Anxiety onset in adolescents: a machine-learning prediction.

Recent longitudinal studies in youth have reported MRI correlates of prospective anxiety symptoms during adolescence, a vulnerable period for the onset of anxiety disorders. However, their predictive value has not been established. Individual prediction through machine-learning algorithms might help bridge the gap to clinical relevance. A voting classifier with Random Forest, Support Vector Machine and Logistic Regression algorithms was used to evaluate the predictive pertinence of gray matter volumes of interest and psychometric scores in the detection of prospective clinical anxiety. Participants with clinical anxiety at age 18-23 (N = 156) were investigated at age 14 along with healthy controls (N = 424). Shapley values were extracted for in-depth interpretation of feature importance. Prospective prediction of pooled anxiety disorders relied mostly on psychometric features and achieved moderate performance (area under the receiver operating curve = 0.68), while generalized anxiety disorder (GAD) prediction achieved similar performance. MRI regional volumes did not improve the prediction performance of prospective pooled anxiety disorders with respect to psychometric features alone, but they improved the prediction performance of GAD, with the caudate and pallidum volumes being among the most contributing features. To conclude, in non-anxious 14 year old adolescents, future clinical anxiety onset 4-8 years later could be individually predicted. Psychometric features such as neuroticism, hopelessness and emotional symptoms were the main contributors to pooled anxiety disorders prediction. Neuroanatomical data, such as caudate and pallidum volume, proved valuable for GAD and should be included in prospective clinical anxiety prediction in adolescents.

Outcomes after laser enucleation of the prostate with and without significant storage symptoms.

OBJECTIVE: To test for differences in recovery of lower urinary tract symptoms (LUTS) between patients with storage-positive vs -negative symptoms after laser enucleation of the prostate (LEP). PATIENTS AND METHODS: Consecutive storage-positive (severe storage symptoms, International Prostate Symptom Score [IPSS] storage subscore >8) vs storage-negative patients treated with LEP (November 2017-September 2022) within our tertiary-care database were identified. Mixed linear models tested for changes in IPSS and quality of life (QoL) at 1, 3 and 12 months after LEP. Multiple linear regression models tested for LUTS and QoL recovery risk factors at 1, 3 and 12 months. RESULTS: Of 291 study patients, 180 (62%) had storage-positive symptoms. There were no differences between storage-positive and -negative patients in mean adjusted total IPSS, IPSS-storage, IPSS-voiding and QoL at 12 months after LEP. In multiple linear regression models, storage-positive status was identified as a risk factor for higher IPSS at 1 month (ß coefficient 2.98, P = 0.004) and 3 months (ß coefficient 2.24, P = 0.04), as well as for more unfavourable QoL at 1 month (ß coefficient 0.74, P = 0.006) and 3 months (ß coefficient 0.73, P = 0.004) after LEP. Conversely, at 12 months there were no differences between storage-positive vs -negative patients. CONCLUSION: Storage-positive patients appear to experience similar long-term benefits from LEP compared to storage-negative patients. However, significant storage symptoms are associated with higher total IPSS and less favourable QoL at 1 and 3 months after LEP. These findings advocate for the consideration of LEP also in storage-positive cases with the need for thorough patient education especially in the initial post-LEP period.

Thulium fiber laser vs. holmium laser enucleation of the prostate: results of a prospective randomized non-inferiority trial.

PURPOSE: Holmium laser enucleation of the prostate (HoLEP) represents the current standard procedure for size-independent surgical therapy of benign prostatic obstruction (BPO). With advent of the novel laser technology thulium fiber laser (TFL), we hypothesized that the functional outcome of TFL enucleation of the prostate (ThuFLEP) is non-inferior compared to HoLEP. METHODS: From October 2021 to October 2022, 150 patients with BPO were recruited for the prospective randomized trial in accordance with CONSORT. Stratified randomization into the arms ThuFLEP (n = 74) or HoLEP (n = 76) was carried out. The primary endpoint was non-inferior international prostate symptom score (IPSS) and quality of life (QoL) at three months after treatment. Secondary endpoints were rates of complications, peak flow, residual urine and operation times. RESULTS: Preoperative characteristics showed no significant differences. Overall IPSS and QoL improved from 21 to 8 and 4 to 1.5, respectively, after three months of follow-up. No statistically significant differences between ThuFLEP and HoLEP were observed regarding median postoperative IPSS (8.5 vs. 7, p > 0.9), QoL (1 vs. 2, p = 0.6), residual urine (48 vs. 30ml, p = 0.065) and peak flow (19 vs. 17ml/s, p > 0.9). Similarly, safety profile was comparable with no statistically significant differences regarding rate of major complications (5.3 vs. 5.4%, p = 0.5), laser hemostasis time (3 vs. 2min, p = 0.2), use of additive electric coagulation (74 vs. 87%, p = 0.06) or electric coagulation time (8 vs. 8min, p = 0.4). CONCLUSIONS: In this prospective, randomized trial ThuFLEP showed non-inferior results compared to HoLEP in terms of functional outcomes measured by IPSS and QoL as primary endpoint. TRIAL REGISTRATION NUMBER: DRKS00032699 (18.09.2023, retrospectively registered).

Physical activity and psychopathology: are long-term developmental trajectories of physical activity in children and adolescents associated with trajectories of general mental health problems and of attention-deficit hyperactivity (ADHD) symptoms?

A medium-to-high level of physical activity (PA) may have at least a short-term positive effect on psychopathology in children and adolescents. Hence, the objective of this study was to investigate the long-term effects of PA in non-adult age groups on their general mental health problems and/or ADHD symptoms, using trajectories of concurrent development over a period of 10 years. This study employed data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) collected at three time points (baseline, Wave 1, Wave 2, over 10 years) from 17,640 children and adolescents. Using parent-reported data from the Strengths and Difficulties Questionnaire (SDQ), different developmental trajectories of general mental health problems (SDQ-total) and ADHD symptoms (SDQ-H/I) were identified with latent class mixed models (LCMM) statistics. This was also applied to parent- and self-reported data of three levels of PA. The latter was assessed according to WHO recommendations. The joint probability of class membership for SDQ-total as well as ADHD symptoms with PA was calculated to generate the concurrent developmental trajectories between variables. Results showed a 4-class trajectory model for both SDQ-total and ADHD symptoms among boys and girls. The majority of children and adolescents showed "low general difficulties" and "low ADHD symptoms" over the period of 10 years. Three distinct trajectories in boys and four distinct trajectories in girls were found for PA. Most of the participants showed an "increasing-decreasing activity" trajectory. No statistically significant correlations were found between the different SDQ-total or ADHD symptom trajectories and the trajectories of PA in the two genders. Taken together, our findings did not indicate any significant relationship between waxing and waning PA course over 10 years and various classes of mental health problems for children and adolescents. In contrast to our cross-sectional findings, no steady long-term medium/high-level of PA was present, which could (at least partly) explain the non-significant findings.

Translational PK/PD Modeling of Tumor Growth Inhibition and Target Inhibition to Support Dose Range Selection of the LMP7 Inhibitor M3258 in Relapsed/Refractory Multiple Myeloma.

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, ß5i, PSMB8) proteolytic subunit of the immunoproteasome, a component of the cellular protein degradation machinery, highly expressed in malignant hematopoietic cells including multiple myeloma. Here we describe the fit-for-purpose pharmacokinetic (PK)/pharmacodynamic (PD)/efficacy modeling of M3258 based on preclinical data from several species. The inhibition of LMP7 activity (PD) and tumor growth (efficacy) were tested in human multiple myeloma xenografts in mice. PK and efficacy data were correlated yielding a free M3258 concentration of 45 nM for half-maximal tumor growth inhibition (KC50). As M3258 only weakly inhibits LMP7 in mouse cells, both in vitro and in vivo bridging studies were performed in rats, monkeys, and dogs for translational modeling. These data indicated that the PD response in human xenograft models was closely reflected in dog PBMCs. A PK/PD model was established, predicting a free IC50 value of 9 nM for M3258 in dogs in vivo, in close agreement with in vitro measurements. In parallel, the human PK parameters of M3258 were predicted by various approaches including in vitro extrapolation and allometric scaling. Using PK/PD/efficacy simulations, the efficacious dose range and corresponding PD response in human were predicted. Taken together, these efforts supported the design of a phase Ia study of M3258 in multiple myeloma patients (NCT04075721). At the lowest tested dose level, the predicted exposure matched well with the observed exposure while the duration of LMP7 inhibition was underpredicted by the model. SIGNIFICANCE STATEMENT: M3258 is a novel inhibitor of the immunoproteasome subunit LMP7. The human PK and human efficacious dose range of M3258 were predicted using in vitro-in vivo extrapolation and allometric scaling methods together with a fit-for-purpose PK/PD and efficacy model based on data from several species. A comparison with data from the Phase Ia clinical study showed that the human PK was accurately predicted, while the extent and duration of PD response were more pronounced than estimated.

Assessment of the potential of the MET inhibitor tepotinib to affect the pharmacokinetics of CYP3A4 and P-gp substrates.

Tepotinib is a highly selective, potent, mesenchymal-epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer harboring MET exon 14 skipping alterations. The aims of this work were to investigate the potential for drug-drug interactions via cytochrome P450 (CYP) 3A4/5 or P-glycoprotein (P-gp) inhibition. In vitro studies were conducted in human liver microsomes, human hepatocyte cultures and Caco-2 cell monolayers to investigate whether tepotinib or its major metabolite (MSC2571109A) inhibited or induced CYP3A4/5 or inhibited P-gp. Two clinical studies were conducted to investigate the effect of multiple dose tepotinib (500 mg once daily orally) on the single dose pharmacokinetics of a sensitive CYP3A4 substrate (midazolam 7.5 mg orally) and a P-gp substrate (dabigatran etexilate 75 mg orally) in healthy participants. Tepotinib and MSC2571109A showed little evidence of direct or time-dependent CYP3A4/5 inhibition (IC50 > 15 µM) in vitro, although MSC2571109A did show mechanism-based CYP3A4/5 inhibition. Tepotinib did not induce CYP3A4/5 activity in vitro, although both tepotinib and MSC2571109A increased CYP3A4 mRNA. In clinical studies, tepotinib had no effect on the pharmacokinetics of midazolam or its metabolite 1'-hydroxymidazolam. Tepotinib increased dabigatran maximum concentration and area under the curve extrapolated to infinity by 38% and 51%, respectively. These changes were not considered to be clinically relevant. Tepotinib was considered safe and well tolerated in both studies. The potential of tepotinib to cause clinically relevant DDI with CYP3A4- or P-gp-dependent drugs at the clinical dose is considered low. Study 1 (midazolam): NCT03628339 (registered 14 August 2018). Study 2 (dabigatran): NCT03492437 (registered 10 April 2018).

Long-term changes in serum levels of lipoproteins in children and adolescents with attention-deficit/hyperactivity disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder affecting approximately 5% of children worldwide. The causal mechanisms of ADHD remain unclear as the aetiology of this disorder seems to be multifactorial. One research field addresses the impact on lipid metabolism and particularly serum lipid fractions on the development of ADHD symptoms. This post hoc analysis aimed to investigate long-term changes in serum levels of lipoproteins in children and adolescents with ADHD and controls. Data of German children and adolescents from the nationwide and representative "Kinder- und Jugendgesundheitssurvey (KiGGS)" study were analysed at baseline and at a ten-year follow-up. At the two time points, participants in the control group were compared with those in the ADHD group, both before and after propensity score matching. Differences in total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL) and triglycerides were assessed between matched children with and without ADHD. In addition, subgroups with versus without methylphenidate use were compared at both time points. At baseline before matching, there were no significant differences for lipid parameters between participants in the ADHD group (n = 1,219) and the control group (n = 9,741): total cholesterol (Exp(ß) = 0.999, 95%-CI 0.911-1.094, p = .979), LDL (Exp(ß) = 0.967, 95%-CI 0.872-1.071, p = .525), HDL (Exp(ß) = 1.095, 95%-CI 0.899-1.331, p = .366) and triglycerides (Exp(ß) = 1.038, 95%-CI 0.948-1.133, p = .412). Propensity score matching confirmed the non-significant differences between the ADHD and non-ADHD group at baseline. At the 10-year follow-up, n = 571 participants fulfilled complete inclusion criteria, among them 268 subjects were classified as ADHD. The two groups did not significantly differ in lipid fractions, neither cross-sectionally nor with regard to long-term changes. There was also no significant difference between methylphenidate subgroups. In this sample of children and adolescents we could not reveal any significant associations between serum lipid fractions and the diagnosis of ADHD, neither cross-sectionally nor longitudinally; even when methylphenidate use was considered. Thus, further studies using larger sample sizes are required to investigate putative long-term changes in serum lipid fractions related to ADHD.

Comparison of peri- and intraoperative outcomes of open vs robotic-assisted partial nephrectomy for renal cell carcinoma: a propensity-matched analysis.

BACKGROUND: Partial nephrectomy (PN) is the gold standard surgical treatment for resectable renal cell carcinoma (RCC) tumors. However, the decision whether a robotic (RAPN) or open PN (OPN) approach is chosen is often based on the surgeon's individual experience and preference. To overcome the inherent selection bias when comparing peri- and postoperative outcomes of RAPN vs. OPN, a strict statistical methodology is needed. MATERIALS AND METHODS: We relied on an institutional tertiary-care database to identify RCC patients treated with RAPN and OPN between January 2003 and January 2021. Study endpoints were estimated blood loss (EBL), length of stay (LOS), rate of intraoperative and postoperative complications, and trifecta. In the first step of analyses, descriptive statistics and multivariable regression models (MVA) were applied. In the second step of analyses, to validate initial findings, MVA were applied after 2:1 propensity-score matching (PSM). RESULTS: Of 615 RCC patients, 481 (78%) underwent OPN vs 134 (22%) RAPN. RAPN patients were younger and presented with a smaller tumor diameter and lower RENAL-Score sum, respectively. Median EBL was comparable, whereas LOS was shorter in RAPN vs. OPN. Both intraoperative (27 vs 6%) and Clavien-Dindo > 2 complications (11 vs 3%) were higher in OPN (both < 0.05), whereas achievement of trifecta was higher in RAPN (65 vs 54%; p = 0.028). In MVA, RAPN was a significant predictor for shorter LOS, lower rates of intraoperative and postoperative complications as well as higher trifecta rates. After 2:1 PSM with subsequent MVA, RAPN remained a statistical and clinical predictor for lower rates of intraoperative and postoperative complications and higher rates of trifecta achievement but not LOS. CONCLUSIONS: Differences in baseline and outcome characteristics exist between RAPN vs. OPN, probably due to selection bias. However, after applying two sets of statistical analyses, RAPN seems to be associated with more favorable outcomes regarding complications and trifecta rates.

Epidemiology of Unconventional Histological Subtypes of Urethral Cancer.

INTRODUCTION: The aim of the study was to examine cancer-specific mortality (CSM) of unconventional urethral cancers. METHODS: Within the SEER (2004-2016) database, we analyzed CSM of 165 patients with unconventional urethral-cancer histology. Kaplan-Meier plots were used to test the effect of unconventional histologies in urethral cancer on CSM. RESULTS: Of 165 eligible patients, the Mullerian type accounted for 55 (33.3%) versus melanocytic (26.7%) versus neuroendocrine 25 (15.2%) versus lymphoma 22 (13.3%) versus mesenchymal/sarcoma 15 (9.1%) versus spindle cell 4 (2.1%) patients. Median age at diagnosis was 81 years in spindle cell, 75 in melanocytic, 74 in neuroendocrine and mesenchymal/sarcoma, 67 in lymphoma, and 62 years Mullerian type (p < 0.001). Of all, 116 (70.3%) were female. The Mullerian type exhibited the highest female ratio (96.4%) versus the lowest female ratio in neuroendocrine (24.0%). The Mullerian type was most frequent in African-American females. In Caucasian females, the melanocytic type was most frequent (49.1%). In African-American (38.9%) and Caucasian males (33.3%), neuroendocrine histology was most frequent. Three-year CSM was, respectively, 27.5%, 23.1% 22.3%, 20.5%, and 16.1% for melanocytic, mesenchymal/sarcoma, Mullerian type, neuroendocrine, and lymphoma histology. Median cancer-specific survival was 106 versus 10 months for combined nonmetastatic versus metastatic nonconventional histologies. CONCLUSION: Important age, sex, racial/ethnic group distribution, and survival differences exist between each unconventional urethral-cancer histological subtypes.

Anesthetic Technique (Spinal vs. General Anesthesia) in Holmium Laser Enucleation of the Prostate: Retrospective Analysis of Procedural and Functional Outcomes among 1,159 Patients.

OBJECTIVE: The aim of the study was to compare procedural efficacy, early and late functional outcomes in holmium laser enucleation of the prostate (HoLEP) under spinal anesthesia (SA) versus general anesthesia (GA). METHODS: We retrospectively reviewed patients undergoing HoLEP at our institution between 2012 and 2017. Standard pre-, peri-, and postoperative characteristics were compared according to anesthetic technique. Multivariable logistic regression analyses (MVAs) were employed to study the impact of SA on procedural efficacy and postoperative complications. RESULTS: Our study cohort consisted of 1,159 patients, of whom 374 (32%) underwent HoLEP under SA. While a medical history of any anticoagulation/antiplatelet therapy except low-dose acetylsalicylic acid was significantly more common among patients undergoing GA (16% vs. 10%, p = 0.001), no other significant differences in preoperative characteristics were noted including age, body mass index, American Society of Anesthesiologists Classification (ASA), prostate size, or International Prostate Symptom Score (IPSS), and quality of life scores. Patients under SA exhibited shorter times of enucleation 42 min (interquartile range [IQR]:27-59 vs. 45 min [IQR: 31-68], p = 0.002), and combined time of enucleation/morcellation/coagulation (57 min [IQR: 38-85] vs. 64 min [IQR: 43-93], p = 0.002), as well as fewer complications (Clavien-Dindo ≥3) (12 [3.2%] vs. 55 [7%], p = 0.013). These associations were confirmed in MVA. Patients did not differ significantly with regard to early micturition including post-void residual volume and maximum flow-rate improvement. At a median follow-up of 33 months (IQR: 32-44), patients with SA had a lower IPSS score (median 3 [IQR: 1-6] vs. 4 [IQR: 2-7], p = 0.039). However, no significant differences were observed with respect to any urinary incontinence, urge symptoms, and postoperative pain. CONCLUSION: In this large retrospective series, HoLEP under SA was a safe and efficacious procedure with comparable early and long-term functional outcomes.

Cognitive and brain development is independently influenced by socioeconomic status and polygenic scores for educational attainment.

Genetic factors and socioeconomic status (SES) inequalities play a large role in educational attainment, and both have been associated with variations in brain structure and cognition. However, genetics and SES are correlated, and no prior study has assessed their neural associations independently. Here we used a polygenic score for educational attainment (EduYears-PGS), as well as SES, in a longitudinal study of 551 adolescents to tease apart genetic and environmental associations with brain development and cognition. Subjects received a structural MRI scan at ages 14 and 19. At both time points, they performed three working memory (WM) tasks. SES and EduYears-PGS were correlated (r = 0.27) and had both common and independent associations with brain structure and cognition. Specifically, lower SES was related to less total cortical surface area and lower WM. EduYears-PGS was also related to total cortical surface area, but in addition had a regional association with surface area in the right parietal lobe, a region related to nonverbal cognitive functions, including mathematics, spatial cognition, and WM. SES, but not EduYears-PGS, was related to a change in total cortical surface area from age 14 to 19. This study demonstrates a regional association of EduYears-PGS and the independent prediction of SES with cognitive function and brain development. It suggests that the SES inequalities, in particular parental education, are related to global aspects of cortical development, and exert a persistent influence on brain development during adolescence.

Social and Nonsocial Autism Symptom Domains in Children and Adolescents with Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder: Insights into Their Symptomatological Interplay.

INTRODUCTION: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) share overlapping symptomatology, particularly with regard to social impairments (including peer relationship difficulties), and they frequently co-occur. However, the nature of their co-occurrence remains unclear. Therefore, the current study aimed to examine the nature of the transdiagnostic link between ASD and ADHD from a symptomatological point of view measured with the Autism Diagnostic Observation Schedule (ADOS Module 3) and the Autism Diagnostic Interview-Revised (ADI-R). METHODS: We analyzed the social and nonsocial ASD symptom domain scores from both diagnostic instruments in 4 clinically referred groups (i.e., ASD, ADHD, ASD + ADHD, and no psychiatric diagnosis) without other co-occurring mental disorders using a two-by-two full-factorial MANOVA design with the factors ASD (yes/no) and ADHD (yes/no). RESULTS: We found no ASD by ADHD interaction effects across all symptom domain scores of ADOS and ADI-R, except for ADOS imagination/creativity. There were only main effects of the factor ASD but no main effects of ADHD. Follow-up contrasts showed that exclusively, ASD had an impact on the measured symptomatology in case of co-occurring ASD + ADHD. CONCLUSION: Overall, the results support an additive model of the symptomatology across areas of communication, social interaction, and stereotyped behaviors and restricted interests in case of the co-occurrence of ASD and ADHD when assessed with ADOS/ADI-R. Thus, one can assume that the phenotypic overlap of ASD + ADHD may be less complicated than suspected - at least with regard to ASD symptomatology - and that in the presence of ADHD, ASD symptomatology is generally well measurable with best-practice diagnostic instruments.

Survival rates with external beam radiation therapy in newly diagnosed elderly metastatic prostate cancer patients.

BACKGROUND: The survival benefit of primary external beam radiation therapy (EBRT) has never been formally tested in elderly men who were newly diagnosed with metastatic prostate cancer (mPCa). We hypothesized that elderly patients may not benefit of EBRT to the extent as younger newly diagnosed mPCa patients, due to shorter life expectancy. METHODS: We relied on Surveillance, Epidemiology and End Results (2004-2016) to identify elderly newly diagnosed mPCa patients, aged >75 years. Kaplan-Meier, univariable and multivariable Cox regression models, as well as Competing Risks Regression models tested the effect of EBRT versus no EBRT on overall mortality (OM) and cancer-specific mortality (CSM). RESULTS: Of 6556 patients, 1105 received EBRT (16.9%). M1b stage was predominant in both EBRT (n = 823; 74.5%) and no EBRT (n = 3908; 71.7%, p = 0.06) groups, followed by M1c (n = 211; 19.1% vs. n = 1042; 19.1%, p = 1) and M1a (n = 29; 2.6% vs. n = 268; 4.9%, p < 0.01). Median overall survival (OS) was 23 months for EBRT and 23 months for no EBRT (hazard ratio [HR]: 0.97, p = 0.6). Similarly, median cancer-specific survival (CSS) was 29 months for EBRT versus 30 months for no EBRT (HR: 1.04, p = 0.4). After additional multivariable adjustment, EBRT was not associated with lower OM or lower CSM in the entire cohort, as well as after stratification for M1b and M1c substages. CONCLUSIONS: In elderly men who were newly diagnosed with mPCa, EBRT does not affect OS or CSS. In consequence, our findings question the added value of local EBRT in elderly newly diagnosed mPCa patients.

Non-organ confined stage and upgrading rates in exclusive PSA high-risk prostate cancer patients.

BACKGROUND: The pathological stage of prostate cancer with high-risk prostate-specific antigen (PSA) levels, but otherwise favorable and/or intermediate risk characteristics (clinical T-stage, Gleason Grade group at biopsy [B-GGG]) is unknown. We hypothesized that a considerable proportion of such patients will exhibit clinically meaningful GGG upgrading or non-organ confined (NOC) stage at radical prostatectomy (RP). MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results database (2010-2015) we identified RP-patients with cT1c-stage and B-GGG1, B-GGG2, or B-GGG3 and PSA 20-50 ng/ml. Rates of GGG4 or GGG5 and/or rates of NOC stage (≥ pT3 and/or pN1) were analyzed. Subsequently, separate univariable and multivariable logistic regression models tested for predictors of NOC stage and upgrading at RP. RESULTS: Of 486 assessable patients, 134 (28%) exhibited B-GGG1, 209 (43%) B-GGG2, and 143 (29%) B-GGG3, respectively. The overall upgrading and NOC rates were 11% and 51% for a combined rate of upgrading and/or NOC stage of 53%. In multivariable logistic regression models predicting upgrading, only B-GGG3 was an independent predictor (odds ratio [OR]: 5.29; 95% confidence interval [CI]: 2.21-14.19; p < 0.001). Conversely, 33%-66% (OR: 2.36; 95% CI: 1.42-3.95; p = 0.001) and >66% of positive biopsy cores (OR: 4.85; 95% CI: 2.84-8.42; p < 0.001), as well as B-GGG2 and B-GGG3 were independent predictors for NOC stage (all p ≤ 0.001). CONCLUSIONS: In cT1c-stage patients with high-risk PSA baseline, but low- to intermediate risk B-GGG, the rate of upgrading to GGG4 or GGG5 is low (11%). However, NOC stage is found in the majority (51%) and can be independently predicted with percentage of positive cores at biopsy and B-GGG.

Linked patterns of biological and environmental covariation with brain structure in adolescence: a population-based longitudinal study.

Adolescence is a period of major brain reorganization shaped by biologically timed and by environmental factors. We sought to discover linked patterns of covariation between brain structural development and a wide array of these factors by leveraging data from the IMAGEN study, a longitudinal population-based cohort of adolescents. Brain structural measures and a comprehensive array of non-imaging features (relating to demographic, anthropometric, and psychosocial characteristics) were available on 1476 IMAGEN participants aged 14 years and from a subsample reassessed at age 19 years (n = 714). We applied sparse canonical correlation analyses (sCCA) to the cross-sectional and longitudinal data to extract modes with maximum covariation between neuroimaging and non-imaging measures. Separate sCCAs for cortical thickness, cortical surface area and subcortical volumes confirmed that each imaging phenotype was correlated with non-imaging features (sCCA r range: 0.30-0.65, all PFDR < 0.001). Total intracranial volume and global measures of cortical thickness and surface area had the highest canonical cross-loadings (|ρ| = 0.31-0.61). Age, physical growth and sex had the highest association with adolescent brain structure (|ρ| = 0.24-0.62); at baseline, further significant positive associations were noted for cognitive measures while negative associations were observed at both time points for prenatal parental smoking, life events, and negative affect and substance use in youth (|ρ| = 0.10-0.23). Sex, physical growth and age are the dominant influences on adolescent brain development. We highlight the persistent negative influences of prenatal parental smoking and youth substance use as they are modifiable and of relevance for public health initiatives.

Outcomes of robotic-assisted versus open radical cystectomy in a large-scale, contemporary cohort of bladder cancer patients.

BACKGROUND AND OBJECTIVES: To test for differences in perioperative outcomes and total hospital costs (THC) in nonmetastatic bladder cancer patients undergoing open (ORC) versus robotic-assisted radical cystectomy (RARC). METHODS: We relied on the National Inpatient Sample database (2016-2019). Statistics consisted of trend analyses, multivariable logistic, Poisson, and linear regression models. RESULTS: Of 5280 patients, 1876 (36%) versus 3200 (60%) underwent RARC versus ORC. RARC increased from 32% to 41% (estimated annual percentage change [EAPC]: + 8.6%; p = 0.02). Rates of transfusion (8% vs. 16%), intraoperative (2% vs. 3%), wound (6% vs. 10%), and pulmonary (6% vs. 10%) complications were lower in RARC patients (all p < 0.05). Moreover, median length of stay (LOS) was shorter in RARC (6 vs. 7days; p < 0.001). Conversely, median THC (31,486 vs. 27,162$; p < 0.001) were higher in RARC. Multivariable logistic regression-derived odds ratios addressing transfusion (0.49), intraoperative (0.53), wound (0.68), and pulmonary (0.71) complications favored RARC (all p < 0.01). In multivariable Poisson and linear regression models, RARC was associated with shorter LOS (Rate ratio:0.86; p < 0.001), yet higher THC (Coef.:5,859$; p < 0.001). RARC in-hospital mortality was lower (1% vs. 2%; p = 0.04). CONCLUSIONS: RARC complications, LOS, and mortality appear more favorable than ORC, but result in higher THC. The favorable RARC profile contributes to its increasing popularity throughout the United States.

The Impact of Preoperative Double-J Stent on Perioperative Complications, Recurrence, and Quality of Life in Adult Patients Undergoing Pyeloplasty.

PURPOSE: This study aimed to evaluate the impact of preoperative double-J stent (DJ) in pyeloplasty patients on perioperative complications, recurrence, and quality of life (QoL). METHODS: Pyeloplasties due to ureteropelvic junction obstructions between January 2010 and December 2020 were consecutively identified. A standardized follow-up questionnaire was used. Tabulation was made according to preoperative DJ versus no DJ. Subgroup analyses addressed primary robotic pyeloplasties. RESULTS: Of 95 pyeloplasty patients, 62% received a preoperative DJ. Patients with preoperative DJ exhibited higher rates of Clavien-Dindo (CD) 2 (22 vs. 11%) complications, but not of CD3 (8.5 vs. 8.3%, p = 0.5). After a median follow-up of 61 months, 9 patients exhibited a recurrence, of whom 7 had a preoperative DJ. In QoL assessment, comparable findings were made between patients with and without preoperative DJ. In robotic pyeloplasty patients (n = 73), patients with preoperative DJ (58%, n = 42) experienced higher CD3 complication rates, compared to patients without preoperative DJ (12 vs. 6.5%). Moreover, higher rates of recurrences were observed in preoperative DJ patients (12 vs. 3.2%). CONCLUSION: In a contemporary pyeloplasty cohort, the midterm success rate was good with 91%. Our findings suggest that preoperative DJ is associated with higher recurrence rates. However, QoL did not differ between patients with and without preoperative DJ.

Performance Evaluation of GNSS Position Augmentation Methods for Autonomous Vehicles in Urban Environments.

Global Navigation Satellite Systems provide autonomous vehicles with precise position information through the process of position augmentation. This paper presents a series of performance tests aimed to compare the position accuracy of augmentation techniques such as classical Differential Global Navigation Satellite System, Real-time Kinematic and Real-time eXtended. The aim is to understand the limitations and choose the best position augmentation technique in order to obtain accurate, trustworthy position estimates of a vehicle in urban environments. The tests are performed in and around the German cities of Wuppertal and Duesseldorf, using a vehicle fitted with the navigation system POS-LV 220, developed by Applanix Corporation. In order to evaluate the real-time performance of position augmentation techniques in a highly challenging environment, a total of four test regions are selected. The four test regions are characterized mainly by uneven terrain with tall buildings around the University of Wuppertal, flat terrain with roads of varying width in the city centre of Wuppertal and Duesseldorf and flat terrain in a tunnel section located in the city of Wuppertal. The performances of the different position augmentation are compared using a Root Mean Square (RMS) error estimate obtained as an output from the Applanix system. Furthermore, a High-Definition map of the environment is used for the purpose of model validation, which justifies the use of RMS error estimate as an evaluation metric for the performance analysis tests. According to the performance tests carried out as per the conditions specified in this paper, the Real-time eXtended (RTX) position augmentation method enables to obtain a more robust position information of the vehicle than Real-time Kinematic (RTK) method, with a typical accuracy of a few centimeter in an urban environment.

Dysregulation profile (DP) as a transdiagnostic psychopathological factor in clinically referred children - comparisons between disorders and latent structure.

BACKGROUND: Dysregulation Profile (DP) describes the psychopathological construct of concurrent impairments in the ability to regulate emotion, behaviour, and cognition measured by the Child Behaviour Checklist (CBCL). Such transdiagnostic dimensions of psychopathology play an important role in addition to core symptoms of psychiatric diagnosis in clinical practice. Evaluation of DP in children with different mental disorders may improve our understanding and treatment of both contents. METHODS: 911 clinically referred children between 6 and 18 years were investigated. The sample consisted of five 'pure' disorders groups, that is, tic disorder (TIC), anxiety disorder, obsessive compulsive disorder, depression, Attention Deficit Hyperactivity Disorder (ADHD), and two comorbid disorder group, that is, ADHD + TIC and ADHD + oppositional defiant disorder (ODD). DP level and latent structure were compared across groups. RESULTS: The rate of severe/abnormal dysregulation rates varied from 15% to 44% when the 210 cut-off was used, and 5% to 18% when stringent cut-off was used (i.e. ≥70 on all DP-subscales). The most affected population were children with comorbid ADHD with ODD/TIC, while least were those with TIC only. Five different latent phenotypes of DP were found. CONCLUSION: DP above clinical cut-off level widely exists in clinically referred children in parallel to core symptoms of their diagnosis, especially among children with comorbidities. During clinical assessment it would be worth to clarify the role of DP-related problems within the general psychosocial impairment of the patient to improve a personalized approach.

Incidence rates and contemporary trends in primary urethral cancer.

PURPOSE: We assessed contemporary incidence rates and trends of primary urethral cancer. METHODS: We identified urethral cancer patients within Surveillance, Epidemiology and End Results registry (SEER, 2004-2016). Age-standardized incidence rates per 1,000,000 (ASR) were calculated. Log linear regression analyses were used to compute average annual percent change (AAPC). RESULTS: From 2004 to 2016, 1907 patients with urethral cancer were diagnosed (ASR 1.69; AAPC: -0.98%, p = 0.3). ASR rates were higher in males than in females (2.70 vs. 0.55), respectively and did not change over the time (both p = 0.3). Highest incidence rates were recorded in respectively ≥75 (0.77), 55-74 (0.71) and ≤54 (0.19) years of age categories, in that order. African Americans exhibited highest incidence rate (3.33) followed by Caucasians (1.72), other race groups (1.57) and Hispanics (1.57), in that order. A significant decrease occurred over time in Hispanics, but not in other race groups. In African Americans, male and female sex-stratified incidence rates were higher than in any other race group. Urothelial histological subtype exhibited highest incidence rate (0.92), followed by squamous cell carcinoma (0.41), adenocarcinoma (0.29) and other histologies (0.20). In stage stratified analyses, T1N0M0 stage exhibited highest incidence rate. However, it decreased over time (-3.00%, p = 0.02) in favor of T1-4N1-2M0 stage (+ 2.11%, p = 0.02). CONCLUSION: Urethral cancer is rare. Its incidence rates are highest in males, elderly patients, African Americans and in urothelial histological subtype. Most urethral cancer cases are T1N0M0, but over time, the incidence of T1N0M0 decreased in favor of T1-4N1-2M0.