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.

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.

Clinical characteristics indexing genetic differences in schizophrenia: a systematic review.

Genome-wide studies are among the best available tools for identifying etiologic processes underlying psychiatric disorders such as schizophrenia. However, it is widely recognized that disorder heterogeneity may limit genetic insights. Identifying phenotypes indexing genetic differences among patients with non-affective psychotic disorder will improve genome-wide studies of these disorders. The present study systematically reviews existing literature to identify phenotypes that index genetic differences among patients with schizophrenia and related disorders. We systematically reviewed family-based studies and genome-wide molecular-genetic studies investigating whether phenotypic variation in patients with non-affective psychotic disorders (according to DSM or equivalent systems) was associated with genome-wide genetic variation (PROSPERO number CRD42019136169). An electronic database search of PubMed, EMBASE, and PsycINFO from inception until 17 May 2019 resulted in 4347 published records. These records included a total of 813 relevant analyses from 264 articles. Two independent raters assessed the quality of all analyses based on methodologic rigor and power. We found moderate to strong evidence for a positive association between genetic/familial risk for non-affective psychosis and four phenotypes: early age of onset, negative/deficit symptoms, chronicity, and functional impairment. Female patients also tended to have more affected relatives. Severity of positive symptoms was not associated with genetic/familial risk for schizophrenia. We suggest that phenotypes with the most evidence for reflecting genetic difference in participating patients should be measured in future large-scale genetic studies of schizophrenia to improve power to discover causal variants and to facilitate discovery of modifying genetic variants.

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.

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.

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.

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.

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.

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.

Renal cell carcinoma with inferior vena cava thrombus: did we make progress in oncologic outcomes and complications?

PURPOSE OF REVIEW: Surgery for renal cell carcinoma (RCC) with inferior vena cava tumor thrombus (TT) remains one of the most complex surgeries performed with high rates of associated complications and perioperative mortality. Surgical techniques and neoadjuvant therapies have an important role to play in improving outcomes. This review provides a narrative analysis of recent literature on patients with RCC and TT. RECENT FINDINGS: Several imaging techniques are emerging that may improve diagnostic staging of tumor thrombus level. Robotic approaches to surgical resection for all thrombi levels is feasible and safe, while longer term outcomes for higher level thrombi continues to mature. Early data on neoadjuvant immunotherapy and radiotherapy have shown improvements in complication rates and intermediate term oncologic outcomes. SUMMARY: Data suggests that neoadjuvant therapies and minimally invasive techniques may improve outcomes in patients undergoing surgical resection for RCC with tumor thrombus. Larger multiinstitutional series are needed to confirm the benefit of these techniques as well as the durable long term oncologic outcomes.

Trapped Electrons and Ions as Particle Detectors.

Electrons and ions trapped with electromagnetic fields have long served as important high-precision metrological instruments, and more recently have also been proposed as a platform for quantum information processing. Here we point out that these systems can also be used as highly sensitive detectors of passing charged particles, due to the combination of their extreme charge-to-mass ratio and low-noise quantum readout and control. In particular, these systems can be used to detect energy depositions many orders of magnitude below typical ionization scales. As illustrations, we suggest some applications in particle physics. We outline a nondestructive time-of-flight measurement capable of sub-eV energy resolution for slowly moving, collimated particles. We also show that current devices can be used to provide competitive sensitivity to models where ambient dark matter particles carry small electric millicharges ≪e. Our calculations may also be useful in the characterization of noise in quantum computers coming from backgrounds of charged particles.

An Active Inference Model of Collective Intelligence.

Collective intelligence, an emergent phenomenon in which a composite system of multiple interacting agents performs at levels greater than the sum of its parts, has long compelled research efforts in social and behavioral sciences. To date, however, formal models of collective intelligence have lacked a plausible mathematical description of the relationship between local-scale interactions between autonomous sub-system components (individuals) and global-scale behavior of the composite system (the collective). In this paper we use the Active Inference Formulation (AIF), a framework for explaining the behavior of any non-equilibrium steady state system at any scale, to posit a minimal agent-based model that simulates the relationship between local individual-level interaction and collective intelligence. We explore the effects of providing baseline AIF agents (Model 1) with specific cognitive capabilities: Theory of Mind (Model 2), Goal Alignment (Model 3), and Theory of Mind with Goal Alignment (Model 4). These stepwise transitions in sophistication of cognitive ability are motivated by the types of advancements plausibly required for an AIF agent to persist and flourish in an environment populated by other highly autonomous AIF agents, and have also recently been shown to map naturally to canonical steps in human cognitive ability. Illustrative results show that stepwise cognitive transitions increase system performance by providing complementary mechanisms for alignment between agents' local and global optima. Alignment emerges endogenously from the dynamics of interacting AIF agents themselves, rather than being imposed exogenously by incentives to agents' behaviors (contra existing computational models of collective intelligence) or top-down priors for collective behavior (contra existing multiscale simulations of AIF). These results shed light on the types of generic information-theoretic patterns conducive to collective intelligence in human and other complex adaptive systems.

Guideline of guidelines: social media in urology.

The use of social media is rapidly expanding. This technology revolution is changing the way healthcare providers share information with colleagues, patients, and other stakeholders. As social media use increases in urology, maintaining a professional online identity and interacting appropriately with one's network are vital to engaging positively and protecting patient health information. There are many opportunities for collaboration and exchange of ideas, but pitfalls exist without adherence to proper online etiquette. The purpose of this article is to review professional guidelines on the use of social media in urology, and outline best practice principles that urologists and other healthcare providers can reference when engaging in online networks.

Update on the guideline of guidelines: non-muscle-invasive bladder cancer.

Non-muscle-invasive bladder cancer (NMIBC) is the most common form of bladder cancer, with frequent recurrences and risk of progression. Risk-stratified treatment and surveillance protocols are often used to guide management. In 2017, BJUI reviewed guidelines on NMIBC from four major organizations: the American Urological Association/Society of Urological Oncology, the European Association of Urology, the National Comprehensive Cancer Network, and the National Institute for Health and Care Excellence. The present update will review major changes in the guidelines and broadly summarize new recommendations for treatment of NMIBC in an era of bacillus Calmette-Guérin shortage and immense novel therapy development.

Cooling a Harmonic Oscillator by Optomechanical Modification of Its Bath.

Optomechanical systems show tremendous promise for the high-sensitivity sensing of forces and modification of mechanical properties via light. For example, similar to neutral atoms and trapped ions, laser cooling of mechanical motion by radiation pressure can take single mechanical modes to their ground state. Conventional optomechanical cooling is able to introduce an additional damping channel to mechanical motion while keeping its thermal noise at the same level, and, as a consequence, the effective temperature of the mechanical mode is lowered. However, the ratio of the temperature to the quality factor remains roughly constant, preventing dramatic advances in quantum sensing using this approach. Here we propose an approach for simultaneously reducing the thermal load on a mechanical resonator while improving its quality factor. In essence, we use the optical interaction to dynamically modify the dominant damping mechanism, providing an optomechanically induced effect analogous to a phononic band gap. The mechanical mode of interest is assumed to be weakly coupled to its heat bath but strongly coupled to a second mechanical mode, which is cooled by radiation pressure coupling to a red-detuned cavity field. We also identify a realistic optomechanical design that has the potential to realize this novel cooling scheme.