Functional changes in sleep-related arousal after ketamine administration in individuals with treatment-resistant depression.

The glutamatergic modulator ketamine is associated with changes in sleep, depression, and suicidal ideation (SI). This study sought to evaluate differences in arousal-related sleep metrics between 36 individuals with treatment-resistant major depression (TRD) and 25 healthy volunteers (HVs). It also sought to determine whether ketamine normalizes arousal in individuals with TRD and whether ketamine's effects on arousal mediate its antidepressant and anti-SI effects. This was a secondary analysis of a biomarker-focused, randomized, double-blind, crossover trial of ketamine (0.5 mg/kg) compared to saline placebo. Polysomnography (PSG) studies were conducted one day before and one day after ketamine/placebo infusions. Sleep arousal was measured using spectral power functions over time including alpha (quiet wakefulness), beta (alert wakefulness), and delta (deep sleep) power, as well as macroarchitecture variables, including wakefulness after sleep onset (WASO), total sleep time (TST), rapid eye movement (REM) latency, and Post-Sleep Onset Sleep Efficiency (PSOSE). At baseline, diagnostic differences in sleep macroarchitecture included lower TST (p = 0.006) and shorter REM latency (p = 0.04) in the TRD versus HV group. Ketamine's temporal dynamic effects (relative to placebo) in TRD included increased delta power earlier in the night and increased alpha and delta power later in the night. However, there were no significant diagnostic differences in temporal patterns of alpha, beta, or delta power, no ketamine effects on sleep macroarchitecture arousal metrics, and no mediation effects of sleep variables on ketamine's antidepressant or anti-SI effects. These results highlight the role of sleep-related variables as part of the systemic neurobiological changes initiated after ketamine administration. Clinical Trials Identifier: NCT00088699.

Ordinal state-trait regression for intensive longitudinal data.

In many psychological studies, in particular those conducted by experience sampling, mental states are measured repeatedly for each participant. Such a design allows for regression models that separate between- from within-person, or trait-like from state-like, components of association between two variables. But these models are typically designed for continuous variables, whereas mental state variables are most often measured on an ordinal scale. In this paper we develop a model for disaggregating between- from within-person effects of one ordinal variable on another. As in standard ordinal regression, our model posits a continuous latent response whose value determines the observed response. We allow the latent response to depend nonlinearly on the trait and state variables, but impose a novel penalty that shrinks the fit towards a linear model on the latent scale. A simulation study shows that this penalization approach is effective at finding a middle ground between an overly restrictive linear model and an overfitted nonlinear model. The proposed method is illustrated with an application to data from the experience sampling study of Baumeister et al. (2020, Personality and Social Psychology Bulletin, 46, 1631).

[Cross-sectoral patient care in the district of Hamburg Harburg: an example of urological cooperation]. / Sektorenübergreifende Versorgung im Landkreis Hamburg-Harburg: Beispiel einer urologischen Kooperation.

BACKGROUND: Ensuring future urological care at the interface between out- and inpatient care is challenging due to demographic developments with an increasing proportion of urological diseases, the simultaneous threat of a shortage of physicians, and the increasing outpatient treatment of complex urological diseases. OBJECTIVES: The cross-sectoral cooperation model between a university maximum care provider and the urologic joint practice with a hospital affiliation (BAG) presented below can serve as an ideal model for outpatient-inpatient care. MATERIALS AND METHODS: Since 2016, there has been close cooperation between the BAG in Winsen/Buchholz and the University Medical Center Hamburg-Eppendorf (UKE). In addition to direct patient transfer and the continuous pre- and posttreatment of patients, two residents from the UKE rotate to the BAG every year. RESULTS: The BAG benefits from this cooperation through planning security and support in everyday patient care, while the UKE benefits from patient transfer as well as surgical and "basic urological" training of residents. By avoiding duplicate examinations and earlier discharge of patients into outpatient follow-up care, resources are spared. Meaningful patient preselection enables minor interventions to be performed close to home via the BAG, whereas complex cases are carried out at a center of excellence. CONCLUSIONS: The cooperation is seen positively by all parties without exception and, above all, as a benefit for the patient's wellbeing. The optimal training and further education of young urologists in this expanding field can thus be supported and should be integrated into urological resident training.

Generalized reliability based on distances.

The intraclass correlation coefficient (ICC) is a classical index of measurement reliability. With the advent of new and complex types of data for which the ICC is not defined, there is a need for new ways to assess reliability. To meet this need, we propose a new distance-based ICC (dbICC), defined in terms of arbitrary distances among observations. We introduce a bias correction to improve the coverage of bootstrap confidence intervals for the dbICC, and demonstrate its efficacy via simulation. We illustrate the proposed method by analyzing the test-retest reliability of brain connectivity matrices derived from a set of repeated functional magnetic resonance imaging scans. The Spearman-Brown formula, which shows how more intensive measurement increases reliability, is extended to encompass the dbICC.

Everyday Thoughts in Time: Experience Sampling Studies of Mental Time Travel.

Time is among the most important yet mysterious aspects of experience. We investigated everyday mental time travel, especially into the future. Two community samples, contacted at random points for 3 (Study 1; 6,686 reports) and 14 days (Study 2; 2,361 reports), reported on their most recent thought. Both studies found that thoughts about the present were frequent, thoughts about the future also were common, whereas thoughts about the past were rare. Thoughts about the present were on average highly happy and pleasant but low in meaningfulness. Pragmatic prospection (thoughts preparing for action) was evident in thoughts about planning and goals. Thoughts with no time aspect were lower in sociality and experiential richness. Thoughts about the past were relatively unpleasant and involuntary. Subjective experiences of thinking about past and future often were similar-while both differed from present focus, consistent with views that memory and prospection use similar mental structures.

Negative Self-Perception and Self-Attitude of Sexuality Is a Risk Factor for Patient Dissatisfaction Following Penile Surgery with Small Intestinal Submucosa Grafting for the Treatment of Severe Peyronie's Disease.

OBJECTIVE: To assess patient satisfaction with surgical outcome, body related self-perceptions, self-attitudes of sexuality, and health related quality of life after penile surgery with small intestinal submucosa (SIS) grafting for the treatment of severe Peyronie's disease (PD). MATERIAL AND METHODS: This retrospective study included 82 patients, who were treated with SIS grafting for severe PD between 2009 and 2013 at the University Medical Center Hamburg-Eppendorf. Patients were asked to complete standardized questionnaires including the International Index of Erectile Function Erectile Function domain (IIEF-EF), Short-Form (SF)-8 Health Survey, and Frankfurt Body Concept Scale-Sexuality (FKKS-SEX). RESULTS: Follow-up was available in 58 (69.9%) patients. SIS grafting resulted in subjective straightening of the penis in 53 (91.3%) patients. After a mean follow-up of 28.9 ± 16.5 months, 24 (41.4%) patients were satisfied or very satisfied with surgical outcome. Postoperatively, the mean FKKS-SEX was 23.5 ± 5.9. In total, 36 (62.1%), 18 (31%), and four (6.9%) patients had FKKS-SEX scores corresponding to positive, neutral, and negative self-perception and self-attitude of sexuality, respectively. The mean postoperative SF-8 was 15.2 ± 6.4. Compared to the mean for German controls, patients achieved lower mean scores in the domains social functioning (50.4 ± 7.1), mental health (49.5 ± 9.2), and emotional roles (48.5 ± 6.8). Subjective shortening of the penis (Odds ratio (OR): 2.0), negative body related self-perceptions, and self-attitudes of sexuality (OR: 3.6) as well as IIEF-EF score (OR: 0.9) were risk factors for patient dissatisfaction (p-values ≤ 0.02). CONCLUSION: A relevant number of patients is not satisfied with surgical outcome after SIS grafting for the treatment of severe PD. Subjective shortening of the penis, negative body related self-perceptions, and self-attitudes of sexuality as well as IIEF-EF score were risk factors for patient dissatisfaction.

A Time-Varying Measure of Dyadic Synchrony for Three-Dimensional Motion.

We propose a novel approach to the analysis of synchronized three-dimensional motion in dyads. Motion recorded at high time resolution, as with a gaming device, is preprocessed in each of the three spatial dimensions by spline smoothing. Synchrony is then defined, at each time point, as the cosine between the two individuals' estimated velocity vectors. The approach is extended to allow a time lag, allowing for the analysis of leader-follower dynamics. Mean square cosine over the time range is proposed as a scalar summary of dyadic synchrony, and this measure is found to be positively associated with cognitive empathy.

Cross-sectional versus longitudinal designs for function estimation, with an application to cerebral cortex development.

Motivated by studies of the development of the human cerebral cortex, we consider the estimation of a mean growth trajectory and the relative merits of cross-sectional and longitudinal data for that task. We define a class of relative efficiencies that compare function estimates in terms of aggregate variance of a parametric function estimate. These generalize the classical design effect for estimating a scalar with cross-sectional versus longitudinal data, and are shown to be bounded above by it in certain cases. Turning to nonparametric function estimation, we find that longitudinal fits may tend to have higher aggregate variance than cross-sectional ones, but that this may occur because the former have higher effective degrees of freedom reflecting greater sensitivity to subtle features of the estimand. These ideas are illustrated with cortical thickness data from a longitudinal neuroimaging study.

Interpretable High-Dimensional Inference Via Score Projection with an Application in Neuroimaging.

In the fields of neuroimaging and genetics, a key goal is testing the association of a single outcome with a very high-dimensional imaging or genetic variable. Often, summary measures of the high-dimensional variable are created to sequentially test and localize the association with the outcome. In some cases, the associations between the outcome and summary measures are significant, but subsequent tests used to localize differences are underpowered and do not identify regions associated with the outcome. Here, we propose a generalization of Rao's score test based on projecting the score statistic onto a linear subspace of a high-dimensional parameter space. The approach provides a way to localize signal in the high-dimensional space by projecting the scores to the subspace where the score test was performed. This allows for inference in the high-dimensional space to be performed on the same degrees of freedom as the score test, effectively reducing the number of comparisons. Simulation results demonstrate the test has competitive power relative to others commonly used. We illustrate the method by analyzing a subset of the Alzheimer's Disease Neuroimaging Initiative dataset. Results suggest cortical thinning of the frontal and temporal lobes may be a useful biological marker of Alzheimer's disease risk.

Substitution Urethroplasty with Closure Versus Nonclosure of the Buccal Mucosa Graft Harvest Site: A Randomized Controlled Trial with a Detailed Analysis of Oral Pain and Morbidity.

BACKGROUND: Optimal surgical management of the buccal mucosa harvest site in patients with urethral stricture disease during buccal mucosa graft urethroplasty (BMGU) remains controversial. OBJECTIVE: To analyze in detail intensity and quality of pain as well as oral morbidity following closure (C) versus nonclosure (NC) of the donor site. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial on 135 patients treated with BMGU between October 15, 2014 and December 18, 2015. INTERVENTION: Following computer-based randomization, 63 and 72 patients, respectively, received C and NC of the donor site at the inner cheek. Preoperatively, on days 1, 5, and 21 as well as at 3 and 6 mo postoperatively, patients completed standardized questionnaires, including validated questions on intensity and quality of pain as well as oral morbidity. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The coprimary end points were intensity and quality of oral pain. Secondary end points included oral morbidity and intensity of pain of the perineogenital region. Generalized linear mixed models evaluated the effect of various covariates on intensity and quality of oral pain, oral morbidity, as well as intensity of pain of the perineogenital region. RESULTS AND LIMITATIONS: There was noninferiority for NC versus C in intensity and affective quality of oral pain at every time point following BMGU. Oral morbidity and complications included pain, bleeding, swelling, numbness, alteration of salivation and taste, as well as impairment of mouth opening, smiling, whistling, diet, and speech. Time from BMGU had significant effects on intensity (p<0.001) and quality of oral pain (sensory pain: p<0.001, affective pain: p<0.001, total pain: p<0.001). Length of buccal mucosa graft had significant effects on intensity (p=0.001) and quality of oral pain (sensory pain: p=0.020, total pain: p=0.042). CONCLUSIONS: NC is noninferior to C of the donor site in intensity and quality of oral pain, and offers a treatment alternative. Time from BMGU and length of the buccal mucosa graft have effects on oral morbidity and complications. PATIENT SUMMARY: We investigated pain, morbidity, and complications following closure (C) versus nonclosure (NC) of the buccal mucosa harvest site in patients undergoing buccal mucosa graft urethroplasty (BMGU). We found that NC is not worse than C regarding oral pain. In addition, time from BMGU and length of the buccal mucosa graft have effects on oral morbidity and complications.

Penalized nonparametric scalar-on-function regression via principal coordinates.

A number of classical approaches to nonparametric regression have recently been extended to the case of functional predictors. This paper introduces a new method of this type, which extends intermediate-rank penalized smoothing to scalar-on-function regression. In the proposed method, which we call principal coordinate ridge regression, one regresses the response on leading principal coordinates defined by a relevant distance among the functional predictors, while applying a ridge penalty. Our publicly available implementation, based on generalized additive modeling software, allows for fast optimal tuning parameter selection and for extensions to multiple functional predictors, exponential family-valued responses, and mixed-effects models. In an application to signature verification data, principal coordinate ridge regression, with dynamic time warping distance used to define the principal coordinates, is shown to outperform a functional generalized linear model.

Methods for scalar-on-function regression.

Recent years have seen an explosion of activity in the field of functional data analysis (FDA), in which curves, spectra, images, etc. are considered as basic functional data units. A central problem in FDA is how to fit regression models with scalar responses and functional data points as predictors. We review some of the main approaches to this problem, categorizing the basic model types as linear, nonlinear and nonparametric. We discuss publicly available software packages, and illustrate some of the procedures by application to a functional magnetic resonance imaging dataset.

Form follows function: Morphological and immunohistological insights into epithelial-mesenchymal transition characteristics of tumor buds.

In cancer biology, the architectural concept "form follows function" is reflected by cell morphology, migration, and epithelial-mesenchymal transition protein pattern. In vivo, features of epithelial-mesenchymal transition have been associated with tumor budding, which correlates significantly with patient outcome. Hereby, the majority of tumor buds are not truly detached but still connected to a major tumor mass. For detailed insights into the different tumor bud types and the process of tumor budding, we quantified tumor cells according to histomorphological and immunohistological epithelial-mesenchymal transition characteristics. Three-dimensional reconstruction from adenocarcinomas (pancreatic, colorectal, lung, and ductal breast cancers) was performed as published. Tumor cell morphology and epithelial-mesenchymal transition characteristics (represented by zinc finger E-box-binding homeobox 1 and E-Cadherin) were analyzed qualitatively and quantitatively in a three-dimensional context. Tumor buds were classified into main tumor mass, connected tumor bud, and isolated tumor bud. Cell morphology and epithelial-mesenchymal transition marker expression were assessed for each tumor cell. Epithelial-mesenchymal transition characteristics between isolated tumor bud and connected tumor bud demonstrated no significant differences or trends. Tumor cell count correlated significantly with epithelial-mesenchymal transition and histomorphological characteristics. Regression curve analysis revealed initially a loss of membranous E-Cadherin, followed by expression of cytoplasmic E-Cadherin and subsequent expression of nuclear zinc finger E-box-binding homeobox 1. Morphologic changes followed later in this sequence. Our data demonstrate that connected and isolated tumor buds are equal concerning immunohistochemical epithelial-mesenchymal transition characteristics and histomorphology. Our data also give an insight in the process of tumor budding. While there is a notion that the epithelial-mesenchymal transition zinc finger E-box-binding homeobox 1-E-Cadherin cascade is initiated by zinc finger E-box-binding homeobox 1, our results are contrary and outline other possible pathways influencing the regulation of E-Cadherin.

Pointwise influence matrices for functional-response regression.

We extend the notion of an influence or hat matrix to regression with functional responses and scalar predictors. For responses depending linearly on a set of predictors, our definition is shown to reduce to the conventional influence matrix for linear models. The pointwise degrees of freedom, the trace of the pointwise influence matrix, are shown to have an adaptivity property that motivates a two-step bivariate smoother for modeling nonlinear dependence on a single predictor. This procedure adapts to varying complexity of the nonlinear model at different locations along the function, and thereby achieves better performance than competing tensor product smoothers in an analysis of the development of white matter microstructure in the brain.

Two-way principal component analysis for matrix-variate data, with an application to functional magnetic resonance imaging data.

Many modern neuroimaging studies acquire large spatial images of the brain observed sequentially over time. Such data are often stored in the forms of matrices. To model these matrix-variate data we introduce a class of separable processes using explicit latent process modeling. To account for the size and two-way structure of the data, we extend principal component analysis to achieve dimensionality reduction at the individual level. We introduce necessary identifiability conditions for each model and develop scalable estimation procedures. The method is motivated by and applied to a functional magnetic resonance imaging study designed to analyze the relationship between pain and brain activity.

Can school counselors deliver cognitive-behavioral treatment for social anxiety effectively? A randomized controlled trial.

BACKGROUND: Social anxiety disorder (SAD) typically onsets in adolescence and is associated with multiple impairments. Despite promising clinical interventions, most socially anxious adolescents remain untreated. To address this clinical neglect, we developed a school-based, 12-week group intervention for youth with SAD, Skills for Academic and Social Success (SASS). When implemented by psychologists, SASS has been found effective. To promote dissemination and optimize treatment access, we tested whether school counselors could be effective treatment providers. METHOD: We randomized 138, ninth through 11th graders with SAD to one of three conditions: (a) SASS delivered by school counselors (C-SASS), (b) SASS delivered by psychologists (P-SASS), or (c) a control condition, Skills for Life (SFL), a nonspecific counseling program. Blind, independent, evaluations were conducted with parents and adolescents at baseline, post-intervention, and 5 months beyond treatment completion. We hypothesized that C-SASS and P-SASS would be superior to the control, immediately after treatment and at follow-up. No prediction was made about the relative efficacy of C-SASS and P-SASS. RESULTS: Compared to controls, adolescents treated with C-SASS or P-SASS experienced significantly greater improvement and reductions of anxiety at the end of treatment and follow-up. There were no significant differences between SASS delivered by school counselors and psychologists. CONCLUSION: With training, school counselors are effective treatment providers to adolescents with social anxiety, yielding benefits comparable to those obtained by specialized psychologists. Questions remain regarding means to maintain counselors' practice standards without external support.

Mode of Anisotropy Reveals Global Diffusion Alterations in Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Diffusion tensor imaging (DTI) can identify structural connectivity alterations in attention-deficit/hyperactivity disorder (ADHD). Most ADHD DTI studies have concentrated on regional differences in fractional anisotropy (FA) despite its limited sensitivity to complex white matter architecture and increasing evidence of global brain differences in ADHD. Here, we examine multiple DTI metrics in separate samples of children and adults with and without ADHD with a principal focus on global between-group differences. METHOD: Two samples: adults with ADHD (n = 42) and without (n = 65) and children with ADHD (n = 82) and without (n = 80) were separately group matched for age, sex, and head motion. Five DTI metrics (FA, axial diffusivity, radial diffusivity, mean diffusivity, and mode of anisotropy) were analyzed via tract-based spatial statistics. Group analyses tested for diagnostic differences at the global (averaged across the entire white matter skeleton) and regional level for each metric. RESULTS: Robust global group differences in diffusion indices were found in adults, with the largest effect size for mode of anisotropy (MA; Cohen's d = 1.45). Global MA also differed significantly between groups in the pediatric sample (d = 0.68). In both samples, global MA increased classification accuracy compared to the model with clinical Conners' ADHD ratings alone. Regional diagnostic differences did not survive familywise correction for multiple comparisons. CONCLUSION: Global DTI metrics, particularly the mode of anisotropy, which is sensitive to crossing fibers, capture connectivity abnormalities in ADHD across both pediatric and adult samples. These findings highlight potential diffuse white matter microarchitecture differences in ADHD.

Psychometric validation of a German language version of a PROM for urethral stricture surgery and preliminary testing of supplementary ED and UI constructs.

PURPOSE: To validate a German language version of the patient-reported outcome measurement (PROM) following urethral stricture surgery (USS) in a cohort of men undergoing one-stage buccal mucosa graft urethroplasty (BMGU) for urethral stricture. Furthermore, to explore the responsiveness of erectile function (EF) and urinary incontinence (UI) constructs in the context of this intervention. METHODS: The USS-PROM captures voiding symptoms (ICIQ-MLUTS) and health-related quality of life (HRQoL) (EQ-5D). To evaluate EF and UI, the IIEF-5 and ICIQ-UI SF were included. Between March 2012 and April 2013, all patients undergoing BMGU at our institution were prospectively enrolled in this study. Psychometric assessment included internal consistency, test-retest reliability, criterion validity and responsiveness. RESULTS: Ninety-three men completed the USS-PROM before and 3 months after surgery, with 40 (43 %) also completing the USS-PROM 6 months after surgery to assess reliability. Internal consistency: for the ICIQ-MLUTS, Cronbach's α was 0.83. The test-retest intraclass correlation coefficient was 0.94. There was a negative correlation between change in ICIQ-MLUTS total score and change in Q max (r = -0.40). All values exceeded our predefined thresholds. Significant improvements of voiding symptoms and HRQoL demonstrate responsiveness to change (all p values <0.001). While ICIQ-UI scores did not change (p > 0.05), IIEF-5 scores improved significantly (p = 0.048). CONCLUSIONS: The German language USS-PROM shows similar psychometric properties to the English language version. This instrument can be improved by assessing EF by the use of IIEF-5. Further studies with larger patient cohorts are needed to evaluate the significance of measuring UI in urethroplasty patients.

The ARTUS device: the first feasibility study in human cadavers.

INTRODUCTION: The aim was to perform a feasibility study of the new artificial sphincter device ARTUS in human cadavers. ARTUS is a new electro-mechanical device, which may prevent urethral damage due to a new working principle which is to perform only sequential pressure on successive parts of the urethra. MATERIAL AND METHODS: The implantation of the ARTUS device was performed in six cadavers (3 males, 3 females) with different body mass indices. Subsequently the basic operation data (operation time, cuff size, length of wires, complication) were assessed. RESULTS: The implantation of the ARTUS device is performed easily by the same technique which is commonly used for the AMS 800 implantation. The mean operation time was 20 minutes. The mean cuff size was 4.5 cm in male and 6 cm in female cadavers. The average length of the wires was 12 cm. The necessary subcutaneous pouch had to be bigger than the space used for the tubes of the AMS 800 device. The study is limited by its preclinical setting. CONCLUSIONS: Our results demonstrate that this new artificial urinary sphincter device can be easily implanted. The technical and surgical approaches are similar to those which are applied in the case of the AMS 800 device. Therefore experienced surgeons will be able to adapt their technique easily.