrations. Mean cortisol concentrations and urinary catecholamine excretion were comparable in both groups. However, mean plasma growth hormone concentrations were higher in NW women than in obese women (1.81 +/- 0.98 compared with 0.74 +/- 0.52 mU/L; P = 0.046). The relative change in lipolysis tended to correlate with mean plasma growth hormone concentrations (r = 0.515, P = 0.059). Conclusion: Abdominal obesity-associated hyposomatotropism may be involved in the blunted increase in lipolysis during fasting

Lipolysis (the breakdown of fat) is generally estimated using stable isotopes, where the rate of appearance (Ra) of glycerol is calculated using Steele's equations. These equations are based on single-compartment differential equations for tracer and tracee where rate of change is approximated by the change in concentration from one time point to the next. We demonstrate an alternative approach to estimate metabolic processes, and to determine relationships between hormones and their actions. Growth hormone (GH) or saline was administered in a double-blind randomized crossover design to eight normal weight (NW) and eight obese (OB) subjects, and differences in the effects of GH on lipolysis were investigated. The relationship between the plasma GH concentration and glycerol Ra (as an index of lipolysis) was described using PK/PD modeling. The model incorporated the plasma GH, glycerol and D5-glycerol concentration profiles, and two sequential effect compartments to account for the delay in response. The estimated time-profile of glycerol Ra was compared with estimates obtained using Steele's equations. NONMEM (Version V) FOCE was used for parameter estimation, four differential equations were used, and glycerol and D5-glycerol were estimated simultaneously. The model adequately described both primary variables (glycerol) and derived variables (glycerol Ra as obtained using Steele's equations). Modeling allowed the assessment of potential differences in GH sensitivity in the two groups, and indicated the importance of GH in lipolysis.