Faculty Bibliography

Individual differences in perception are widespread. Considering inter-individual variability, synesthetes experience stable additional sensations; schizophrenia patients suffer perceptual deficits in, eg, perceptual organization (alongside hallucinations and delusions). Is there a unifying principle explaining inter-individual variability in perception? There is good reason to believe perceptual experience results from inferential processes whereby sensory evidence is weighted by prior knowledge about the world. Perceptual variability may result from different precision weighting of sensory evidence and prior knowledge. We tested this hypothesis by comparing visibility thresholds in a perceptual hysteresis task across medicated schizophrenia patients (N = 20), synesthetes (N = 20), and controls (N = 26). Participants rated the subjective visibility of stimuli embedded in noise while we parametrically manipulated the availability of sensory evidence. Additionally, precise long-term priors in synesthetes were leveraged by presenting either synesthesia-inducing or neutral stimuli. Schizophrenia patients showed increased visibility thresholds, consistent with overreliance on sensory evidence. In contrast, synesthetes exhibited lowered thresholds exclusively for synesthesia-inducing stimuli suggesting high-precision long-term priors. Additionally, in both synesthetes and schizophrenia patients explicit, short-term priors-introduced during the hysteresis experiment-lowered thresholds but did not normalize perception. Our results imply that perceptual variability might result from differences in the precision afforded to prior beliefs and sensory evidence, respectively.

BACKGROUND:Survival rates for highly invasive bladder cancer (BC) patients have been very low, with a 5-year survival rate of 6%. Accurate prediction of tumor progression and survival is important for diagnosis and therapeutic decisions for BC patients. Our study aims to develop an autophagy-related-gene (ARG) signature that helps to predict the survival of BC patients. METHODS:RNA-seq data of 403 BC patients were retrieved from The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) database. Univariate Cox regression analysis was performed to identify overall survival (OS)-related ARGs. The Lasso Cox regression model was applied to establish an ARG signature in the TCGA training cohort (N = 203). The performance of the 11-gene ARG signature was further evaluated in a training cohort and an independent validation cohort (N = 200) using Kaplan-Meier OS curve analysis, receiver operating characteristic (ROC) analysis, as well as univariate and multivariate Cox regression analysis. RESULTS:. The ARGs-derived high-risk bladder cancer patients exhibited significantly poor OS in both training and validation cohorts. The prognostic model showed good predictive efficacy, with the area under the ROC curve (AUCs) for 1-year, 3-year, and 5-year overall survival of 0.702 (0.695), 0.744 (0.640), and 0.794 (0.658) in the training and validation cohorts, respectively. A prognostic nomogram, which included the ARGs-derived risk factor, age and stage for eventual clinical translation, was established. CONCLUSION/CONCLUSIONS:We identified a novel ARG signature for risk-stratification and robust prediction of overall survival for BC patients.

In order to understand the transmission and virulence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is necessary to understand the functions of each of the gene products encoded in the viral genome. One feature of the SARS-CoV-2 genome that is not present in related, common coronaviruses is ORF10, a putative 38-amino acid protein-coding gene. Proteomic studies found that ORF10 binds to an E3 ubiquitin ligase containing Cullin-2, Rbx1, Elongin B, Elongin C, and ZYG11B (CRL2^ZYG11B). Since CRL2^ZYG11B mediates protein degradation, one possible role for ORF10 is to "hijack" CRL2^ZYG11B in order to target cellular, antiviral proteins for ubiquitylation and subsequent proteasomal degradation. Here, we investigated whether ORF10 hijacks CRL2^ZYG11B or functions in other ways, for example, as an inhibitor or substrate of CRL2^ZYG11B While we confirm the ORF10-ZYG11B interaction and show that the N terminus of ORF10 is critical for it, we find no evidence that ORF10 is functioning to inhibit or hijack CRL2^ZYG11B Furthermore, ZYG11B and its paralog ZER1 are dispensable for SARS-CoV-2 infection in cultured cells. We conclude that the interaction between ORF10 and CRL2^ZYG11B is not relevant for SARS-CoV-2 infection in vitro.

OBJECTIVE:Cerebral aneurysms in the pediatric population are rare and optimal treatment strategies are not as well characterized as in adults. The Pipeline embolization device (PED) is an endoluminal flow diverter that is commonly used to treat aneurysms in adults, but experience with this device in children is limited. The authors sought to further characterize PED use and outcomes in this specific population by performing both a systematic review of patient-level data from studies reporting the use of the PED to treat pediatric aneurysms and a retrospective review of their experience. METHODS:A systematic review of the PubMed, Embase, and Scopus databases was performed to identify studies reporting the use of the PED in pediatric patients (age ≤ 18 years). Disaggregated data regarding demographics, aneurysm characteristics, treatment, and outcomes were collected. Retrospective data from the authors' two institutions were also included. RESULTS:Thirty studies comprising patient-level data on 43 pediatric patients with 47 aneurysms were identified. An additional 9 patients with 9 aneurysms were included from the authors' institutions for a total of 52 patients with 56 aneurysms. The mean patient age was 11.1 years. Presentations included aneurysm rupture (17.3%) and symptomatic mass effect (23.1%). Aneurysms were located in the anterior circulation in 55.4% of cases, and 73.2% were described as nonsaccular. Imaging follow-up was available for 89.3% with a mean follow-up of 13.3 months. Aneurysm occlusion was reported in 75%, with 1 case each (1.8%) demonstrating significant in-stent stenosis and parent vessel occlusion. Clinical follow-up was reported in 90.4% with a mean follow-up of 14.7 months. Good functional outcomes (modified Rankin Scale score of 0-1 or Glasgow Outcome Scale score of 5) were reported in 65.4% of the total population. Two major complications were reported, including 1 death. CONCLUSIONS:Despite substantial differences in aneurysm location and type between published pediatric and adult patient populations treated with the PED, the use of the PED in the pediatric population appears to be safe. While the short-term effectiveness is also similar to that of adults, additional studies are needed to further characterize the long-term outcomes and better define the use of this device in pediatric patients.

OBJECTIVE:To evaluate the safety, tolerability, and pharmacokinetics of soticlestat, a first-in-class cholesterol 24-hydroxylase inhibitor, in adults with developmental and/or epileptic encephalopathies (DEE). METHODS:The study comprised a 30-day, randomized, double-blind, placebo-controlled phase (Part A), followed by a 55-day open-label phase (Part B) (ClinicalTrials.gov ID: NCT03166215) . In Part A, patients with DEE and at least one bilateral motor seizure during the 4-week prospective baseline period were randomized 4:1 to receive soticlestat or placebo, in addition to their usual antiseizure medication. In Part B, all patients received open-label soticlestat. Soticlestat doses were titrated according to tolerability to a maximum of 300 mg twice daily (BID). Safety evaluations included the incidence of treatment-emergent adverse events (TEAEs). Plasma soticlestat concentrations were measured at various times for determination of multiple-dose pharmacokinetics and 24S-hydroxycholesterol (24HC). Efficacy was assessed by evaluation of changes in seizure frequency from baseline. RESULTS:Eighteen patients (median age, 28.5 years) were enrolled and randomized, and 14 (78 %) completed the study. In Part A, TEAEs occurred in 71.4 % of soticlestat-treated patients and 100 % of placebo-treated patients. In Part B, the overall incidence of TEAEs was 68.8 %. In Part A, TEAEs that occurred in more than one patient in the soticlestat group were dysarthria (n = 3, 21.4 %), lethargy (n = 2, 14.3 %), upper respiratory tract infection (n = 2, 14.3 %), fatigue (n = 2, 14.3 %), and headache (n = 2, 14.3 %). Four patients discontinued treatment because of TEAEs, of whom two reported drug-related seizure clusters as serious TEAEs. There were no deaths. Pharmacokinetic analysis showed dose-dependent increases in systemic exposure and peak plasma soticlestat concentrations. At the end of Part B, the overall mean percent change from baseline in plasma 24HC was -80.97 %. Changes from baseline in median seizure frequency were +16.71 % and +22.16 % in the soticlestat and placebo groups, respectively, in Part A, and -36.38 % in all participants in Part B. CONCLUSION/CONCLUSIONS:Soticlestat was well tolerated at doses of up to 300 mg BID and was associated with a reduction in median seizure frequency over the study duration. Further studies are warranted to assess the possible efficacy of soticlestat as adjunctive therapy in patients with DEEs such as Dravet syndrome and Lennox-Gastaut syndrome.

Despite being cognitively intact, patients with Guillain Barre Syndrome are often unable to communicate. Because of this, goals-of-care decisions may need to be made by family members/surrogates. Here, I describe a patient with Guillain Barre Syndrome whose voice was initially stifled by dysarthria, then hypophonia, then intubation, but who ultimately managed to express herself and convey her wishes regarding goals-of-care.

OBJECTIVE:Cognitive deficits following a traumatic brain injury (TBI) are a leading cause of disability in young adults and there is a critical need for novel approaches to improve cognitive outcomes in TBI survivors. Transcranial direct current stimulation (tDCS) paired with cognitive remediation has emerged as a viable, cost-effective, noninvasive approach for treating cognitive impairments in a wide variety of neurological conditions. Here, we report the first case study utilizing remotely supervised tDCS (RS-tDCS) protocol paired with cognitive remediation in a 29-year-old man with persisting cognitive and emotional sequelae following TBI. METHOD/METHODS:Neuropsychological measures were administered before and after the patient completed 20 daily sessions of RS-tDCS (2.0 mA × 20 minutes, left anodal dorsolateral prefrontal cortex montage). During the daily stimulation period, he completed adaptive cognitive training. All treatment procedures were delivered at home and monitored in real time via videoconference with a study technician. RESULTS:Following 20 RS-tDCS and cognitive training sessions, he had significant improvements (>1 SD) on tests of attention and working memory, semantic fluency, and information processing speed. Mood was also improved. CONCLUSIONS:This is the first demonstration of at-home telerehabilitation with RS-tDCS and cognitive training to improve cognitive outcomes following TBI.