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95 Background: Most pts with prostate cancer with bone metastasis experience symptomatic skeletal events (SSEs) [PMID: 23884473], leading to increased morbidity and mortality. BMAs have been approved since 2007 and are recommended in mCRPC to prevent SSEs in pts with bone metastases or a high risk of osteoporotic fracture. Herein, we sought to assess the real-world trends of BMA administration in pts with mCRPC. Methods: We used the de-identified nationwide Flatiron Health electronic health record (EHR)-derived database to extract pt-level data. Inclusion criteria: pts with mCRPC with available date of diagnosis of mCRPC and information on receipt of BMA. Pts were categorized into 2 cohorts based on BMA receipt (e.g., bisphosphonates, denosumab, teriparatide, romosozumab) or not. Treatment trends of BMA by year of mCRPC diagnosis were summarized using frequency and percentages. Baseline characteristics at the time of mCRPC diagnosis (age, race-ethnicity, practice type, insurance) were compared between cohorts using the Wilcoxon rank-sum and Chi-squared tests. Results: Of 24,105 pts with metastatic prostate cancer in the dataset, 14,112 with mCRPC were eligible and included. 7,990 (56.6%) received BMA while 6,122 (43.4%) did not. In BMA receipt cohort: median age was 75 (IQR 67 – 81), majority were White (61%), treated in community practice (87%) and had commercial health plan (80%). In BMA non receipt cohort: median age was 75 (IQR 68 – 82), majority were White (61%), treated in a community practice (78%), and had commercial health plan (76%). The use of BMA decreased over time from 56% in 2013 to 46% in 2024 (Table). Statistically significant differences existed between cohorts in race-ethnicity, practice type, and insurance (p < 0.001) and will be presented at the meeting. Conclusions: Despite recommendations to use BMAs in pts with mCRPC and bone metastasis or high risk of osteoporotic fracture, our findings reveal a low utilization rate of BMAs in mCRPC setting with a notable decline over time. This highlights the need to incorporate the use of BMAs in clinical practice and improve access to these agents. Trends by year of mCRPC diagnosis in receipt of the first BMA and frequency and percentage of each agent. Year 2013N = 549 2014N = 1035 2015N = 1223 2016N = 1345 2017N = 1441 2018N = 1346 2019N = 1469 2020N = 1380 2021N = 1352 2022N = 1393 2023N = 1196 2024N = 383 Receipt of BMA, n (%) 316 (56) 674 (65) 792 (65) 837 (62) 886 (61) 766 (57) 816 (56) 766 (56) 692 (51) 713 (51) 556 (46) 176 (46) Denosumab, n (%) 190 (60.1) 450 (66.8) 557 (70.3) 599 (71.6) 606 (68.4) 533 (70) 526 (64.5) 488 (63.7) 410 (59.2) 414 (58.1) 290 (52.2) 94 (53) Zoledronic acid, n (%) 120 (38) 220 (32.6) 228 (28.7) 233 (27.8) 270 (30.5) 225 (29) 281 (34.4) 273 (35.6) 277 (40) 295 (41.4) 258 (46.4) 82 (47) Teriparatide, other bisphosphonates, n (%) 6 (1.9) 4 (0.6) 7 (1) 5 (0.6) 10 (1.1) 8 (1) 9 (1.1) 5 (0.7) 5 (0.7) 4 (0.5) 8 (1.4) 0

90 Background: Poly(ADP) ribose polymerase inhibitors and pembrolizumab are approved for patients with metastatic prostate cancer (mPC) with susceptible genomic alterations based on NGS testing. We recently reported that the rate of NGS testing in mPC remains low at 29.3% in the United States (1). Herein, we investigated the rates of NGS testing at the end of life in a real-world patient population. Methods: This study utilized the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Eligibility: diagnosis of mPC, with information on receipt of NGS testing (blood/tissue) and recorded date of death. The time between each patient’s first NGS testing result date and date of death was measured and categorized into 3 groups: NGS test results delivered more than 3 months (mo) before death, within 3 mo of death, and delivered after death. Frequencies and percentages of these 3 categories were reported, also by the year of death. Results: Out of 24,105 patients with mPC in the database, 3,397 had both a recorded date of death and underwent NGS testing and were eligible and included. The median age was 74 (IQR 67–80), 70% were White non-Hispanic, and 83% were treated in a community-based practice. In these patients, 2,901 (85.4%) NGS results were reported more than 3 mo before death, 457 (13.5%) within 3 mo of death, and 39 (1.1%) after death. From 2015 to 2024, the percentage of patients receiving their result more than 3 mo before death increased from 27% to 91%, while those receiving it within 3 mo before death decreased from 55% to 8.5%, and the percentage of NGS results reported after death declined from 18% to 0.6%. Baseline characteristics (including race-ethnicity, insurance plan, practice type [academic vs. community]) in these categories will be presented at the meeting. Conclusions: Despite the availability of life-prolonging targeted therapies based on NGS testing results for patients with mPC, in ∼14% of patients, the first NGS testing results were reported within 3 mo before death or after death. The lack of timely NGS testing limits patients' access to life-prolonging personalized treatments in earlier settings, resulting in missed opportunities for improved outcomes. 1. Hage Chehade, Swami, JAMA Network Open, 2024.

104 Background: Androgen deprivation therapy (ADT) intensification [ADT + androgen receptor-pathway inhibitor (ARPIs) +/- docetaxel] has been shown to improve survival outcomes in pts with mHSPC and is recommended as standard of care by all major guidelines. However, prior studies have shown underutilization of ADT intensification [PMID: 39191549]. There are limited updated and large-scale studies on the use of ADT intensification, beyond January 2023. In this study, we aimed to assess the treatment patterns of ADT intensification in real-world pts with mHSPC in the US, including data on those treated since January 2023. Methods: This retrospective study utilized the nationwide Flatiron Health Electronic Health Record (EHR) derived de-identified database. Eligibility: Pts diagnosed with mHSPC and availability of treatment information (ADT and/or line of therapy in mHSPC). The data cut-off date was 5/31/2024. Treatment patterns were summarized using frequency and percentages. All analysis was done using R version 4.2.3. Results: Among 24,105 pts with metastatic prostate cancer in the database, a total of 14,084 were eligible and included. The median age at metastatic diagnosis was 72 years (IQR 65 – 79), and 60% were White non-Hispanic. In the overall cohort (1/1/2013–5/15/2024), 56.8% received ADT monotherapy, and 37.7% received ADT intensification. Table summarizes the treatment patterns by year, highlightinga consistent increase in adoption of intensified ADT regimens, and a decline in use of ADT monotherapy. Notably, since January 2023, 76.8% pts with mHSPC received ADT intensification while only 17.3% of pts received ADT monotherapy. Conclusions: To our knowledge, this is the first and largest study to evaluate the current use of ADT intensification. These data indicate a notable improvement in the adoption of level 1 evidence (ADT intensification) in the treatment of pts with mHSPC. These encouraging data emphasize the benefits of continued efforts to promote guideline-concordant care and provide the current treatment landscape to design clinical trials. Treatment patterns by year in pts with mHSPC. Treatment 2013–2017n = 5,263(%) 2018n = 1,313 (%) 2019n = 1,407(%) 2020n = 1,353(%) 2021n = 1,483(%) 2022n = 1,556(%) 2023n = 1,459(%) 2024n = 250(%) ADT monotherapy 4,095 (77.8) 856 (65.2) 819 (58.2) 664 (49) 698 (47.1) 569 (36.6) 291 (20) 5 (2) ADT + ARPI 155 (2.9) 238 (18) 354 (25.1) 452 (33) 555 (37.4) 695 (44.7) 842 (58) 154 (61.6) ADT + Docetaxel 709 (13.5) 156 (12) 175 (12.4) 156 (12) 134 (9.0) 117 (7.5) 78 (5.3) 19 (7.6) Triplet(ADT + ARPI + Docetaxel) 6 (0.1) 2 (0.2) 1 (0.1) 2 (0.1) 9 (0.6) 82 (5.2) 166 (11.1) 53 (21.2) Other therapies 298 (5.7) 61 (4.6) 58 (4.1) 79 (5.8) 87 (5.9) 93 (6) 82 (5.6) 19 (7.6)

Abstract In this study, we examined the role of AKAP12, in endothelial cell motility, with a specific focus on AKAP12 variants AKAP12v1 and AKAP12v2. Previous work has shown that AKAP12, a multivalent A-kinase anchoring protein that binds to PKA and several other proteins regulating protein phosphorylation, is expressed at low levels in most endothelia in vivo but at higher levels in cells in vitro . Here, we found that AKAP12 expression in endothelial cell (HUVEC) cultures was cell density-dependent, with the expression being highest in subconfluent cultures and lowest in confluent cultures. AKAP12 expression was also elevated in cells at the wound edge of wounded endothelial cell monolayers. Knockdown of variants 1 and 2 inhibited cell migration, whereas CRISPR/Cas9 knockout of AKAP12v1 enhanced migration, indicating that the absence of this variant and the presence of AKAP12v2 may shift the signaling pathways. Further analysis using bulk RNA sequencing revealed that the loss of AKAP12v1 affects genes associated with cell migration and intercellular junctions. We propose that AKAP12v1 and AKAP12v2 work together to modulate endothelial cell migration, providing insights into their distinct yet complementary roles in endothelial function and potential implications for cardiovascular health.

Purpose To determine the relationship between cam morphology of the hip and ipsilateral sacroiliac motion compared to the native hip in a cadaveric model. Methods A simulated cam state was created using a 3‐dimensional printed cam secured to the head‐neck junction of 5 cadaveric hips. Hips were studied using a computed tomography–based optic metrology system and a 6 degree‐of‐freedom robot to exert an internal rotation torque at 3 different torque levels (6 N‐m, 12 N‐m, 18 N‐m). Outcomes included translational and rotational movement about 3 axes and composite (total) translational motion at the ipsilateral sacroiliac (SI) joint. Statistical analysis included a linear mixed model regression with repeated measures. Results The presence of a simulated cam was associated with medial motion in the coronal plane ( P = .03) and posterior motion in the sagittal plane ( P < .01) but not composite motion ( P = .37). Motion in the axial plane was in an inferior direction ( P = .08). Cam morphology significantly changed rotation in the sagittal plane ( P < .01) but not in the coronal ( P = .63) or axial plane ( P = .18). Composite motion was related to the amount of torque applied to the hip ( P < .01). The amount of torque applied to the hip was related to rotation in the coronal plane ( P < .01), axial plane ( P < .01), and sagittal plane ( P < .01) with increased effects as torque increased. Torque was not associated with translation movement in any of the anatomic planes. Conclusions The presence of simulated cam morphology is associated with motion in a more medial, inferior, and posterior direction at the ipsilateral SI joint relative to a native state. Increasing torque affects the magnitude of translation, but not its direction, which in this study is primarily influenced by cam morphology. Clinical Relevance This biomechanical connection between cam‐type femoroacetabular impingement syndrome and the ipsilateral SI joint provides insight into SI joint dysfunction in patients with femoroacetabular impingement syndrome.

Background:Previous reports suggest that lipid droplets (LDs) in the hepatocyte can be catabolized by a direct engulfment from nearby endolysosomes (microlipophagy). Further, it is likely that this process is compromised by chronic ethanol (EtOH) exposure leading to hepatic steatosis. This study investigates the hepatocellular machinery supporting microlipophagy and EtOH-induced alterations in this process with a focus on the small, endosome-associated, GTPase Rab5.Methods and Results:Here we report that this small Ras-related GTPase is a resident component of LDs, and its activity is important for hepatocellular LD-lysosome proximity and physical interactions. We find that Rab5 siRNA knockdown causes an accumulation of LDs in hepatocytes by inhibiting lysosome dependent LD catabolism. Importantly, Rab5 appears to support this process by mediating the recruitment of early endosomal and or multivesicular body compartments to the LD surface before lysosome fusion. Interestingly, while wild-type or a constituently active GTPase form (Q79L) of Rab5 supports LD-lysosome transport, this process is markedly reduced in cells expressing a GTPase dead (S34N) Rab5 protein or in hepatocytes exposed to chronic EtOH.Conclusions:These findings support the novel premise of an early endosomal/multivesicular body intermediate compartment on the LD surface that provides a “docking” site for lysosomal trafficking, not unlike the process that occurs during the hepatocellular degradation of endocytosed ligands that is also known to be compromised by EtOH exposure.

Background: Bystander CPR (BCPR) strongly influences survival from OHCA yet is provided in a minority of cases. The AHA has promulgated guidelines on provision of pre-arrival Hands-Only dispatcher-assisted telephone CPR (TCPR) instructions to increase the proportion of arrests receiving early BCPR; however, the impact of those guidelines is unknown. Objective: Evaluate the impact of implementing the TCPR guidelines on: recognition of OHCA by 911 dispatchers, time from call receipt to start of TCPR instructions, time to first chest compression (CC), prehospital ROSC, survival, and favorable neuro outcome (FNO). Methods: Dispatch audio records of OHCA in 3 large dispatch centers in Arizona (10/10-3/13) were reviewed using a standardized time-stamp methodology. Data were entered into a structured TCPR database linked to EMS and hospital outcome data. Intervention: Implementation of a 3.5-hour staff training and a guideline-based change in dispatch protocol. Results: There were 860 pre-implementation (P1) and 799 post-implementation (P2) cases. A total of 1265 cases met inclusion criteria. Outcome data collection and linkage is ongoing: ROSC, survival and neuro outcomes were available in 26%, 24% and 22% of cases, respectively. The proportion of cases receiving TCPR increased: P1 (28.7%); P2 (49.9%, p<0.001). Median time to beginning TCPR instructions decreased significantly: P1 (153 sec); P2 (129 sec, p<0.001) as did median time to first CC: P1 (198 sec); P2 (162 sec, p<0.001). Outcomes - see Table. Conclusion: The implementation of the AHA pre-arrival TCPR guidelines was associated with a significant improvement in the time-to-CPR instructions and time-to-first CCs and rate of provision of telephone-assisted bystander CPR. This small, preliminary analysis of prehospital ROSC, survival, and FNO revealed higher, but statistically non-significant, rates after the interventions.

Background: Bystander cardiopulmonary resuscitation (BCPR) significantly improves survival from out-of-hospital cardiac arrest (OHCA). Telecommunicator CPR (TCPR) has been shown to increase BCPR rates, yet TCPR performance varies widely. We assess whether a bundled TCPR protocol, training, and continuous quality improvement (CQI) intervention improves TCPR performance. Methods: The intervention was implemented at a regional 9-1-1 dispatch center and had three main components: (1) the installation of the AHA-recommended 2-question TCPR protocol, (2) training to enhance telecommunicator OHCA recognition and (3) CQI with system and case-level feedback. Training included a two-hour lecture, 30 minutes of video training, and one hour of simulation training. Audio recordings of suspected OHCAs from pre (P1, 10/5/10 - 11/6/11) and post-intervention (P2, 11/7/11 - 11/4/13) periods were collected by searching center archives for calls originally processed as cardiac arrests. Recordings were analyzed according to six key TCPR metrics. Times to telecommunicator recognition of cardiac arrest, start of TCPR instructions, and initiation of chest compressions were measured using a standardized timestamp format. Results: Rates of OHCA recognition (80% to 95%, p<0.0001), TCPR instructions started (32% to 72%, p<0.0001), and bystander chest compressions initiated (18% to 70%, p<0.001) all increased significantly. Reductions in the time from call receipt to the start of TCPR instructions (176s to 133s, p<0.0001) and to the start of compressions (265s to 162s, p<0.0001) were also observed. Conclusion: This bundled protocol, training and CQI intervention was associated with a significant increase in TCPR rates and a reduction in the time to first chest compression.

Background: Bystander CPR (BCPR) and telephone CPR (TCPR) are associated with improved OHCA outcomes. It has been shown that BCPR increases the proportion of patients with an initial shockable cardiac rhythm (VF/VT) when encountered by EMS. It is unknown whether TCPR does the same. Objective: To assess whether TCPR is independently associated with an increase in initial shockable cardiac rhythms during OHCA. Methods: Data from 9-1-1 audio recordings, first care EMS reports and hospital records were linked for OHCAs of presumed cardiac origin (1/2011-12/2014). Three cohorts were analyzed: TCPR, BCPR or no CPR. Using no CPR as the reference group, we assessed whether TCPR and BCPR were independently associated with initial shockable rhythms in a logistic regression model controlling for gender, event location, witness status and EMS response interval. Results: After exclusions, 2715 adult OHCA events with linked outcome data were analyzed (median age: 63; male: 66.8%; 33.3% witnessed arrest). Median response interval was 5 min. The BCPR rate (lay rescuer CPR without telephone instructions) was 24.8% and survival in this group was 15.4%. The TCPR rate (lay rescuer CPR with telephone instructions) was 40.2% and survival in this group was 11.7%. For the no-CPR group, 20.5% had an initial shockable rhythm. For the BCPR group, 34.6 % had an initial shockable rhythm. For the TCPR group, 23.2% had an initial shockable rhythm. Provision of BCPR and of TCPR were each independently associated with shockable rhythms [aOR (BCPR) = 1.7, 95% CI: 1.33-2.17, p=0.0001; aOR (TCPR) = 1.3, 95% CI: 1.04-1.63, p=0.0001]. Conclusion: The provision of both BCPR and TCPR were independently associated with an increased rate of initial shockable cardiac rhythms and an increase in survival to hospital discharge compared to no CPR.

ABSTRACT In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology research is paramount and oversight frameworks should be reviewed periodically. Changes should be made with care, however, to avoid impeding science that is essential for rapidly reducing and responding to pandemic threats as well as addressing more common challenges caused by infectious diseases. Decades of research uniquely positioned the US to be able to respond to the COVID-19 crisis with astounding speed, delivering life-saving vaccines within a year of identifying the virus. We should embolden and empower this strength, which is a vital part of protecting the health, economy, and security of US citizens. Herein, we offer our perspectives on priorities for revised rules governing virology research in the US.