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Item does not contain fulltext CONTEXT: Intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease. OBJECTIVE: To update the International Bladder Cancer Group (IBCG) guidance and provide practical recommendations on IR NMIBC management. EVIDENCE ACQUISITION: A collaborative review of published randomized clinical trials, meta-analyses, systematic reviews, and clinical practice guidance on IR NMIBC published before January 2022 was undertaken using PubMed/Medline. EVIDENCE SYNTHESIS: Variation exists between guidelines in defining IR NMIBC. The IBCG recommends defining IR NMIBC as any TaLG tumor that is either recurrent or multifocal or has size ≥3 cm, OR any T1LG tumor. If the 3 tier grading system is used, than any TaG2 tumor would also be considered IR diease regardless of whether new diagnosis or recurrent. Accurate grading and staging of tumor, particularly in ruling out HG/G3 disease and/or carcinoma in situ, are crucial. The IBCG recommends that management of IR NMIBC should be further based on the following risk factors: multifocal tumor (more than one), early recurrence (1/yr), tumor size (≥3 cm), and failure of prior intravesical treatment. Patients with no risk factors are best managed by one dose of postoperative intravesical chemotherapy. Patients with one to two risk factors should be offered additional adjuvant induction intravesical chemotherapy (or bacillus Calmette-Guérin (BCG) if prior chemotherapy has been used). Patients with three or more risk factors should be offered induction plus 1-yr maintenance BCG. Where BCG is not available or recurrent disease following BCG is present, alternative intravesical treatments such as chemotherapy (single agent, combination, or chemohyperthermia) or a clinical trial are recommended. CONCLUSIONS: Standardizing the definition of IR NMIBC is critical for appropriate management of patients and for allowing a comparison of outcomes across clinical trials. The IBCG recommends defining IR NMIBC as any TaLG tumor that is either recurrent or multifocal or ≥3 cm, OR any T1LG tumor. If the 3 tier grading system is used, than any TaG2 tumor would also be considered IR disease regardless of whether new diagnosis or recurrent. Adjunctive management should then be based on established risk factors. PATIENT SUMMARY: Standardizing the definition of intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC), which is a heterogeneous disease, is critical for appropriate management of patients. The International Bladder Cancer Group recommends classification of IR NMIBC tumors and personalized management based on the following risk factors: multifocal tumor (more than one), early recurrence (1/yr), tumor size (≥3 cm), and previous intravesical treatment.

Surgical repair in anomalous aortic origin of a coronary artery aims at mitigating the risk of sudden cardiac death in a subset of patients. The pattern and behavior of electrocardiogram changes in a large cohort of these patients are lacking. We aim to describe postoperative electrocardiogram changes in this population and its clinical implications on follow-up.All patients aged less than 21 years who underwent surgical repair for anomalous aortic origin of a coronary artery between December 2012 and June 2020 at our institution were considered for inclusion. Electrocardiograms were reviewed at 5 defined time intervals, from preoperative to 90-day follow-up, with attention to significant findings of ST-segment changes, abnormal T waves, and pathologic Q waves. The electrocardiogram changes were analyzed for correlation with surgical reintervention and medium-term outcomes.Sixty-two patients met inclusion criteria (median age 13.7 years, 61% male). ST-segment changes in the initial postoperative period were seen in 52 patients (84%), all resolving over time. Abnormal T waves were seen in 19 patients (31%), occurred commonly at the predischarge period, and mostly resolved over time. Pathologic Q waves were observed in only 1 patient and associated with reintervention due to coronary artery stenosis. There was no association between postoperative electrocardiogram changes and inducible myocardial ischemia, ventricular dysfunction, or restriction from exercise at follow-up.ST-segment changes and T-wave abnormalities are commonly seen in the postoperative period after anomalous aortic origin of a coronary artery repair, tend to resolve over time, and are not associated with adverse medium-term outcomes. Pathologic Q waves were associated with the need for early coronary reintervention.

Low testosterone levels in males have been linked with increase in proinflammatory cytokines-a primary culprit in COVID-19 disease progression-and with adverse COVID-19 outcomes. To date, however, no published studies have assessed the effect of testosterone therapy on COVID-19 outcomes in older men.To examine whether testosterone therapy reduced disease progression in older men diagnosed with COVID-19.Nested within a national cohort of older (aged ≥50 years) male patients diagnosed with COVID-19 between January 1, 2020 and July 1, 2021 from the Optum electronic health record COVID-19 database, two matched case-control studies of COVID-19 outcomes were conducted. Cases-defined, respectively, as persons who (a) were hospitalized ≤30 days after COVID-19 diagnosis (n = 33,380), and (b) were admitted to the intensive care unit or received mechanical ventilation during their COVID-19 hospitalization (n = 10,273)-were matched 1:1 with controls based on demographic and clinical factors.Testosterone therapy was defined based on receipt of prescription at ≤60, ≤90, or ≤120 days before COVID-19 diagnosis.Adjusted odds ratios (ORs) for the risk of hospitalization within 30 days of COVID-19 diagnosis and intensive care unit admission/mechanical ventilation during COVID-19 hospitalization.The use of testosterone therapy was not associated with decreased odds of hospitalization (≤60 days: OR = 0.92, 95% confidence interval [CI] = 0.70-1.20; ≤90 days: OR = 0.87, 95% CI = 0.68-1.13; ≤120 days: OR = 0.97, 95% CI = 0.72-1.32) or intensive care unit admission/mechanical ventilation (≤60 days: OR = 0.67, 95% CI = 0.37-1.23; ≤90 days: OR = 0.63, 95% CI = 0.36-0.11; ≤120 days: OR = 0.58, 95% CI = 0.29-1.19).This study showed that testosterone therapy was not associated with decreased risks of COVID-19 adverse outcomes. These findings may provide clinically relevant information regarding testosterone treatment in older men with COVID-19 and other respiratory viral infections with similar pathogenesis.

Endoscopic mucosal resection (EMR) is a cornerstone in the management of large (≥20 mm) non-pedunculated colorectal polyps. Clinically significant post-EMR bleeding occurs in 7% of cases and is most frequently encountered in the right colon. We aimed to assess the use of prophylactic clip closure in preventing clinically significant post-EMR bleeding within the right colon.We conducted a randomised controlled trial at a tertiary centre in Australia. Patients referred for the EMR of large non-pedunculated colorectal polyps in the right colon were eligible. Patients were randomly assigned (1:1) into the clip or control (no clip) group, using a computerised random-number generator. The primary endpoint was clinically significant post-EMR bleeding, defined as haematochezia necessitating emergency department presentation, hospitalisation, or re-intervention within 14 days post-EMR, which was analysed on the basis of intention-to-treat principles. The trial is registered with ClinicalTrials.gov, NCT02196649, and has been completed.Between Feb 4, 2016, and Dec 15, 2020, 231 patients were randomly assigned: 118 to the clip group and 113 to the control group. In the intention-to-treat analysis, clinically significant post-EMR bleeding was less frequent in the clip group than in the control group (four [3·4%] of 118 patients vs 12 [10·6%] of 113; p=0·031; absolute risk reduction 7·2% [95% CI 0·7-13·8]; number needed to treat 13·9). There were no differences between groups in adverse events, including delayed perforation (one [1%] in the clip group vs one [1%] in the control group) and post-EMR pain (four [3%] vs six [5%]). No deaths were reported.Prophylactic clip closure can be performed following the EMR of large non-pedunculated colorectal polyps of 20 mm or larger in the right colon to reduce the risk of clinically significant post-EMR bleeding.None.

There is an unmet need for development of non-invasive tests for the diagnostic assessment and monitoring of nonalcoholic fatty liver disease (NAFLD).Using modified-aptamer proteomics, we assayed 5220 proteins in each of 2852 single serum samples from 636 individuals with histologically confirmed NAFLD. We developed and validated dichotomized protein-phenotype models for clinically relevant severity of steatosis (grade 0 vs 1-3), hepatocellular ballooning (0 vs 1 or 2), lobular inflammation (0-1 versus 2-3) and fibrosis (stages 0-1 vs 2-4).Results for the 4 protein models, based on 37 analytes (18 not previously linked to NAFLD), in training/paired validation were: fibrosis (AUC 0.92/0.85); steatosis (AUC 0.95/0.79), inflammation (AUC 0.83/0.72), and ballooning (AUC 0.87/0.83). An additional outcome, at risk NASH, defined as steatohepatitis with NAS ≥ 4 with one or more points in each of the components and fibrosis stage 2 or higher, was created by multiplying the outputs of each individual component model (AUC 0.93/0.85). We further evaluated their ability to detect change in histology following treatment with placebo, pioglitazone, vitamin E or obeticholic acid (OCA). Component model scores significantly improved in the active therapies vs. placebo, and differential effects of vitamin E, pioglitazone, and OCA were identified.Serum protein scanning identified signatures corresponding to the key components of liver biopsy in NAFLD. The models developed were sufficiently sensitive to characterize the longitudinal change for three different drug interventions. These data support continued validation of these proteomic models to enable a "liquid biopsy"-based assessment of NAFLD.Individuals with NASH may have liver inflammation and scarring, along with fat in their liver, all of which are assessed by liver biopsy. In this study, we use an innovative protein scanning technology to develop and validate blood-based signatures of liver damage that have the potential to replace liver biopsy for NASH diagnosis and monitoring response to treatment. These signatures can also provide NASH drug developers with insights into treatment-mediated responses and mechanisms of action.An aptamer-based protein scan of serum proteins was performed to identify diagnostic signatures of the key histological features of nonalcoholic steatohepatitis for which there are no approved non-invasive diagnostic tools currently available. Specific protein signatures related to presence and severity of NASH and its histological components that were also sensitive to change over time were identified. These are fundamental initial steps in establishing a serum-proteome based diagnostic signature of NASH and provide a rationale for using these signatures to test treatment response and to identify several novel targets for evaluation in the pathogenesis of NASH.Not applicable.

To determine the geographic distribution of muscle-invasive bladder cancer mortality according to race in the United States (US). African Americans (AAs) have up to two times the risk of bladder cancer mortality compared to Caucasians. Bladder cancer mortality increases exponentially once it invades the muscle. Geographic heterogeneity in bladder cancer mortality according to race remains to be determined.Analysis of Surveillance, Epidemiology, and End Results (SEER)-Medicare data for 6,044 patients aged 66-85 diagnosed with clinical stage T2-T4 N0M0 bladder cancer from 1 January 2002 to 31 December 2011. Fine and Gray-competing risks regression models were used to assess the association of race with bladder cancer-specific mortality (BCSM) according to tumor registry.Out of 6,044 patients, 5,408 (89.5%) were Caucasian, 352 (5.82%) were non-Hispanic AA, 85 (1.4%) were Hispanic, and 199 (3.29%) were other. Of the 18 registries, AAs with bladder cancer were largely concentrated in Louisiana (19%), New Jersey (17.9%), and Georgia (17.6%). New Jersey was the only registry where AAs had increased risk of BCSM than Caucasians and only for stage T2 disease: (AHR, 1.74; 95% CI 1.22-2.47, p = 0.002). According to treatment, AAs in New Jersey had worse BCSM than Caucasians when they underwent radical cystectomy (AHR, 2.05; 95% CI 1.26-3.35, p = 0.0039) and radiotherapy or chemotherapy alone (AHR, 1.55; 95% CI 1.03-2.35, p = 0.0367).We observed geographic variation in bladder cancer mortality which impacted only one registry with one of the largest population of AAs. These findings support further investigation into the social determinants of race (i.e., socioeconomic status and distance to healthcare facility) and culturally centered healthcare decision making which may drive these results.

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.

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.

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.

Physiological changes such as hypoxia in the tumor microenvironment (TME) endow cancer cells with malignant properties, leading to tumor recurrence and rapid progression. Here, we assessed the effect of hypoxia (1% Oxygen) on the tumor suppressor Annexin A6 (AnxA6) and the response of triple-negative breast cancer (TNBC) cells to epidermal growth factor receptor (EGFR) and androgen receptor (AR) targeted therapies. We demonstrate that brief exposure of TNBC cells to hypoxia (within 24 h) is associated with down regulation of AnxA6 while > 24 h exposure cell type dependently stimulated the expression of AnxA6. Hypoxia depicted by the expression and stability of HIF-1/2α led to up regulation of the HIF target genes SLC2A1, PGK1 as well as AR and the AR target genes FABP-4 and PPAR-γ, but the cellular levels of AnxA6 protein decreased under prolonged hypoxia. Down regulation of AnxA6 in TNBC cells inhibited, while AnxA6 over expression enhanced the expression and cellular levels of HIF-1/2α, SLC2A1 and PGK1. RNAi mediated inhibition of hypoxia induced AnxA6 expression also strongly inhibited glucose uptake and ROS production in AnxA6 expressing TNBC cells. Using a luciferase reporter assay, we confirm that short-term exposure of cells to hypoxia inhibits while prolonged exposure of cells to hypoxia enhances AnxA6 promoter activity in HEK293T cells. Compared to cells cultured under normoxia, TNBC cells were more resistant to lapatinib under hypoxic conditions, and the downregulation of AnxA6 sensitized the cells to EGFR as well as AR antagonists. These data suggest that AnxA6 is a hypoxia inducible gene and that targeting AnxA6 upregulation may be beneficial in overcoming TNBC resistance to EGFR and/or AR targeted therapies.

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.

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.

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.

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).

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique used to modulate cortical excitability in the human brain. However, one major challenge with rTMS is that the responses to stimulation are highly variable across individuals. The underlying reasons why responses to rTMS are highly variable between individuals still remain unclear. Here, we investigated whether the response to continuous theta-burst stimulation (cTBS) - an effective rTMS protocol for decreasing cortical excitability - is related to individual differences in glutamate and GABA neurotransmission. We acquired resting-state magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging (fMRI) during semantic processing. Then, we applied cTBS over the anterior temporal lobe (ATL), a hub for semantic representation, to explore the relationship between the baseline neurochemical profiles in this region and the response to cTBS. We found that the baseline excitation-inhibition balance (glutamate + glutamine/GABA ratio) in the ATL was associated with individual cTBS responsiveness during semantic processing. Specifically, individuals with lower excitation-inhibition balance showed stronger inhibitory effect - poorer semantic performance. Our results revealed that non-responders (subjects who did not show an inhibitory effect of cTBS on subsequent semantic performance) had higher excitatory-inhibitory balance in the ATL, which led to up-regulated task-induced regional activity as well as increased ATL-connectivity with other semantic regions compared to responders. These results disclose that the baseline neurochemical state of a cortical region can be a significant factor in predicting responses to cTBS.

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.

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.

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.

Context Urothelial carcinoma can exhibit a wide range of variant morphologies. Many variants present diagnostic challenges and carry clinical implications that inform prognosis and treatment decisions. Objective To provide an overview of the diagnostic, therapeutic, and prognostic significance of histological variants of urothelial carcinoma. Evidence acquisition A PubMed/MEDLINE-based literature search was conducted using the key terms “urothelial carcinoma”, “variant histology”, “nested”, “micropapillary”, “microcystic”, “sarcomatoid”, “squamous differentiation”, “glandular differentiation”, “clear cell”, “plasmacytoid”, “lymphoepithelioma-like carcinoma”, “squamous cell carcinoma”, “small cell carcinoma”, “adenocarcinoma”, “radiotherapy”, “neoadjuvant chemotherapy”, and “adjuvant chemotherapy”. Evidence synthesis The incidence of variant histology is increasing due to improved recognition. Nonetheless, diagnosis can pose challenges due to sampling limitations and interobserver variability. Although associated with advanced disease at presentation, survival outcomes for most variants do not differ significantly compared with pure urothelial carcinoma of the same stage. Controversy exists regarding optimal management due to the low quality of available evidence. For most cases, radical cystectomy with pelvic lymph node dissection (with neoadjuvant chemotherapy when appropriate) represents the standard of care. Small cell carcinoma and lymphoepithelioma-like carcinoma appear to be particularly chemosensitive. Conclusions Accurate identification of variant histological subtypes is an important part of risk stratification, as these variants exhibit aggressive biological behaviour. Variant histology tumours are associated with advanced disease at presentation, which must be considered when counselling patients regarding survival outcomes. Optimal management remains to be defined but in most cases; neoadjuvant chemotherapy and radical cystectomy with pelvic lymph node dissection remains the mainstay of treatment. Patient summary It is important to recognise histological variants of urothelial carcinoma as they indicate aggressive disease. When compared with patients with pure urothelial carcinoma of the same disease stage, survival does not appear to be significantly worse. In most cases, patients with invasive variant histology should be treated with neoadjuvant chemotherapy and radical cystectomy. Take Home Messages Accurate identification of variant histology is important as it exhibits aggressive biological behaviour and affects treatment. Although associated with advanced disease at presentation, with appropriate treatment, survival outcomes are not significantly different compared with pure urothelial carcinoma of the same stage.

This study aimed to qualitatively develop a conceptual framework for organizational health, within the setting of GP practices in the UK, through a qualitative interview study utilizing aspects from grounded theory. Data saturation was reached after 33 interviews revealing six themes: Strategy, Resources, Leadership, Staff Wellbeing, Capacity for change and Ways of working. The structure of each theme is discussed in detail. By unpicking the elements of organizational health in GP practices in this way, we hope to shift focus from considering down-stream clinical outcomes in isolation to practices taking a more long-term view centered around fostering ongoing high performance.

Dendritic computations have a central role in rodent neocortical circuit function, which are signaled into neuronal output by the initiation and propagation of regenerative dendritic spikes. However, it remains poorly explored whether these mechanisms are operational in the human neocortex. To directly examine the dendritic computational properties of the most numerous class of pyramidal neuron in the human and rat neocortex we made simultaneous electrical recordings from the soma and apical dendrites of layer 2/3 pyramidal neurons maintained in acute brain slices of analogous cortical areas under identical experimental conditions. In both species correlated dendritic excitatory input led to the initiation of sodium channel-mediated dendritic spikes with conserved biophysical properties. Dendritic sodium spikes in human and rat layer 2/3 pyramidal neurons could be generated across a similar wide input range, exhibited a similar frequency range of activation, and forward propagated with high fidelity to drive neuronal output to implement stereotyped computations. Our findings therefore reveal that the dendritic computational properties of human layer 2/3 pyramidal neurons are phylogenetically conserved.

Low-risk non-muscle-invasive bladder cancer (NMIBC) is associated with extremely low rates of progression and cancer-specific mortality; however, patients with low-risk NMIBC may often receive non-guideline-recommended and potentially costly surveillance testing and treatment.To describe current surveillance and treatment practices, cancer outcomes, and costs of care for low-grade papillary stage Ta (low-grade Ta) NMIBC and identify factors associated with increased cost of care.This population-based cohort study identified 13 054 older adults (aged 66-90 years) diagnosed with low-grade Ta tumors in the Surveillance, Epidemiology and End Results-linked Medicare database from January 1, 2004, through December 31, 2013. Medicare claims data through December 31, 2014, were also reviewed. Data were analyzed from April 1 to October 6, 2021.Surveillance testing and treatment among patients with low-grade Ta NMIBC.The primary outcome was patterns in population-level surveillance and treatment practice over time among patients with low-grade Ta NMIBC. Secondary outcomes were recurrence (defined as receipt of subsequent transurethral resection of bladder tumor3 months after index diagnosis of NMIBC and initial transurethral resection of bladder tumor), progression (defined as receipt of definitive treatment for bladder cancer), and costs of care.Among 13 054 patients who met inclusion criteria, 9596 (73.5%) were male and 3458 (26.5%) were female, with a median age of 76 years (IQR, 71-81 years). A total of 403 patients (3.1%) were Black, 120 (0.9%) were Hispanic, 12 123 (92.9%) were White, and 408 (3.1%) were of other races and/or ethnicities. Rates of surveillance cystoscopy increased over the study period (from 79.3% in 2004 to 81.5% in 2013; P = .007), with patients receiving a median of 3.0 cystoscopies per year (IQR, 2.0-4.0 per year). Rates of upper tract imaging (particularly computed tomography or magnetic resonance imaging) also increased over the study period (from 30.4% in 2004 to 47.0% in 2013; P .001), with most patients receiving a median of 2.0 imaging tests per year (IQR, 1.0-2.0 per year). The use of urine cytologic testing or other urine biomarker assessment also increased (from 44.8% in 2004 to 54.9% in 2013; P .001). Rates of adherence to current guidelines were similar over time (eg, a median of 4398 patients [55.2%] received ≤2 cystoscopies per year in 2004-2008 vs a median of 2736 patients [53.8%] in 2009-2013; P = .11), suggesting overuse of all surveillance testing modalities. With regard to treatment, 2250 patients (17.2%) received intravesical bacillus Calmette-Guérin, and 792 patients (6.1%) received intravesical chemotherapy (excluding receipt of a single perioperative dose). Among all patients with low-grade Ta NMIBC, 217 (1.7%) experienced disease recurrence and 52 (0.4%) experienced disease progression. The total annual median costs of low-grade Ta surveillance testing and treatment increased by 60% (from $34 792 in 2004 to $53 986 in 2013), with higher 1-year median expenditures noted among those with disease recurrence ($76 669) vs no disease recurrence ($53 909) at the end of the study period.In this cohort study, despite low rates of disease recurrence and progression, rates of surveillance testing increased during the study period. The annual cost of care also increased over time, particularly among patients with recurrent disease. Efforts to improve adherence to current practice guidelines, with the focus on limiting overuse of surveillance testing and treatment, may mitigate associated increasing costs of care.

The expression of the melanoma/cancer-testis antigen MAGEC2/CT10 is restricted to germline cells, but like most cancer-testis antigens, it is frequently upregulated in advanced breast tumors and other malignant tumors. However, the physiological cues that trigger the expression of this gene during malignancy remain unknown. Given that malignant breast cancer is often associated with skeletal metastasis and co-morbidities such as cancer-induced hypercalcemia, we evaluated the effect of high Ca2+ on the calcium-sensing receptor (CaSR) and potential mechanisms underlying the survival of triple-negative breast cancer (TNBC) cells at high Ca2+. We show that chronic exposure of TNBC cells to high Ca2+ decreased the sensitivity of CaSR to Ca2+ but stimulated tumor cell growth and migration. Furthermore, high extracellular Ca2+ also stimulated the expression of early response genes such as FOS/FOSB and a unique set of genes associated with malignant tumors, including MAGEC2. We further show that the MAGEC2 proximal promoter is Ca2+ inducible and that FOS/FOSB binds to this promoter in a Ca2+- dependent manner. Finally, downregulation of MAGEC2 strongly inhibited the growth of TNBC cells in vitro. These data suggest for the first time that MAGEC2 is a high Ca2+ inducible gene and that aberrant expression of MAGEC2 in malignant TNBC tissues is at least in part mediated by an increase in circulating Ca2+via the AP-1 transcription factor.

To systematically review the literature to investigate racial disparities among bladder cancer clinical trial enrollees.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.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.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.

Background Upper tract urothelial carcinoma (UTUC) is a heterogeneous disease that presents a clinical management challenge for the urologic surgeon. We assessed treatment patterns, costs, and survival outcomes among patients with nonmetastatic UTUC. Methods We identified 4114 patients diagnosed with nonmetastatic UTUC from 2004 to 2013 in the Survival Epidemiology, and End Results–Medicare population-based database. Patients were stratified into low- or high-risk disease groups. Median total costs from 30 days prior to diagnosis through 365 days after diagnosis were compared between groups. Overall and cancer-specific survival were evaluated using Cox proportional hazards regression. All statistical tests were 2-sided. Results After risk stratification, 1027 (24.9%) and 3087 (75.0%) patients were classified into low- vs high-risk UTUC groups. Most patients underwent at least 1 surgical intervention (95.1%); 68.4% underwent at least 1 endoscopic intervention. Patients diagnosed with high- vs low-risk UTUC were more likely to undergo nephroureterectomy (83.6% vs 72.0%; P Conclusions UTUC continues to be managed primarily with nephroureterectomy, regardless of risk stratification, and patients with high-risk UTUC have worse overall and cancer-specific survival. Substantial costs are associated with management of low- and high-risk UTUC, with the latter being more costly up to 1 year from diagnosis.

Proteins are effector molecules that mediate the functions of genes1,2 and modulate comorbidities3–10, behaviors and drug treatments11. They represent an enormous potential resource for personalized, systemic and data-driven diagnosis, prevention, monitoring and treatment. However, the concept of using plasma proteins for individualized health assessment across many health conditions simultaneously has not been tested. Here, we show that plasma protein expression patterns strongly encode for multiple different health states, future disease risks and lifestyle behaviors. We developed and validated protein-phenotype models for 11 different health indicators: liver fat, kidney filtration, percentage body fat, visceral fat mass, lean body mass, cardiopulmonary fitness, physical activity, alcohol consumption, cigarette smoking, diabetes risk and primary cardiovascular event risk. The analyses were prospectively planned, documented and executed at scale on archived samples and clinical data, with a total of ~85 million protein measurements in 16,894 participants. Our proof-of-concept study demonstrates that protein expression patterns reliably encode for many different health issues, and that large-scale protein scanning12–16 coupled with machine learning is viable for the development and future simultaneous delivery of multiple measures of health. We anticipate that, with further validation and the addition of more protein-phenotype models, this approach could enable a single-source, individualized so-called liquid health check. Large-scale aptamer-based scanning of plasma proteins coupled with machine learning demonstrates proof-of-concept and feasibility of an individualized health check using a single blood sample.

Objective Length of hospital stay for patients following radical cystectomy is an important determinant for improved quality of care. We sought to develop and validate a predictive model for length of hospital stay following radical cystectomy. Methods Patients aged 66 to 90 years diagnosed with clinical stage T2-4a muscle-invasive bladder cancer who underwent radical cystectomy were included from January 1, 2002 through December 31, 2011 using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Linear regression analyses were used to develop and validate a predictive model for length of hospital stay. Results A total of 2,448 patients met inclusion criteria. After random assignment, 1,224 patients were included in the discovery cohort and 1,224 patients included in the validation cohort. The cohorts were well balanced with no significant difference in any of the preoperative variables. A best model was developed using marital status, Surveillance, Epidemiology, and End Results (SEER) region, clinical stage, Charlson comorbidity index, logarithm of hospital cystectomy volume, and use of neoadjuvant chemotherapy in a backward selection to predict the length of stay. There was robust internal validation (sum square error (SSE): 258.1 vs. predicted sum of squares (PRESS): 264.0 at SLS = 0.10), consistent with the external validation (average square error (ASE): discovery (0.248) vs. validation (0.258)) cohort. The strength of the model in predicting length of stay for the entire cohort was (R2 = 0.048). Conclusion In this large population-based study, we developed and validated a model to predict length of hospital stay following radical cystectomy. Identification of at-risk patients for prolonged hospital stay may aid in targeted interventions to reduce length of stay, improve quality of care, and decrease healthcare costs.

Objective To develop and validate a claims-based comorbidity score for patients undergoing major surgery, and compare its performance with established comorbidity scores. Data source Five percent Medicare data from 2007 to 2014. Study design Retrospective cohort study of patients aged ≥65 years undergoing six major operations (N = 99 250). Data collection One-year mortality was the primary outcome. Secondary outcomes were hospital mortality, 30-day mortality, 30-day readmission, and length of stay. The comorbidity score was developed in the derivation cohort (70 percent sample) using logistic regression model. The comorbidity score was calibrated and validated in the validation cohort (30 percent sample), and compared against the Charlson, Elixhauser, and Centers for Medicare and Medicaid Services Hierarchical Condition Categories (CMS-HCC) comorbidity scores using c-statistic, net reclassification improvement, and integrated discrimination improvement. Principal findings In the validation cohort, the surgery-specific comorbidity score was well calibrated and performed better than the Charlson, Elixhauser, and CMS-HCC comorbidity scores for all outcomes; the performance was comparable to the CMS-HCC for 30-day readmission. For example, the surgery-specific comorbidity score (c-statistic = 0.792; 95% CI, 0.785-0.799) had greater discrimination than the Charlson (c-statistic = 0.747; 95% CI, 0.739-0.755), Elixhauser (c-statistic = 0.747; 95% CI, 0.735-0.755), or CMS-HCC (c-statistic = 0.755; 95% CI, 0.747-0.763) scores in predicting 1-year mortality. The net reclassification improvement and integrated discrimination improvement were greater for surgery-specific comorbidity score compared to the Charlson, Elixhauser, and CMS-HCC scores. Conclusions Compared to commonly used comorbidity measures, a surgery-specific comorbidity score better predicted outcomes in the surgical population.

BACKGROUND Although skeletal-related events (SREs) are linked with a reduced quality of life and worse outcomes, to the authors' knowledge the factors that predict SREs are minimally understood. The objective of the current study was to identify predictors of SREs and all-cause mortality among men with metastatic castration-resistant prostate cancer (mCRPC). METHODS Data were collected on 837 men with bone mCRPC at 8 Veterans Affairs medical centers within the Shared Equal Access Regional Cancer Hospital (SEARCH) database from 2000 through 2017. Patients were followed to assess development of SREs (pathological fracture, radiotherapy to bone, spinal cord compression, or surgery to bone). Cox proportional hazards models were used to evaluate predictors of SREs and mortality. RESULTS Of the 837 men with bone mCRPC, 287 developed a SRE and 740 men died (median follow-up, 26 months). Bone pain was found to be the strongest predictor of SREs (hazard ratio [HR], 2.96; 95% CI, 2.25-3.89). A shorter time from CRPC to the development of metastasis (HR, 0.92; 95% CI, 0.85-0.99), shorter progression to CRPC (HR, 0.94; 95% CI, 0.91-0.98), and visceral metastasis at the time of diagnosis of bone metastasis (HR, 1.91; 95% CI, 1.18-3.09) were associated with an increased risk of SREs. Ten or more bone metastases (HR, 2.17; 95% CI, 1.72-2.74), undergoing radical prostatectomy (HR, 0.73; 95% CI, 0.61-0.89), shorter progression to CRPC (HR, 0.97; 95% CI, 0.94-0.99), older age (HR, 1.03; 95% CI, 1.02-1.04), higher prostate-specific antigen level at the time of diagnosis of metastasis (HR, 1.21; 95% CI, 1.14-1.28), bone pain (HR, 1.44; 95% CI, 1.23-1.70), and visceral metastasis (HR, 1.72; 95% CI, 1.23-2.39) were associated with an increased mortality risk. CONCLUSIONS Among men with bone mCRPC, bone pain was found to be the strongest predictor of SREs and the number of bone metastases was a strong predictor of mortality. If validated, these factors potentially may be used for risk stratification and for SRE prevention strategies.

Virtually all tumors are genetically heterogeneous, containing mutationally-defined subclonal cell populations that often have distinct phenotypes. Single-cell RNA-sequencing has revealed that a variety of tumors are also transcriptionally heterogeneous, but the relationship between expression heterogeneity and subclonal architecture is unclear. Here, we address this question in the context of Acute Myeloid Leukemia (AML) by integrating whole genome sequencing with single-cell RNA-sequencing (using the 10x Genomics Chromium Single Cell 5’ Gene Expression workflow). Applying this approach to five cryopreserved AML samples, we identify hundreds to thousands of cells containing tumor-specific mutations in each case, and use the results to distinguish AML cells (including normal-karyotype AML cells) from normal cells, identify expression signatures associated with subclonal mutations, and find cell surface markers that could be used to purify subclones for further study. This integrative approach for connecting genotype to phenotype is broadly applicable to any sample that is phenotypically and genetically heterogeneous., The advent of single-cell RNA sequencing has revealed significant transcriptional heterogeneity in cancer, but its relationship to genomic heterogeneity remains unclear. Focusing on acute myeloid leukemia samples, the authors describe a general approach for linking mutation-containing cells to their transcriptional phenotypes using single-cell RNA sequencing data.

Clinical factors and barriers affecting adoption of active surveillance (AS) for low-risk prostate cancer (PCa) remain poorly understood. We performed a national survey of radiation oncologists (RO) and urologists (URO) about the perceptions and recommendations of AS for low-risk PCa.In 2017, we surveyed 915 RO and 940 URO about AS for low-risk PCa in the United States. Survey items queried respondents about their attitudes toward AS and recommendations of AS for low-risk PCa. Pearson chi-square and multivariable logistic regression identified clinical and physician factors related toward AS for low-risk PCa.Overall, the response rate was 37.3% (n = 691) and was similar for RO and URO (35.7% vs. 38.7%; P = .18). RO were less likely to consider AS effective for low-risk PCa (86.5% vs. 92.0%; P = .04) and more likely to rate higher patient anxiety on AS (49.5% vs. 29.5%; P .001) than URO. Recommendations of AS varied modestly on the basis of age, prostate-specific antigen (PSA), and number of cores positive for Gleason 3 + 3 PCa. For a 55-year-old man with PSA 8 with 6 cores of Gleason 6 PCa, both RO and URO infrequently recommended AS (4.4% vs. 5.2%; adjusted odds ratio = 0.6; P = .28). For a 75-year-old patient with PSA 4 with 2 cores of Gleason 6 PCa, URO and RO most often recommended AS (89.6% vs. 83.4%; adjusted odds ratio = 0.5; P = .07).RO and URO consider AS to be effective in the clinical management of low-risk PCa, but this varies by clinical and physician factors.

Background Among patients with cancer, prior research suggests that patients with mental illness may have reduced survival. The objective was to assess the impact of psychiatric utilisation (PU) prior to cancer diagnosis on survival outcomes. Methods All residents of Ontario diagnosed with one of the top 10 malignancies (1997–2014) were included. The primary exposure was psychiatric utilisation gradient (PUG) score in 5 years prior to cancer: 0: none, 1: outpatient, 2: emergency department, 3: hospital admission. A multivariable, cause-specific hazard model was used to assess the effect of PUG score on cancer-specific mortality (CSM), and a Cox proportional hazard model for effect on all-cause mortality (ACM). Results A toal of 676,125 patients were included: 359,465 (53.2%) with PUG 0, 304,559 (45.0%) PUG 1, 7901 (1.2%) PUG 2, and 4200 (0.6%) PUG 3. Increasing PUG score was independently associated with worse CSM, with an effect gradient across the intensity of pre-diagnosis PU (vs PUG 0): PUG 1 h 1.05 (95% CI 1.04–1.06), PUG 2 h 1.36 (95% CI 1.30–1.42), and PUG 3 h 1.73 (95% CI 1.63–1.84). Increasing PUG score was also associated with worse ACM. Conclusions Pre-cancer diagnosis PU is independently associated with worse CSM and ACM following diagnosis among patients with solid organ malignancies.

Context Despite established guidelines for the treatment of muscle-invasive bladder cancer, it has been reported that radical cystectomy (RC) is markedly underused, especially among patients of advanced age and those with higher comorbidity burden and lower access to care. Understanding the interactions between patient, provider, and hospital factors may inform targeted interventions to optimize RC utilization. Objective To systematically review the literature regarding factors associated with RC utilization. Evidence acquisition A systematic search was conducted using Ovid and Medline according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to identify studies between 1970 and 2017 reporting on RC utilization. Prospective and retrospective studies were included. Evidence synthesis There are no published randomized control trials on RC utilization. Variations in study quality and design precluded a formal statistical meta-analysis. RC receipt significantly depended on patient, provider, and hospital factors. Patient factors associated with lower RC use included advanced age, African American and Hispanic race/ethnicity, higher comorbidity burden, unmarried marital status, higher tumor stage and grade, and lower socioeconomic status. Provider factors associated with underutilization included lower surgeon volume and a metropolitan location. Finally, hospital factors associated with lower RC use included low hospital volume, nonacademic affiliation, and hospital location in the Midwest. Conclusions RC is reportedly underutilized. We found that age, race, marital status, socioeconomic factors, cancer severity, comorbidity burden, surgeon volume, and facility type and location significantly determined RC receipt. Improved understanding of the varying contributions of the risk factors according to patient, provider, and hospital determinants may assist in developing targeted interventions to improve RC utilization. Patient summary In this review we explored the clinical evidence for factors predicting the utilization of radical cystectomy for muscle-invasive bladder cancer. Many factors related to the patient, provider, and hospital determine whether patients receive this guideline-recommended treatment. However, there remains a lack of understanding on characterization and targeted interventions according to these levels, which may improve use.

MBD5-associated neurodevelopmental disorder (MAND) is an autism spectrum disorder (ASD) characterized by intellectual disability, motor delay, speech impairment and behavioral problems; however, the biological role of methyl-CpG-binding domain 5, MBD5, in neurodevelopment and ASD remains largely undefined. Hence, we created neural progenitor cells (NPC) derived from individuals with chromosome 2q23.1 deletion and conducted RNA-seq to identify differentially expressed genes (DEGs) and the biological processes and pathways altered in MAND. Primary skin fibroblasts from three unrelated individuals with MAND and four unrelated controls were converted into induced pluripotent stem cell (iPSC) lines, followed by directed differentiation of iPSC to NPC. Transcriptome analysis of MAND NPC revealed 468 DEGs (q

Introduction Plasma proteins affect biological processes and are common drug targets but their role in the development of Alzheimer's disease and related dementias remains unclear. We examined associations between 4953 plasma proteins and cognitive decline and risk of dementia in two cohort studies with 20-year follow-ups. Methods In the Whitehall II prospective cohort study proteins were measured using SOMAscan technology. Cognitive performance was tested five times over 20 years. Linkage to electronic health records identified incident dementia. The results were replicated in the Atherosclerosis Risk in Communities (ARIC) study. Results Fifteen non-amyloid/non-tau-related proteins were associated with cognitive decline and dementia, were consistently identified in both cohorts, and were not explained by known dementia risk factors. Levels of six of the proteins are modifiable by currently approved medications for other conditions. Discussion This study identified several plasma proteins in dementia-free people that are associated with long-term risk of cognitive decline and dementia.

Background In contrast to studies that relied on volunteers or convenience sampling, there are few population-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence investigations and most were conducted early in the pandemic. The health department of the fourth largest US city recognized that sound estimates of viral impact were needed to inform decision making. Methods Adapting standardized disaster research methodology, in September 2020 the city was divided into high and low strata based on reverse-transcriptase polymerase chain reaction (RT-PCR) positivity rates; census block groups within each stratum were randomly selected with probability proportional to size, followed by random selection of households within each group. Using 2 immunoassays, the proportion of infected individuals was estimated for the city, by positivity rate and sociodemographic and other characteristics. The degree of underascertainment of seroprevalence was estimated based on RT-PCR–positive cases. Results Seroprevalence was estimated to be 14% with near 2-fold difference in areas with high (18%) versus low (10%) RT-PCR positivity rates and was 4 times higher compared to case-based surveillance data. Conclusions Seroprevalence was higher than previously reported and greater than estimated from RT-PCR data. Results will be used to inform public health decisions about testing, outreach, and vaccine rollout.

Objective To determine the estimated budget impact to practices that incorporate blue light cystoscopy (BLC) with hexaminolevulinate HCl (HAL) for the surveillance of non-muscle-invasive bladder cancer (NMIBC) in the clinic setting. With the introduction of advanced technologies in the clinic setting such as HAL, further cost comparative research is needed to justify HAL as a high value option. Material and methods A budget impact model was developed from the facility perspective assessing projected costs at 2 years for a simulated facility with 50 newly diagnosed bladder cancer patients. Treatment and surveillance cystoscopy intervals were based on clinical guidelines. Clinical inputs, including tumor stage and grade at diagnosis, rates of recurrence and relative risk reduction when using BLC with HAL, were derived from published studies. Cost inputs were based on Medicare reimbursement rates and facility costs. Results Use of BLC identified 9 additional recurrences over two years compared to white light cystoscopy alone. Use of flexible BLC for surveillance marginally increased costs to the practice, with a net difference of $0.76 per cystoscopy over 2 years. Conclusions From the office/clinic perspective, the model suggests that the use of flexible BLC for the surveillance of NMIBC may not impact cost per cystoscopy and identifies 9 recurrences over 2 years that would be missed using white light cystoscopy alone. These findings could have important implications in the management of NIMBC and help guide clinical practice guidelines that promote cost-effective care and improved patient outcomes.

To describe overall and categorical cost components in the management of patients with non-metastatic upper tract urothelial carcinoma (UTUC) according to treatment.We identified 4,114 patients diagnosed with non-metastatic UTUC from 2004 to 2013 in the Survival Epidemiology and End Results-Medicare linked database. Patients were stratified into renal preservation (RP) vs. radical nephroureterectomy (NU) groups. Total Medicare costs within 1 year of diagnosis were compared for patients managed with RP vs. NU using inverse probability of treatment-weighted propensity score models.A total of 1,085 (26%) and 3,029 (74%) patients underwent RP and NU, respectively. Median costs were significantly lower for RP vs. NU at 90 days (median difference -$4,428, Hodges-Lehmann [H-L] 95% confidence interval [CI], -$7,236 to -$1,619) and 365 days (median difference -$7,430, H-L 95% CI, -$13,166 to -$1,695), respectively. Median costs according to categories of services were significantly less for RP vs. NU patients by hospitalization, office visits, emergency room/critical care, consultations, and anesthesia. The only category which was significantly higher for RP vs. NU was inpatient visits ($1,699 vs. $1,532; median difference $152; HL 95% CI, $19-$286).Median costs were significantly lower for RP vs. NU up to 1-year and by hospitalization, office visits, emergency room/critical care, consultations, and anesthesia costs. In appropriately selected patients, such as patients with low-risk disease, these findings suggest the utility of RP as a suitable high-value management option in UTUC.

Earlier studies on the cost of muscle-invasive bladder cancer treatments are limited to short-term costs of care. We determined the 2- and 5-year costs associated with trimodal therapy (TMT) vs. radical cystectomy (RC).We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Total Medicare costs at 2 and 5 years following RC vs. TMT were compared using inverse probability of treatment-weighted propensity score models.A total of 2,537 patients aged 66 to 85 years were diagnosed with clinical stage T2-4a muscle-invasive bladder cancer. Total median costs for patients that received no definitive treatment(s) were $73,780 and $88,275 at 2-and 5-years. Costs were significantly higher for TMT than RC at 2-years ($372,839 vs. $191,363, Median Difference $127,815, Hodges-Lehmann Estimate (H-L) 95% Confidence Interval (CI), $112,663-$142,966) and 5-years ($424,570 vs. $253,651, Median Difference $124,466, H-L 95% CI, $105,711-$143,221). TMT had higher outpatient costs than RC (2-years: $318,221 vs. $100,900; 5-years: $367,092 vs. $146,561) with significantly higher costs with radiology, medications, pathology/laboratory, and other professional services. RC had higher inpatient costs than TMT (2-years: $62,240 vs. $33,631, Median Difference $-29,174, H-L 95% CI, $-32,364-$-25,984; 5-years: $75,499 vs. $45,223, Median Difference $-29,843, H-L 95% CI, $-33,905-$-25,781).The excess spending associated with trimodal therapy vs. radical cystectomy was largely driven by outpatient expenditures. The relatively high long-term trimodal therapy costs are prime targets for cost containment strategies to optimize future value-based care.

EphB4 is a membrane tyrosine kinase receptor involved in a number of physiologic and pathologic conditions, cancer being the one drawing the highest attention. In mammalians, EphB4 regulates blood vessel growth and differentiation. EphB4 also mediates a number of cancer promoting effects including angiogenesis, invasion, and metastasis. Its effects have been linked to both EphrinB2-dependent and to EphrinB2-independent mechanisms. In spite of its emerging role in physiology and disease, the regulation of EphB4 cellular expression has been poorly described until recently. The present mini-review summarizes the latest findings on EphB4 regulation at the transcriptional and post-transcriptional level and discusses the biologic implications of such novel findings. Perspective on the scenarios opened by such findings and the open questions in EphB4 research is also provided.