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The determination of toxicokinetic parameters is an essential component in the risk assessment of potential harmful chemicals. It is a key step to analyse the processes involved in the formation of DNA adducts which are connected with the development of chemical-induced cancer. A general problem is the extrapolation of toxicological data fromexperimental animals to the human organism. The basis of toxicokinetic species extrapolation are physiologically-based pharmacokinetic models, which require detailed information about physiological parameters as well as about the kinetic processes involved. Fundamental in the extrapolation from one species to another is the characterisation of processes valid for the whole species, i.e. of population mean parameters instead of sets of parameters for different individuals. These, again, may vary between repeated experiments at the same or at different administered doses. Nevertheless, these differences are of great importance in obtaining a more precise insight into the variabilitystructure of process investigated within the test animal population,so that a valid basis for further research is the final result. The theory of hierarchical models provides a procedure which incorporatesboth modelling of the variability structure and estimation of population mean parameter vectors. The present study was designed to elucidate interindividual and interoccasion variabilities of toxicokinetic parameters relevant for the biological transformation of one of the basic petrochemical industrial compounds, ethylene (ethene), which is also a physiological body constituent, to its metabolite, ethylene oxide, which is a proven carcinogen. In particular, this aspect has a potential impact for legal regulations of weak genotoxins in general. [ABSTRACT FROM AUTHOR]

Urinary bladder cancer, a smoking and occupation related disease, was subject of several genome-wide association studies (GWAS). However, studies on the course of the disease based on GWAS findings differentiating between muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC) are rare. Thus we investigated 4 single nucleotide polymorphisms (SNPs) detected in GWAS, related to the genes coding for TACC3 (transforming, acidic coiled-coil containing protein 3), for FGFR3 (fibroblast growth factor receptor 3), for PSCA (prostate stem cell antigen) and the genes coding for CBX6 (chromobox homolog 6) and APOBEC3A (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A). This study is based on 712 bladder cancer patients and 875 controls from 3 different case control studies in Germany. The 4 SNPs of interest (PSCA rs2294008 and rs2978974, FGFR3-TACC3 rs798766, and CBX6-APOBEC3A rs1014971) were determined by real-time polymerase chain reaction. The distribution of the 4 SNPs does not vary significantly between cases and controls in the entire study group and in the 3 local subgroups, including two former highly industrialized areas and a region without such history. Also, no significant differences in the bladder cancer subgroups of MIBC and NMIBC were observed. The 4 investigated SNPs do not noticeably contribute differently to the bladder cancer risk for the bladder cancer subgroups of MIBC and NMIBC., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Kadhum et al.)

Background: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology., Objective: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data., Design, Setting, and Participants: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis., Outcome Measurements and Statistical Analyses: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking., Results and Limitations: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10 -8 ) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2; multiplicative p value for interaction [p M-I ] = 0.004), 8q21.13 (PAG1; p M-I  = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; p M-I  = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44-1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers., Conclusions: We report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer., Patient Summary: We identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer., (Published by Elsevier B.V.)

Background: This study aimed to analyze the extent and direction of disagreement between self- and proxy-reported quality of life (QoL) and the factors associated with QoL overestimation and underestimation by caregivers compared with self-reports., Methods: This study used data from population-based questionnaire surveys conducted in 2012-2013 and 2015-2016 with 11- to 17-year-olds with a duration of type 1 diabetes of 10 years or longer and their caregivers (n = 1058). QoL in youth was assessed via 10-item KIDSCREEN (KIDSCREEN-10) self- and proxy-reported questionnaires. The scores ranged from 0 to 100, with higher scores indicating better QoL. Depression screening was performed via the Center for Epidemiological Studies Depression Scale for Children for youths (CES-DC screen positive: score > 15) and WHO-5 Well-being Index for parents/caregivers (WHO-5 screen positive: score ≤ 50)., Results: The mean self- and proxy-reported normalized KIDSCREEN-10 scores were 64.2 (standard deviation [SD] 11.4) and 66.1 (11.5), respectively. More caregivers overestimated (self-reported minus proxy-reported score < - 0.5*SD self-reported score) than underestimated (self-reported minus proxy-reported score > 0.5*SD self-reported score) youths' QoL (37% versus 23%, p < 0.001). Youths who screened positive for depression (18%) were at higher risk of their QoL being overestimated and lower risk of their QoL being underestimated by caregivers than youths who screened negative for depression (RR Overestimation 1.30 [95% CI 1.10-1.52], RR Underestimation 0.27 [0.15-0.50]). Caregivers who screened positive for depression (28%) overestimated the QoL of their children less often and underestimated the QoL of their children more often than caregivers who screened negative for depression (RR Overestimation 0.73 [0.60-0.89], RR Underestimation 1.41 [1.14-1.75])., Conclusions: Caregivers often over- or underestimated their children's QoL. Positive screens for depression among both youths and caregivers contributed to the observed differences between self- and caregiver-reported QoL., (© 2022. The Author(s).)

Aims: The aims of this study were to screen 14- to 30-year-olds with early-onset type 1 diabetes for generalized anxiety disorder (GAD) and to compare the characteristics of the study participants who had a positive result for GAD with those who had a negative result., Methods: This study used data from a questionnaire survey conducted from 2018 to 2019. The GAD-7 questionnaire was used to screen for GAD (positive: GAD-7 score ≥ 10). All regression analyses were adjusted for age, sex, depression diagnosis and considered multiple testing., Results: The 713 participants had a mean GAD-7 score of 4.32 (SD 4.18). A total of 12% of the study population (10% of adolescents, 13% of adults) was screened positive for GAD. Positive screening results were associated with impairments in various domains, such as self-assessed physical performance (RR poor versus good 3.03 [95% CI 1.85-4.96]), difficulty falling asleep (RR ≥3 times/week versus not during the last 4 weeks 5.36 [2.86-10.07]), glycemic control (RR HbA1c per 1% 1.16 [1.03-1.31]), and diabetes treatment satisfaction (RR poor versus good 2.67 [1.43-5.00])., Conclusions: Diabetologists should be aware that adolescents and young adults with GAD symptoms might experience extensive impairments in their daily lives., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: To investigate the value of second-opinion evaluation of multiparametric prostate magnetic resonance imaging (MRI) by subspecialised uroradiologists for the detection of significant cancer in transperineal fusion prostate biopsy., Methods: The evaluated data included age, PSA (ng/ml), PSA density, Gleason score, digital rectal examination (DRE), prostate volume of 149 patients. Twenty-seven patients (18%) had no previous prostate biopsy, 114 patients (77%) had a previous negative biopsy, and 8 patients (5%) were on active surveillance. Using PI-RADS v2 scores for mpMRI a second report was performed by a specialist uroradiologist. In all cases a subsequent transperineal biopsy was performed with at least 2 cores per target and additional background systemic cores. Initial and second-opinion radiology reports were evaluated for detection of any cancer and Gleason score (GS) 7-10 cancer, including positive predictive value and negative (NPV) and compared by Fisher's exact test., Results: At transperineal biopsy, 51 % (76/149) of patients had a GS 6-10 prostate cancer (PCa), 27 % (40/149) of patients had a GS 3 + 3 PCa and 12 % (18/149) a GS 3 + 4 and 12 % (18/149) had a GS ≥4 + 3 PCa. Agreement between initial and second-opinion reads was observed in 57.7% (86/149; kappa value = 0.32). The detection of clinically significant cancers with second-opinion reads was significantly higher (0.61; 17/28) compared to initial reads (0.35; 17/49); P = 0.034., Conclusions: Second reading of prostate mpMRIs by subspecialised uroradiologists significantly improved the positive predictive value for detection of clinically significant prostate cancer and showed a trend towards improved NPV for MRI-negative cases where biopsy could be safely avoided. Urologists should be aware that the experience of the reporter will affect the report when making decisions if and how to obtain biopsies. Reporter experience may help to reduce overcalling and avoid over-targeting of lesions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: This study aims to analyze the patient-reported outcome (PRO) of treatment satisfaction in a sample of children, adolescents and young adults with long-duration type 1 diabetes and to determine potential risk factors for poor treatment satisfaction and the intraindividual changes over a 3-year period., Methods: This study used data from two population-based questionnaire surveys conducted in 2015-2016 and 2018-2019. The participants were 11 to 27 years old and had a type 1 diabetes duration of 10 years or longer in 2015-2016 (n = 575). Factors that were potentially associated with poor treatment satisfaction (moderate, poor or very poor) compared to the reference group (very good or good treatment satisfaction) were analyzed by log binomial regression adjusted for sex and age group., Results: In 2015-2016 (2018-2019), 26% (33%) of the respondents rated their diabetes treatment/consultation as "very good", 53% (46%) as "good", and 20% (21%) as "poor". Based on the 2018-2019 data, girls/women had an increased risk of poor treatment satisfaction (RR girls/women : 1.64 (1.10; 2.44), p = 0.016). In addition, people with hemoglobin A1c (HbA1c) values ≥ 7.5% had a more than twice the risk of poor treatment satisfaction than people with HbA1c values < 7.5% (RR HbA1c ≥7.5% : 2.43 (1.63; 3.63), p < 0.001). A total of 42% of people with poor treatment satisfaction in 2015-2016 also reported poor treatment satisfaction at follow-up., Conclusions: Most study participants were satisfied with their diabetes treatment. However, we identified risk groups that would benefit from targeted interventions to improve this important PRO.

Background: Diabetes therapies have enormously changed during past decades, but only few studies have analyzed the association between family structure and diabetes management and outcomes., Objective: To analyze cross-sectionally the associations of family structure with type 1 diabetes (T1D) management and various diabetes outcomes., Methods: A total of 1635 11- to 17-year-old participants and their parents completed one of three baseline surveys as part of a nationwide, population-based cohort study on early-onset, long-standing T1D. Associations between family structure and outcome variables were analyzed by multivariable linear/logistic regression., Results: Compared to adolescents living with both parents (reference), HbA 1c was 0.48% (95% confidence interval 0.24; 0.71) / 5.2 (2.6; 7.8) mmol/mol higher in adolescents living with one parent and 0.34% (0.08; 0.59) / 3.7 (0.9; 6.5) mmol/mol higher in those living with one parent and her/his partner. The blood glucose self-monitoring (SMBG) frequency was lower (single parent: -0.6 (-1.1; -0.2), parent and partner:-0.5 (-1.0; 0.0)) and parents reported more long-term consequences related to school or work (OR single-parent 1.52 (0.90; 2.57), OR parent + partner 1.50 (0.86; 2.60)). While living with one parent was associated with increased odds of insulin injection vs. insulin pump therapy (OR 1.61 [1.13; 2.29]), the odds of low hypoglycemia awareness (OR 1.75 [1.00; 3.08]) and diabetes complications (1.32 [0.78; 2.22]) were higher in people living with a parent and her/his partner., Conclusions: Living with only one parent with or without a new partner was associated with less SMBG and pump use and poor diabetes outcomes. Future studies to explore the underlying mechanisms are required., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: High-dose-rate brachytherapy (HDR-BT) with external beam radiation therapy (EBRT) is a common treatment option for locally advanced prostate cancer. Quality of life is an important factor when discussing therapy options for high-risk prostate cancer. This study evaluated adverse effects and health-related quality of life (HRQOL)., Materials and Methods: Ninety male patients (median age, 71 years; range, 50 to 79 years) with high-risk prostate cancer underwent HDR-BT after EBRT between December 2009 and January 2017 with a median follow-up of 43 months. A total of 57 patients (69.5%) answered the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life of Cancer Patients questionnaire (QLQ-C30; ver. 3.0), and 8 patients died during follow-up. In order to put the results of this study in context, we compared the results with reference data from the EORTC QLQ-C30 Scoring Manual. Correlations of prostate-specific antigen (PSA) values, International Prostate Symptom Score, and HRQOL measures were calculated., Results: The study participants reported better physical functioning and better global health compared with the reference data, but worse social, role, and cognitive functioning. We found negative statistically significant correlations between the last-measured PSA value and social functioning (p>0.01), cognitive functioning, pain, and constipation (all p<0.05). Toxicity rates were 10.0% for gastrointestinal and 12.2% for genitourinary adverse effects. All reported complications for toxicity were Grade I., Conclusions: The described therapy results in high biochemical control rates with minimal adverse effects. Compared with reference groups, the HRQOL of this study cohort was acceptable. PSA values during follow-up seem to be a possible indicator to influence HRQOL., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose., (© The Korean Urological Association, 2020.)

Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents today. In comparison with adult disease, paediatric NAFLD may show a periportal localization, which is associated with advanced fibrosis. This study aimed to assess the role of genetic risk variants for histological disease pattern and severity in childhood NAFLD., Methods: We studied 14 single nucleotide polymorphisms (SNP) in a cohort of 70 adolescents with biopsy-proven NAFLD. Genotype was compared to an adult control cohort (n = 200) and analysed in relation to histological disease severity and liver tissue proteomics., Results: Three of the 14 SNPs were significantly associated with paediatric NAFLD after FDR adjustment, rs738409 (PNPLA3, P = 2.80 × 10 -06 ), rs1044498 (ENPP1, P = 0.0091) and rs780094 (GCKR, P = 0.0281). The severity of steatosis was critically associated with rs738409 (OR=3.25; 95% CI: 1.72-6.52, FDR-adjusted P = 0.0070). The strongest variants associated with severity of fibrosis were rs1260326, rs780094 (both GCKR) and rs659366 (UCP2). PNPLA3 was associated with a portal pattern of steatosis, inflammation and fibrosis. Proteome profiling revealed decreasing levels of GCKR protein with increasing carriage of the rs1260326/rs780094 minor alleles and downregulation of the retinol pathway in rs738409 G/G carriers. Computational metabolic modelling highlighted functional relevance of PNPLA3, GCKR and UCP2 for NAFLD development., Conclusions: This study provides evidence for the role of PNPLA3 as a determinant of portal NAFLD localization and severity of portal fibrosis in children and adolescents, the risk variant being associated with an impaired hepatic retinol metabolism., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Many medical studies aim to identify factors associated with a time to an event such as survival time or time to relapse. Often, in particular, when binary variables are considered in such studies, interactions of these variables might be the actual relevant factors for predicting, e.g., the time to recurrence of a disease. Testing all possible interactions is often not possible, so that procedures such as logic regression are required that avoid such an exhaustive search. In this article, we present an ensemble method based on logic regression that can cope with the instability of the regression models generated by logic regression. This procedure called survivalFS also provides measures for quantifying the importance of the interactions forming the logic regression models on the time to an event and for the assessment of the individual variables that take the multivariate data structure into account. In this context, we introduce a new performance measure, which is an adaptation of Harrel's concordance index. The performance of survivalFS and the proposed importance measures is evaluated in a simulation study as well as in an application to genotype data from a urinary bladder cancer study. Furthermore, we compare the performance of survivalFS and its importance measures for the individual variables with the variable importance measure used in random survival forests, a popular procedure for the analysis of survival data. These applications show that survivalFS is able to identify interactions associated with time to an event and to outperform random survival forests.

N-Acetyltransferase 2 (NAT2) genotyping by PCR and RFLP-based methods provides information on seven single nucleotide polymorphisms (SNPs) without deriving the chromosomal phase (haplotype). So genotyping results must be processed to get all possible NAT2 haplotype (or allele) combinations. Here we describe the procedure for genotyping and present a program based on Microsoft ® Access ® which automatically generates all possible haplotype pairs for a given unphased NAT2 genotype. NAT2 haplotypes are important to predict the NAT2 phenotype.

Little is known whether genetic variants identified in genome-wide association studies interact to increase bladder cancer risk. Recently, we identified two- and three-variant combinations associated with a particular increase of bladder cancer risk in a urinary bladder cancer case-control series (Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), 1501 cases, 1565 controls). In an independent case-control series (Nijmegen Bladder Cancer Study, NBCS, 1468 cases, 1720 controls) we confirmed these two- and three-variant combinations. Pooled analysis of the two studies as discovery group (IfADo-NBCS) resulted in sufficient statistical power to test up to four-variant combinations by a logistic regression approach. The New England and Spanish Bladder Cancer Studies (2080 cases and 2167 controls) were used as a replication series. Twelve previously identified risk variants were considered. The strongest four-variant combination was obtained in never smokers. The combination of rs1014971[AA] near apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A (APOBEC3A) and chromobox homolog 6 (CBX6), solute carrier family 1s4 (urea transporter), member 1 (Kidd blood group) (SLC14A1) exon single nucleotide polymorphism (SNP) rs1058396[AG, GG], UDP glucuronosyltransferase 1 family, polypeptide A complex locus (UGT1A) intron SNP rs11892031[AA] and rs8102137[CC, CT] near cyclin E1 (CCNE1) resulted in an unadjusted odds ratio (OR) of 2.59 (95% CI = 1.93-3.47; P = 1.87 × 10-10), while the individual variant ORs ranged only between 1.11 and 1.30. The combination replicated in the New England and Spanish Bladder Cancer Studies (ORunadjusted = 1.60, 95% CI = 1.10-2.33; P = 0.013). The four-variant combination is relatively frequent, with 25% in never smoking cases and 11% in never smoking controls (total study group: 19% cases, 14% controls). In conclusion, we show that four high-risk variants can statistically interact to confer increased bladder cancer risk particularly in never smokers., (© The Author 2017. Published by Oxford University Press.)