Prediction of Incontinence after Robot-Assisted Radical Prostatectomy: Development and Validation of a 24-Month Incontinence Nomogram.

Incontinence after robot-assisted radical prostatectomy (RARP) is feared by most patients with prostate cancer. Many risk factors for incontinence after RARP are known, but a paucity of data integrates them. Prospectively acquired data from 680 men who underwent RARP January 2008-December 2015 and met inclusion/exclusion criteria were queried retrospectively and then divided into model development (80%) and validation (20%) cohorts. The UCLA-PCI-Short Form-v2 Urinary Function questionnaire was used to categorize perfect continence (0 pads), social continence (1-2 pads), or incontinence (≥3 pads). The observed incontinence rates were 26% at 6 months, 7% at 12 months, and 3% at 24 months. Logistic regression was used for model development, with variables identified using a backward selection process. Variables found predictive included age, race, body mass index, and preoperative erectile function. Internal validation and calibration were performed using standard bootstrap methodology. Calibration plots and receiver operating curves were used to evaluate model performance. The initial model had 6-, 12-, and 24-month areas under the curves (AUCs) of 0.64, 0.66, and 0.80, respectively. The recalibrated model had 6-, 12-, and 24-month AUCs of 0.52, 0.52, and 0.76, respectively. The final model was superior to any single clinical variable for predicting the risk of incontinence after RARP.

The Two-Point Technique for Fluoroscopic-Guided Endoscopic Procedures in Urology: A Validation Study.

Introduction: The widespread use of diagnostic and therapeutic ionizing radiation raises concerns regarding excessive occupational and patient exposure. In this study, we test a novel fluoroscopic technique that has the potential to minimize radiation dose during urologic procedures. Materials and Methods: A prospective evaluation of all patients undergoing endoscopic urologic procedures in our institution was conducted. A "two-point technique (TPT)" is described in which the fluoroscope image intensifier (c-arm) is shifted between caudal and cephalad set points of the operative field. We wished to determine whether patient radiation exposure was lower with TPT than with a non-structured conventional technique, referred to as the cognitive fluoroscopic technique (CFT), in which the manipulation of the c-arm was at the discretion of the user. We obtained all clinical, radiographic, and fluoroscopic data of patients in the study period and used unpaired nonparametric statistical analysis of univariates entered stepwise into a logistic regression model. Results: A total of 106 endoscopic urologic procedures from January 2016 to November 2018 were reviewed. Forty-four (41.5%) cases were performed using TPT and 62 (58.5%) using CFT. The mean fluoroscopy time of TPT vs CFT was 71.1 (±60.8) seconds vs 104.5 (±91.6) seconds, respectively (p = 0.04), and the mean radiation dose on TPT vs CFT was 11.6 (±10.6) mGy vs 20.3 (±24.3) mGy, respectively (p = 0.03). TPT was an independent predictor of reduced operative room (OR) time and fluoro time (p < 0.05), while body mass index, age, and operator were not. Conclusion: The "TPT" helps reducing radiation dose and fluoroscopic time during endoscopic urologic procedures. The TPT is useful to lower radiation exposure to patients and OR staff.

Comparison of spinocerebellar ataxia type 3 mouse models identifies early gain-of-function, cell-autonomous transcriptional changes in oligodendrocytes.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a polyglutamine-encoding CAG repeat expansion in the ATXN3 gene. This expansion leads to misfolding and aggregation of mutant ataxin-3 (ATXN3) and degeneration of select brain regions. A key unanswered question in SCA3 and other polyglutamine diseases is the extent to which neurodegeneration is mediated through gain-of-function versus loss-of-function. To address this question in SCA3, we performed transcriptional profiling on the brainstem, a highly vulnerable brain region in SCA3, in a series of mouse models with varying degrees of ATXN3 expression and aggregation. We include two SCA3 knock-in mouse models: our previously published model that erroneously harbors a tandem duplicate of the CAG repeat-containing exon, and a corrected model, introduced here. Both models exhibit dose-dependent neuronal accumulation and aggregation of mutant ATXN3, but do not exhibit a behavioral phenotype. We identified a molecular signature that correlates with ATXN3 neuronal aggregation yet is primarily linked to oligodendrocytes, highlighting early white matter dysfunction in SCA3. Two robustly elevated oligodendrocyte transcripts, Acy3 and Tnfrsf13c, were confirmed as elevated at the protein level in SCA3 human disease brainstem. To determine if mutant ATXN3 acts on oligodendrocytes cell-autonomously, we manipulated the repeat expansion in the variant SCA3 knock-in mouse by cell-type specific Cre/LoxP recombination. Changes in oligodendrocyte transcripts are driven cell-autonomously and occur independent of neuronal ATXN3 aggregation. Our findings support a primary toxic gain of function mechanism and highlight a previously unrecognized role for oligodendrocyte dysfunction in SCA3 disease pathogenesis.

A knockin mouse model of spinocerebellar ataxia type 3 exhibits prominent aggregate pathology and aberrant splicing of the disease gene transcript.

Polyglutamine diseases, including spinocerebellar ataxia type 3 (SCA3), are caused by CAG repeat expansions that encode abnormally long glutamine repeats in the respective disease proteins. While the mechanisms underlying neurodegeneration remain uncertain, evidence supports a proteotoxic role for the mutant protein dictated in part by the specific genetic and protein context. To further define pathogenic mechanisms in SCA3, we generated a mouse model in which a CAG expansion of 82 repeats was inserted into the murine locus by homologous recombination. SCA3 knockin mice exhibit region-specific aggregate pathology marked by intranuclear accumulation of the mutant Atxn3 protein, abundant nuclear inclusions and, in select brain regions, extranuclear aggregates localized to neuritic processes. Knockin mice also display altered splicing of the disease gene, promoting expression of an alternative isoform in which the intron immediately downstream of the CAG repeat is retained. In an independent mouse model expressing the full human ATXN3 disease gene, expression of this alternatively spliced transcript is also enhanced. These results, together with recent findings in other polyglutamine diseases, suggest that CAG repeat expansions can promote aberrant splicing to produce potentially more aggregate-prone isoforms of the disease proteins. This report of a SCA3 knockin mouse expands the repertoire of existing models of SCA3, and underscores the potential contribution of alternative splicing to disease pathogenesis in SCA3 and other polyglutamine disorders.