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Simple Summary: In this work, we evaluated the need for frequent laboratory assessments in patients with metastatic renal cell carcinoma treated with nivolumab and nivolumab+ipilimumab during the TITAN-RCC clinical trial. We analysed how often reached criteria for dose delay or permanent discontinuation of therapy would have been missed if the frequency of laboratory testing had been reduced, in order to avoid over-sampling patients and to optimise clinical workflow and staffing. Our study showed that if the frequency of laboratory tests had been reduced, reached dose delay criteria would hardly have been missed. This would have affected up to 1% (2/207) of patients. An exception was dose delay due to the elevation of lipase blood levels which would have been missed in up to 7% (15/207) of patients. However, these patients presented with symptoms and would have been identified based thereupon. Discontinuation criteria would have only been overlooked for lipase (2% [4/207] of patients) and amylase (0.5% [1/207] of patients). Again, these patients would have been identified, since only symptomatic patients would have needed to discontinue treatment due to amylase or lipase laboratory values. In conclusion, in asymptomatic patients in our setting, laboratory analyses do not seem to be necessary before every treatment application. In clinical trials, laboratory values are assessed with high frequency. This can be stressful for patients, resource intensive, and difficult to implement, for example in office-based settings. In the prospective, multicentre phase 2 TITAN-RCC trial (NCT02917772), we investigated how many relevant changes in laboratory values would have been missed if laboratory values had been assessed less frequently. Patients with metastatic renal cell carcinoma (n = 207) received a response-based approach with nivolumab and nivolumab+ipilimumab boosts for non-response. We simulated that laboratory values were obtained before every second dose instead of every dose of the study drug(s). We assessed elevated leukocyte counts, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, amylase, lipase, and thyroid-stimulating hormone. Dose delay and discontinuation criteria were defined according to the study protocol. With the reduced frequency of laboratory analyses, dose delay criteria were rarely missed: in a maximum of <0.1% (3/4382) of assessments (1% [2/207] of patients) during nivolumab monotherapy and in a maximum of 0.2% (1/465) of assessments (1% [1/132] of patients) during nivolumab+ipilimumab boosts. An exception was lipase-related dose delay which would have been missed in 0.6% (25/4204) of assessments (7% [15/207] of patients) during nivolumab monotherapy and in 0.8% (4/480) of assessments (3% [4/134] of patients) during nivolumab+ipilimumab boosts, but would have required the presence of symptoms. Discontinuation criteria would have only been missed for amylase (<0.1% [1/3965] of assessments [0.5% (1/207) of patients] during nivolumab monotherapy, none during nivolumab+ipilimumab boosts) and lipase (0.1% [5/4204] of assessments [2% (4/207) of patients] during nivolumab monotherapy; 0.2% [1/480] of assessments [0.7% (1/134) of patients] during nivolumab+ipilimumab boosts). However, only symptomatic patients would have had to discontinue treatment due to amylase or lipase laboratory values. In conclusion, a reduced frequency of laboratory testing appears to be acceptable in asymptomatic patients with metastatic renal cell carcinoma treated with nivolumab or nivolumab+ipilimumab. [ABSTRACT FROM AUTHOR]

COPHES/DEMOCOPHES has its origins in the European Environment and Health Action Plan of 2004 to "develop a coherent approach on human biomonitoring (HBM) in Europe". Within this twin-project it was targeted to collect specimens from 120 mother-child-pairs in each of the 17 participating European countries. These specimens were investigated for six biomarkers (mercury in hair; creatinine, cotinine, cadmium, phthalate metabolites and bisphenol A in urine). The results for mercury in hair are described in a separate paper. Each participating member state was requested to contract laboratories, for capacity building reasons ideally within its borders, carrying out the chemical analyses. To ensure comparability of analytical data a Quality Assurance Unit (QAU) was established which provided the participating laboratories with standard operating procedures (SOP) and with control material. This material was specially prepared from native, non-spiked, pooled urine samples and was tested for homogeneity and stability. Four external quality assessment exercises were carried out. Highly esteemed laboratories from all over the world served as reference laboratories. Web conferences after each external quality assessment exercise functioned as a new and effective tool to improve analytical performance, to build capacity and to educate less experienced laboratories. Of the 38 laboratories participating in the quality assurance exercises 14 laboratories qualified for cadmium, 14 for creatinine, 9 for cotinine, 7 for phthalate metabolites and 5 for bisphenol A in urine. In the last of the four external quality assessment exercises the laboratories that qualified for DEMOCOPHES performed the determinations in urine with relative standard deviations (low/high concentration) of 18.0/2.1% for cotinine, 14.8/5.1% for cadmium, 4.7/3.4% for creatinine. Relative standard deviations for the newly emerging biomarkers were higher, with values between 13.5 and 20.5% for bisphenol A and between 18.9 and 45.3% for the phthalate metabolites. Plausibility control of the HBM results of all participating countries disclosed analytical shortcomings in the determination of Cd when using certain ICP/MS methods. Results were corrected by reanalyzes. The COPHES/DEMOCOPHES project for the first time succeeded in performing a harmonized pan-European HBM project. All data raised have to be regarded as utmost reliable according to the highest international state of the art, since highly renowned laboratories functioned as reference laboratories. The procedure described here, that has shown its success, can be used as a blueprint for future transnational, multicentre HBM projects., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Purpose: Thinness in adolescence has not been studied as extensively as overweight or obesity. The aim of this study was to assess the prevalence, characteristics, and health impacts of thinness in a European adolescent population. Methods: This study included 2711 adolescents (1479 girls, 1232 boys). Blood pressure, physical fitness, sedentary behaviors, physical activity (PA), and dietary intake were assessed. A medical questionnaire was used to report any associated diseases. A blood sample was collected in a subgroup of the population. Thinness and normal weight were identified using the IOTF scale. Thin adolescents were compared with adolescents of normal weight. Results: Two hundred and fourteen adolescents (7.9%) were classified as being thin; the prevalence rates were 8.6% in girls and 7.1% in boys. Systolic blood pressure was significantly lower in adolescents with thinness. The age at the first menstrual cycle was significantly later in thin female adolescents than in those with normal weight. Upper-body muscular strength measured in performance tests and time spent in light PA were significantly lower in thin adolescents. The Diet Quality Index was not significantly lower in thin adolescents, but the percentage of adolescents who skipped breakfast was higher in adolescents with a normal weight (27.7% vs 17.1%). Serum creatinine level and HOMA-insulin resistance were lower and vitamin B12 level was higher in thin adolescents. Conclusions: Thinness affects a notable proportion of European adolescents with no physical adverse health consequences. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) is associated with worse outcomes and increased morbidity and mortality in pediatric intensive care unit (PICU) patients. The renal angina index (RAI) has been proposed as an early prediction tool for AKI development. Objectives: The objective was to evaluate outcomes of RAI-positive patients and to compare RAI performance with traditional AKI markers across different patient groups (medical/post-surgical). This was an observational retrospective study. All children admitted to a tertiary hospital PICU over a 3-year period were included. Electronic medical records were reviewed. Day 1 RAI was calculated, as was the presence and staging of day 3 AKI. Results: A total of 593 patients were included; 56% were male, the mean age was 55 months, and 17% had a positive RAI. This was associated with day 3 AKI development and worse outcomes, such as greater need for kidney replacement therapy, longer duration of mechanical ventilation, vasoactive support and PICU stay, and higher mortality. For all-stage kidney injury, RAI presented a sensitivity of 87.5% and a specificity of 88.1%. Prediction of day 3 all-stage AKI by RAI had an AUC=0.878; its performance increased for severe AKI (AUC = 0.93). RAI was superior to serum creatinine increase and KDIGO AKI staging on day 1 in predicting severe AKI development. The performance remained high irrespective of the type of admission. Conclusions: The RAI is a simple and inexpensive tool that can be used with medical and post-surgical PICU patients to predict AKI development and anticipate complications, allowing for the adoption of preventive measures. [ABSTRACT FROM AUTHOR]

Summary: In several deceased donor kidney allocation systems, organs from elderly donors are allocated primarily to elderly recipients. The Eurotransplant Senior Program (ESP) was implemented in 1999, and since then, especially in Europe, the use of organs from elderly donors has steadily increased. The proportion of ≥60‐year‐old donors reported to the Collaborative Transplant Study (CTS) by European centers has doubled, from 21% in 2000–2001 to 42% in 2016–2017. Therefore, in the era of organ shortage it is a matter of debate whether kidney organs from elderly donors should only be allocated to elderly recipients or whether <65‐year‐old recipients can also benefit from these generally as "marginal" categorized organs. To discuss this issue, a European Consensus Meeting was organized by the CTS on April 12, 2018, in Heidelberg, in which 36 experts participated. Based on available evidence, it was unanimously concluded that kidney organs from 65‐ to 74‐year‐old donors can also be allocated to 55‐ to 64‐year‐old recipients, especially if these organs are from donors with no history of hypertension, no increased creatinine, no cerebrovascular death, and no other reasons for defining a marginal donor, such as diabetes or cancer. [ABSTRACT FROM AUTHOR]

Purpose: As a component of thyroid hormones, adequate iodine intake is essential during pregnancy for fetal neurodevelopment. Across Europe, iodine deficiency is common in pregnancy, but data are lacking on the predictors of iodine status at this life stage. We, therefore, aimed to explore determinants of iodine status during pregnancy in three European populations of differing iodine status. Methods: Data were from 6566 pregnant women from three prospective population-based birth cohorts from the United Kingdom (ALSPAC, n = 2852), Spain (INMA, n = 1460), and The Netherlands (Generation R, n = 2254). Urinary iodine-to-creatinine ratio (UI/Creat, µg/g) was measured in spot-urine samples in pregnancy (≤ 18-weeks gestation). Maternal dietary intake, categorised by food groups (g/day), was estimated from food-frequency questionnaires (FFQs). Multivariable regression models used dietary variables (energy-adjusted) and maternal characteristics as predictors of iodine status. Results: Median UI/Creat in pregnant women of ALSPAC, INMA, and Generation R was 121, 151, and 210 µg/g, respectively. Maternal age was positively associated with UI/Creat in all cohorts (P < 0.001), while UI/Creat varied by ethnicity only in Generation R (P < 0.05). Of the dietary predictors, intake of milk and dairy products (per 100 g/day) was positively associated with UI/Creat in all cohorts [ALSPAC (B = 3.73, P < 0.0001); INMA (B = 6.92, P = 0.002); Generation R (B = 2.34, P = 0.001)]. Cohort-specific dietary determinants positively associated with UI/Creat included fish and shellfish in ALSPAC and INMA, and eggs and cereal/cereal products in Generation R. Conclusions: The cohort-specific dietary determinants probably reflect not only dietary habits but iodine-fortification policies; hence, public-health interventions to improve iodine intake in pregnancy need to be country-specific. [ABSTRACT FROM AUTHOR]

In patients with renal insufficiency, dose adjustments based on creatinine clearance and body weight have been a component of imipenem dosage instructions. The objective of the current analysis was to provide revised dosing recommendations by evaluating the impact of creatinine clearance and body weight on the pharmacokinetics of imipenem. A population pharmacokinetics model was developed with data from 465 patients and 3300 pharmacokinetic samples. Simulations provided data to support revision of the dosing recommendations to remove body weight–adjusted dosing, and the analysis formed the basis for updates that are reflected on the current imipenem label for both the United States and Europe. The optimized regimen provided an advantage in terms of improved target attainment at breakpoint minimum inhibitory concentration values of 1 and 2 μg/mL, as low‐body‐weight patients maintained >90% probability of target attainment compared to <90% probability of target attainment achieved with the previously approved regimen. It was concluded that additional dose adjustments for body weight were not necessary and the new scheme would simplify dosing while maintaining patient safety and efficacy. [ABSTRACT FROM AUTHOR]

Studies using 24 h urine collections need to incorporate ways to validate the completeness of the urine samples. Models to predict urinary creatinine excretion (UCE) have been developed for this purpose; however, information on their usefulness to identify incomplete urine collections is limited. We aimed to develop a model for predicting UCE and to assess the performance of a creatinine index using para-aminobenzoic acid (PABA) as a reference. Data were taken from the European Food Consumption Validation study comprising two non-consecutive 24 h urine collections from 600 subjects in five European countries. Data from one collection were used to build a multiple linear regression model to predict UCE, and data from the other collection were used for performance testing of a creatinine index-based strategy to identify incomplete collections. Multiple linear regression (n 458) of UCE showed a significant positive association for body weight (β = 0·07), the interaction term sex × weight (β = 0·09, reference women) and protein intake (β = 0·02). A significant negative association was found for age (β = − 0·09) and sex (β = − 3·14, reference women). An index of observed-to-predicted creatinine resulted in a sensitivity to identify incomplete collections of 0·06 (95 % CI 0·01, 0·20) and 0·11 (95 % CI 0·03, 0·22) in men and women, respectively. Specificity was 0·97 (95 % CI 0·97, 0·98) in men and 0·98 (95 % CI 0·98, 0·99) in women. The present study shows that UCE can be predicted from weight, age and sex. However, the results revealed that a creatinine index based on these predictions is not sufficiently sensitive to exclude incomplete 24 h urine collections. [ABSTRACT FROM PUBLISHER]

Aim Ethyl glucuronide (EtG) is used commonly as a marker for the detection of non-compliance of patients in alcohol withdrawal therapy in psychiatric hospitals in Europe and in work-place monitoring programmes in the United States. With the increased use of this new marker, questions related to an unintentional uptake of ethanol resulting in detectable EtG concentrations have been discussed. The aim of this study was to determine the concentration ranges of EtG and ethyl sulphate (EtS) after the consumption of very small amounts of ethanol (1 and 3 g), which are more likely to be incidental than intended. Methods Drinking experiments with ethanol amounts of 1 and 3 g, respectively, were performed on a total of 31 volunteers. EtG and EtS analysis in urine was performed by electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS), and creatinine concentration was determined using the Jaffé reaction. Furthermore, data obtained from this experimentation were then compared to data from literature. Results and conclusions The maximum concentration of EtG normalized to creatinine after the uptake of 1 g and 3 g of ethanol was found to be 0.32 mg/l and 1.53 mg/l, respectively, and 0.15 mg/l and 1.17 mg/l for EtS; these peak concentrations are considered to be positive by many laboratories testing urine for ethanol conjugates in work-place testing progammes. [ABSTRACT FROM AUTHOR]