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PURPOSE Understanding treatment patterns and effectiveness for patients with metastatic prostate cancer (mPCa) is dependent on accurate assessment of metastatic status. The objective was to develop a natural language processing (NLP) model for identifying patients with mPCa and evaluate the model's performance against chart-reviewed data and an International Classification of Diseases (ICD) 9/10 code–based method. METHODS In total, 139,057 radiology reports on 6,211 unique patients from the Department of Veterans Affairs were used. The gold standard was metastases by detailed chart review of radiology reports. NLP performance was assessed by sensitivity, specificity, positive predictive value, negative predictive value, and date of metastases detection. Receiver operating characteristic curves was used to assess model performance. RESULTS When compared with chart review, the NLP model had high sensitivity and specificity (85% and 96%, respectively). The NLP model was able to predict patient-level metastasis status with a sensitivity of 91% and specificity of 81%, whereas sensitivity and specificity using ICD9/10 billing codes were 73% and 86%, respectively. For the NLP model, date of metastases detection was exactly concordant and within < 1 week in 55% and 58% of patients, compared with 8% and 17%, respectively, using the ICD9/10 billing codes method. The area under the curve for the NLP model was 0.911. A limitation is the NLP model was developed on the basis of a subset of patients with mPCa and may not be generalizable to all patients with mPCa. CONCLUSION This population-level NLP model for identifying patients with mPCa was more accurate than using ICD9/10 billing codes when compared with chart-reviewed data. Upon further validation, this model may allow for efficient population-level identification of patients with mPCa.

A new study combines large-scale proteomics and machine learning to identify proteins that can be used to identify individuals with isolated impaired glucose tolerance, who would otherwise only be detectable with oral glucose tolerance tests.The implementation of recommendations for type 2 diabetes (T2D) screening and diagnosis focuses on the measurement of glycated hemoglobin (HbA1c) and fasting glucose. This approach leaves a large number of individuals with isolated impaired glucose tolerance (iIGT), who are only detectable through oral glucose tolerance tests (OGTTs), at risk of diabetes and its severe complications. We applied machine learning to the proteomic profiles of a single fasted sample from 11,546 participants of the Fenland study to test discrimination of iIGT defined using the gold-standard OGTTs. We observed significantly improved discriminative performance by adding only three proteins (RTN4R, CBPM and GHR) to the best clinical model (AUROC = 0.80 (95% confidence interval: 0.79-0.86), P = 0.004), which we validated in an external cohort. Increased plasma levels of these candidate proteins were associated with an increased risk for future T2D in an independent cohort and were also increased in individuals genetically susceptible to impaired glucose homeostasis and T2D. Assessment of a limited number of proteins can identify individuals likely to be missed by current diagnostic strategies and at high risk of T2D and its complications.

Objective Transarterial radioembolization (TARE) offers a minimally invasive and safe treatment option for primary and metastatic hepatic malignancies. The benefits of TARE are manifold including prolonged overall survival, low associated morbidities, and improved time to progression allowing prolonged treatment-free intervals. The rapid development of new systemic therapies including immunotherapy has radically changed the treatment landscape for primary and metastatic liver cancer. Given the current climate, it is critical for interventional oncologists to understand the benefits of TARE relative to these other therapies. Therefore, this report aims to review quality-of-life outcomes and the cost comparisons of TARE as compared with systemic therapies.

Objectives As we pass the anniversary of the declaration of a global pandemic by the World Health Organisation, it invites us to reflect upon the inescapable changes that coronavirus has wrought upon ENT and, in particular, rhinological practice. As it remains unclear when we will globally emerge from the shadow of COVID-19, a critical analysis of the evidence base on both the assessment and mitigation of risk is vital for ENT departments worldwide. This article presents a systematic review of the literature examining articles which consider either the quantification of risk or strategies to mitigate risk specifically in the setting of rhinological surgery. Design Systematic literature review. Results The literature search yielded a total of 3406 returns with 24 articles meeting eligibility criteria. A narrative synthesis stratified results into two broad themes: (1) those which made an assessment as to the aerosolisation of droplets during sinus surgery, further subdivided into work which considered macroscopically visible droplets and that which considered smaller particles; (2) and those studies which examined the mitigation of this risk. Conclusion Studies considering the aerosolisation of both droplets and smaller particles suggest endonasal surgery carries significant risk. Whilst results both highlight a range of innovative adjunctive strategies and support suction as an important variable to reduce aerosolisation, appropriate use of personal protective equipment (PPE) should be considered mandatory for all healthcare professionals involved in rhinological surgery given studies have demonstrated that close adherence to PPE use is effective at preventing COVID-19 infection.

Measurements in the field on dry days indicate that when the traps of Dionaea muscipula (Venus’ flytraps) close, they capture prey about 40% of the time at one site and 44% at another. The 60% and 56% of traps that close but do not catch prey reach their maximum closure on average in about 10 minutes, begin reopening in about 7 hours and completely reopen in 22 hours. Traps that have captured prey tighten along their rims, sealing the lobes and forcing the margins outward into a “narrowed” condition that takes 4 to 6 hours to achieve. Reopening of narrowed traps begins, on average, after 9.2 days and they are fully open in 12.8 days. A few traps that capture large prey never reopen. In dry weather closure frequency of traps capable of closure was low, averaging 3.5%/day at one site and 3.1%/day at another. At both sites the capture frequency of traps capable of closing was only 1.4%/day. The low frequency of capture, and high percentage of closures that result in capture, indicate that the low capture frequency is due to a low number potential prey entering and triggering the trap rather than a low efficiency of capturing the prey that enters. Traps that close, but fail to capture prey, have been observed to be triggered by insects, spiders, snails, and even toads that were far too large to be captured. A few captured beetles have been observed to force their way out of trap lobes. Dionaea traps capture prey at all hours of the day. The capture frequencies are variable and are not significantly higher in any specific time period. Both nocturnal and diurnal animals were captured.

Objectives Anecdotal evidence suggests that oropharyngeal squamous cell carcinoma (OPSCC) should be suspected in patients presenting with symptoms of peritonsillar abscess (PTA) or cellulitis (PTC). The aim of this study was to estimate the prevalence of OPSCC in patients presenting with symptoms of PTA/PTC. Method, Setting and Participants We retrospectively identified all adults with a coded diagnosis of PTA or PTC who presented between 2012-2016 inclusive, across six ENT units in ——–. Records were compared to that of the centralised regional head and neck cancer database. The clinical records of a subset of patients were reviewed for the purposes of data validation. Results A total of 1975 patients with PTA/PTC were identified. Three patients were subsequently diagnosed with OPSCC. None of the three actually had an objective underlying diagnosis of PTA/PTC on the same side. The prevalence of OPSCC in patients admitted with symptoms of PTA/PTC was 0.15%, or approximately 1:650 admissions. The records of 510 patients who presented over a one-year period (2016) were reviewed in even greater detail. There were 298 patients with PTA (59.4%), 151 with PTC (29.1%) and 61 had an alternative diagnosis (11.9%). High risk features (age ≥40, tonsillar asymmetry or tonsillar lesion) were present in 106 patients (24%). Urgent follow up was expedited for 77 patients (73%). Conclusion This study estimates the risk of OPSCC in patients with peritonsillar symptoms. The prevalence is low, even in a region with a relatively heavy disease burden. Clinicians should, however, retain a high level of suspicion in patients with persistent symptoms.

A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c -statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a “universal” surrogate end point for cardiovascular risk.

Background: We sought to determine whether differences in subtype distribution and differentially expressed genes exist between African Americans (AAs) and European Americans (EAs) in patients with high-risk nonmuscle-invasive bladder cancer (NMIBC). Methods: We performed a retrospective cohort study including 26 patients (14 AAs and 12 EAs) from the University of Texas Medical Branch and the Durham Veterans Affair Health Care System from 2010 to 2020 among treatment naïve, high-risk NMIBC. Profiled gene expressions were performed using the UROMOL classification system. Results: UROMOL racial subtype distributions were similar with class 2a being most common with 10 genes commonly upregulated in AAs compared to EAs including EFEMP1, S100A16, and MCL1 which are associated with progression to muscle-invasive bladder cancer, mitomycin C resistance, and bacillus Calmette-Guérin durability, respectively. We used single nuclei analysis to map the malignant cell heterogeneity in urothelial cancer which 5 distinct malignant epithelial subtypes whose presence has been associated with different therapeutic response prediction abilities. We mapped the expression of the 10 genes commonly upregulated by race as a function of the 5 malignant subtypes. This showed borderline (P = 0.056) difference among the subtypes suggesting AAs and EAs may be expected to have different therapeutic responses to treatments for bladder cancer. AAs were enriched with immune-related, inflammatory, and cellular regulation pathways compared to EAs, yet appeared to have reduced levels of the aggressive C3/CDH12 bladder tumor cell population. Conclusions: While premature, gene expression differed between AAs and EAs, supporting potential race-based etiologies for muscle-invasion, response to treatments, and transcriptome pathway regulations.

To examine differences in survival outcomes for muscle-invasive bladder cancer patients stratified by new mental health diagnosis.Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified patients diagnosed with muscle-invasive bladder cancer between 2008 and 2014. Our primary outcome was cancer-specific and overall hazards of mortality. As a secondary outcome, we reported predictors of developing a new mental health diagnosis after bladder cancer diagnosis. We used Cox proportional hazards models to determine the impact of palliative care and mental health diagnoses on survival outcomes after adjusting for grade, stage, comorbidity index, and baseline demographics.Of the 3794 patients who met inclusion criteria, 1193 (31%) were diagnosed with a mental health illness after their bladder cancer diagnosis during the 6 years in the study period. The most common diagnoses were depression (13%), alcohol and drug abuse (12%), and anxiety (11%). Patients with a post-bladder cancer mental health diagnosis had a 57% higher hazard of overall mortality (HR 1.57, P = .048) and an 80% higher hazard of bladder cancer-specific mortality (HR 1.81, P = .037) CONCLUSIONS: New mental health diagnoses are associated with worse survival in patients with muscle invasive bladder cancer. This suggests that a multimodal approach to bladder cancer treatment should include addressing the non-oncologic needs of the patient to optimize survival outcomes.

Advances in functional magnetic resonance spectroscopy (fMRS) have enabled the quantification of activity-dependent changes in neurotransmitter concentrations in vivo. However, the physiological basis of the large changes in GABA and glutamate observed by fMRS (>10%) over short time scales of less than a minute remain unclear as such changes cannot be accounted for by known synthesis or degradation metabolic pathways. Instead, it has been hypothesized that fMRS detects shifts in neurotransmitter concentrations as they cycle from presynaptic vesicles, where they are largely invisible, to extracellular and cytosolic pools, where they are detectable. The present paper uses a computational modelling approach to demonstrate the viability of this hypothesis. A new mean-field model of the neural mechanisms generating the fMRS signal in a cortical voxel is derived. The proposed macroscopic mean-field model is based on a microscopic description of the neurotransmitter dynamics at the level of the synapse. Specifically, GABA and glutamate are assumed to cycle between three metabolic pools: packaged in the vesicles; active in the synaptic cleft; and undergoing recycling and repackaging in the astrocytic or neuronal cytosol. Computational simulations from the model are used to generate predicted changes in GABA and glutamate concentrations in response to different types of stimuli including pain, vision, and electric current stimulation. The predicted changes in the extracellular and cytosolic pools corresponded to those reported in empirical fMRS data. Furthermore, the model predicts a selective control mechanism of the GABA/glutamate relationship, whereby inhibitory stimulation reduces both neurotransmitters, whereas excitatory stimulation increases glutamate and decreases GABA. The proposed model bridges between neural dynamics and fMRS and provides a mechanistic account for the activity-dependent changes in the glutamate and GABA fMRS signals. Lastly, these results indicate that echo-time may be an important timing parameter that can be leveraged to maximise fMRS experimental outcomes.

Purpose: To systematically review the literature to investigate racial disparities among bladder cancer clinical trial enrollees. Methods: A systematic review was conducted using Ovid, MEDLINE® to identify clinical trials between 1970 and 2020. Articles were reviewed and were included if they assessed race in their outcomes reporting among bladder cancer patients enrolled in clinical trials. The review was conducted in accordance with the PRISMA statement. Results: We identified 544 clinical trials meeting our initial search criteria, with only 24 (4.4%) studies reporting racial demographic data. Enrollees were largely Caucasian (81–98%), with a strikingly small proportion of enrolled patients consisting of African-Americans (2–8%) and Hispanics (2–5%). Only one of the studies reported results on the efficacy and safety/tolerability of the tested treatment separately for racial groups and performed analyses stratified by race. Conclusion: Race is poorly studied in bladder cancer clinical trials. Trial cohorts may not reflect multicultural populations. The potential association between race and efficacy, safety or tolerability of the tested interventions is unknown. Given the up to twofold increase in bladder cancer-specific death among African-Americans, further research is needed to address the impact of race in clinical trials, while encompassing socioeconomic factors and disease risk factor exposures.

Primary care healthcare organizations are complex and multidimensional, and there has been much discussion about the potential dangers of focusing on outcomes as quality indicators in isolation without understanding the processes and system characteristics that drive them. Organizational health, as a concept, shifts the focus of measurement upstream and considers the elements needed for sustainable long-term success. This study has both designed and tested the first survey seeking to measure organizational health specifically within the context of primary care. A stepwise approach was taken to ensure that the validity and reliability of the survey was examined at multiple stages.Supplemental data for this article is available online at https://doi.org/10.1080/00185868.2021.1947164.

BACKGROUND The objective of this study was to describe bladder cancer outcomes as a function of race among patients with high-risk non-muscle-invasive bladder cancer (NMIBC) in an equal-access setting. METHODS A total of 412 patients with high-risk NMIBC who received bacille Calmette-Guerin (BCG) from January 1, 2010, to December 31, 2015, were assessed. The authors used the Kaplan-Meier method to estimate event-free survival and Cox regression to determine the association between race and recurrence, progression, disease-specific, and overall survival outcomes. RESULTS A total of 372 patients who had complete data were included in the analysis; 48 (13%) and 324 (87%) were Black and White, respectively. There was no difference in age, sex, smoking status, or Charlson Comorbidity Index by race. White patients had a higher socioeconomic status with a greater percentage of patients living above the poverty level in comparison with Black patients (median, 85% vs 77%; P < .001). A total of 360 patients (97%) received adequate induction BCG, and 145 patients (39%) received adequate maintenance BCG therapy. There was no significant difference in rates of adequate induction or maintenance BCG therapy according to race. There was no significant difference in recurrence (hazard ratio [HR], 1.53; 95% confidence interval [CI], 0.64-3.63), progression (HR, 0.77; 95% CI, 0.33-1.82), bladder cancer-specific survival (HR, 1.01; 95% CI, 0.30-3.46), or overall survival (HR, 0.97; 95% CI, 0.56-1.66) according to Black race versus White race. CONCLUSIONS In this small study from an equal-access setting, there was no difference in the receipt of BCG or any differences in bladder cancer outcomes according to race.

Dionaea muscipula traps, in a natural setting, are sometimes triggered to close without capturing prey. In the Florida panhandle, in dry weather, time-lapse photographs show the frequency of closure without capture to be 2.1 closures/% of active-traps/day. A sudden burst of intense rain can increase this by two to three orders of magnitude for a brief time. Frequencies of 15.5 closures/% of active-traps/hour and 148 closures/% of active-traps/hour have been measured. The large increase in closures occurs when rain first starts, because the most exposed and most sensitive traps are triggered early, leaving traps in a more sheltered position and those with a less sensitive response open. Only 6 to 12% of the traps in the field of view were closed by intense rain. Even rain so heavy that the traps were submerged in water left most of the traps open. Gentle rain can close traps, but this is not a common event. The necessity of two or more stimuli to close a trap accounts for traps general lack of responsiveness to raindrops in light rainfall. Traps observed to be closed by raindrops began reopening in an average of 4.5 hours and full reopening averaged 15.8 hours. Since partially open traps are capable of capturing prey, the average trap closed by rain is effective at trapping in about 12 hours. Rainfall is only a minor factor interfering with traps’ ability to catch prey.

Trail cameras can be used for the study of the interaction between plants and insects if they have a close-up lens and the capability of doing time-lapse photographs or videos. Typical trail cameras are mounted vertically, often on unstable camera stands. We have used the Bushnell NatureView HD Cam Model# 119740 and RC Williams Co. TopView Quick-Mount camera-stand to study the behavior of insects interacting with Venus flytraps (Dionaea muscipula). The combination allows photographs and videos to be made of insects and plants from above, with the camera held in a position that allows the plants to be observed from the exact same position for months at a time. Every five minutes a photograph and a one-minute video are recorded. We have developed methods of searching through this data for important events that involve producing “slide shows” of the photographs overlain by a grid, that can be quickly scanned for events of interest. Video of these events near the time of the sequentially numbered photograph can then be viewed. The slides and videos can also be sampled at intervals for more gradual changes.

Dionaea flowers are pollinated by insects, primarily bees, in both their native habitat in the Carolinas and in the population growing from seed scattered many years ago in the Florida panhandle, the location of this study. The green sweat bee (Augochlorella sp. is a major pollinator in both habitats, while various flower visiting beetles play a prominent role in the Carolinas and bumblebees (Bombus sp.) play a major role in the Florida population. Flowers open in late morning and pollen is on anthers arrayed directly above the center of the flower by 11:30 EST. Twenty-four hours later the stamens have bent so that the anthers are at the periphery of the flower and the stigma has expanded, presenting a papillate surface receptive to pollen. Insects visit the flower between 11:30 EST and 18:00 EST. Rewards for pollinators are pollen and nectar from glands at the base of the petals. Possible attractants include the bright white radially symmetrical corolla with radiating grey veins, and on the second day, the radially displayed stamens that may act as a 'nectar guide'. No markings on the petals are visible in the ultraviolet light but the pollen-laden anthers are UV-fluorescent and would stand out as a ring of dots to any UV-perceptive insect.

OBJECTIVE Older patients diagnosed with cancer are at increased risk of physical and emotional distress; however, prescription utilization patterns largely remain to be elucidated. Our objective was to comprehensively assess prescription patterns and predictors in older patients with bladder cancer. METHODS A total of 10,516 older patients diagnosed with clinical stage T1-T4a, N0, M0 bladder urothelial carcinoma from 1 January 2008 to 31 December 2012 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare were analyzed. We used multivariable analysis to determine predictors associated with psychotropic prescription rates (one or more). Medication possession ratio (MPR) was used as an index to measure adherence in intervals of 3 months, 6 months, 1 year, and 2 years. Evaluation of psychotropic prescribing patterns and adherence across different drugs and demographic factors was done. RESULTS Of the 10,516 older patients, 5621 (53%) were prescribed psychotropic drugs following cancer diagnosis. Overall, 3972 (38%) patients had previous psychotropic prescriptions prior to cancer diagnosis, and these patients were much more likely to receive a post-cancer diagnosis prescription. Prescription rates for psychotropic medications were higher among patients with higher stage BC (p

INTRODUCTION Endoscopic mucosal resection (EMR) is an effective therapy for naive large nonpedunculated colorectal polyps (N-LNPCPs). The best approach for the treatment of previously attempted LNPCPs (PA-LNPCPs) is undetermined. METHODS EMR performance for PA-LNPCPs was evaluated in a prospective observational cohort of LNPCPs ≥20 mm. Efficacy was measured by technical success (removal of all visible polypoid tissue during index EMR) and recurrence at first surveillance colonoscopy (SC1). Safety was assessed by clinically significant intraprocedural bleeding, deep mural injury types III-V, clinically significant post-EMR bleeding, and delayed perforation. RESULTS From January 2012 to October 2019, 158 PA-LNPCPs and 1,134 N-LNPCPs underwent EMR. Median PA-LNPCP size was 30 mm (interquartile range 25-46 mm). Technical success was 93.0% and increased to 95.6% after adjusting for 2-stage EMR. Cold-forceps avulsion with adjuvant snare-tip soft coagulation (CAST) was required for nonlifting polypoid tissue in 73 (46.2%). Median time to SC1 was 6 months (interquartile range 5-7 months). Recurrence occurred in 9 (7.8%). No recurrence was identified among 65 PA-LNPCPs which underwent margin thermal ablation at SC1 vs 9 (18.0%; P < 0.001) which did not. There were significant differences in resection duration (35 vs 25 minutes; P < 0.001), technical success (93.0% vs 96.6%; P = 0.026), and use of CAST (46.2% vs 7.6%; P < 0.001), between PA-LNPCPs and N-LNPCPs. When adjusting for 2-stage EMR, no difference in technical success was identified (95.6% vs 97.8%; P = 0.100). No differences in adverse events or recurrence were identified. DISCUSSION EMR, using auxillary techniques where necessary, can achieve high technical success and low recurrence frequencies for PA-LNPCPs.

Nitrogen (N) loss through ammonia $$({\mathrm{NH}}_{3})$$ volatilization in agricultural soils is a significant source of atmospheric $${\mathrm{NH}}_{3}$$ , contributing to low N use efficiency in crops, risk to human health, environmental pollution, and is an indirect source of nitrous oxide $$({\mathrm{N}}_{2}\mathrm{O})$$ emissions. Our objective was to develop an ammonia volatilization method within the DayCent ecosystem model that incorporates key 4R N management practices (right type, right rate, right placement, and right timing) that influence $${\mathrm{NH}}_{3}$$ volatilization associated with application of urea-based nitrogen fertilizers to agricultural soils. The $${\mathrm{NH}}_{3}$$ volatilization method was developed with Bayesian calibration using sampling importance resampling methods and Bayes factors to select the level of complexity in the model that best represents $${\mathrm{NH}}_{3}$$ volatilization given the observed data. The final model included urea hydrolysis and the influence of urease inhibitors; short-term soil pH changes following fertilization; fertilizer incorporation into the soil (mechanically and through irrigation/precipitation); and specification of the fertilizer placement method (i.e. broadcast vs. banding and surface vs incorporated). DayCent predicts $${\mathrm{NH}}_{3}$$ volatilization with a root-mean-squared error of 158 (95% interval ranging from 133 to 192), bias of 7 (95% interval ranging from − 106 to 102) g NH3-N ha−1 day−1, and with a Bayesian R2 value of 0.39 (95% interval ranging from 0.17 to 0.62). Furthermore, the model incorporates key management options influencing $${\mathrm{NH}}_{3}$$ volatilization related to placement method and fertilizer type with and without urease inhibitors that can be used to evaluate management and policy options for reducing losses of NH3 from urea fertilization.

We used the 10x Genomics Visium platform to define the spatial topography of gene expression in the six-layered human dorsolateral prefrontal cortex (DLPFC). We identified extensive layer-enriched expression signatures, and refined associations to previous laminar markers. We overlaid our laminar expression signatures onto large-scale single nuclei RNA sequencing data, enhancing spatial annotation of expression-driven clusters. By integrating neuropsychiatric disorder gene sets, we showed differential layer-enriched expression of genes associated with schizophrenia and autism spectrum disorder, highlighting the clinical relevance of spatially-defined expression. We then developed a data-driven framework to define unsupervised clusters in spatial transcriptomics data, which can be applied to other tissues or brain regions where morphological architecture is not as well-defined as cortical laminae. We lastly created a web application for the scientific community to explore these raw and summarized data to augment ongoing neuroscience and spatial transcriptomics research (http://research.libd.org/spatialLIBD).

Muscle-invasive bladder cancer (BC) often occurs in patients with competing mortality risks, while also being associated with the highest rate of second primary nonurothelial cancers (SNUC) of all solid malignancies. We investigated the incidence, risk factors, and timing of SNUC as a competing mortality risk factor in patients with BC who were treated with curative intent radical cystectomy (RC).We performed a retrospective cohort study assessing patients who underwent RC for cT2-4 N0M0 BC from January 1, 2005 to December 31, 2018 at a single, high volume tertiary care referral center. The Fine-Gray multivariable regression model was used to evaluate predictive factors for SNUC. Cumulative incidence of mortality (CIM) was estimated with modified Kaplan-Meier analysis.The median follow-up time for the 693 patients who underwent RC was 3.7 years (interquartile range [IQR] 1.9-5.9 years). SNUC developed in 85 (12.3%) patients at a median 3.0 years post-RC (IQR 1.2-5.5 years). On multivariable analysis, the only significant predictor for developing SNUC was freedom from BC recurrence or metastasis (HR 1.54, 95% CI 1.12-1.76, P = 0.019). The most common SNUCs were primary lung cancer (24, 3.2% of cohort) and colon cancer (9, 1.3% of cohort). BC surveillance imaging diagnosed SNUC in 35/52 (67.3%) patients with solid-organ visceral primaries. The overall mortality rate for any SNUC was 38.8%, with the 3 most lethal cancer types being pancreatic, lung, and colon (62.5%, 54.2%, and 44.4% mortality, respectively). The incidence of SNUC uniformly increased postoperatively, with a cumulative incidence of 22.1% (95% CI, 16.8-27.9%) at 12-years post-RC. 163 patients (23.5%) died from BC, 33 patients (4.8%) died from SNUC, and 94 patients (13.6%) died from other causes. While the CIM for BC plateaued around 5-years post-RC at 24%, the incidence of other-cause mortality uniformly rose throughout the postoperative period. By post-RC year 9 there was no significant difference in CIM between BC (CIM 27.2%, 95% CI, 23.5-31.1%) and other-causes (CIM 20.0%, 95% CI, 15.8-24.6%).The cumulative incidence of SNUC at 12-years post-RC was 22%, with the majority identified on BC surveillance imaging. While BC mortality plateaued around 5-years post-RC, mortality related to SNUC or other causes rose steadily in the postoperative period. These data have clinical significance with regards to patient counseling, survivorship and oncologic surveillance in the highly comorbid muscle-invasive BC population.

Impaired cognition is associated with lower quality of life and poor outcomes in schizophrenia. Brain glutamate may contribute to both clinical outcomes and cognition, but these relationships are not well-understood. We studied a multicentre cohort of 85 participants with non-affective psychosis using proton magnetic resonance spectroscopy. Glutamate neurometabolites were measured in the anterior cingulate cortex (ACC). Cognition was assessed using the Brief Assessment for Cognition in Schizophrenia (BACS). Patients were categorised as antipsychotic responders or non-responders based on treatment history and current symptom severity. Inverted U-shaped associations between glutamate or Glx (glutamate + glutamine) with BACS subscale and total scores were examined with regression analyses. We then tested for an interaction effect of the antipsychotic response group on the relationship between glutamate and cognition. ACC glutamate and Glx had a positive linear association with verbal memory after adjusting for age, sex and chlorpromazine equivalent dose (glutamate, β = 3.73, 95% CI = 1.26–6.20, P = 0.004; Glx, β = 3.38, 95% CI = 0.84–5.91, P = 0.01). This association did not differ between good and poor antipsychotic response groups. ACC glutamate was also positively associated with total BACS score (β = 3.12, 95% CI = 0.01–6.23, P = 0.046), but this was not significant after controlling for antipsychotic dose. Lower glutamatergic metabolites in the ACC were associated with worse verbal memory, and this relationship was independent of antipsychotic response. Further research on relationships between glutamate and cognition in antipsychotic responsive and non-responsive illness could aid the stratification of patient groups for targeted treatment interventions.

Bladder cancer (BC) represents a significant health problem due to the potential morbidity and mortality associated with disease burden, which has remained largely unaltered over time.To provide an expert collaborative review and describe the incidence, prevalence, and mortality of BC and to evaluate current evidence for BC screening and prevention.Data on the estimated incidence and mortality of BC for 2020 in 185 countries were derived from the International Agency for Research on Cancer GLOBOCAN database. A review of English-language articles published over the past 5 yr was conducted using PubMed/MEDLINE to identify risk factors in addition to contemporary evidence on BC screening and prevention.BC is the tenth most common cancer worldwide, with 573 278 cases in 2020. BC incidence is approximately fourfold higher in men than women. Tobacco smoking remains the principal risk factor, accounting for approximately 50% of cases. There is insufficient evidence to recommend routine BC screening. However, targeted screening of high-risk individuals (defined according to smoking history or occupational exposure) may reduce BC mortality and should be the focus of prospective randomized trials. In terms of disease prevention, smoking cessation represents the most important intervention, followed by a reduction in exposure to occupational and environmental carcinogens.BC confers a significant disease burden. An understanding of BC epidemiology and risk factors provides an optimal foundation for disease prevention and the care of affected patients.Bladder cancer is the tenth most common cancer worldwide and is approximately four times more common among men than among women. The main risk factors are tobacco smoking, followed by exposure to carcinogens in the workplace or the environment. Routine screening is not currently recommended, but may be beneficial in individuals at high risk, such as heavy smokers. Primary prevention is extremely important, and smoking cessation represents the most important action for reducing bladder cancer cases and deaths.

SummaryThe RNA modification N6-methyladenosine (m6A) is critically involved in the regulation of gene activity underlying experience-dependent plasticity, and is necessary for the functional interplay between RNA and RNA binding proteins (RBPs) in the nucleus. However, the complete repertoire of m6A-modified RNA interacting RBPs in the synaptic compartment, and whether they are involved in fear extinction, have yet to be revealed. Using RNA immunoprecipitation followed by mass spectrometry, we discovered 12 novel, synapsespecific, learning-induced m6A readers in the medial prefrontal cortex of male C57/B6 mice. m6A RNA-sequencing also revealed a unique population of learning-related m6A-modified RNAs at the synapse, which includes a variant of the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (Malat1). m6A-modified Malat1 binds to a subset of novel m6A readers, including cytoplasmic FMR1 interacting protein 2 (CYFIP2) and dihydropyrimidase-related protein 2 (DPYSL2) and a cell-type-specific, state-dependent, and synapse-specific reduction in m6A-modified Malat1 disrupts the interaction between Malat1 and DPYSL2 and impairs fear extinction. The consolidation of fear-extinction memory therefore relies on an interaction between m6A-modified Malat1 and select RBPs in the synaptic compartment.

Recent advances in spatial transcriptomics (ST) enable gene expression measurements from a tissue sample while retaining its spatial context. This technology enables unprecedented in situ resolution of the regulatory pathways that underlie the heterogeneity in the tumor and its microenvironment (TME). The direct characterization of cellular co-localization with spatial technologies facilities quantification of the molecular changes resulting from direct cell-cell interaction, as occurs in tumor-immune interactions. We present SpaceMarkers, a novel bioinformatics algorithm to infer molecular changes from cell-cell interaction from latent space analysis of ST data. We apply this approach to infer molecular changes from tumor-immune interactions in Visium spatial transcriptomics data of metastasis, invasive and precursor lesions, and immunotherapy treatment. Further transfer learning in matched scRNA-seq data enabled further quantification of the specific cell types in which SpaceMarkers are enriched. Altogether, SpaceMarkers can identify the location and context-specific molecular interactions within the TME from ST data.

Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

In 1997 an international group of scientists organized a meeting in Barcelona, Spain, to discuss the use of biomarkers in the management of patients with bladder cancer. This meeting was the offspring of an - initially informal - group that finally resulted in the foundation and incorporation of the International Bladder Cancer Network (IBCN) e.V. in 2005. Over the years the group has supported several research initiatives and generated several recommendations on the use of biomarkers in the diagnosis and treatment of bladder cancer. Meeting quality was generated by inviting experts presenting state-of-the-art lectures or work in progress reports, interdisciplinarity and the limited number of participants supporting an open and personal exchange resulted in a format increasingly attracting participants from all over the world. The recent limitations caused by the Covid-19 pandemic were partially met by organizing several well attended webinars. The future challenge is to maintain the IBCN meeting spirit despite an increasing interest of the scientific community and industrial partners to participate. However, the integration of and interaction between increasingly more specialized disciplines is a challenge that can be better catalyzed by an international multidisciplinary network than mostly national professional associations.

Rationale Chronic fatigue syndrome (CFS) is a common and burdensome illness with a poorly understood pathophysiology, though many of the characteristic symptoms are likely to be of brain origin. The use of high-field proton magnetic resonance spectroscopy (MRS) enables the detection of a range of brain neurochemicals relevant to aetiological processes that have been linked to CFS, for example, oxidative stress and mitochondrial dysfunction. Methods We studied 22 CFS patients and 13 healthy controls who underwent MRS scanning at 7 T with a voxel placed in the anterior cingulate cortex. Neurometabolite concentrations were calculated using the unsuppressed water signal as a reference. Results Compared to controls, CFS patients had lowered levels of glutathione, total creatine and myo-inositol in anterior cingulate cortex. However, when using N-acetylaspartate as a reference metabolite, only myo-inositol levels continued to be significantly lower in CFS participants. Conclusions The changes in glutathione and creatine are consistent with the presence of oxidative and energetic stress in CFS patients and are potentially remediable by nutritional intervention. A reduction in myo-inositol would be consistent with glial dysfunction. However, the relationship of the neurochemical abnormalities to the causation of CFS remains to be established, and the current findings require prospective replication in a larger sample.

PURPOSE Mortality from bladder cancer (BC) increases exponentially once it invades the muscle, with inherent challenges delineating at the population level. We sought to develop and validate a natural language processing (NLP) model for automatically identifying patients with muscle-invasive bladder cancer (MIBC). METHODS All patients with a Current Procedural Terminology code for transurethral resection of bladder tumor (TURBT; n = 76,060) were selected from the Department of Veterans Affairs (VA) database. A sample of 600 patients (with 2,337 full-text notes) who had TURBT and confirmed pathology results were selected for NLP model development and validation. The NLP performance was assessed by calculating the sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and overall accuracy at the individual note and patient levels. RESULTS In the validation cohort, the NLP model had average overall accuracies of 94% and 96% at the note and patient levels. Specifically, the F1 score and overall accuracy for predicting muscle invasion at the patient level were 0.87% and 96%, respectively. The model classified nonmuscle-invasive bladder cancer (NMIBC) with overall accuracies of 90% and 93% at the note and patient levels. When applying the model to 71,200 patients VA-wide, the model classified 13,642 (19%) as having MIBC and 47,595 (66%) as NMIBC and was able to identify invasion status for 96% of patients with TURBT at the population level. Inherent limitations include a relatively small training set, given the size of the VA population. CONCLUSION This NLP model, with high accuracy, may be a practical tool for efficiently identifying BC invasion status and aid in population-based BC research.

BACKGROUND: Disparity in mental health care among cancer patients remains understudied. METHODS: We conducted a large, retrospective, single tertiary-care institution cohort study based on de-identified electronic health record data of 54,852 adult cancer patients without prior mental health diagnosis (MHD) diagnosed at the University of California, San Francisco between 1/2012 and 9/2019. The exposure of interest was early onset MHD with or without psychotropic medication (PM) within 12 months of cancer diagnosis and primary outcome was all-cause mortality. RESULTS: 8.2% of patients received a new MHD at a median of 197 days (interquartile-range [IQR] 61-553) after incident cancer diagnosis, 31.0% received a PM prescription, and 3.7% a MHRV. 62.6% of patients were non-Hispanic white (NHW), 10.8% Asian, 9.8% Hispanic, and 3.8% Black. Compared to NHWs, minority cancer patients had reduced adjusted odds of MHDs, PM prescriptions, and MHRVs, particularly for generalized anxiety (Asian: odds ratio [OR] 0.66, 95% confidence interval 0.55-0.78; Black: OR 0.60, 0.45-0.79; Hispanic: OR 0.72, 0.61-0.85) and selective-serotonin-reuptake-inhibitors (SSRI; Asian: OR 0.43, 0.37-0.50; Black: OR 0.51, 0.40-0.61; Hispanic: OR 0.79, 0.70-0.89). New early MHD with PM was associated with elevated all-cause mortality (12-24 months: hazard ratio [HR] 1.43, 1.25-1.64) that waned by 24-36 months (HR 1.18, 0.95-1.45). CONCLUSIONS AND RELEVANCE: New mental health diagnosis with psychotropic medication was a marker of early mortality among cancer patients. Minority cancer patients were less likely to receive documentation of mental health diagnoses or treatment, which may represent missed opportunities to identify and treat cancer related mental health conditions.

With an increasing proportion of UK healthcare delivered by independent sector providers (ISPs) it is important that performance data is reviewed with a similar rigour as within the public sector. However, there is a relative paucity of work considering quotients of performance in the independent healthcare sector. This study sets out to measure organizational health within ISPs in the UK and juxtapose this with contemporaneous data taken from public sector NHS organizations. Survey data was tested for construct validity with fit of the existing factor structure of the Healthcare-OH survey examined using confirmatory factor analysis (CFA). Multiple-group CFA was used to establish measurement invariance to permit comparison of latent sum scores between ISP and NHS organizations. Measurement invariance analysis evaluated the fit of sequential invariance models, proceeding iteratively to establish partial metric and scalar invariance. Latent sum scores comparisons demonstrated ISPs outperformed NHS trusts across all elements of organizational health. This is the first time organizational health has been measured in ISPs explicitly for comparison with results in the public sector. Comparative measurement and analysis in this way is novel and has the potential of fostering a two-way learning process for the ultimate benefit of both NHS and ISP organizations.

Context Immune therapy has emerged as a powerful treatment of metastatic urothelial carcinoma. Over 20 ongoing studies are exploring this strategy in the neoadjuvant setting in patients with localized muscle-invasive bladder cancer. Objective To summarize the rationale and the clinical outcomes regarding the use of immune checkpoint blockade in the neoadjuvant setting before radical cystectomy. Evidence acquisition A systematic review of the literature in the MEDLINE database was performed. The central search strategy used the terms bladder cancer, urothelial carcinoma, mice, human, immunotherapy, neoadjuvant therapy, atezolizumab, pembrolizumab, durvalumab, nivolumab, avelumab, ipilimumab, and tremelimumab. The search was limited to publications between January 2008 and February 2020. Publicly available relevant abstracts from recent meetings were also included. Evidence synthesis Phase II trials investigating neoadjuvant immune checkpoint blockade as a single agent before radical cystectomy reported a rate of pathological complete response (CR), ranging from 31% with an anti–PD-L1 monoclonal antibody (mAb) atezolizumab (n = 27/88) to 37% with anti–PD-1 mAb pembrolizumab (n = 42/114). Overall, 92% (n = 87/95) and 98% (n = 112/114) of the patients underwent radical cystectomy. Neoadjuvant immune checkpoint blockade did not delay planned surgery. Checkpoint inhibitor monotherapy was well tolerated, with no unexpected toxicity in the presurgical setting. Early phase I/II trials investigating neoadjuvant combination chemotherapy strategies with immune checkpoint blockers reported enhanced antitumor efficacy, with a pathological CR ranging from 33% to 50%. Conclusions Although limited clinical data are available on long-term survival, neoadjuvant immune checkpoint blockade demonstrated effective antitumor efficacy for localized muscle-invasive bladder cancer. Phase III trials are currently investigating this strategy in the presurgical setting. Patient summary Immunotherapy prior to surgery has been evaluated for patients with muscle-invasive bladder cancer. Although long-term survival benefit is unknown, such treatment strategy revealed a promising antitumor response rate for patients who underwent radical cystectomy. Ongoing prospective clinical trials will define the potential advantage of this approach over current cisplatin-based chemotherapeutic regimens alone or in combination.

Enhanced Recovery After Surgery (ERAS) is a perioperative approach to managing surgical patients. The impact of ERAS on radical cystectomy (RC) outcomes remains understudied.To review the literature regarding ERAS protocols and RC outcomes. The primary outcome was hospital length of stay (LOS).A systematic review of the articles published from 1970 through 2018 was conducted. Individual patient data (IPD) were requested and a meta-analysis was performed.A total of 4197 articles were retrieved and 22 (reporting 4048 patients) were selected for the review. LOS followed by 30-d and that followed by 90-d complications were the most common endpoints. ERAS use was associated with reduced morbidity, quicker bowel recovery, and shorter LOS, without affecting mortality. IPD were obtained for 2077 patients from 11 studies. In multivariable models, LOS was associated with ERAS use (regression coefficient: -4.54 [95% confidence interval {CI}: -5.79 to -3.28] d with ERAS p 0.001) and Charlson Comorbidity Index (+1.64 [1.38-1.90] d for each point increase, p 0.001), and varied between hospitals (from -1.59 [-3.03 to -0.14] to +4.55 [1.89-7.21] d, p 0.03). Individual ERAS components associated with shorter LOS included no nasogastric (NG) tube (-8.70 [-11.9 to -5.53] d, p 0.001) and local anesthesia blocks compared with regional anesthesia (-3.29 [-6.31 to -0.27] d, p = 0.03).ERAS protocols were associated with reduced LOS and postoperative complication rate. Avoidance of NG tubes and use of local anesthesia blocks were significantly associated with reduced LOS. These findings reflect different components of recovery, which ERAS can optimize and further support documentation of the use of ERAS components when reporting RC outcomes.Use of enhanced recovery in patients undergoing surgery to remove the bladder is associated with fewer surgical complications and a shorter hospital stay. Avoidance of nasogastric tubes and use of local anesthesia after the operation were associated with a shorter length of stay.