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AbstractBACKGROUNDDelirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long‐term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology.METHODSThe Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts.RESULTSMeeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium‐spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations.DISCUSSIONThe DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes.Highlights Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning.

Introduction: Post-transcatheter aortic valve replacement (TAVR) outcome of patients is an important research topic. To accurately assess post-TAVR mortality, we examined a family of new echo-parameters (augmented systolic blood pressure (AugSBP) and arterial mean pressure parameters (AugMAP)) derived from blood pressure and aortic valve gradient ( Figure 1 ). Methods: Patients in the Mayo Clinic National Cardiovascular Diseases Registry-TAVR database who underwent TAVR between January 1, 2012, and June 30, 2017, were identified to retrieve baseline clinical, echocardiographic, and mortality data. The median of AugSBP and AugMAP were used to stratify patients in Kaplan-Meier analysis. Results: The final cohort contained 974 patients with a mean age of 81.4±8.3 years old, and 56.6% were male. The mean Society of Thoracic Surgeons risk score was 8.2±5.2. The median follow-up duration was 354 days, and the one-year all-cause mortality rate was 14.2%. Detailed characteristics are summarized in Table 1. AugMAP1 < 102.5 mmHg (median) was associated with a 3-fold risk of all-cause mortality post-TAVR at 1 year (hazard ratio 3.0, 95%confidence interval 2.0-4.5, p<0.0001)( Figure 1 ). Conclusions: Augmented mean arterial pressure provides clinicians with a simple but effective approach to quickly identify patients at risk and potentially improve post-TAVR prognosis.

5094 Background: In prior studies, basal vs. luminal differentiation portends differential response to a) androgen suppression (AS) duration for high-risk prostate cancer (PCa) (NRG-GU-TS006) and b) docetaxel chemotherapy (CT) and AS for metastatic hormone-sensitive disease (CHAARTED). In NRG-GU-TS006, basal tumors appeared to benefit the most from longer duration of AS while those with luminal subtype did not whereas, in CHAARTED, luminal subtype had greater benefit from addition of CT. Herein, we examined basal-luminal subtyping to predict differential response to the addition of CT in the setting of high-risk PCa treated with AS and definitive radiotherapy (AS + RT) in NRG/RTOG 0521. Methods: Per pre-specified and approved NCI analysis plan (Navigator #1061), we obtained available NRG biobank biopsy specimens from patients enrolled on the NRG/RTOG 0521 phase III trial, which randomized patients to AS + RT +/- CT. The highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays (Veracyte, San Diego, CA). Basal-luminal subtypes were generated using a 215-gene PCa subtyping classifier (PSC), a second generation PAM50 basal-luminal model. Treatment effects in Luminal Proliferating (LP) and non-LP subtypes were examined with Cox (for overall survival, OS, and metastasis-free survival, MFS) and Fine & Gray (for distant metastasis, DM) multivariable (MVA) models adjusted for age and trial risk stratification, as well as with restricted mean survival times (RMST). Results: Of 183 samples available for analysis (91 from control and 92 from the CT arm), 52 (28%) were classified as LP subtype. Median follow-up for OS was 9.9 years. No significant differences in clinical or pathological variables were observed between LP and non-LP subtypes. In MVA, we did not detect any significant LP subtype-by-CT treatment interaction but observed evidence of non-proportional hazards (Grambsch-Therneau test, p<0.05). In unselected patients, 5- and 10-year RMST difference between the arms was 0.9 (95% CI [-1.5, 3.4], p=0.46) and 5.7 (95% CI [-2.5, 13.9], p=0.17) months of OS. Stratifying by tumor subtype, at 5 years the RMST difference in months was 3.8 (95% CI [0.3, 7.2], p=0.03) for LP and -0.2 ([-3.4, 2.9], p=0.89) for non-LP. The RMST difference in months at 10-years was 13.7 (95% CI [-0.2, 27.5], p=0.053) for LP and 2.5 ([-7.6, 12.5], p=0.63) for non-LP. Conclusions: In pre-treatment biopsy samples from a Phase 3 trial cohort of localized high-risk men, luminal-basal subtyping of tumors demonstrated differential response to docetaxel CT. Similar to results from the CHAARTED trial of metastatic disease, LP tumors may derive greater benefit from addition of CT. Validation of these findings may enable effective earlier use of CT in men with PCa.

Background: Post-transcatheter aortic valve replacement (TAVR) patient outcome is an important research topic. To accurately assess post-TAVR mortality, we examined a family of new echo parameters (augmented systolic blood pressure (AugSBP) and arterial mean pressure (AugMAP)) derived from blood pressure and aortic valve gradients. Methods: Patients in the Mayo Clinic National Cardiovascular Diseases Registry-TAVR database who underwent TAVR between 1 January 2012 and 30 June 2017 were identified to retrieve baseline clinical, echocardiographic and mortality data. AugSBP, AugMAP and valvulo-arterial impedance (Zva) (Zva) were evaluated using Cox regression. Receiver operating characteristic curve analysis and the c-index were used to assess the model performance against the Society of Thoracic Surgeons (STS) risk score. Results: The final cohort contained 974 patients with a mean age of 81.4 ± 8.3 years old, and 56.6% were male. The mean STS risk score was 8.2 ± 5.2. The median follow-up duration was 354 days, and the one-year all-cause mortality rate was 14.2%. Both univariate and multivariate Cox regression showed that AugSBP and AugMAP parameters were independent predictors for intermediate-term post-TAVR mortality (all p < 0.0001). AugMAP1 < 102.5 mmHg was associated with a 3-fold-increased risk of all-cause mortality 1-year post-TAVR (hazard ratio 3.0, 95%confidence interval 2.0–4.5, p < 0.0001). A univariate model of AugMAP1 surpassed the STS score model in predicting intermediate-term post-TAVR mortality (area under the curve: 0.700 vs. 0.587, p = 0.005; c-index: 0.681 vs. 0.585, p = 0.001). Conclusions: Augmented mean arterial pressure provides clinicians with a simple but effective approach to quickly identify patients at risk and potentially improve post-TAVR prognosis.

AbstractBackgroundProstate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression‐based subtyping model based on prostate‐specific biological processes was sought.MethodsUnsupervised machine learning of gene expression profiles from prospectively collected primary prostate tumors (training, n = 32,000; evaluation, n = 68,547) was used to create a prostate subtyping classifier (PSC) based on basal versus luminal cell expression patterns and other gene signatures relevant to PCa biology. Subtype molecular pathways and clinical characteristics were explored in five other clinical cohorts.ResultsClustering derived four subtypes: luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), and basal neuroendocrine (BN). LP and LD tumors both had higher androgen receptor activity. LP tumors also had a higher expression of cell proliferation genes, MYC activity, and characteristics of homologous recombination deficiency. BI tumors possessed significant interferon γactivity and immune infiltration on immunohistochemistry. BN tumors were characterized by lower androgen receptor activity expression, lower immune infiltration, and enrichment with neuroendocrine expression patterns. Patients with LD tumors had less aggressive tumor characteristics and the longest time to metastasis after surgery. Only patients with BI tumors derived benefit from radiotherapy after surgery in terms of time to metastasis (hazard ratio [HR], 0.09; 95% CI, 0.01–0.71; n = 855). In a phase 3 trial that randomized patients with metastatic PCa to androgen deprivation with or without docetaxel (n = 108), only patients with LP tumors derived survival benefit from docetaxel (HR, 0.21; 95% CI, 0.09–0.51).ConclusionsWith the use of expression profiles from over 100,000 tumors, a PSC was developed that identified four subtypes with distinct biological and clinical features.Plain language summary Prostate cancer can behave in an indolent or aggressive manner and vary in how it responds to certain treatments. To differentiate prostate cancer on the basis of biological features, we developed a novel RNA signature by using data from over 100,000 prostate tumors—the largest data set of its kind. This signature can inform patients and physicians on tumor aggressiveness and susceptibilities to treatments to help personalize cancer management.

241 Background: We previously reported on the use of gene expression profiling to characterize four primary subtypes in an analysis of over 100,000 prostate cancer primary tumors. Here we examine these subtypes and response to radiation (RT) after prostatectomy or chemotherapy in addition to androgen deprivation therapy (ADT) in hormone-sensitive metastatic prostate cancer (mHSPC). Methods: We examined a 215-gene prostate subtyping classifier (PSC) which groups luminal and basal gene expression profiles into one of four subtypes; luminal differentiated (LD), luminal proliferating (LP), basal immune (BI) and basal neuroendocrine-like (BN). The log-rank method was used to compare (i) metastasis-free survival between patients who did and did not receive salvage RT in the META855 cohort of localized disease patients treated with radical prostatectomy (n=855) and the (ii) overall survival of patients on the Phase III mHSPC EA3805 CHAARTED trial of ADT or ADT + docetaxel chemotherapy (n=160). Results: After radical prostatectomy, patients with BI tumors derived benefit from RT in terms of metastasis-free survival ( P=9.23e-4) while those with other subtype tumors did not (Each Log-rank P≥0.5). Patients with metastatic disease and LP tumors derived benefit from docetaxel (Log-rank P=0.002) while those with other subtypes tumors did not (Log-rank P=0.2). Conclusions: Basal-luminal subtyping segments tumors by relevant biological processes with potential implications for identifying patients who benefit from salvage radiation post prostatectomy and addition of docetaxel to ADT in mHSPC.

ABSTRACT Aims The management of congestion is one of the key treatment targets in heart failure. Assessing congestion is, however, difficult. The purpose of this study was to investigate the safety and dynamic response of a novel, passive, inferior vena cava (IVC) sensor in a chronic ovine model. Methods and results A total of 20 sheep divided into three groups were studied in acute and chronic in vivo settings. Group I and Group II included 14 sheep in total with 12 sheep receiving the sensor and two sheep receiving a control device (IVC filter). Group III included an additional six animals for studying responses to volume challenges via infusion of blood and saline solutions. Deployment was 100% successful with all devices implanted; performing as expected with no device-related complications and signals were received at all observations. At similar volume states no significant differences in IVC area normalized to absolute area range were measured (55 ± 17% on day 0 and 62 ± 12% on day 120, p = 0.51). Chronically, the sensors were completely integrated with a thin, reendothelialized neointima with no loss of sensitivity to infused volume. Normalized IVC area changed significantly from 25 ± 17% to 43 ± 11% (p = 0.007) with 300 ml infused. In contrast, right atrial pressure required 1200 ml of infused volume prior to a statistically significant change from 3.1 ± 2.6 mmHg to 7.5 ± 2.0 mmHg (p = 0.02). Conclusion In conclusion, IVC area can be measured remotely in real-time using a safe, accurate, wireless, and chronic implantable sensor promising to detect congestion with higher sensitivity than filling pressures.

Importance The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown. Objective To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups. Data Sources For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database’s inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a “living” auto search was created with weekly updates to identify new evidence as it became available. Study Selection Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC. Data Extraction and Synthesis Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022. Main Outcomes and Measures Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life. Results This report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT. Conclusions and Relevance The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.

Abstract Objective To evaluate the safety and outcomes of cochlear implantation (CI) in patients with ventriculoperitoneal (VP) shunts to inform clinical practice. Study Design Historical cohort study. Setting Tertiary referral centers. Methods A multi‐institutional historical cohort of patients with VP shunts and CI was identified and analyzed. Results A total of 46 patients (median age 8 years [interquratile range, IQR: 2‐46]) with VP shunts and CI were identified. Of these, 41 (89%) patients had a VP shunt prior to CI. Based on institutional preference and individual patient factors, CI was performed contralateral to a pre‐existing VP shunt in 24 of these 41 cases (59%) and ipsilateral in 17 (41%). Furthermore, pre‐CI relocation of the VP shunt was performed in 3 cases (7%), and 2 patients (5%) underwent planned revision of their VP shunt concurrent with CI. In total, 2 of 27 pediatric patients (7%) required unanticipated revision shunt surgery, both contralateral to CI device placement, given VP shunt malfunction. One of 19 adult patients (5%) required shunt revision during CI due to shunt damage noted intraoperatively. Among 43 patients with available follow‐up, 38 (88%) are regular CI users, with a median consonant‐nucleus vowel‐consonant word: score of 58% (IQR: 28‐72). Conclusion CI can be performed at low risk, either contralateral or ipsilateral, to a VP shunt, and does not mandate shunt revision in most cases. Additional considerations regarding CI receiver‐stimulator placement are necessary with programmable shunts to mitigate device interaction. Preoperative planning, including coordination of care with neurosurgery, is important to achieving optimal outcomes.

SummaryPaediatric weight management (PWM) programs in the United States (US) face challenges in providing sustainable multidisciplinary care for patients. The aim of this study was to report PWM program approaches to sustaining program delivery. A survey of 39 PWM programs was administered to identify challenges and solutions to program sustainability. Common and useful strategies for optimizing reimbursement for services included the use of applicable reimbursable diagnostic codes and management, billing for assessments and non‐medical personnel services, and the use of hospital outpatient department clinic billing. Increasing clinical breadth and capacity was achieved by offering telemedicine and other services, such as psychotherapy, pharmacotherapy, and metabolic and bariatric surgery, as well as active management of schedules. Securing institutional and extramural funding was also reported. One of the positive changes during the pandemic was the fast adoption of telemedicine services. Although delivering sustainable evidence‐based multidisciplinary PWM under the current US payment models has its challenges, PWM programs implement practical operational strategies to support this work.