Rapid onset severe hyperkalemia during robotic radical cystectomy: a case report.

Radical cystectomy is a preferred treatment for muscle-invasive bladder cancer.  Despite known complications, rapid onset, severe hyperkalemia necessitating abortion of surgery has not been reported.  In this case report, a patient with end stage renal disease (ESRD) undergoing attempted cystectomy developed severe intraoperative hyperkalemia and acidosis that led to abortion of surgery and transfer to the medical intensive care unit for emergent hemodialysis.  The multifactorial etiology was related to respiratory acidosis, ESRD, patient positioning, clipping of ureters, and body habitus, as well as an idiopathic element.  Knowledge of hyperkalemia etiologies can assist in diagnosis and treatment of this serious condition.

Opioid prescription following radical orchiectomy associated with new persistent opioid use.

INTRODUCTION: Opioid dependence represents a public health crisis and can be observed after outpatient urologic procedures. The purpose of this study was to evaluate the risk of persistent opioid usage after radical orchiectomy for testicular cancer. MATERIALS AND METHODS: The TriNetX Research network database was queried for men between 15 and 45 years undergoing radical orchiectomy for a diagnosis of testicular cancer. All patients with N+ or M+ disease, prior opioid use, and patients who underwent chemotherapy, radiotherapy, or retroperitoneal lymph node dissection were excluded. Patients were stratified whether they were prescribed opioids or not at time of orchiectomy. The incidence of new, persistent opioid use, defined as a prescription for opioids between 3 and 15 months after orchiectomy, was evaluated. RESULTS: A total of 2,911 men underwent radical orchiectomy for testicular cancer, of which 89.8% were prescribed opioids at time of orchiectomy. After propensity score matching for age, race, and history of psychiatric diagnosis, 592 patients were included (296 received opioids, 296 did not). Overall, 0% of patients who did not receive postoperative opioids developed new persistent opioid use, whereas 10.5% of patients who received postoperative opioids developed new persistent opioid use. Patients prescribed postoperative opioids for orchiectomy had statistically higher risk difference of developing new persistent opioid use (Risk Difference: 10.5%; 95% CI: 7.0-14.0; Z: 5.7; P < 0.01). CONCLUSIONS: Postoperative opioid prescription following radical orchiectomy is significantly associated with developing new persistent opioid use, with 1 in 10 young men who received postoperative opioids obtaining a new prescription for opioids well beyond the postoperative period. Future efforts should emphasize nonopioid pathways for pain control following this generally minor procedure.

Observational cohort study of long-term outcomes of liver transplantation in haemophilia.

INTRODUCTION: Gene therapy is now a reality for individuals with haemophilia, yet little is known regarding the quality-of-life impact of factor correction. As few data exist, and recognizing the analogy to liver transplantation (OLTX), we identified OLTX+ and OLTX- men in the ATHNdataset to compare post-OLTX factor VIII and IX on quality of life (QoL) by Haem-A-QoL and PROMIS-29. METHODS: OLTX- were matched to OLTX+ by age, race, and haemophilia type and severity. Deidentified demographic data, including post-transplant factor levels, genotype and target joint disease were analysed by descriptive statistics. Haem-A-Qol and PROMIS-29 were compared in OLTX+ and OLTX- by student's t-test and univariate regression models. RESULTS: Of 86 people with haemophilia A (HA) or haemophilia B (HB) cared for at 10 haemophilia treatment centers (HTCs), 21 (24.4%) OLTX+ and 65 (75.6%) OLTX- were identified. OLTX+ and OLTX- had a similar frequency of target joint disease (p = .806), HA genotypes, null versus non-null (p = .696), and HIV infection (p = .316). At a median 9.2 years post-OLTX, median FVIII, .63 IU/mL [IQR 0.52-0.97] and FIX, .91 IU/mL [IQR .63-1.32], Haem-A-QoL, PROMIS-29, and HOT scores were comparable. Severe HA/HB had lower post-OLTX 'dealing with haemophilia' scores (p = .022) and higher 'sports and leisure' (p = .010) and 'view of yourself' scores (p = .024) than OLTX+ non-severe participants. Non-caucasian OLTX+ had significantly lower scores in sports and leisure (p = .042), future expectations (p = .021) and total score (p = .010). CONCLUSION: Nine years after OLTX, QoL is comparable to OLTX-, but significantly better in OLTX+ with severe than non-severe disease and in caucasians than non-caucasians.

A systematic review of pN0 testicular seminoma: a new clinical entity and future directions.

Retroperitoneal lymph node dissection (RPLND) for testicular seminoma with enlarged retroperitoneal lymph nodes has received increased consideration and exposed a new clinical entity: pN0 disease. Enlarged, nonmetastatic retroperitoneal lymph nodes provide insight into the natural history of seminoma while offering a benchmark for improving the accuracy of staging. The purpose of this systematic review was to report the pN0 rates, describe risk factors associated with it, and discuss emerging research that may reduce its incidence. We performed a systemic review of published literature on PubMed, Embase, Web of Science, as well as oncology meeting abstracts evaluating histology of lymph nodes in patients with testicular seminoma treated primarily with retroperitoneal lymph node dissection. Studies were excluded if histology was not reported. A total of 15 publications and abstracts were included. Although study designs were heterogeneous, there was a minimal risk of bias. Overall, the reported pN0 rates were 0% to 22%. In prospective clinical trials it was 9% to 16%. The presence of pN0 was associated with preoperative smaller lymph nodes, a solitary enlarged lymph node, or negative serum miRNA-371. The incidence of pN0 seminoma is concerning as it points to a potential historical overtreatment; however, it also represents an important inflection for testicular cancer research as quantifiable improvements in clinical staging will translate to clear benefits to patients.

Treatment of Low-grade Intermediate-risk Nonmuscle-invasive Bladder Cancer With UGN-102 ± Transurethral Resection of Bladder Tumor Compared to Transurethral Resection of Bladder Tumor Monotherapy: A Randomized, Controlled, Phase 3 Trial (ATLAS).

PURPOSE: Low-grade intermediate-risk nonmuscle-invasive bladder cancer is a chronic illness commonly treated by repetitive transurethral resection of bladder tumor. We compared the efficacy and safety of intravesical chemoablation with UGN-102 (a reverse thermal gel containing mitomycin), with or without subsequent transurethral resection of bladder tumor, to transurethral resection of bladder tumor alone in patients with low-grade intermediate-risk nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: This prospective, randomized, phase 3 trial recruited patients with new or recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer to receive initial treatment with either UGN-102 once weekly for 6 weeks or transurethral resection of bladder tumor. Patients were followed quarterly by endoscopy, cytology, and for-cause biopsy. The primary end point was disease-free survival. All patients were followed for adverse events. RESULTS: Trial enrollment was halted by the sponsor to pursue an alternative development strategy after 282 of a planned 632 patients were randomized to UGN-102 ± subsequent transurethral resection of bladder tumor (n=142) or transurethral resection of bladder tumor monotherapy (n=140), rendering the trial underpowered to perform hypothesis testing. Patients were predominantly male and ≥65 years of age. Tumor-free complete response 3 months after initial treatment was achieved by 92 patients (65%) who received UGN-102 and 89 patients (64%) treated by transurethral resection of bladder tumor. The estimated probability of disease-free survival 15 months after randomization was 72% for UGN-102 ± transurethral resection of bladder tumor and 50% for transurethral resection of bladder tumor (hazard ratio 0.45). The most common adverse events (incidence ≥10%) in the UGN-102 group were dysuria, micturition urgency, nocturia, and pollakiuria. CONCLUSIONS: Primary, nonsurgical chemoablation with UGN-102 for the management of low-grade intermediate-risk nonmuscle-invasive bladder cancer offers a potential therapeutic alternative to immediate transurethral resection of bladder tumor monotherapy and warrants further investigation.

Factor activity levels and bleeding scores in pediatric hemophilia carriers enrolled in the ATHNdataset.

BACKGROUND: Multiple studies have now shown that a significant proportion of hemophilia carriers meet the criteria for having hemophilia and/or report abnormal bleeding. However, to date, investigations of hemophilia carriers have almost exclusively involved women over 18 years of age. Little is known about factor activity levels and bleeding scores in carriers during childhood. We queried a large deidentified database of subjects with bleeding disorders residing in the United States to determine factor activity levels and bleeding scores. PROCEDURES: The ATHNdataset was queried for hemophilia carriers under 18 years of age. Collected information included demographics, factor activity levels, and bleeding scores. RESULTS: Over 700 carriers in the pediatric age group were identified, of which 626 submitted factor activity levels. Nearly half had factor activity levels less than 40 IU/dL, thereby meeting criteria for having hemophilia. Of those reporting bleeding scores, only 13.5% reported an abnormal bleeding score for age. The proportion reporting abnormal bleeding scores was higher in those with factor levels less than 40 IU/dL (23%) than those greater than 40 IU/dL (9.7%). CONCLUSIONS: The proportion of pediatric carriers with hemophilia was double of that previously reported for adults. Of those with hemophilia reporting a bleeding score, the majority (77%) did not report an abnormal bleeding score for age. However, nearly 10% of pediatric carriers not meeting criteria for having hemophilia reported abnormal bleeding scores for age. Similar results are reported in adults suggesting that factor activity levels may not be predictive of bleeding symptoms in carriers.

Metastatic Testicular Cancer Patterns and Predictors: A Contemporary Population-based SEER Analysis.

OBJECTIVE: To elucidate clinical and demographic predictors of metastatic testicular cancer (TC) at presentation and study the impact of these factors on prognosis. Patients with metastatic TC experience poorer outcomes than those with localized or locoregional disease. Social determinants of health may compound this trend. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried to identify 16,528 patients aged ≥18 with TC diagnosed from 2010 to 2016. Descriptive statistics were analyzed using Fisher exact test and Pearson chi-square test for continuous and categorical variables. Predictors of specific metastases and factors impacting cancer-specific mortality (CSM) were evaluated using multivariate logistic regression analysis and competing risks regression, respectively. RESULTS: Of 16,474 patients with complete data, 1877 (11.39%) had distant metastases at diagnosis. These patients more commonly featured disease-specific and demographic variables associated with worse health outcomes (all P < .001). Lung metastases were the predominant site of synchronous and solitary metastases. Disease-specific predictors of metastasis included T stage, histology, tumor size, lymphovascular invasion, and cryptorchidism. Patient-specific predictors included age, geography, ethnicity, race, marital status, and socioeconomic status. Nearly one-fourth of patients with metastases died. Poor CSM was predicted by histology, age, insurance status, and socioeconomic status. All metastatic sites except bone were associated with worse CSM, with lung metastases conferring the greatest risk. CONCLUSION: This cross-sectional study identifies variables associated with TC metastasis and survival, particularly highlighting the importance of social determinants of health in TC mortality. These findings can facilitate a risk-stratified approach to staging and management while supporting new approaches to target disparities.

Multimodal Pain Control Utilizing Buprenorphine for Robotic-assisted Laparoscopic Prostatectomy: A Quality Improvement Comparison to Conventional Opioid Management.

INTRODUCTION: This study investigated the effectiveness of buprenorphine as an alternative to the use of conventional opioids perioperatively in an effort to help mitigate the impact of the use of perioperative conventional opioids for patients undergoing robotic-assisted laparoscopic prostatectomy. METHODS: Outcomes of patients with localized prostate cancer undergoing robotic-assisted laparoscopic prostatectomy were examined before and after implementation of novel quality improvement study that included receiving buprenorphine compared to conventional opioids for pain control intraoperatively and postoperatively. The primary end point was adequate pain control with secondary end points being analgesic consumption at home, opioid-related side effects, and patient satisfaction. RESULTS: When analyzing the secondary end point of oral morphine milligram equivalents, the buprenorphine group received significantly less morphine milligram equivalent compared to the conventional opioid group (15.19 vs 47.91, P = .006). The buprenorphine group also had lower reported pain scores at discharge (4.3; scale 1-10) compared to the conventional opioid group (5.4), though this did not reach significance (P = .069). In the buprenorphine group, 76.9% strongly agreed that their pain was adequately controlled in the hospital compared to 57.5% of the conventional opioid group (P = .223). There was no difference in overall satisfaction at postoperative day 5 (P = .358). CONCLUSIONS: Our study demonstrates buprenorphine's analgesic capabilities to maintain adequate pain control and patient satisfaction compared to conventional opioids during robotic-assisted laparoscopic prostatectomy, while decreasing perioperative opioid use.

The patient experience with localized upper tract urothelial cancer.

OBJECTIVE: To understand the experiences of patients with low-grade upper tract urothelial carcinoma via in-depth interviews covering the diagnosis, treatment, and follow-up. METHODS: A qualitative study was performed using 60 minutes interviews with patients diagnosed with low-grade UTUC. The participants received either endoscopic treatment (ET), radical nephroureterectomy (RNU) or intracavity mitomycin gel for the pyelocaliceal system. Interviews were conducted by trained interviewers via telephone using a semi-structured questionnaire. The raw interviews were coded into discrete phrases that were grouped together based on similarity of meaning. Inductive data analysis methodology was used. Themes were identified and refined to overarching themes striving to encompass the original meaning and intent of participant's words. RESULTS: Twenty individuals were enrolled; 6 were treated with ET, 8 were treated with a RNU, and 6 were treated with intracavitary mitomycin gel. The median age was 74 years (52-88) and half of participants were women. Most endorsed good, very good, or excellent health. Four unique themes were identified: 1. Misunderstandings of the nature of disease; 2. Importance of physical symptoms during treatment as a proxy for recovery; 3. Competing desires for kidney preservation versus expeditious treatment; and 4. Trust in doctors and minimal perceived shared decision-making. CONCLUSIONS: Low grade UTUC is a disease with a diverse clinical presentation and an evolving landscape of available treatments. This study provides insight into patients' perspective and can help guide counseling and treatment selection.

Surgery in Early Metastatic Seminoma: A Phase II Trial of Retroperitoneal Lymph Node Dissection for Testicular Seminoma With Limited Retroperitoneal Lymphadenopathy.

PURPOSE: The long-term toxicities of chemotherapy and radiotherapy can represent a significant burden to testicular cancer survivors. Retroperitoneal lymph node dissection (RPLND) is an established treatment for testicular germ cell tumors with minimal late morbidity although little data exist on its efficacy in early metastatic seminoma. Surgery in early metastatic seminoma is a prospective phase II single-arm, multi-institutional trial of RPLND as first-line treatment for testicular seminoma with clinically low-volume retroperitoneal lymphadenopathy. PATIENTS AND METHODS: Twelve sites in the United States and Canada prospectively enrolled adult patients with testicular seminoma and isolated retroperitoneal lymphadenopathy (1-3 cm). Open RPLND was performed by certified surgeons with a primary end point of 2-year recurrence-free survival (RFS). Complication rates, pathologic up/downstaging, recurrence patterns, adjuvant therapies, and treatment-free survival were assessed. RESULTS: A total of 55 patients were enrolled, with a median (IQR) largest clinical lymph node size of 1.6 cm (1.3-1.9). RPLND pathology demonstrated a median (IQR) largest lymph node size of 2.3 cm (0.9-3.5); nine patients (16%) were pN0, 12 (22%) pN1, 31 (56%) pN2, and 3 (5%) pN3. One patient received adjuvant chemotherapy. With a median (IQR) follow-up of 33 months (12.0-61.6), 12 patients experienced recurrence, with a 2-year RFS of 81% and a recurrence rate of 22%. Of the patients who experienced recurrence, 10 were treated with chemotherapy and two underwent additional surgery. At last follow-up, all patients who experienced a recurrence were disease-free and the 2-year overall survival was 100%. Four patients (7%) experienced short-term complications, and four patients experienced long-term complications including incisional hernia (1) and anejaculation (3). CONCLUSION: RPLND is a treatment option for testicular seminoma with clinically low-volume retroperitoneal lymphadenopathy and is associated with low long-term morbidity.

Detailed cadaveric analysis of perivesical lymph nodes in cystectomy specimens.

INTRODUCTION: Perivesical lymph nodes were added to the 8th edition of American Joint Committee on Cancer (AJCC) staging for bladder cancer. Currently, these nodes are inconsistently evaluated at the time of radical cystectomy. The objective of this study was to provide a detailed anatomic evaluation of perivesical lymph nodes. MATERIALS AND METHODS: A radical cystectomy was performed on six un-embalmed cadavers with wide resection of perivesical tissue and meticulous care to separate the pelvic sidewall lymph nodes (e.g. obturator, external iliac) from the bladder and perivesical en-bloc specimen. Perivesical tissue dissection in 2 mm slices was performed with a board-certified pathologist. Lymph node size and location were recorded. RESULTS: Gross tissue resembling lymph nodes were identified in the perivesical tissue in 50% (3/6) of the specimens, with a total of six grossly identified lymph nodes. The mean size was 7.5 mm (2-16 mm). On histologic analysis, 4 of 6 (66%) putative gross lymph nodes had confirmed lymphoid tissue. The mean distance of the lymph nodes from bladder wall was 9 mm (3-15 mm). Eight anatomic locations for perivesical nodes were developed: urachal, anterior bladder wall, posterior peritoneum, bladder neck, bilateral pedicle, bilateral lateral bladder wall. CONCLUSION: This cadaveric study with meticulous dissection of the perivesical space confirms that perivesical lymph nodes are a distinct entity and separate from other lymph nodes in the true pelvis. Perivesical lymph nodes are not present in all subjects and pathologic evaluation is more difficult owing to the surrounding fat. We herein propose perivesical regions for evaluation which can serve as a foundation for future studies and anatomic grossing techniques.

Single Circuit in V1 Capable of Switching Contexts During Movement Using an Inhibitory Population as a Switch.

As animals adapt to their environments, their brains are tasked with processing stimuli in different sensory contexts. Whether these computations are context dependent or independent, they are all implemented in the same neural tissue. A crucial question is what neural architectures can respond flexibly to a range of stimulus conditions and switch between them. This is a particular case of flexible architecture that permits multiple related computations within a single circuit. Here, we address this question in the specific case of the visual system circuitry, focusing on context integration, defined as the integration of feedforward and surround information across visual space. We show that a biologically inspired microcircuit with multiple inhibitory cell types can switch between visual processing of the static context and the moving context. In our model, the VIP population acts as the switch and modulates the visual circuit through a disinhibitory motif. Moreover, the VIP population is efficient, requiring only a relatively small number of neurons to switch contexts. This circuit eliminates noise in videos by using appropriate lateral connections for contextual spatiotemporal surround modulation, having superior denoising performance compared to circuits where only one context is learned. Our findings shed light on a minimally complex architecture that is capable of switching between two naturalistic contexts using few switching units.

Durability of Response to Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, a Mitomycin-Containing Reverse Thermal Gel: OLYMPUS Trial Final Report.

PURPOSE: Our goal was to evaluate long-term safety and durability of response to UGN-101, a mitomycin-containing reverse thermal gel, as primary chemoablative treatment for low-grade upper tract urothelial carcinoma. MATERIALS AND METHODS: In this open-label, single-arm, multicenter, phase 3 trial (NCT02793128), patients ≥18 years of age with primary or recurrent biopsy-proven low-grade upper tract urothelial carcinoma received 6 once-weekly instillations of UGN-101 via retrograde catheter to the renal pelvis and calyces. Those with complete response (defined as negative ureteroscopic evaluation, negative cytology and negative for-cause biopsy) 4-6 weeks after the last instillation were eligible for up to 11 monthly maintenance instillations and were followed for ≥12 months with quarterly evaluation of response durability. Durability of complete response was determined by ureteroscopic evaluation; duration of response was estimated by the Kaplan-Meier method. Treatment-emergent adverse events (TEAEs) were monitored. RESULTS: Of 71 patients who initiated treatment, 41 (58%) had complete response to induction therapy and consented to long-term followup; 23/41 patients (56%) remained in complete response after 12 months (95% CI 40, 72), comprising 6/12 (50%) who did not receive any maintenance instillations and 17/29 (59%) who received ≥1 maintenance instillation. Kaplan-Meier analysis of durability was estimated as 82% (95% CI 66, 91) at 12 months. Ureteric stenosis was the most frequently reported TEAE (31/71, 44%); an increasing number of instillations appeared to be associated with increased incidence of urinary TEAEs. CONCLUSIONS: Durability of response to UGN-101 with or without maintenance treatment is clinically meaningful, offering a kidney-sparing therapeutic alternative for patients with low-grade disease.

Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial.

PURPOSE: Low-grade intermediate-risk nonmuscle-invasive bladder cancer (LG IR NMIBC) is a recurrent disease, thus requiring repeated transurethral resection of bladder tumor under general anesthesia. We evaluated the efficacy and safety of UGN-102, a mitomycin-containing reverse thermal gel, as a primary chemoablative therapeutic alternative to transurethral resection of bladder tumor for patients with LG IR NMIBC. MATERIALS AND METHODS: This prospective, phase 2b, open-label, single-arm trial recruited patients with biopsy-proven LG IR NMIBC to receive 6 once-weekly instillations of UGN-102. The primary end point was complete response (CR) rate, defined as the proportion of patients with negative endoscopic examination, negative cytology and negative for-cause biopsy 3 months after treatment initiation. Patients with CR were followed quarterly up to 12 months to assess durability of treatment effect. Safety and adverse events were monitored throughout the trial. RESULTS: A total of 63 patients (38 males and 25 females 33-96 years old) enrolled and received ≥1 instillation of UGN-102. Among the patients 41 (65%) achieved CR at 3 months, of whom 39 (95%), 30 (73%) and 25 (61%) remained disease-free at 6, 9 and 12 months after treatment initiation, respectively. A total of 13 patients had documented recurrences. The probability of durable response 9 months after CR (12 months after treatment initiation) was estimated to be 73% by Kaplan-Meier analysis. Common adverse events (incidence ≥10%) included dysuria, urinary frequency, hematuria, micturition urgency, urinary tract infection and fatigue. CONCLUSIONS: Nonsurgical primary chemoablation of LG IR NMIBC using UGN-102 resulted in significant treatment response with sustained durability. UGN-102 may provide an alternative to repetitive surgery for patients with LG IR NMIBC.

Structure and function of axo-axonic inhibition.

Inhibitory neurons in mammalian cortex exhibit diverse physiological, morphological, molecular, and connectivity signatures. While considerable work has measured the average connectivity of several interneuron classes, there remains a fundamental lack of understanding of the connectivity distribution of distinct inhibitory cell types with synaptic resolution, how it relates to properties of target cells, and how it affects function. Here, we used large-scale electron microscopy and functional imaging to address these questions for chandelier cells in layer 2/3 of the mouse visual cortex. With dense reconstructions from electron microscopy, we mapped the complete chandelier input onto 153 pyramidal neurons. We found that synapse number is highly variable across the population and is correlated with several structural features of the target neuron. This variability in the number of axo-axonic ChC synapses is higher than the variability seen in perisomatic inhibition. Biophysical simulations show that the observed pattern of axo-axonic inhibition is particularly effective in controlling excitatory output when excitation and inhibition are co-active. Finally, we measured chandelier cell activity in awake animals using a cell-type-specific calcium imaging approach and saw highly correlated activity across chandelier cells. In the same experiments, in vivo chandelier population activity correlated with pupil dilation, a proxy for arousal. Together, these results suggest that chandelier cells provide a circuit-wide signal whose strength is adjusted relative to the properties of target neurons.

Adaptation supports short-term memory in a visual change detection task.

The maintenance of short-term memories is critical for survival in a dynamically changing world. Previous studies suggest that this memory can be stored in the form of persistent neural activity or using a synaptic mechanism, such as with short-term plasticity. Here, we compare the predictions of these two mechanisms to neural and behavioral measurements in a visual change detection task. Mice were trained to respond to changes in a repeated sequence of natural images while neural activity was recorded using two-photon calcium imaging. We also trained two types of artificial neural networks on the same change detection task as the mice. Following fixed pre-processing using a pretrained convolutional neural network, either a recurrent neural network (RNN) or a feedforward neural network with short-term synaptic depression (STPNet) was trained to the same level of performance as the mice. While both networks are able to learn the task, the STPNet model contains units whose activity are more similar to the in vivo data and produces errors which are more similar to the mice. When images are omitted, an unexpected perturbation which was absent during training, mice often do not respond to the omission but are more likely to respond to the subsequent image. Unlike the RNN model, STPNet produces a similar pattern of behavior. These results suggest that simple neural adaptation mechanisms may serve as an important bottom-up memory signal in this task, which can be used by downstream areas in the decision-making process.