Network Analysis of Persistent Somatic Symptoms in Two Clinical Patient Samples.

OBJECTIVE: Previous attempts to group persistent somatic symptoms (PSSs) with factor-analytic approaches have obtained heterogeneous results. An alternative approach that seems to be more suitable is the network theory. Compared with factor analysis, which focuses on the underlying factor of symptoms, network analysis focuses on the dynamic relationships and interactions among different symptoms. The main aim of this study is to apply the network approach to examine the heterogeneous structure of PSS within two clinical samples. METHODS: The first data set consisted of n = 254 outpatients who were part of a multicenter study. The second data set included n = 574 inpatients, both with somatoform disorders. Somatic symptom severity was assessed with the Screening of Somatoform Disorder (SOMS-7T). RESULTS: Results indicate that there are five main symptom groups that were found in both samples: neurological, gastrointestinal, urogenital, cardiovascular, and musculoskeletal symptoms. Although patterns of symptoms with high connection to each other look quite similar in both networks, the order of the most central symptoms (e.g., symptoms with a high connection to other symptoms in the network) differs. CONCLUSIONS: This work is the first to estimate the structure of PSS using network analysis. A next step could be first to replicate our findings before translating them into clinical practice. Second, results may be useful for generating hypotheses to be tested in future studies, and the results open new opportunities for a better understanding for etiology, prevention, and intervention research.

Predicting optimal treatment outcomes using the Personalized Advantage Index for patients with persistent somatic symptoms.

Objective: Because individual patients with persistent somatic symptoms (PSS) respond differently to treatments, a better understanding of the factors that predict therapy outcomes are of high importance. Aggregating a wide selection of information into the treatment-decision process is a challenge for clinicians. Using the Personalized Advantage Index (PAI) this study aims to deal with this. Methods: Data from a multicentre RCT comparing CBT (N = 128) versus CBT enriched with emotion regulation training (ENCERT) (N = 126) for patients diagnosed with somatic symptom disorder were used to identify based on two machine learning approaches predictors of therapy outcomes. The identified predictors were used to calculate the PAI. Results: Five treatment unspecific predictors (pre-treatment somatic symptom severity, depression, symptom disability, health-related quality of life, age) and five treatment specific moderators (global functioning, early childhood traumatic events, gender, health anxiety, emotion regulation skills) were identified. Individuals assigned to their PAI-indicated optimal treatment had significantly lower somatic symptom severity at the end of therapy compared to those randomised to their non-optimal condition. Conclusion: Allowing patients to choose a personalised treatment seems to be meaningful. This could help to improve outcomes for PSS and reduce its high costs to the health care system.

Symptom change trajectories in patients with persistent somatic symptoms and their association to long-term treatment outcome.

OBJECTIVE: This study investigated symptom change trajectory for patients with persistent somatic symptoms (PSS) during psychotherapy and the association of these patterns with pre-treatment characteristics and long-term outcome. METHODS: Growth mixture modeling was used to identify trajectory curves in a sample of N = 210 outpatients diagnosed with PSS and treated either with conventional cognitive behavioral therapy (CBT) or CBT enriched with emotion regulation training (ENCERT). RESULTS: We identified three subgroups of patients with similar symptom change patterns over the course of treatment (a "no change," "strong response," and "slow change" subgroup). Higher initial anxiety symptoms were significantly associated with the no change and strong response subgroups; symptom-related disability in daily routine with no changes. Patients with a strong response had the highest proportion of reliable improvement at termination and at six-month-follow-up. CONCLUSION: Our results indicate that, instead of one common change pattern, patients with PSS respond differently to treatment. Due to the high association of symptom curves with long-term outcome, the identification and prediction of an individual's trajectory could provide important information for clinicians to identify non-responding patients that are at risk for failure. Selecting personalized treatment interventions could increase the effectiveness of psychotherapy.Trial registration: ClinicalTrials.gov identifier: NCT01908855..

Persistent myopathy despite release of partial obstruction: in vivo reversal of dysfunction and transcriptional responses using rapamycin.

Current and potential medical therapy for obstruction-induced myopathic bladder dysfunction (from benign prostatic hyperplasia or posterior urethral valves) focuses on symptoms. The persistent tissue pathology and dysfunction after release of obstruction is often deemed irreversible without any systematic therapeutic approaches. As rapamycin can attenuate bladder smooth muscle hypertrophy and dysfunction during the genesis of partial obstruction in vivo, we tested whether rapamycin could improve persistent function after release of obstruction (de-obstruction or REL). Female Sprague-Dawley rat bladders were partially obstructed (PBO) by suturing around both the urethra and a para-urethral steel rod, then removing the rod. One day prior to release of obstruction (preREL), voiding parameters and residual urine volume of preREL+future rapa, preREL+future veh groups were recorded. Release of obstruction (REL) was performed by suture removal following 6 weeks of PBO. For 4 more weeks after the de-obstruction, REL animals were randomized to rapamycin (REL+rapa) or vehicle (REL+veh). PBO for 6 weeks were used as positive controls. In shams, the urethra was exposed, but no suture tied. Voiding parameters and residual urine volume were measured prior to sacrifice of sham and REL+veh or REL+rapa, and PBO. Rapamycin efficacy was tested by pair-wise comparison of changes in individual voiding data from preREL+future veh or preREL+future rapa versus REL+veh or REL+rapa, respectively, as well as by comparisons of REL+veh to REL+rapa groups. Bladders were weighed and processed for a high-throughput QPCR array, and histopathology. Bladder/body mass ratios with PBO increased significantly and remained higher in the release phase in REL+veh animals. REL+rapa versus REL+veh improved residual volumes and micturition fractions toward sham levels. Three genes encoding extracellular proteins, BMP2, SOD3, and IGFBP7, correlated with functional improvement by Pearson's correlations. The promoters of these genes showed enrichment for several motifs including circadian E-boxes. While obstruction and REL augmented CLOCK and NPAS2 expression above sham levels, rapamycin treatment during release significantly blocked their expression. This experimental design of pharmaco-intervention during the de-obstruction phase revealed a novel pathway dysregulated during the clinically relevant treatment phase of obstructive bladder myopathy.

Longitudinal Changes of Cognitive Deficits and Treatment Outcome of Cognitive Behavioral Therapy for Major Depression.

ABSTRACT: The current study examined neuropsychological changes over the course of cognitive behavioral therapy (CBT) in outpatients with major depressive disorder and the influence of cognitive deficits as predictors of clinical outcome in depression. A neuropsychological test battery was carried out on depressed outpatients (N = 54) at the beginning and at the end of CBT. Small improvements were found in divided attention, figural memory, and processing speed from pre- to posttreatment. Cognitive deficits in executive functions before treatment predicted the clinical outcome at the end of CBT. The present study reveals that attention and memory deficits are most likely to improve over the course of treatment, whereas executive functions remain stable in the long term. Depressed patients with worse executive functions at the beginning of treatment seem to benefit more from long-term CBT therapy.

Turning a new "page": ways to decrease the number of pages after hours without compromising patient care

Background: Pages to house staff after hours, especially overnight, lead to interrupted sleep and fatigue the next day. Although some pages are urgent, others may not need an immediate response. In this study we aimed to identify unwarranted pages and to establish ways to reduce them. Methods: Over 2 months, all pages to the Department of Pediatric Urology at the Hospital for Sick Children in Toronto, Canada, during call hours were documented, including the assessment of the responding physicians of their medical necessity. After analyzing the reasons for inappropriate pages, we took several steps to try to reduce them without impairing patient care. One year later, pages were tracked again to evaluate the efficacy of our interventions. Results: In the initial measurement period, no calls from parents and approximately 50% of the in-hospital pages (15 of 36 pages from the wards, 27 of 49 pages from the emergency department, 17 of 31 pages requesting consultations, and 8 of 8 pages from the inhouse pharmacy and outside pharmacies) were considered medically urgent. The reasons for unwarranted pages were inconsistent parent teaching, lack of adequate triaging and prioritizing on the ward and lack of awareness of the structure of the on-call provisions among different services in the hospital. Several steps were taken to streamline the teaching of parents and nurses, standardize information, provide alternative means of communication within the hospital and restrict parents' access by phone to the urologist on call. One year later, the number of pages had decreased by 70%. Conclusion: Although physician coverage throughout the day and night is necessary for high-quality and safe patient care, communication with on-call physicians should be only for appropriate reasons. The provision of consistent teaching and alternative communication channels can improve patient care as well as decrease the number of after-hour pages.

Contexte: Les appels au personnel interne par téléavertisseur, surtout la nuit, perturbent le sommeil et entraînent de la fatigue le lendemain. Même si certains de ces appels sont urgents, d'autres ne nécessitent pas de réponse immédiate. Avec cette étude nous avons voulu identifier les appels par téléavertisseur qui sont injustifiés et trouver des façons d'en réduire le nombre. Méthodes: Sur une période 2 mois, nous avons documenté tous les appels par téléavertisseur adressés durant les heures de garde au service d'urologie pédiatrique de l'Hôpital SickKids de Toronto, au Canada, et demandé aux médecins y ayant répondu d'en évaluer le bien-fondé au plan médical. Après avoir analysé les raisons des appels jugés injustifiés, nous avons adopté plusieurs mesures pour en réduire le nombre sans compromettre les soins. Un an plus tard, nous avons de nouveau comptabilisé les appels par téléavertisseur pour mesurer l'efficacité de nos interventions. Résultats: Durant la période de mesure initiale, aucun appel des parents n'a été considéré médicalement urgent, tout comme environ 50 % des appels provenant de l'hôpital même (15 appels sur 36 des unités de soins, 27 appels sur 49 du service des urgences, 17 appels sur 31 pour des demandes de consultation et 8 appels sur 8 de la pharmacie de l'hôpital ou de pharmacies de l'extérieur). Les raisons des appels injustifiés étaient entre autres incohérence dans l'enseignement aux parents, triage et priorisation inadéquats à l'unité de soin et méconnaissance des différents services de l'hôpital quant à la structure et au fonctionnement du système de garde. Plusieurs mesures ont été prises pour simplifier l'enseignement aux parents et au personnel infirmier, standardiser l'information, fournir d'autres moyens de communication dans l'hôpital même et restreindre l'accès des parents à l'urologue de garde par téléphone. Un an plus tard, le nombre d'appels avait diminué de 70 %. Conclusion: Même si les médecins doivent être joignables jour et nuit pour assurer la qualité des soins et la sécurité des patients, les raisons de communiquer avec eux doivent être appropriées. Le rappel des consignes et le recours à d'autres canaux de communication peuvent améliorer les soins aux patients et réduire le nombre d'appels le soir et la nuit.

Cognitive Behaviour Therapy Complemented with Emotion Regulation Training for Patients with Persistent Physical Symptoms: A Randomised Clinical Trial.

INTRODUCTION: Persistent medically unexplained symptoms (MUS) are a major burden for health care. Cognitive behaviour therapy (CBT) is efficacious for patients with MUS, with small to medium effects. The current study investigates whether therapy outcomes of a CBT for MUS patients can be improved by complementing it with emotion regulation training. METHODS: In a multicentre trial 255 patients with at least three persisting MUS were randomised to 20 sessions of either conventional CBT (n = 128) or CBT complemented with emotion regulation training (ENCERT; n = 127). Somatic symptom severity and secondary outcomes were assessed at pre-treatment, therapy session 8, end of therapy, and 6-month follow-up. RESULTS: Linear mixed-effect models revealed medium to large effects in both study arms for almost all outcomes at the end of therapy and 6-month follow-up. ENCERT and CBT did not differ in their effect on the primary outcome (d = 0.20, 95% CI: -0.04 to 0.44). Significant time × group cross-level interactions suggested ENCERT to be of more benefit than conventional CBT for a few secondary outcomes. Moderator analyses revealed higher effects of ENCERT in patients with co-morbid mental disorders. DISCUSSION/CONCLUSIONS: Current findings are based on a representative sample. Results demonstrate that both CBT and ENCERT can achieve strong effects on primary and secondary outcomes in MUS patients. Our results do not indicate that adding a training in emotion regulation skills generally improves the effect of CBT across all patients with MUS. Large effect sizes of both treatments and potential specific benefits of ENCERT for patients with co-morbid mental disorders are discussed.

The role of therapist and patient in-session behavior for treatment outcome in exposure-based cognitive behavioral therapy for panic disorder with agoraphobia.

OBJECTIVE: There is a very limited amount of research on the relationship between therapist and patient in-session behavior and treatment outcome in cognitive behavioral therapy (CBT) for panic disorder with agoraphobia (PD/AG). Additionally, the findings tend to be inconclusive. This study investigates the association between therapist competence, adherence, patient interpersonal behavior, and therapeutic alliance and outcome in a low-control CBT setting by using comprehensive measures. METHODS: Twenty-six patients with PD/AG received 12 sessions of exposure-based CBT. With regard to the outcome, treatments were classified either as problematic or nonproblematic by means of distinct criteria. Two raters evaluated the in-session behavior. RESULTS: Patient interpersonal behavior was significantly associated with outcome at follow-up (r = 0.49). At posttreatment, the correlation did not reach significance ( r = 0.34). Competence, adherence, and alliance were not outcome associated. CONCLUSION: The findings emphasize the need for therapists to pay particular attention to patients' interpersonal behavior during treatment.

Impaired emotion processing and a reduction in trust in patients with somatic symptom disorder.

There is accumulating evidence for deficits in the perception and regulation of one's own emotions, as well as the recognition of others' emotions in somatic symptom disorder (SSD). However, investigations of SSD focusing on specific aspects of emotion processing and how these might interact are missing. We included 35 patients with SSD and 35 healthy controls who completed questionnaires on the perception and regulation of their own emotions, as well as experimental investigations of emotion recognition and trust. In line with previous studies, our results show that SSD patients in comparison to healthy controls have difficulties in the identification and description of own feelings (ηp2  = .381 and ηp2  = .315). Furthermore, we found that patients apply less cognitive reappraisal (ηp2  = .185) but tend to use more expressive suppression (ηp2  = .047). In contrast to previous studies, we found SSD patients to perform superior in emotion recognition, in particular for anger (d = 0.40). In addition, patients with SSD invested less in a trust game (d = 0.73). These results point to a higher sensitivity for negative emotions and less trust in others. Further, these findings suggest a dissociation between the ability to recognize one's own emotions versus others' emotions in SSD. Future interventions targeting emotion processing in SSD might focus on the identification of one's own emotions, prior to the training of emotion regulation.

Readiness to change as a moderator of therapy outcome in patients with somatoform disorders.

OBJECTIVE: A considerable amount of patients with somatoform disorders do not benefit from psychotherapy as much as expected. Our aim was to explore whether readiness to change moderates the relationship between the intensity of symptoms and therapy outcome in the early stages of psychotherapy. METHOD: 144 patients with somatoform disorders received an outpatient cognitive-behavioural intervention. Symptom intensity was measured with the Screening for Somatoform Disorders (SOMS-7). For readiness to change, a German modification of the Pain Stages of Change Questionnaire (PSOCQ) was used, which comprises four subscales (FF-STABS). Regression analyses were carried out, with baseline symptoms and the readiness to change subscales as predictors and symptom reduction as the outcome variable. RESULTS: Moderation analyses revealed significant interaction effects between baseline symptoms and the precontemplation subscale, as well as between baseline symptoms and the action subscale. For preparation and maintenance, no significant interaction effects were found. CONCLUSIONS: The results suggest that readiness to change is a variable that can be used to differentiate between patients, with low precontemplation and action scores indicating a better chance for positive outcome, even with high initial impairment. Rather than using readiness to change sum scores, the sub-aspects of this construct should be the subject of future research.

Cognitive Impairments in Unipolar Depression: The Impact of Rumination.

BACKGROUND: Major depressive disorder (MDD) is associated with impairments in several cognitive domains. People with depression also tend to focus on and think about their problems ("ruminate") more than people without depression. Recent studies indicate that depressive rumination is connected to cognitive impairments in MDD. However, there is little scientific understanding of the role of rumination in these deficits. SAMPLING AND METHODS: The current study examined the performance of 62 outpatients suffering from unipolar major depression with a low tendency to ruminate versus outpatients with a high tendency to ruminate using a neuropsychological battery covering the 5 cognitive domains: attention, memory, working memory, executive functions and processing speed. RESULTS: The results indicated that high ruminators show a lower performance than low ruminators with regard to processing speed and executive function tasks with low effect sizes. However, these findings were not significant after Bonferroni correction. Hierarchical linear regression revealed that the effect on processing speed could be partially attributed to rumination, but an effect on executive functions was not established. CONCLUSIONS: The current study is the first to systematically investigate the impact of rumination on cognitive impairments in MDD, exploring a broad range of cognitive domains. The results partially support the hypothesis that rumination has an impact on single cognitive domains and highlight the necessity for further investigations in order to generalize these findings.

[Dialectical Behavioral Therapy for Male Adolescents with Borderline Symptomatology]. / Dialektisch-Behaviorale Therapie für männliche Jugendliche mit Symptomen einer Borderline-Persönlichkeitsstörung.

Dialectical Behavioral Therapy for Male Adolescents with Borderline Symptomatology The efficacy of Dialectical Behavior Therapy for adolescents (DBT-A) in patients with borderline symptomatology has mainly been shown in female adolescents. However, male adolescents with borderline symptoms are characterized by more aggressive, disruptive, and antisocial behavior. Therefore, the efficacy of the DBT-A has to be investigated in male adolescents. The DBT-A manual was adopted for male adolescents in an inpatient setting. The program has been investigated using a pre-post design in seven male adolescents (on average 14 years of age) with an average of five borderline symptoms according to DSM-IV. Criteria for outcome are symptoms of psychopathology, emotion regulation, aggressive, and self-injurious behavior. After treatment a reduction in aggressive behavior (pre-post effect size d = 1.18) and an improvement in adaptive emotion regulation (d = 0.65) were shown. No improvement could be shown in general symptoms of psychopathology (d = 0.02). The results of these case studies of DBT-A in male adolescents are promising. However, further RCTs with larger sample sizes and a control group will be required.

Efficacy, safety, and tolerability of intravesically administered 0.1% oxybutynin hydrochloride solution in adult patients with neurogenic bladder: A randomized, prospective, controlled multi-center trial.

AIMS: To verify the efficacy, safety and tolerability of intravesical administration of 0.1% oxybutynin hydrochloride compared to its oral administration for treatment of neurogenic detrusor overactivity (NDO) in a randomized, prospective, controlled, open-label, multi-center trial in 35 adult patients. METHODS: NDO was confirmed within the previous 24 months by urodynamic studies (UDS). Group 1 (n = 18) received 10 ml 0.1% oxybutynin hydrochloride intravesically three times per day and group 2 (n = 17) 5 mg oxybutynin hydrochloride orally three times per day for a period of 28 days. Primary efficacy criterion was the change in the maximum bladder capacity between the beginning of the study and after 4 weeks as assessed by UDS. Adverse drug reactions (ADR) were collected and an evaluation of anticholinergic effects was conducted. RESULTS: The increase in maximum bladder capacity was 117 ml with intravesical application (P = 0.0002) versus 18 ml with the oral application (P = 0.51). The difference was statistically significant (P = 0.0086). ADR were reported by 10 (55.6%) of patients with intravesical administration, and by 14 (82.4%) of patients with oral administration. Significant differences in favor of the intravesical application were observed in ADR affecting vision (1/10 vs. 9/14), gastrointestinal tract (8/10 vs. 14/14), nervous system (2/10 vs. 8/14), and skin and subcutis (1/10 vs. 6/14). No serious adverse drug reactions were reported. CONCLUSIONS: This study demonstrates the efficacy and safety of intravesical 0.1% oxybutynin hydrochloride in the treatment of NDO with respect to the increase in maximum bladder capacity. Neurourol. Urodynam. 35:582-588, 2016. © 2015 Wiley Periodicals, Inc.

[Long-term outcome of disorder-specific group therapy for multisomatoform disorders: a 3-year follow-up study]. / Langzeitverlauf nach störungsorientierten Kurzgruppeninterventionen bei somatoformen Störungen mit multiplen Körperbeschwerden: Eine 3-Jahres-Katamnese

Little is known about the long-term effectiveness of disorder-specific group interventions for somatoform disorders. In total 128 patients with somatoform disorders who had participated in 2 different 8-week outpatient group programs (cognitive-behavioral therapy or progressive muscle relaxation) were questioned at baseline and at the end of treatment. On average, there was a follow-up after 6 months and after 3 -years (3-year follow-up response rate: 63.3%). Both interventions were combined for long-term analysis as there were no substantial differences. In 2.5% of cases a possible medical cause was found for complaints originally considered as somatoform. A short disorder-specific group intervention achieved small effect sizes (range: 0.14-0.40; ITT-sample range: 0.06-0.33) in the long term; about 30% of patients can be considered responders. Further efforts are needed to improve the treatment of patients with somatoform disorders.

Epigenetic insights to pediatric uropathology: Celebrating the fundamental biology vision of Tony Khoury.

INTRODUCTION: Many pediatric urology conditions affect putatively normal tissues or appear too commonly to be based solely on specific DNA mutations. Understanding epigenetic mechanisms in pediatric urology, therefore, has many implications that can impact cell and tissue responses to settings, such as environmental and hormonal influences on urethral development, uropathogenic infections, obstructive stimuli, all of which originate externally or extracellularly. Indeed, the cell's response to external stimuli is often mediated epigenetically. In this commentary, we highlight work on the critical role that epigenetic machinery, such as DNA methyltransferases (DNMTs), Enhancer of Zeste Polycomb Repressive Complex 2 Subunit (EZH2), and others play in regulating gene expression and cellular functions in three urological contexts. DESIGN: Animal and cellular constructs were used to model clinical pediatric uropathology. The hypertrophy, trabeculation, and fibrosis of the chronically obstructed bladder was explored using smooth muscle cell models employing disorganised vs. normal extracellular matrix (ECM), as well as a new animal model of chronic obstructive bladder disease (COBD) which retains its pathologic features even after bladder de-obstruction. Cell models from human and murine hypospadias or genital tubercles (GT) were used to illustrate developmental responses and epigenetic dependency of key developmental genes. Finally, using bladder urothelial and organoid culture systems, we examined activity of epigenetic machinery in response to non uropathogenic vs. uropathogenic E.coli (UPEC). DNMT and EZH2 expression and function were interrogated in these model systems. RESULTS: Disordered ECM exerted a principal mitogenic and epigenetic role for on bladder smooth muscle both in vitro and in CODB in vivo. Key genes, e.g., BDNF and KCNB2 were under epigenetic regulation in actively evolving obstruction and COBD, though each condition showed distinct epigenetic responses. In models of hypospadias, estrogen strongly dysregulated WNT and Hox expression, which was normalized by epigenetic inhibition. Finally, DNA methylation machinery in the urothelium showed specific activation when challenged by uropathogenic E.coli. Similarly, UPEC induces hypermethylation and downregulation of the growth suppressor p16INK4A. Moreover, host cells exposed to UPEC produced secreted factors inducing epigenetic responses transmissible from one affected cell to another without ongoing bacterial presence. DISCUSSION: Microenvironmental influences altered epigenetic activity in the three described urologic contexts. Considering that many obstructed bladders continue to display abnormal architecture and dysfunction despite relief of obstruction similar to after resection of posterior valves or BPH, the epigenetic mechanisms described highlight novel approaches for understanding the underlying smooth muscle myopathy of this crucial clinical problem. Similarly, there is evidence for an epigenetic basis of xenoestrogen on development of hypospadias, and UTI-induced pan-urothelial alteration of epigenetic marks and propensity for subsequent (recurrent) UTI. The impact of mechanical, hormonal, infectious triggers on genitourinary epigenetic machinery activity invite novel avenues for targeting epigenetic modifications associated with these non-cancer diseases in urology. This includes the use of deactivated CRISPR-based technologies for precise epigenome targeting and editing. Overall, we underscore the importance of understanding epigenetic regulation in pediatric urology for the development of innovative therapeutic and management strategies.

Rapamycin attenuates bladder hypertrophy during long-term outlet obstruction in vivo: tissue, matrix and mechanistic insights.

PURPOSE: Previous molecular studies showed that the mTOR inhibitor rapamycin prevents bladder smooth muscle hypertrophy in vitro. We investigated the effect of rapamycin treatment in vivo on bladder smooth muscle hypertrophy in a rat model of partial bladder outlet obstruction. MATERIALS AND METHODS: A total of 48 female Sprague-Dawley® rats underwent partial bladder outlet obstruction and received daily subcutaneous injections of rapamycin (1 mg/kg) or vehicle commencing 2 weeks postoperatively. A total of 36 rats underwent sham surgery and received rapamycin or vehicle. Rats were sacrificed 3, 6 and 12 weeks after surgery. Before sacrifice, voiding was observed in a metabolic cage for 24 hours. Bladder-to-body weight in gm bladder weight per kg body weight and post-void residual urine were assessed. We evaluated Col1a1, Col3a1, Eln and Mmp7 mRNA expression and histology. Two-factor ANOVA and the post hoc t test were applied. RESULTS: Bladder outlet obstruction caused a significant increase in bladder weight in all obstructed groups. Three weeks postoperatively (1 week of treatment) there was no difference in the bladder-to-body weight ratio in the obstructed group. However, at 6 and 12 weeks (4 and 10 weeks of treatment, respectively) the bladder-to-body weight ratio of rats with obstruction plus rapamycin was significantly lower than that of rats with obstruction plus vehicle. Post-void residual urine volume after 6 and 12 weeks of obstruction was lower in obstructed rats with rapamycin compared to that in obstructed rats with vehicle. Rapamycin decreased the obstruction induced expression of Col1a1, Col3a1, Eln and Mmp7. CONCLUSIONS: Rapamycin prevents mechanically induced hypertrophy in cardiovascular smooth muscle. In vivo mTOR inhibition may attenuate obstruction induced detrusor hypertrophy and help preserve bladder function.

Contralateral testicular hypertrophy is associated with a higher incidence of absent testis in children with non-palpable testis.

BACKGROUND AND OBJECTIVE: The objective of our study is to examine the impact of monorchism on contralateral testicular size in children with non-palpable testis (NPT). Enhanced contralateral testicular volume or longitudinal diameter (length) serves as a predictor of monorchism. In the present study, we assessed the ability of ultrasound measured enlarged contralateral testicular length for predicting monorchism (and hence a testicular nubbin) in children with NPT. Furthermore, we evaluated the general prevalence of viable versus non-viable testes in patients referred to our institution with unilateral undescended testis between 2005 and 2020. STUDY DESIGN: We analysed the records of 54 patients who underwent diagnostic laparoscopy for NPT between 2005 and 2020 in a European tertiary care centre. Testicular lengths (longitudinal diameter) and testicular volume of the contralateral testis, as well as surgeon (surgeon 1 vs surgeon 2 vs others) and age at surgery (months) were assessed and stratified according to intraoperative findings (presence or absence of a testicular nubbin). Testicular length and volume were evaluated by ultrasound examination in office prior to surgery. Chi-square and t-test for descriptive analyses as well as uni- and multivariable logistic regression analyses were performed using R Version 3.1.0 (R Project for Statistical Computing, www.R-project.org). RESULTS: A total of 15 children presented with viable testes and 39 patients with testicular nubbin. Mean age was 20.5 months in the overall cohort and 22.6 vs 19.7 months in children with viable testis vs testicular nubbin (p = 0.4). In patients with presence of a testicular nubbin, the contralateral testis was larger (median length 17 mm (16-19.2)) as compared to patients with a viable testis (median length 15 mm (14-17), p = 0.001). Similarly, contralateral testicular volume was lower in patients with a present viable testis (0.6 ccm vs 0.8 ccm; p < 0-001). This effect remained statistically significant when logistic regression analyses were adjusted for age and weight at surgery, year of surgery, surgeon, and laterality. OR (odds ratio) for presence of a testicular nubbin was 1.6 (per mm) [95% CI (confidence interval) 1.13-2.17; p = 0.007]. CONCLUSION: Patients with preoperative increased length and volume of the contralateral testis in the ultrasound examination are at significantly higher risk of monorchism than their counterparts with lower testicular length. This should be emphasized during counselling of the parents prior to surgery. In our experience parents cope more easily with the diagnosis of monorchism, once this has already been discussed and explained thoroughly prior to surgery.

EZH2 and matrix co-regulate phenotype and KCNB2 expression in bladder smooth muscle cells.

BACKGROUND: Partial bladder outlet obstruction (PBO) is a widespread cause of urinary dysfunction and patient discomfort, resulting in immense health care costs. Previously, we found that obstruction is associated with altered regulation of epigenetic machinery and altered function. Here we examined if PBO and chronic bladder obstructive disease (COBD) affect epigenetic marks in a proof of principle gene and explored mechanisms of its epigenetic regulation using in vitro models. METHODS: Archival obstruction tissues from COBD had been created in 200-250 g female Sprague-Dawley rats by surgical ligation of the urethra for 6 weeks, followed by removal of the suture and following animals for 6 more weeks. Obstruction (PBO) is the 6-week ligation only. Sham ligations comprise passing the suture behind the urethra. Histone3 lysine27 trimethylation (H3K27me3) was studied by immunostaining and Chromatin immunoprecipitation (ChIP)/PCR. The interaction of matrix with KCNB2 regulation was studied in human bladder SMC plated on damaged matrix and native collagen and treated with vehicle or UNC1999. Cells were analyzed by immunostaining for cell phenotype, and western blotting for KCNB2, H3K27me3 and EZH2. Effects of conditioned media from these cells were also examined on cell phenotype. siRNA against KCNB2 was examined for effects on cell phenotype and gene expression by RT-qPCR. RESULTS: H3K27me3 increased by immunofluorescence during PBO, and by ChIP/PCR during COBD in the CpG Island (CGI) as well as 350 bp upstream. Obstruction vs. sham also showed an increase in H3K27me3 deposition. In SMC in vitro, EZH2 inhibition restored KCNB2 expression and partially restored SMC phenotype. CONCLUSIONS: Regulation of KCNB2 at the promoter demonstrated dynamic changes in H3K27me3 during COBD and obstruction. In vitro models suggest that matrix plays a role in regulation of EZH2, H3K27me3 and KCNB2, which may play a role in the regulation of smooth muscle phenotype in vivo.

Serious and Fatal Complications after Neonatal Circumcision.

Neonatal circumcision (NNC) is the most frequently performed surgical procedure worldwide and is generally considered safe in Western societies. Deaths attributed to NNC are seldom reported and are mostly explained by lack of adherence to medical standards. We reviewed our emergency department database for circumcision-related emergency admissions. During 2000-2013, 19 previously healthy neonates were admitted for acute complications after circumcision. Four were admitted for bleeding, with hemophilia identified in two cases and von Willebrand disease in one. Eight boys required emergency surgery, three for severe bleeding. Four boys with amputation of the glans underwent immediate surgical reconstruction. One infant was taken to the operating room to remove an obstructing Plastibell ring. Seven boys were admitted to the intensive care unit with severe bleeding or sepsis, three of whom ultimately progressed to hemorrhagic or septic shock. Two of these children died of their complications. We estimate that the annual incidence of severe complications requiring hospitalization after NNC in the Greater Toronto Area was approximately 0.01%, and the incidence of fatalities over the 14-yr review period was approximately 0.0012%. Our results indicate that the risk of serious complications and death as a result of NNC is greater than generally assumed.

A comparison of patient and parental experiences and diagnostic quality of suprapubic versus transurethral voiding cystourethrogram in children.

INTRODUCTION: Voiding cystourethrogram (VCUG) used in the radiologic evaluation of the upper and lower urinary tract can be performed by suprapubic puncture (SP) or by transurethral catheterization (TC). Data on which instillation technique is superior are scarce. VCUG tends to be a distressing procedure for both parents and children. METHODS: We evaluated the experience of VCUG analyzing 417 families with focus on contrast medium instillation in groups of single and repeated VCUGs and assessed quality and complication rate. The median age of children who had undergone VCUG was 38.6 months (0 - 159 months). Satisfaction with informed consent (IC), degree of fear and pain in parents and children prior and during VCUG were recorded. VCUG was compared to blood withdrawal and vaccination. RESULTS: Satisfaction with IC was higher for repeated VCUG (p= 0.024) which resulted in a lower degree of fear in parents and children. The fear of children during VCUG was lower when SP was performed rather than TC. This was in contrast to parental fear of SP (all p< 0.05). In repeated VCUGs, children who underwent SP were less afraid. Better diagnostic quality was more commonly reported with SP, yet the complication rate was higher (p=0.035). CONCLUSIONS: Our study highlights the importance of IC as a pivotal necessity before VCUG is conducted. SP might be beneficial over TC in terms of fear and distress in the case of repeated VCUGs. Diagnostic quality is comparable, both methods are safe and complications are low.