Dysregulation of the chromatin environment leads to differential alternative splicing as a mechanism of disease in a human model of autism spectrum disorder.

Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants in ASD. Disruption of the chromatin environment leads to widespread dysregulation of gene expression, which is traditionally thought of as a mechanism of disease pathogenesis associated with ASD. Alternatively, alterations in chromatin dynamics could also lead to dysregulation of alternative splicing, which is understudied as a mechanism of ASD pathogenesis. The anticonvulsant valproic acid (VPA) is a well-known environmental risk factor for ASD that acts as a class I histone deacetylase inhibitor. However, the precise molecular mechanisms underlying defects in human neuronal development associated with exposure to VPA are understudied. To dissect how VPA exposure and subsequent chromatin hyperacetylation influence molecular signatures involved in ASD pathogenesis, we conducted RNA sequencing (RNA-seq) in human cortical neurons that were treated with VPA. We observed that differentially expressed genes (DEGs) were enriched for mRNA splicing, mRNA processing, histone modification and metabolism related gene sets. Furthermore, we observed widespread increases in the number and the type of alternative splicing events. Analysis of differential transcript usage (DTU) showed that exposure to VPA induces extensive alterations in transcript isoform usage across neurodevelopmentally important genes. Finally, we find that DEGs and genes that display DTU overlap with known ASD-risk genes. Altogether, these findings suggest that, in addition to differential gene expression, changes in alternative splicing correlated with alterations in the chromatin environment could act as an additional mechanism of disease in ASD.

Characteristics Contributing to Survival Differences Between Black and White Patients Following Cystectomy.

PURPOSE: Examine patient, tumor, and treatment characteristics effect on the disparity between black and white patients with muscle-invasive bladder cancer (MIBC) who undergo radical cystectomy (RC). METHODS: 1,286 black patients in the 2004 to 2016 National Cancer Database fit inclusion criteria. A tapered match was performed from 17,374 white patients sequentially matched to the black cohort on demographics (age, gender, insurance, income, education, county, diagnosis year), presentation (demographic variables, stage, grade, tumor size, Charlson score), and treatment (demographic and presentation variables, lymph node count, hospital volume, neoadjuvant chemotherapy [NAC], treatment delay), creating 3 matched cohorts. Chi-square and Kruskal-Wallis tests were used to compare cohorts. Kaplan-Meier analysis was used to compare 5-year overall survival (OS). RESULTS: 5-year OS rate was 40.4% and 35.6% for unmatched white and black cohorts (P < 0.001), respectively. Following demographics and presentation match, 5-year OS rate for white patients decreased to 39.2% (P = 0.003) and 39.10% (P = 0.019), respectively. After treatment match, 5-year OS rate decreased to 36.7% for white patient (P = 0.32). Following presentation match, 7.2% of black patients vs. 5.8% of white patients had treatment delay, and 10.1% of black patients vs. 11.2% of white patients received NAC. The treatment match resulted in a 0.3% difference between groups for treatment delay and NAC. CONCLUSIONS: Our analysis demonstrates that disparity between black and white patients with muscle-invasive bladder cancer exists in demographic-, presentation-, and treatment-related variables. Treatment variables may be a large contributing factor to survival disparities. Further research is needed to identify social, biological, and organizational inputs that contribute to these disparities.

Phantosmia Among Pediatric, Adolescent, and Young Adult Patients Receiving Proton Beam Therapy.

Purpose: Phantosmia, an underreported toxicity of brain radiation therapy (RT), is defined as an olfactory disorder resulting in a malodorous phantom smell. This study aimed to characterize the incidence of phantosmia in patients treated with intensity modulated proton therapy (IMPT). Methods and Materials: In this institutional review board-approved retrospective study, the electronic medical record of a pencil beam scanning-only proton center was queried for patients ≤39 years of age who received IMPT for primary intracranial, metastatic intracranial, skull base, nasopharyngeal or sinonasal neoplasms between August 2019 and December 2020. Patient, clinical, and phantosmia-related characteristics were collected. The olfactory region was defined to include the olfactory bulb and tract. Phantosmia severity was graded by intervention use (mild, no intervention; moderate, supportive treatment; severe, RT discontinuation). Results: Ninety-nine patients met the inclusion criteria. Twelve patients (12.1%) reported phantosmia. Patients described perceiving a "chlorine," "broccoli," "stale water," "metallic," or "noxious" smell. Of the patients who reported phantosmia, median age was 17 (12-33) years, 66.7% were male, and 91.7% had intracranial tumors. None of the patients had prior RT. Chemoradiotherapy treatment did not correlate with phantosmia development (odds ratio, 1.09; 95% confidence interval, 0.32-3.70; P = .90). Ten patients experienced accompanying toxicities, including taste changes (n = 3), vision disturbances (n = 5), and nausea/emesis (n = 7). Phantosmia was mild (n = 7) or moderate (n = 5). All patients completed their RT course. Sixty-seven percent received craniospinal irradiation (CSI) while 33% received focal brain RT, with the olfactory region receiving doses as low as 0.5 Gy. Notably, 8 of 27 patients who received CSI (30%) reported phantosmia (odds ratio, 7.66; 95% confidence interval, 2.07-28.34; P = .002). Conclusions: In the first-ever study examining radiation-induced phantosmia among children and young adults treated with IMPT, all affected patients received irradiation dose to the olfactory region. Physician awareness of phantosmia, especially in the context of CSI, may improve the patient experience and treatment compliance. A prospective study is needed to elucidate frequency, severity, and phantosmia mechanism.

The impact of discharge location on outcomes following radical cystectomy.

PURPOSE: Hospital readmission is associated with adverse outcomes and increased cost, and as such, has been identified as a metric for surgical quality and a target for shifts in health policy. However, the disposition of patients who undergo radical cystectomy for bladder cancer and the association between discharge locations and readmission rates is poorly understood. Understanding the patterns and characteristics of readmission after radical cystectomy will help inform discharge planning and expectations and may have long-term impacts on quality and cost of care delivery. We hypothesize that patients will have varying readmission rates based on their discharge location. MATERIALS AND METHODS: An observational analysis of the Nationwide Readmissions Database was performed for all patients who underwent elective radical cystectomy in 2016 to 2017. The patients were grouped by the following criteria: whether they were discharged home, home with care, or to a facility. Univariate analysis was performed using the Chi-square test for categorical variables and the Kruskal-Wallis test for continuous variables. A multivariable logistic regression was conducted to evaluate if discharge locations impact patient readmissions at 30- and 90-days. RESULTS: The final dataset included 4,947 patients discharged home with care, 2,127 patients discharged to home or self-care, and 1,232 patients discharged to a facility. Discharge to a facility was strongly associated with higher 30-day (OR 1.49, CI 1.26-1.76) and 90-day readmission rates (OR 1.46, CI 1.23-1.74). Additionally, home health care was strongly associated with increased 30-day readmission rates (OR 1.22, CI 1.08-1.37) relative to routine discharge home. CONCLUSIONS: Our analysis suggests that discharge location independently predicts readmission following RC. Further study with more granular patient- and system-level data may aid in identifying structural characteristics and processes that can reduce readmissions and their associated economic impact, while maintaining quality of care delivered.

Implementation of a nonopioid protocol following robot-assisted radical cystectomy with intracorporeal urinary diversion.

PURPOSE: The implementation of robot-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) for management of patients with muscle-invasive or high-risk noninvasive bladder cancer has increased in utilization over the last decade. Here, we seek to describe institutional opioid prescription and utilization patterns following implementation of a nonopioid (NOP) perioperative pain management protocol in patients who received RARC with ICUD. MATERIALS AND METHODS: The records of all patients who underwent RARC that utilized a NOP perioperative pain management protocol at a single academic institution from 2016 to 2020 were retrospectively reviewed. Descriptive statistical analyses were performed. For comparison, we included 74 consecutive patients who received the same NOP protocol with extracorporeal urinary diversion (ECUD). RESULTS: A total of 116 patients who received ICUD were included in our analysis. The median operation time for the ICUD group was 305 minutes (interquartile range [IQR]: 262-352). 12.1% (n = 14) of patients who underwent ICUD required narcotics during inpatient hospitalization. For these patients, the median morphine milligram equivalent requirement was 52.0 (IQR: 7.62-157). Additionally, only 12.1% (n = 14) of patients were prescribed opioids postoperatively at discharge. We identified that within 6 months of surgery only 5 (4.3%) patients required a second narcotic prescription. Furthermore, of patients who did not use mu-opioid blockers, a minority experienced postoperative ileus (15.7%, n = 16). 30- and 90-day all Clavien complication rates for patients were 44.8% (n = 52) and 49.1% (n = 57), respectively. Nineteen (16.4%) patients were readmitted within 30 days of discharge, of which none were pain related. When compared to ECUD, patients who received ICUD experienced similar complication and readmission rates. CONCLUSIONS: The implementation of a NOP protocol for patients undergoing RARC with ICUD allows for both decreased postoperative narcotic use and reduced need for narcotic prescriptions at discharge with acceptable complication and readmission rates.

Can anesthetics affect bladder cancer recurrence? Total intravenous versus volatile anesthesia in patients undergoing robot-assisted radical cystectomy: A single institution retrospective analysis.

BACKGROUND: Radical cystectomy is standard of care and part of a multidisciplinary approach for long-term survival in patients with muscle-invasive bladder cancer (MIBC) or high-grade non-MIBC. Recent data have suggested that anesthetic technique can affect long-term survival and recurrence in patients undergoing cancer related surgery. METHODS: The records of all patients who underwent robot-assisted radical cystectomy for high-risk non-MIBC or MIBC at a single academic institution from 2014 to 2020 were retrospectively reviewed. Patients were grouped according to whether they received total intravenous (TIVA) or volatile inhalation anesthesia (VIA). Univariable and multivariable cox proportional hazards models were used to compare hazard ratios for distant recurrence. Kaplan-Meier recurrence-free survival curves were constructed from the date of surgery to recurrence. RESULTS: A total of 231 patients were included, of which 126 (55%) received TIVA and 105 (45%) received VIA. Distant recurrence occurred in 8.7% and 26.7% of patients who received TIVA and VIA, respectively (P < 0.001). Kaplan-Meier analysis demonstrated significant improvement in distant recurrence-free survival with TIVA (log-rank P < 0.001). Multivariable analysis revealed a significant increase in recurrence risk with VIA (HR: 3.4, 95%CI: 1.5-7.7, P < 0.01) and increasing tumor pathological stage (pT2, pT3, pT4, all P < 0.05). CONCLUSIONS: The use of volatile inhalation anesthetics during robot-assisted radical cystectomy may be associated with an increased risk of distant recurrence. Further studies will be necessary to validate these findings.