Survival Outcomes by Race Following Surgical Treatment for Upper Tract Urothelial Carcinoma.

OBJECTIVE: Discrepancies in survival outcomes of various genitourinary tract malignancies have been documented across different racial and ethnic groups. Here we sought to examine long-term survival outcomes of patients with upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy (RNU) when stratified by race. METHODS: A multicenter retrospective analysis using the ROBUUST (ROBotic surgery for Upper tract Urothelial cancer Study) registry identified patients undergoing RNU for UTUC between 2015 and 2022 at 12 centers across the United States, Europe, and Asia. Patients were stratified by race (white, black, Hispanic, and Asian) and primary outcomes of interest-including recurrence-free survival (RFS), metastasis free survival (MFS) and overall survival (OS) - were assessed using univariate analysis, multivariate Cox regression modeling, and Kaplan-Meier analysis. RESULTS: 1446 patients (white n = 652, black n = 70, Hispanic n = 87, and Asian n = 637) who underwent RNU for treatment of the UTUC were included in our analysis. Cox regression modeling demonstrated pathologic nodal staging to be a significant predictor of RFS (HR 2.25; P = .0010), MFS (HR 2.50; P = .0028), and OS (HR 5.11; P < .0001). When using whites as the reference group, there were no significant differences in RFS, MFS, or OS across racial groups. CONCLUSIONS: Unlike other genitourinary tract malignancies, our study failed to demonstrate a survival disadvantage among minority racial groups with UTUC who underwent RNU. Furthermore, a significant difference in RFS, MFS, and OS was not identified across whites, blacks, Asians, or Hispanics with UTUC who underwent RNU.

Long-term outcomes of bladder-sparing therapy vs radical cystectomy in BCG-unresponsive non-muscle-invasive bladder cancer.

OBJECTIVE: To quantify the oncological risks of bladder-sparing therapy (BST) in patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) compared to upfront radical cystectomy (RC). PATIENTS AND METHODS: Pre-specified data elements were collected from retrospective cohorts of patients with BCG-unresponsive NMIBC from 10 international sites. After Institutional Review Board approval, patients were included if they had BCG-unresponsive NMIBC meeting United States Food and Drug Administration criteria. Oncological outcomes were collected following upfront RC or BST. BST regimens included re-resection or surveillance only, repeat BCG, intravesical chemotherapy, systemic immunotherapy, and clinical trials. RESULTS: Among 578 patients, 28% underwent upfront RC and 72% received BST. The median (interquartile range) follow-up was 50 (20-69) months. There were no statistically significant differences in metastasis-free survival, cancer-specific survival, or overall survival between treatment groups. In the BST group, high-grade recurrence rates were 37% and 52% at 12 and 24 months and progression to MIBC was observed in 7% and 13% at 12 and 24 months, respectively. RC was performed in 31.7% in the BST group and nodal disease was found in 13% compared with 4% in upfront RC (P = 0.030). CONCLUSION: In a selected cohort of patients, initial BST offers comparable survival outcomes to upfront RC in the intermediate term. Rates of recurrence and progression increase over time especially in patients treated with additional lines of BST.

Training Psychiatrist-Scientists-Excellence on Both Sides of the Hyphen.

This Viewpoint discusses why it is important for psychiatry residency programs to continue to prioritize the training of psychiatrist-scientists.

Socioeconomic and Demographic Disparities in Immunotherapy Utilization for Advanced Kidney and Bladder Cancer.

OBJECTIVES: Immunotherapy (IO) drugs have been increasingly utilized in locally advanced or metastatic clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma of the bladder (UC). Multiple trials have demonstrated clear survival benefit, however, there are often barriers to access for these advanced therapies which has been demonstrated in other non-urologic malignancies. The goal of this study was to assess socioeconomic and demographic factors associated with the receipt of IO for advanced ccRCC and UC. MATERIALS AND METHODS: We queried the National Cancer Database (NCDB) for patients with stage IV ccRCC and UC. The study period was 2015 to 2020 for ccRCC (FDA approval date of IO) and 2017 to 2020 for UC (FDA approval date of broadened indication for IO, initial limited approval in 2016). The primary outcome of interest was receipt of IO therapy using multivariable logistic regression, adjusting for relevant socioeconomic and demographic variables. RESULTS: We identified 15,926 patients with stage IV ccRCC and 10,380 patients with stage IV UC of which 5,419 (34.0%) and 2,231 (21.5%) received IO therapy, respectively. IO utilization increased with each successive year. In both malignancies, treatment at a non-academic facility, education level, income, and insurance were independently associated with IO utilization. For ccRCC, black (OR = 0.77, 95% CI, 0.64-0.93, P = 0.009) and Hispanic race (OR = 0.73, 95% CI, 0.61-0.86, P = 0.006) were each associated with decreased IO utilization but there were no independent associations between race and receipt of IO in patients with UC. CONCLUSIONS: In the era of FDA-approved IO therapy for advanced ccRCC and UC, this national cohort analysis suggests that IO utilization is increasing over time, but significant disparities exist based on income, education, and insurance status in both malignancies. Additionally, patients treated at non-academic facilities were less likely to receive IO therapy for these specific genitourinary malignancies. In ccRCC, additional disparities were seen black and Hispanic races which each were associated with lower odds of IO receipt. Identifying strategies to mitigate these differences and provide equitable access to IO therapy is of imperative need.

Emotional awareness for self and others and empathic abilities in clinical depression during acute illness and recovery.

BACKGROUND: The present longitudinal investigation had two major goals. First, we intended to clarify whether depressed patients are characterized by impairments of emotional awareness for the self and the other during acute illness and whether these impairments diminish in the course of an inpatient psychiatric treatment program. Previous research based on the performance measure Levels of Emotional Awareness Scale (LEAS) provided inconsistent findings concerning emotional self-awareness in clinical depression. Second, we investigated whether cognitive and affective empathic abilities change from acute illness to recovery in depressed patients. METHODS: Fifty-eight depressed patients were tested on admission and after 6-8 weeks of inpatient psychiatric treatment. A sample of fifty-three healthy individuals were also examined twice at an interval of 6-8 weeks. The LEAS and the Interpersonal Reactivity Index (IRI) were administered to assess emotional awareness and empathic abilities. Written texts were digitalized and then analyzed using the electronic scoring program geLEAS, the German electronic Levels of Emotional Awareness Scale. RESULTS: Depressed patients reported more depressive symptoms than healthy controls and less severe depressive symptomatology at time 2 compared to time 1. Independent of time, depressed individuals tended to show lower geLEAS self scores and had lower geLEAS other scores than healthy individuals. Depressed patients showed higher personal distress scores than healthy individuals at both measurement times. No group differences were observed for the cognitive empathy scales of the IRI (perspective taking and fantasy) and empathic concern, but empathic concern decreased significantly in depressed patients from time 1 to time 2. Empathic abilities as assessed by the IRI were not significantly correlated with emotional awareness for others, neither in the whole sample, nor in the patient and control subsample. CONCLUSIONS: Depressed patients seem to be characterized by impairments in emotional awareness of others during acute illness and recovery, but they also tend to show deficits in emotional self-awareness compared to healthy individuals. Self-reported cognitive empathic abilities seem to be at normal levels in depressed patients, but their heightened self-focused affective empathy may represent a vulnerability factor for depressive disorders.

Machine Learning the Disorder Landscape of Majorana Nanowires.

We develop a practical machine learning approach to determine the disorder landscape of Majorana nanowires by using training of the conductance matrix and inverting the conductance data in order to obtain the disorder details in the system. The inversion carried out through machine learning using different disorder parametrizations turns out to be unique in the sense that any input tunnel conductance as a function of chemical potential and Zeeman energy can indeed be inverted to provide the correct disorder landscape. Our work opens up a qualitatively new direction of directly determining the topological invariant and the Majorana wave-function structure corresponding to a transport profile of a device using simulations that quantitatively match the specific conductance profile. In addition, this also opens up the possibility for optimizing Majorana systems by figuring out the (generally unknown) underlying disorder only through the conductance data. An accurate estimate of the applicable spin-orbit coupling in the system can also be obtained within the same scheme.

The optimal number of induction chemotherapy cycles in clinically lymph node-positive bladder cancer.

OBJECTIVE: To investigate the optimal number of induction chemotherapy cycles needed to achieve a pathological response in patients with clinically lymph node-positive (cN+) bladder cancer (BCa) who received three or four cycles of induction chemotherapy followed by consolidative radical cystectomy (RC) with pelvic lymph node dissection. PATIENTS AND METHODS: We included 388 patients who received three or four cycles of cisplatin/gemcitabine or (dose-dense) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), followed by consolidative RC for cTanyN1-3M0 BCa. We compared pathological complete (pCR = ypT0N0) and objective response (pOR = yp ≤T1N0) between treatment groups. Predictors of pCR and/or pOR were assessed using uni- and multivariable logistic regression analysis. The secondary endpoints were overall (OS) and cancer-specific survival (CSS). We evaluated the association between the number of induction chemotherapy cycles administered and survival outcomes on multivariable Cox regression. RESULTS: Overall, 101 and 287 patients received three or four cycles of induction chemotherapy, respectively. Of these, 72 (19%) and 128 (33%) achieved pCR and pOR response, respectively. The pCR (20%, 18%) and pOR (40%, 31%) rates did not differ significantly between patients receiving three or four cycles (P > 0.05). The number of cycles was not associated with pCR or pOR on multivariable logistic regression analyses. The 2-year OS estimates were 63% (95% confidence interval [CI] 0.53-0.74) and 63% (95% CI 0.58-0.7) for patients receiving three or four cycles, respectively. Receiving three vs four cycles was not associated with OS and CSS on uni- or multivariable Cox regression analyses. CONCLUSION: Pathological response and survival outcomes did not differ between administering three or four induction chemotherapy cycles in patients with cN+ BCa. A fewer cycles (minimum three) may be oncologically sufficient in patients with cN+ BCa, while decreasing the wait for definitive local therapy in those patients who end up without a response to chemotherapy. This warrants further validation.

Genetic contribution to disease-course severity and progression in the SUPER-Finland study, a cohort of 10,403 individuals with psychotic disorders.

Genetic factors contribute to the susceptibility of psychotic disorders, but less is known how they affect psychotic disease-course development. Utilizing polygenic scores (PGSs) in combination with longitudinal healthcare data with decades of follow-up we investigated the contributing genetics to psychotic disease-course severity and diagnostic shifts in the SUPER-Finland study, encompassing 10 403 genotyped individuals with a psychotic disorder. To longitudinally track the study participants' past disease-course severity, we created a psychiatric hospitalization burden metric using the full-coverage and nation-wide Finnish in-hospital registry (data from 1969 and onwards). Using a hierarchical model, ranking the psychotic diagnoses according to clinical severity, we show that high schizophrenia PGS (SZ-PGS) was associated with progression from lower ranked psychotic disorders to schizophrenia (OR = 1.32 [1.23-1.43], p = 1.26e-12). This development manifested already at psychotic illness onset as a higher psychiatric hospitalization burden, the proxy for disease-course severity. In schizophrenia (n = 5 479), both a high SZ-PGS and a low educational attainment PGS (EA-PGS) were associated with increased psychiatric hospitalization burden (p = 1.00e-04 and p = 4.53e-10). The SZ-PGS and the EA-PGS associated with distinct patterns of hospital usage. In individuals with high SZ-PGS, the increased hospitalization burden was composed of longer individual hospital stays, while low EA-PGS associated with shorter but more frequent hospital visits. The negative effect of a low EA-PGS was found to be partly mediated via substance use disorder, a major risk factor for hospitalizations. In conclusion, we show that high SZ-PGS and low EA-PGS both impacted psychotic disease-course development negatively but resulted in different disease-course trajectories.

Testicular Radiomics To Predict Pathology At Time of Postchemotherapy Retroperitoneal Lymph Node Dissection for Nonseminomatous Germ Cell Tumor.

INTRODUCTION: Testicular germ cell tumors are the most common malignancy in young adult males. Patients with metastatic disease receive standard of care chemotherapy followed by retroperitoneal lymph node dissection for residual masses >1cm. However, there is a need for better preoperative tools to discern which patients will have persistent disease after chemotherapy given low rates of metastatic germ cell tumor after chemotherapy. The purpose of this study was to use radiomics to predict which patients would have viable germ cell tumor or teratoma after chemotherapy at time of retroperitoneal lymph node dissection. PATIENTS AND METHODS: Patients with nonseminomatous germ cell tumor undergoing postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) between 2008 and 2019 were queried from our institutional database. Patients were included if prechemotherapy computed tomography (CT) scan and postchemotherapy imaging were available. Semiqualitative and quantitative features of residual masses and nodal regions of interest and radiomic feature extractions were performed by 2 board certified radiologists. Radiomic feature analysis was used to extract first order, shape, and second order statistics from each region of interest. Post-RPLND pathology was compared to the radiomic analysis using multiple t-tests. RESULTS: 45 patients underwent PC-RPLND at our institution, with the majority (28 patients) having stage III disease. 24 (53%) patients had teratoma on RPLND pathology, while 2 (4%) had viable germ cell tumor. After chemotherapy, 78%, 53%, and 33% of patients had cystic regions, fat stranding, and local infiltration present on imaging. After radiomic analysis, first order statistics mean, median, 90th percentile, and root mean squares were significant. Strong correlations were observed between these 4 features;a lower signal was associated with positive pathology at RPND. CONCLUSIONS: Testicular radiomics is an emerging tool that may help predict persistent disease after chemotherapy.

Impact of the extent of lymph node dissection on survival outcomes in clinically lymph node-positive bladder cancer.

OBJECTIVE: To determine the oncological impact of extended pelvic lymph node dissection (ePLND) vs standard PLND (sPLND) during radical cystectomy (RC) in clinically lymph node-positive (cN+) bladder cancer (BCa). PATIENTS AND METHODS: In this retrospective, multicentre study we included 969 patients who underwent RC with sPLND (internal/external iliac and obturator lymph nodes) or ePLND (sPLND plus common iliac and presacral nodes) with or without platin-based peri-operative chemotherapy for cTany N1-3 M0 BCa between 1991 and 2022. We assessed the impact of ePLND on recurrence-free survival (RFS) and the distribution of recurrences (locoregional and distant recurrences). The secondary endpoint was overall survival (OS). We performed propensity-score matching using covariates associated with the extent of PLND in univariable logistic regression analysis. The association of the extent of PLND with RFS and OS was investigated using Cox regression models. RESULTS: Of 969 cN+ patients, 510 were 1:1 matched on propensity scores. The median (interquartile range [IQR]) time to recurrence was 8 (4-16) months, and median (IQR) follow-up of alive patients was 30 (13-51) months. Disease recurrence was observed in 104 patients in the ePLND and 107 in the sPLND group. Of these, 136 (27%), 47 (9.2%) and 19 patients (3.7%) experienced distant, locoregional, or both distant and locoregional disease recurrence, respectively. When stratified by the extent of PLND, we did not find a difference in recurrence patterns (P > 0.05). ePLND improved neither RFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.70-1.19; P = 0.5) nor OS (HR 0.78, 95% CI 0.60-1.01; P = 0.06) compared to sPLND. Stratification by induction chemotherapy did not change outcomes. CONCLUSION: Performing an ePLND at the time of RC in cN+ patients improved neither RFS nor OS compared to sPLND, regardless of induction chemotherapy status. Pretreatment risk stratification is paramount to identify ideal candidates for RC with ePLND as part of a multimodal treatment approach.

XTX301, a Tumor-Activated Interleukin-12 Has the Potential to Widen the Therapeutic Index of IL12 Treatment for Solid Tumors as Evidenced by Preclinical Studies.

IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells in tumors. However, the systemic administration of IL12 has been accompanied by considerable toxicity, prompting interest in researching alternatives to drive preferential IL12 bioactivity in the tumor. Here, we have generated XTX301, a tumor-activated IL12 linked to the human Fc protein via a protease cleavable linker that is pharmacologically inactivated by an IL12 receptor subunit beta 2 masking domain. In vitro characterization demonstrates multiple matrix metalloproteases, as well as human primary tumors cultured as cell suspensions, can effectively activate XTX301. Intravenous administration of a mouse surrogate mXTX301 demonstrated significant tumor growth inhibition (TGI) in inflamed and non-inflamed mouse models without causing systemic toxicities. The superiority of mXTX301 in mediating TGI compared with non-activatable control molecules and the greater percentage of active mXTX301 in tumors versus other organs further confirms activation by the tumor microenvironment-associated proteases in vivo. Pharmacodynamic characterization shows tumor selective increases in inflammation and upregulation of immune-related genes involved in IFNγ cell signaling, antigen processing, presentation, and adaptive immune response. XTX301 was tolerated following four repeat doses up to 2.0 mg/kg in a nonhuman primate study; XTX301 exposures were substantially higher than those at the minimally efficacious dose in mice. Thus, XTX301 has the potential to achieve potent antitumor activity while widening the therapeutic index of IL12 treatment and is currently being evaluated in a phase I clinical trial.

Clinical characteristics indexing genetic differences in bipolar disorder - a systematic review.

Bipolar disorder is a heterogenous condition with a varied clinical presentation. While progress has been made in identifying genetic variants associated with bipolar disorder, most common genetic variants have not yet been identified. More detailed phenotyping (beyond diagnosis) may increase the chance of finding genetic variants. Our aim therefore was to identify clinical characteristics that index genetic differences in bipolar disorder.We performed a systematic review of all genome-wide molecular genetic, family, and twin studies investigating familial/genetic influences on the clinical characteristics of bipolar disorder. We performed an electronic database search of PubMed and PsycInfo until October 2022. We reviewed title/abstracts of 2693 unique records and full texts of 391 reports, identifying 445 relevant analyses from 142 different reports. These reports described 199 analyses from family studies, 183 analyses from molecular genetic studies and 63 analyses from other types of studies. We summarized the overall evidence per phenotype considering study quality, power, and number of studies.We found moderate to strong evidence for a positive association of age at onset, subtype (bipolar I versus bipolar II), psychotic symptoms and manic symptoms with familial/genetic risk of bipolar disorder. Sex was not associated with overall genetic risk but could indicate qualitative genetic differences. Assessment of genetically relevant clinical characteristics of patients with bipolar disorder can be used to increase the phenotypic and genetic homogeneity of the sample in future genetic studies, which may yield more power, increase specificity, and improve understanding of the genetic architecture of bipolar disorder.

Sex hormones as correlates of oxidative stress in the adult brain.

Oxidative stress, an imbalance between the production of reactive oxygen species and available antioxidant capacity, is implicated in multiple psychiatric disorders and neurodegenerative conditions. Peripheral and preclinical studies suggest oxidative stress differs by biological sex and covaries with estrogens. However, limited knowledge exists on the effect of circulating sex hormones on oxidative stress in the brain in humans in vivo. We aimed to examine the relationship of circulating estrogen with regional concentrations of brain glutathione (GSH) as a marker of oxidative stress. GSH was measured using magnetic resonance spectroscopy (MRS) at 7 Tesla in the dorsal anterior cingulate cortex (ACC), ventromedial prefrontal cortex (VMPFC), and left dorsolateral prefrontal cortex (DLPFC) in 34 individuals (18 females and 16 males). We observed an inverse correlation of estradiol with DLPFC GSH, as well as a trend inverse correlation of estrone with DLPFC GSH, in the combined sample of males and females and in females only. No significant sex differences were observed for GSH levels in the brain. Our study provides evidence of diminished DLPFC GSH in females with higher estradiol, suggesting circulating sex hormones may be important factors to consider in future studies examining brain GSH levels related to psychiatric and other disorders.

Development and validation of a computer program for measuring emotional awareness in German-The geLEAS (German electronic Levels of Emotional Awareness Scale).

Introduction: Emotional awareness is the ability to identify, interpret, and verbalize the emotional responses of oneself and those of others. The Levels of Emotional Awareness Scale (LEAS) is an objective performance inventory that accurately measures an individual's emotional awareness. LEAS assessments are typically scored manually and are therefore both time consuming and cognitively demanding. This study presents a German electronic scoring program for the LEAS (geLEAS), the first non-English computerized assessment approach of the LEAS. Methods: Data were collected from a healthy German community sample (N = 208). We developed a modern software for computerizing LEAS scoring, an open-source text-based emotion assessment tool called VETA (Verbal Emotion in Text Assessment). We investigated if the software would arrive at similar results as hand scoring in German and if emotional awareness would show similar associations to sociodemographic information and psychometric test results as in previous studies. Results: The most frequently used scoring method of the geLEAS shows excellent internal consistency (α = 0.94) and high correlations with hand scoring (r = 0.97, p < 0.001). Higher emotional awareness measured by the geLEAS is associated with female gender, older age, and higher academic achievement (all p < 0.001). Moreover, it is linked to the ability to identify emotions in facial expressions (p < 0.001) and more accurate theory of mind functioning (p < 0.001). Discussion: An automated method for evaluating emotional awareness greatly expands the ability to study emotional awareness in clinical care and research. This study aims to advance the use of emotional awareness as a clinical and scientific parameter.

Colloquium: Advances in automation of quantum dot devices control.

Arrays of quantum dots (QDs) are a promising candidate system to realize scalable, coupled qubit systems and serve as a fundamental building block for quantum computers. In such semiconductor quantum systems, devices now have tens of individual electrostatic and dynamical voltages that must be carefully set to localize the system into the single-electron regime and to realize good qubit operational performance. The mapping of requisite QD locations and charges to gate voltages presents a challenging classical control problem. With an increasing number of QD qubits, the relevant parameter space grows sufficiently to make heuristic control unfeasible. In recent years, there has been considerable effort to automate device control that combines script-based algorithms with machine learning (ML) techniques. In this Colloquium, a comprehensive overview of the recent progress in the automation of QD device control is presented, with a particular emphasis on silicon- and GaAs-based QDs formed in two-dimensional electron gases. Combining physics-based modeling with modern numerical optimization and ML has proven effective in yielding efficient, scalable control. Further integration of theoretical, computational, and experimental efforts with computer science and ML holds vast potential in advancing semiconductor and other platforms for quantum computing.

Diagnostic Imaging in the Evaluation of Asymptomatic Microhematuria: Systematic Review and Meta-analysis.

PURPOSE: Microhematuria is a highly prevalent condition with a low associated risk of urothelial and upper tract malignancy. The AUA Guidelines recently changed recommendations for imaging favoring renal ultrasound for low- and intermediate-risk patients with microhematuria. We summarize the diagnostic test characteristics of computed tomography urography, renal ultrasound, and magnetic resonance urography in comparison with surgical pathology for the diagnosis of upper urinary tract cancer in microhematuria and gross hematuria patients. MATERIALS AND METHODS: This study is a systematic review and meta-analysis using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines from evidence collected for the 2020 AUA Microhematuria Guidelines report, including studies assessing imaging following diagnosis of hematuria published from January 2010 through December 2019. RESULTS: The search identified 20 studies which reported the prevalence of malignant and benign diagnoses in relation to imaging modality, of which 6 were included in the quantitative analysis. For the detection of renal cell carcinoma and upper urinary tract carcinoma in patients with microhematuria and gross hematuria, computed tomography urography had a sensitivity of 94% (95% CI, 84%-98%) and a specificity of 99% (95%CI, 97%-100%) with a certainty of evidence rating of very low and low, respectively when 4 studies were pooled. In comparison, ultrasound demonstrated a sensitivity ranging from 14%-96% (low certainty of evidence) and a specificity of 99%-100% in 2 studies (moderate certainty of evidence), while magnetic resonance urography demonstrated a sensitivity of 83% and specificity of 86% in 1 study with a low certainty of evidence. CONCLUSIONS: In a limited data set for each individual imaging modality, computed tomography urography appears the most sensitive imaging modality for the diagnostic evaluation of microhematuria. Future studies will be needed to evaluate the clinical and health system financial impacts of the change in guideline recommendations from computed tomography urography to renal ultrasound in evaluating low- and intermediate-risk patients with microhematuria.