Search

Background: This study’s purpose is to determine if there is a difference in patient-reported outcome measures (PROMs) following shoulder arthroplasty (SA) based upon payer insurance type, with a secondary outcome of determining if any appreciable difference surpasses the minimal clinically important difference (MCID). Methods: Subjects undergoing anatomic and reverse total shoulder arthroplasty were prospectively enrolled between March 2019 and March 2021. Subjects completed patient reported outcomes measurement information system upper extremity (P-UE), the American Shoulder and Elbow Surgeons score (ASES), and the simple shoulder test (SST) preoperatively and at 2 weeks, 6 weeks, 3 months, 6 months, and 12 months, postoperatively. Descriptive statistics of baseline patient characteristics and preoperative PROMs (ASES, SST, and P-UE) were compared between insurance types. Results: 143 patients were identified who met the inclusion criteria for this study. There were 98 patients within the Medicare cohort and 45 patients with private insurance. Patients in the Medicare cohort were older (mean age 70.5 vs. 61.3 years), with high proportion of smokers, diabetics, and reverse total shoulder arthroplasty compared to the private payor cohort. There were no significant differences between the two cohorts with respect to outcomes scores except for significantly better SST in the private insurance cohort (69.3 vs. 79.4, P = .02). No significant differences were noted for the achievement of MCID between cohorts [P-UE (P = 1.0), ASES (P = .25), and SST (0.52)] and pre-to-postoperative improvements for P-UE (P = .62), ASES (P = .4), or SST (0.66). Conclusion: Our study demonstrates that, at a tertiary-level academic institution in a metropolitan city, payor type does not have significant impact on achieving MCID or pre-to-postoperative improvements in PROMs after SA.

Objective: The optimal method for cerebral protection during aortic arch reconstruction in neonates and infants is unknown. We compare the outcomes of deep hypothermic circulatory arrest and selective antegrade cerebral perfusion strategies in neonatal and infant cardiac surgery. Methods: We retrospectively identified all patients aged less than 1 year who underwent aortic arch reconstruction from 2012 to 2023. Patients were categorized on the cerebral perfusion strategy used during their procedure. Comparative analyses of perioperative and outcome variables were conducted to assess differences between cerebral protection strategies. A secondary analysis further stratifying by complexity of repair was performed. Examples of “complex” repair included the Norwood procedure, and “simple” repairs included isolated arch reconstructions. Adjusted regression models were used to identify specific outcomes associated with cerebral perfusion strategy used. Results: There were 165 cases included in our cohort (114 [69%] selective antegrade cerebral perfusions and 51 [31%] deep hypothermic circulatory arrests). Overall, hospital mortality was 7% (selective antegrade cerebral perfusion 9% vs deep hypothermic circulatory arrest 2%, P = .17). There were 6 total neurologic events in 4 patients after surgery in the selective antegrade cerebral perfusion group and none in the deep hypothermic circulatory arrest group. Irrespective of the cerebral perfusion strategy, there were no differences in mortality, stroke, seizures, renal failure, and catheterization reinterventions observed after surgery. This finding held true even when stratifying cerebral perfusion methods by complexity of repair. Regression analysis showed no associations for cerebral perfusion strategy with any outcome even after adjusting for age and complexity of repair. Conclusions: There were no significant short-term differences and a low rate of neurologic events in both groups during aortic arch reconstruction among neonates and infants. Longer follow-up is necessary to evaluate the impact of cerebral perfusion strategy on neurocognitive development later in life.

Purpose: As rates of lung transplants in the US grow, waitlist mortality increases. While the literature reports similar survival outcomes of DBD and DCD transplants, research should investigate improvements to DCD lung recovery protocols to increase the total number recovered. Recently, Choi et al. presented donor variables indicative of ultimate lung recovery1. However, expansion of DCD lung transplants requires a comparison of these indicators to DBD donors for application of similar parameters to increase the rate of DCD lung recovery to ensure that viable DCD organs are not discarded due to overly stringent donor and organ requirements. Methods: We performed a retrospective analysis of United Network for Organs Sharing (UNOS) Organ Procurement and Transplantation Network/UNOS STAR (Standard Analysis and Research) database. Donors who donated ≥1 organ from 10/1999–01/2019 were extracted and stratified according to DBD and DCD status. Associated characteristics of potential DCD and DBD lung donors were compared, and a multivariable logistic regression model with ≥1 transplanted lung was constructed to evaluate the independent effects of important predictors. Results: Our data included 179,228 potential lung donors, 162,157 DBD (31,486 donated, 19.4% recovery) and 17,071 DCD (526 donated, 3.1% recovery). Odds of lung non-use between DBD and DCD donors were significantly associated with blood type, alcohol use, cause of death, smoking history, drug use, death circumstance, ethnicity, gender, hypertension, cancer, age, and lung pO2 on 100% P/F ratio (P 50 in both DBD and DCD. However, likelihood of procurement is 1.84 [95% 1.42, 2.38, p 50 in DBD vs DCD donors. In addition, for each era, the odds for procuring DCD vs. DBD lungs consistently improved [95% 1.46–2.57, p

Background: The adoption of digital pathology has transformed the field of pathology, however, the economic impact and cost analysis of implementing digital pathology solutions remain a critical consideration for institutions to justify. Digital pathology implementation requires a thorough evaluation of associated costs and should identify and optimize resource allocation to facilitate informed decision-making. A dynamic cost calculator to estimate the financial implications of deploying digital pathology systems was needed to estimate the financial effects on transitioning to a digital workflow. Methods: A systematic approach was used to comprehensively assess the various components involved in implementing and maintaining a digital pathology system. This consisted of: (1) identification of key cost categories associated with digital pathology implementation; (2) data collection and analysis of cost estimation; (3) cost categorization and quantification of direct and indirect costs associated with different use cases, allowing customization of each factor based on specific intended uses and market rates, industry standards, and regional variations; (4) opportunities for savings realized by digitization of glass slides and (5) integration of the cost calculator into a unified framework for a holistic view of the financial implications associated with digital pathology implementation. The online tool enables the user to test various scenarios specific to their institution and provides adjustable parameters to assure organization specific relatability. Results: The Digital Pathology Association has developed a web-based calculator as a companion tool to provide an exhaustive list of the necessary concepts needed when assessing the financial implications of transitioning to a digital pathology system. The dynamic return on investment (ROI) calculator successfully integrated relevant cost and cost-saving components associated with digital pathology implementation and maintenance. Considerations include factors such as digital pathology infrastructure, clinical operations, staffing, hardware and software, information technology, archive and retrieval, medical–legal, and potential reimbursements. The ROI calculator developed for digital pathology workflows offers a comprehensive, customizable tool for institutions to assess their anticipated upfront and ongoing annual costs as they start or expand their digital pathology journey. It also offers cost-savings analysis based on specific user case volume, institutional geographic considerations, and actual costs. In addition, the calculator also serves as a tool to estimate number of required whole slide scanners, scanner throughput, and data storage (TB). This tool is intended to estimate the potential costs and cost savings resulting from the transition to digital pathology for business plan justifications and return on investment calculations. Conclusions: The digital pathology online cost calculator provides a comprehensive and reliable means of estimating the financial implications associated with implementing and maintaining a digital pathology system. By considering various cost factors and allowing customization based on institution-specific variables, the calculator empowers pathology laboratories, healthcare institutions, and administrators to make informed decisions and optimize resource allocation when adopting or expanding digital pathology technologies. The ROI calculator will enable healthcare institutions to assess the financial feasibility and potential return on investment on adopting digital pathology, facilitating informed decision-making and resource allocation.

Background: Digital pathology systems (DPS) are emerging as capable technologies for clinical practice. Studies have analyzed pathologists' diagnostic concordance by comparing reviews of whole slide images (WSIs) to glass slides (e.g., accuracy). This observational study evaluated the reproducibility of pathologists' diagnostic reviews using the Aperio GT 450 DX under slightly different conditions (precision). Method: Diagnostic precision was tested in three conditions: intra-system (within systems), inter-system/site (between systems/sites), and intra- and inter-pathologist (within and between pathologists). A total of five study/reading pathologists (one pathologist each for intra-system, inter-system/site, and three for intra-pathologist/inter-pathologist analyses) were assigned to the respective sub-studies.A panel of 69 glass slides with 23 unique histological features was used to evaluate the WSI system's precision. Each glass slide was scanned to generate a unique WSI. From each WSI, the field of view (FOV) was generated (at least 2 FOVs/WSI), which included the selected features (1–3 features/FOV). Each pathologist reviewed the digital slides and identified which morphological features, if any, were present in each defined FOV. To minimize recall bias, an additional 12 wild card slides from different organ types were used for which FOVs were extracted. The pathologists also read these wild card slides FOVs; however, the corresponding feature identification was not included in the final data analysis. Results: Each measured endpoint met the pre-defined acceptance criteria of the lower bound of the 95% confidence interval (CI) overall agreement (OA) rate being ≥85% for each sub-study. The lower bound of the 95% CI for the intra-system OA rate was 95.8%; for inter-system analysis, it was 94.9%; for intra-pathologist analysis, 92.4%, whereas for inter-pathologist analyses, the lower bound of the 95% CI of the OA was 90.6%. Conclusion: The study results indicate that pathologists using the Aperio GT 450 DX WSI system can precisely identify histological features that may be required for accurately diagnosing anatomic pathology cases.

Chronic social defeat stress (SDS) is a widely employed preclinical model of depression involving repeated exposure to physical defeats using a resident-intruder model in male mice. Exposure to SDS induces depressive-like phenotypes including anhedonia, social withdrawal, and increased drug and alcohol consumption. Previously, we found that expression of the neurokinin-1 receptor (NK1R) is increased in the nucleus accumbens (NAC) of mice that are sensitive to this stressor and increase their alcohol intake. The NK1R is the endogenous receptor for the neuropeptide substance P (SP) and plays a prominent role in stress, anxiety, and addiction. In the present study, we assessed changes in NK1R protein levels in the NAC shell and implemented viral vector strategies to demonstrate a functional role of the NK1R in sensitivity to SDS. Specifically, we found that NK1R protein levels were increased in the NAC shell following SDS exposure. Next, we found that NK1R overexpression in the NAC shell increased the sensitivity to SDS and stress-induced alcohol consumption. Together, these experiments provide evidence for a role of the NK1R in the NAC shell in the sensitivity to SDS and the subsequent escalation in alcohol intake.

Introduction: Eftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, triggers antigen-presenting cell and T-cell (CD4+ and CD8+) activation and helps overcome resistance to programmed cell death protein 1 or programmed cell death-ligand 1 (PD-(L)1) inhibitors. We assessed efti plus pembrolizumab in second-line anti–PD-(L)1-refractory metastatic patients with NSCLC. Methods: After confirmed progression on anti-PD-(L)1-based first-line therapy, patients received efti (30 mg subcutaneously every 2 weeks for eight 3-week cycles and then every 3 weeks for up to 54 weeks) plus pembrolizumab (200 mg intravenously every 3 weeks for up to 105 weeks). The primary endpoint was the objective response rate by modified Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based therapies. Secondary endpoints included disease control rate, progression-free survival, overall survival (OS), and tolerability. Exploratory endpoints included tumor growth kinetics and predefined subgroup analyses. Programmed cell death-ligand 1 tumor proportion score was assessed centrally. Results: Thirty-six patients were enrolled from April 2019 to August 2021 using Simon’s two-stage design. Most patients (81.8%) had low or negative (

Fuchs endothelial corneal dystrophy (FECD), the leading indication for corneal transplantation in the U.S., causes loss of corneal endothelial cells (CECs) and corneal edema leading to vision loss. FECD pathogenesis is linked to impaired response to oxidative stress and environmental ultraviolet A (UVA) exposure. Although UVA is known to cause nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation, ferroptosis has not been characterized in FECD. We investigated the roles of genetic background and UVA exposure in causing CEC degeneration in FECD. Using ungenotyped FECD patient surgical samples, we found increased levels of cytosolic ferrous iron (Fe2+) and lipid peroxidation in end-stage diseased tissues compared with healthy controls. Using primary and immortalized cell cultures modeling the TCF4 intronic trinucleotide repeat expansion genotype, we found altered gene and protein expression involved in ferroptosis compared to controls including elevated levels of Fe2+, basal lipid peroxidation, and the ferroptosis-specific marker transferrin receptor 1. Increased cytosolic Fe2+ levels were detected after physiologically relevant doses of UVA exposure, indicating a role for ferroptosis in FECD disease progression. Cultured cells were more prone to ferroptosis induced by RSL3 and UVA than controls, indicating ferroptosis susceptibility is increased by both FECD genetic background and UVA. Finally, cell death was preventable after RSL3 induced ferroptosis using solubilized ubiquinol, indicating a role for anti-ferroptosis therapies in FECD. This investigation demonstrates that genetic background and UVA exposure contribute to iron-mediated lipid peroxidation and cell death in FECD, and provides the basis for future investigations of ferroptosis-mediated disease progression in FECD.

Photoacoustic microscopy offers functional information regarding tissue vasculature while ultrasound characterizes tissue structure. Combining these two modalities provides novel clinical applications including response assessment among rectal cancer patients undergoing therapy. We have previously demonstrated the capabilities of a co-registered photoacoustic and ultrasound device in vivo, but multiple challenges limited broad adoption. In this paper, we report significant improvements in an acoustic resolution photoacoustic microscopy and ultrasound (ARPAM/US) system characterized by simulation and phantom study, focusing on resolution, optical coupling, and signal characteristics. In turn, higher in-probe optical coupling efficiency, higher signal-to-noise ratio, higher data throughput, and better stability with minimal maintenance requirements were all accomplished. We applied the system to 19 ex vivo resected colorectal cancer samples and found significantly different signals between normal, cancer, and post-treatment tumor tissues. Finally, we report initial results of the first in vivo imaging study.

Metabolic rewiring is essential for tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. We have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic program characterized by increased HIF-1α activity and dependence on glycolysis. Here, we confirm by in vivo stable isotope tracing analysis (SITA) that liver-metastatic breast cancer cells retain a glycolytic profile when grown as mammary tumors or liver metastases. However, hepatic metastases exhibit unique metabolic adaptations including elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to mammary tumors. Accordingly, breast-cancer-liver-metastases exhibited enhanced de novo GSH synthesis. Confirming their increased capacity to mitigate ROS-mediated damage, liver metastases display reduced levels of 8-Oxo-2′-deoxyguanosine. Depletion of the catalytic subunit of the rate-limiting enzyme in glutathione biosynthesis, glutamate-cysteine ligase (GCLC), strongly reduced the capacity of breast cancer cells to form liver metastases, supporting the importance of these distinct metabolic adaptations.Loss of GCLC also affected the early steps of the metastatic cascade, leading to decreased numbers of circulating tumor cells (CTCs) and impaired metastasis to the liver and the lungs. Altogether, our results indicate that GSH metabolism could be targeted to prevent the dissemination of breast cancer cells.

Objectives: To identify patient and process factors that contribute to the high cost of lung transplantation (LTx) in the perioperative period, which may allow transplant centers to evaluate situations in which transplantation is most cost-effective to inform judicious resource allocation, avoid futile care, and reduce costs. Methods: The MarketScan Research databases were used to identify 582 privately insured patients undergoing single or bilateral LTx between 2013 and 2019. The patients were subdivided into groups by disease etiology using the United Network of Organ Sharing classification system. Multivariable generalized linear models using a gamma distribution with a log link were fit to examine the associations between the etiology of lung disease and costs during the index admission, 3 months before admission, and 3 months after discharge. Results: Our results indicate that the index admission contributed the most to the total transplantation costs compared to the 3 months before admission and after discharge. The regression-adjusted mean index hospitalization cost was 35% higher for patients with pulmonary vascular disease compared to those with obstructive lung disease ($527,156 vs $389,055). The use of extracorporeal membrane oxygenation, mechanical ventilation, and surgical complications in the post-transplantation period were associated with higher costs during the index admission. Surprisingly, age ≥55 was associated with lower costs during the index admission. Conclusions: This analysis identifies pivotal factors influencing the high cost of LTx, emphasizing the significant impact of the index admission, particularly for patients with pulmonary vascular disease. These insights offer transplant centers an opportunity to enhance cost-effectiveness through judicious resource allocation and service bundling, ultimately reducing overall transplantation costs.

Background: Peak oxygen consumption and oxygen pulse along with their respective percent predicted measures are gold standards of exercise capacity. To date, no studies have investigated the relationship between percent predicted peak oxygen pulse (%PredO2P) and ventricular-vascular response (VVR) and the association of %PredO2P with all-cause mortality in heart failure with preserved ejection fraction (HFpEF) patients. Objectives: The authors investigated the association between: 1) CPET measures of %PredO2P and VVR; and 2) %PredO2P and all-cause mortality in HFpEF patients. Methods: Our cohort of 154 HFpEF patients underwent invasive CPET and were grouped into %PredO2P tertiles. The association between percent predicted Fick components and markers of VVR (ie, proportionate pulse pressure, effective arterial elastance) was determined with correlation analysis. The Cox proportional hazards model was used to identify predictors of mortality. Results: The participants’ mean age was 57 ± 15 years. Higher %PredO2P correlated with higher exercise capacity. In terms of VVR, higher %PredO2P correlated with a lower pressure for a given preload (effective arterial elastance r = −0.45, P

Background: Patient-reported outcome measurements (PROMs) are important metrics for monitoring improvements following shoulder surgery. Despite the easy accessibility of electronic PROM surveys, completion rates vary, and factors predictive of survey completion for patients enrolled in medical survey follow-up after shoulder surgery remain largely unknown. The purpose of this study is to investigate survey completion rates for common shoulder procedures and identify factors predictive of PROM completion at one-year postoperatively. We hypothesize that the response rate to shoulder PROMs may vary by the shoulder procedure type after surgery. Methods: Patients undergoing total shoulder arthroplasty (TSA), rotator cuff repair (RCR), and instability surgery (Latarjet procedure [LP], and arthroscopic Bankart repair [ABR]) from 2019 to 2021 were prospectively enrolled. Each patient was administered PROM surveys via email preoperatively and at 2-weeks, 6-weeks, 3-months, 6-months, and 12-months following surgery. Demographics and socioeconomic characteristics were collected from our institutional database. The primary outcome studied was survey completion rate by procedure. Multivariable logistic regression was performed to identify factors predictive of completing 12-month follow-up. Results: A total of 514 (251 TSA, 194 RCR, and 69 instability surgery (35 LP, 34 ABR)) patients with an average age of 58 ± 15 years were included in this study. Overall, the 12-month survey completion rate for all procedures was 57.2%. TSA had the highest completion rate (64.9%), followed by RCR (52.1%), ABR (44.2%), and LP (42.9%). ABR and LP demonstrated more than a 50% drop in survey response at 2 weeks, and the RCR cohort demonstrated an increased attrition in survey response at the 6-month mark. Patients who completed the 12-month follow-up survey were older [61 ± 14 vs. 54 ± 17; P

Background: The purpose of our study was to compare the outcomes and complications after a two- vs. six-week duration of sling immobilization following reverse total shoulder arthroplasty (rTSA). Methods: We conducted a retrospective review from our institutional database on 960 patients treated by primary rTSA between 2011 and 2021. Patients were separated into two cohorts of postoperative sling immobilization (a two-week and six-week group). Multivariate analysis was conducted to evaluate what factors were associated with patients experiencing either a postoperative complication or requiring reoperation. Results: A total of 276 patients were instructed to keep their operative arm in a sling for six weeks postoperatively, and 684 patients discontinued use at two weeks. There was no difference in postoperative complication rate (15.0% vs. 12.0%, P = .21), dislocation rate (P = .79), acromion stress fractures (P = .06), implant loosening (P = .15), and periprosthetic joint infections (P = .48) between the six- and two-week sling cohorts. In the immediate 90-day postoperative time period, no difference was seen in the reoperation rates (P = .73). Discussion: Shorter duration of sling immobilization (two weeks) does not incur additional risk of complications compared to standard duration (six weeks) of sling immobilization following rTSA.

Population monitoring is an essential component of biodiversity conservation and management, but low detection probabilities for rare and/or cryptic species makes estimating abundance and occupancy challenging. Passive acoustic monitoring combined with machine learning algorithms represents a potential path forward to effectively and efficiently monitor the occurrence of rare vocalizing species across entire forest landscapes. Our objectives were to develop and implement a convolutional neural network (PNW-Cnet) to identify vocalizations of a rare and threatened forest nesting bird species – the marbled murrelet (Brachyramphus marmoratus) – in the Pacific Northwest, U.S.A., 2018–2021. We used PNW-Cnet predictions from broadscale passive acoustic monitoring data to examine spatiotemporal patterns in the distribution of murrelets. PNW-Cnet showed sufficiently high prediction accuracy (overall precision > 0.9) to enable broadscale population monitoring. Spatiotemporal analysis showed that annual peak murrelet call abundance occurs in ordinal weeks 28–32 (late July–Mid August) but this varied by study area. The greatest number of detections typically occurred in the Olympic Peninsula and Oregon Coast Range where late-successional forest dominates and nearer to ocean habitats. We demonstrate that passive acoustic monitoring can be used to understand intensity of use across broad scales for a rare and cryptic species in addition to the typical detection/non-detection data that are often collected. Passive acoustic monitoring combined with PNW-Cnet offers considerable promise for species distribution modeling and long-term population monitoring for rare species.

Summary: Transcription factors (TFs) are important mediators of aberrant transcriptional programs in cancer cells. In this study, we focus on TF activity (TFa) as a biomarker for cell-line-selective anti-proliferative effects, in that high TFa predicts sensitivity to loss of function of a given gene (i.e., genetic dependencies [GDs]). Our linear-regression-based framework identifies 3,047 pan-cancer and 3,952 cancer-type-specific candidate TFa-GD associations from cell line data, which are then cross-examined for impact on survival in patient cohorts. One of the most prominent biomarkers is TEAD1 activity, whose associations with its predicted GDs are validated through experimental evidence as proof of concept. Overall, these TFa-GD associations represent an attractive resource for identifying innovative, biomarker-driven hypotheses for drug discovery programs in oncology.

Objectives: Many orbital fracture patients are transferred to tertiary care centers for immediate ophthalmology consultation, though few require urgent ophthalmic evaluation or intervention. This overutilizes limited resources and overburdens patients and the health care system with travel and emergency department (ED) expenses. A simple, easy-to-use, clinical decision-making tool is needed to aid local EDs and triage services in effectively identifying orbital fracture patients who need urgent ophthalmic evaluation. Design: Single center, retrospective cohort study. Subjects: Orbital fracture patients aged ≥ 18 years who presented to the study institution’s emergency department and received an ophthalmology consultation. Methods: Ocular injuries that required close monitoring or an intervention within the first few hours after presentation were termed urgent. Two Hawkeye Orbital Fracture Prioritization and Evaluation (HOPE) algorithms were developed to identify orbital fracture patients needing urgent evaluation; including 1 algorithm incorporating computerized tomography (CT) scans interpreted by ophthalmology (HOPE+CT). Algorithms were compared with 3 previously published protocols: the University of Texas Health Science Center at Houston (UTH), the South Texas Orbital Fracture Protocol (STOP), and Massachusetts Eye and Ear (MEE) algorithms. Main Outcome Measures: Correct triage of patients with orbital fractures who have urgent ocular or orbital conditions. Results: In the study institution’s ED, 134 adult patients (145 orbits) were seen with orbital fractures in 2019. Eighteen (13.4%) had ocular or orbital conditions categorized as urgent. The HOPE tool resulted in 100% sensitivity and 78.4% specificity. The HOPE+CT tool resulted in 100.0% sensitivity and 94.0% specificity. The UTH algorithm was 91.7% sensitive and 76.5% specific. South Texas Orbital Fracture Protocol and MEE were both 100% sensitive but only 35.1% and 32.8% specific, respectively. Conclusions: The HOPE and HOPE+CT algorithms were superior or equal to the UTH, STOP, and MEE algorithms in terms of specificity while detecting all urgent cases. Implementation of a triage protocol that uses the HOPE or HOPE+CT algorithms could improve resource utilization and reduce health care costs through identification of orbital fracture patients needing urgent evaluation. An online tool that deploys the HOPE+CT algorithm in a user-friendly interface has been developed and is undergoing prospective validation before public dissemination. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Significant efforts have focused on identifying targetable genetic drivers that support the growth of solid tumors and/or increase metastatic ability. During tumor development and progression to metastatic disease, physiological and pharmacological selective pressures influence parallel adaptive strategies within cancer cell sub-populations. Such adaptations allow cancer cells to withstand these stressful microenvironments. This Darwinian model of stress adaptation often prevents durable clinical responses and influences the emergence of aggressive cancers with increased metastatic fitness. However, the mechanisms contributing to such adaptive stress responses are poorly understood. We now demonstrate that the p66ShcA redox protein, itself a ROS inducer, is essential for survival in response to physiological stressors, including anchorage independence and nutrient deprivation, in the context of poor outcome breast cancers. Mechanistically, we show that p66ShcA promotes both glucose and glutamine metabolic reprogramming in breast cancer cells, to increase their capacity to engage catabolic metabolism and support glutathione synthesis. In doing so, chronic p66ShcA exposure contributes to adaptive stress responses, providing breast cancer cells with sufficient ATP and redox balance needed to withstand such transient stressed states. Our studies demonstrate that p66ShcA functionally contributes to the maintenance of aggressive phenotypes and the emergence of metastatic disease by forcing breast tumors to adapt to chronic and moderately elevated levels of oxidative stress.

Although anthropogenic climate change has resulted in significant alterations of ocean environments, the degree to which marine organisms can respond behaviorally to climate effects remains poorly understood, especially for species with increased extinction risk. We monitored marine space use and movement of the threatened marbled murrelet (Brachyramphus marmoratus) along the central coast of Oregon, USA during the 2017–2019 breeding seasons to quantify marine habitat selection patterns across a range of ocean conditions. We hypothesized that marine locations characterized by upwelling, nearshore areas adjacent to old-growth forest nesting habitat, and protected marine areas would be preferentially selected by tagged birds. Using >4800 locations collected from >180 individuals, we found that murrelets selected areas near small estuaries and with localized upwelling (as characterized by decreased sea-surface temperatures and high salinity), both of which are expected to lead to greater food availability during periods when sea-surface temperatures are elevated and coastal upwelling is reduced (i.e., poor ocean conditions). In addition, we found that individuals did not preferentially select marine areas adjacent to potential old-growth nesting habitat, and that murrelets exhibited limited overlap with protected marine areas regardless of ocean conditions. Unexpectedly, the majority (62%) of tagged individuals moved beyond the boundaries of our 135-km long study area in the year with the poorest ocean conditions (2017), with 15% of birds moving >500 km from their capture location. Our results confirm that marine habitat selection in murrelets becomes decoupled from terrestrial nesting habitat during periods of poor ocean conditions, and that such conditions are associated with low breeding propensity and long-distance movements during the breeding season. In addition to demonstrating murrelets undertake fine- and coarse-scale movements to buffer against poor ocean conditions, our study also emphasizes the importance of considering broad spatial scales in the marine environment when undertaking measures to conserve murrelet populations.

Purpose: We describe a case of traumatic cataract after improper use of a percussion massage gun over the periorbital area. Observations: A 38-year-old female with a history of high myopia and fibromyalgia presented to the emergency department with painless monocular vision loss OS, noticed two days prior and described as a “white film” over her eye. BCVA was 20/20 OD and 20/600 OS. IOP was normal. Slit lamp examination OS showed a dense posterior subcapsular cataract in a rosette pattern without signs of zonular instability. B-scan ultrasonography showed a clear vitreous cavity without structural globe anomalies. No other abnormalities were apparent. After ruling out other causes, vision loss was attributed to development of a traumatic cataract secondary to percussive massage gun use over the left temple and periorbital area, including directly over the eye, during the past few weeks as an attempt to relieve intractable headaches. Conclusion and importance: Improper use of massage guns can lead to severe ocular side effects including traumatic cataracts that may be difficult to manage. There is a need to educate patients about potential harms as well as require manufacturers to clearly display safety information.

Purpose: To investigate the histology of Bruch’s membrane (BM) calcification in pseudoxanthoma elasticum (PXE) and correlate this to clinical retinal imaging. Design: Experimental study with clinicopathological correlation. Subjects and Controls: Six postmortem eyes from 4 PXE patients and 1 comparison eye from an anonymous donor without PXE. One of the eyes had a multimodal clinical image set for comparison. Methods: Calcification was labeled with OsteSense 680RD, a fluorescent dye specific for hydroxyapatite, and visualized with confocal microscopy. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy (SEM-EDX) and time-of-flight secondary ion mass spectrometry (TOF-SIMs) were used to analyze the elemental and ionic composition of different anatomical locations. Findings on cadaver tissues were compared with clinical imaging of 1 PXE patient. Main Outcome Measures: The characteristics and topographical distribution of hydroxyapatite in BM in eyes with PXE were compared with the clinical manifestations of the disease. Results: Analyses of whole-mount and sectioned PXE eyes revealed an extensive, confluent OsteoSense labeling in the central and midperipheral BM, transitioning to a speckled labeling in the midperiphery. These areas corresponded to hyperreflective and isoreflective zones on clinical imaging. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy and TOF-SIMs analyses identified these calcifications as hydroxyapatite in BM of PXE eyes. The confluent fluorescent appearance originates from heavily calcified fibrous structures of both the collagen and the elastic layers of BM. Calcification was also detected in an aged comparison eye, but this was markedly different from PXE eyes and presented as small snowflake-like deposits in the posterior pole. Conclusions: Pseudoxanthoma elasticum eyes show extensive hydroxyapatite deposition in the inner and outer collagenous and elastic BM layers in the macula with a gradual change toward the midperiphery, which seems to correlate with the clinical phenotype. The snowflake-like calcification in BM of an aged comparison eye differed markedly from the extensive calcification in PXE. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Dominance status has extensive effects on physical and mental health, and an individual's relative position can be shaped by experiential factors. A variety of considerations suggest that the experience of behavioral control over stressors should produce winning in dominance tests and that winning should blunt the impact of later stressors, as does prior control. To investigate the interplay between competitive success and stressor control, we first examined the impact of stressor controllability on subsequent performance in a warm spot competition test modified for rats. Prior experience of controllable, but not physically identical uncontrollable, stress increased later effortful behavior and occupation of the warm spot. Controllable stress subjects consistently ranked higher than did uncontrollable stress subjects. Pharmacological inactivation of the prelimbic (PL) cortex during behavioral control prevented later facilitation of dominance. Next, we explored whether repeated winning experiences produced later resistance against the typical sequelae of uncontrollable stress. To establish dominance status, triads of rats were given five sessions of warm spot competition. The development of stable dominance was prevented by reversible inactivation of the PL or NMDA receptor blockade in the dorsomedial striatum. Stable winning blunted the later stress-induced increase in dorsal raphe nucleus serotonergic activity, as well as prevented uncontrollable stress-induced social avoidance. In contrast, endocrine and neuroimmune responses to uncontrollable stress were unaffected, indicating a selective impact of prior dominance. Together, these data demonstrate that instrumental control over stress promotes later dominance, but also reveal that winning experiences buffer against the neural and behavioral outcomes of future adversity.

Summary: Amino acids are required for cell growth and proliferation, but it remains unclear when and how amino acid availability impinges on the proliferation-quiescence decision. Here, we used time-lapse microscopy and single-cell tracking of cyclin-dependent kinase 2 (CDK2) activity to assess the response of individual cells to withdrawal of single amino acids and found strikingly different cell-cycle effects depending on the amino acid. For example, upon leucine withdrawal, MCF10A cells complete two cell cycles and then enter a CDK2-low quiescence, whereas lysine withdrawal causes immediate cell-cycle stalling. Methionine withdrawal triggers a restriction point phenotype similar to serum starvation or Mek inhibition: upon methionine withdrawal, cells complete their current cell cycle and enter a CDK2-low quiescence after mitosis. Modulation of restriction point regulators p21/p27 or cyclin D1 enables short-term rescue of proliferation under methionine and leucine withdrawal, and to a lesser extent lysine withdrawal, revealing a checkpoint connecting nutrient signaling to cell-cycle entry.

Background: Transcranial focused ultrasound has the potential to noninvasively modulate deep brain circuits and impart sustained, neuroplastic effects. Objective: Bring the approach closer to translations by demonstrating sustained modulation of deep brain circuits and choice behavior in task-performing non-human primates. Methods: Low-intensity transcranial ultrasound of 30 s in duration was delivered in a controlled manner into deep brain targets (left or right lateral geniculate nucleus; LGN) of non-human primates while the subjects decided whether a left or a right visual target appeared first. While the animals performed the task, we recorded intracranial EEG from occipital screws. The ultrasound was delivered into the deep brain targets daily for a period of more than 6 months. Results: The brief stimulation induced effects on choice behavior that persisted up to 15 minutes and were specific to the sonicated target. Stimulation of the left/right LGN increased the proportion of rightward/leftward choices. These effects were accompanied by an increase in gamma activity over visual cortex. The contralateral effect on choice behavior and the increase in gamma, compared to sham stimulation, suggest that the stimulation excited the target neural circuits. There were no detrimental effects on the animals' discrimination performance over the months-long course of the stimulation. Conclusion: This study demonstrates that brief, 30-s ultrasonic stimulation induces neuroplastic effects specifically in the target deep brain circuits, and that the stimulation can be applied daily without detrimental effects. These findings encourage repeated applications of transcranial ultrasound to malfunctioning deep brain circuits in humans with the goal of providing a durable therapeutic reset.

Background: The purpose of this study was to identify prognostic factors that are associated with improvements in patient-reported outcomes measures (PROMs) related to upper extremity function and pain in those suffering from idiopathic adhesive capsulitis. Methods: All patients treated conservatively for primary idiopathic adhesive capsulitis were identified from our institutional database between 2019 and 2021. Exclusion criteria included any patients treated surgically, follow-up less than one year, or incomplete survey results. PROMs including Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity Computer Adaptive Test Version 2.0 (P-UE), Pain Interference (P-Interference), Pain Intensity (P-Intensity), and visual analog scale (VAS) pain scores. They were obtained at initial consultation and at one year to assess patient-perceived impact of their condition. Multiple linear and multivariable logistic regressions were performed to identify factors associated with improvement in patient-perceived pain and shoulder function using final PROM scores and difference in PROM scores from initial consultation. An independent t-test was used to compare baseline and one-year minimum follow-up PROMs. Odds ratios and their 95% confidence intervals were calculated for each factor; a P value of < .05 was considered statistically significant. Results: A total of 56 patients (40 females and 16 males) were enrolled in the study with an average age of 54.7 ± 7.7 years. A significant improvement (P

Introduction: Traditionally, Nottingham prognostic index (NPI) informed prognosis in patients with estrogen receptor positive, human epidermal growth factor receptor-2 negative, node negative (ER+/HER2-/LN-) breast cancer. At present, OncotypeDX© Recurrence Score (RS) predicts prognosis and response to adjuvant chemotherapy (AC). Aims: To compare NPI and RS for estimating prognosis in ER + breast cancer. Methods: Consecutive patients with ER+/HER2-/LN- disease were included. Disease-free (DFS) and overall survival (OS) were determined using Kaplan-Meier and Cox regression analyses. Results: 1471 patients met inclusion criteria. The mean follow-up was 110.7months. NPI was calculable for 1382 patients: 19.8% had NPI≤2.4 (291/1471), 33.0% had NPI 2.41–3.4 (486/1471), 30.0% had NPI 3.41–4.4 (441/1471), 10.9% had NPI 4.41–5.4 (160/1471), and 0.3% had NPI>5.4 (4/1471). In total, 329 patients underwent RS (mean RS: 18.7) and 82.1% had RS

High tunnel (HT) vegetable cultivation stands out as a superior choice when compared to open field (OF) production due to its numerous production benefits. However, intensive cultivation practices involving excessive use of inorganic fertilizer (IF) in HT production systems may lead to degradation of soil health, and ultimately poor crop yields. Therefore, this study investigated the effect of liquid organic fertilizer (LOF) and IF on growth and yield of eggplant (Solanum melongena L.) cultivars in HT and OF production systems. Two experiments were conducted in a split-split plot design with production systems (HT and OF) as main plot, fertilizers (LOF and IF) as sub-plot, and cultivars (‘Angela’ and ‘Jaylo’) as sub-sub plot factors. Throughout the growing season, daily average temperature and relative humidity were greater by 2 to 4 ​°C and 2 to 4%, respectively, under HT compared to OF conditions. In contrast, average daily light integral of HT decreased 18 to 24% compared to OF. Results from pooled growth and yield data of both experiments indicate HT produced 61% taller plants with 62% thicker stem diameter compared to OF. However, eggplant height and stem diameter did not differ significantly between fertilizer treatments or between cultivars. Due to a greater fruit count for each plant (63%) and average fruit weight (9%), total yield was 84% greater in HT compared to OF. Eggplant cultivar ‘Jaylo’ yielded 33% greater fruit count for each plant and 38% greater fruit yield compared to ‘Angela’ cultivar. However, no differences in fruit count, fruit weight, and the total yield were observed between LOF and IF. Results indicate that HT production offered a favorable microclimate which encouraged plant growth and greater fruit yield of eggplant compared to OF conditions. LOF and ‘Jaylo’ could be successfully used in organic eggplant production in HT and OF systems.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Introduction: The incidence of post-operative urinary retention (POUR) following inguinal hernia repair (IHR) is approximately 0.4% - 22.0%. POUR may lead to patient discomfort and catheter-related complications including urinary tract infection, urethral trauma, bladder overdistension and subsequent permanent bladder dysfunction. We aimed to perform a systematic review and meta-analysis of randomised control trials (RCT) evaluating the impact of administration of perioperative alpha-blockade to reduce the incidence of acute POUR following IHR. Methods: A systematic review was performed as per PRISMA guidelines. The incidence of POUR in the alpha-blocker and control groups were expressed as dichotomous outcomes, reported as odds ratios (ORs) expressed with 95% confidence intervals (CIs) following estimation using the Mantel-Haenszel method. Results: Eight RCTs with a combined total of 918 patients were included. Of these, 53.7% (493/918) received alpha-blockers while 46.3% (425/918) did not. Five studies used tamsulosin, two used prazosin and one used phenoxybenzamine. Overall, the prescription of prophylactic alpha-blockers in the preoperative setting significantly reduced POUR compared to the control group (7.9% (39/493) vs 21.2% (90/425), OR: 0.31, 95% CI: 0.12–0.80, P = 0.020). Conclusion: Preoperative prescription of alpha-blockers reduced the incidence of POUR following inguinal hernia repair. The next generation of prospective randomised trials may identify which patients should be prescribed this medication prior to surgery.

Background: The purpose of our study was to examine the clinical outcomes after arthroscopic scapulothoracic bursectomy for the treatment of scapulothoracic bursitis at a minimum of 2-year follow-up. Methods: Twenty patients who underwent arthroscopic scapulothoracic bursectomy for the treatment of symptomatic snapping scapula syndrome were identified from a single surgeon’s database. Patients were indicated for surgery if their symptoms persisted for more than 6 months and if they failed nonoperative treatment. Acquired data included patient demographics, shoulder range of motion, American Shoulder and Elbow Surgeon score, visual analog scale scores for pain, and the following Patient-Reported Outcomes Measurement Information System scores: Upper Extremity Computer Adaptive Test Version 2.0, pain intensity, and pain interference scores. Patient satisfaction and subjective shoulder value were also recorded out of 100. Fisher's test and unpaired t tests were performed for statistical analysis, and P values

ABSTRACT: Objectives: This study aimed to evaluate the efficacy and safety of ceftolozane/tazobactam (C/T) plus metronidazole versus meropenem plus placebo for the treatment of complicated intra-abdominal infection (cIAI) in Chinese adult participants. Methods: In this phase III clinical trial (NCT03830333), Chinese adult participants with cIAI were randomized 1:1 to receive C/T plus metronidazole or meropenem plus placebo. The primary objective was to assess C/T plus metronidazole for noninferiority versus meropenem for clinical response rate at the test of cure (TOC; 28 ± 2 days after study start) visit in the clinically evaluable population. Secondary endpoints included clinical and microbiologic responses at the TOC and end-of-treatment (≤24 hours after last dose) visits and adverse event rates. Results: Clinical cure at the TOC visit in the clinically evaluable population was 95.2% and 93.1% for C/T plus metronidazole and meropenem, respectively (between-treatment difference: 2.1% [95% confidence interval: -4.7%, 8.8%]); thus, noninferiority was met. Clinical responses at the TOC and end-of-treatment visits and microbiologic responses at the TOC visit were consistent with the primary efficacy endpoint. Safety was comparable between study treatment groups. Conclusion: In Chinese adult participants with cIAI, C/T plus metronidazole was noninferior to meropenem, with comparable safety.

Objective: A buildup of skeletal muscle plasma membrane (PM) cholesterol content in mice occurs within 1 week of a Western-style high-fat diet and causes insulin resistance. The mechanism driving this cholesterol accumulation and insulin resistance is not known. Promising cell data implicate that the hexosamine biosynthesis pathway (HBP) triggers a cholesterolgenic response via increasing the transcriptional activity of Sp1. In this study we aimed to determine whether increased HBP/Sp1 activity represented a preventable cause of insulin resistance. Methods: C57BL/6NJ mice were fed either a low-fat (LF, 10% kcal) or high-fat (HF, 45% kcal) diet for 1 week. During this 1-week diet the mice were treated daily with either saline or mithramycin-A (MTM), a specific Sp1/DNA-binding inhibitor. A series of metabolic and tissue analyses were then performed on these mice, as well as on mice with targeted skeletal muscle overexpression of the rate-limiting HBP enzyme glutamine-fructose-6-phosphate-amidotransferase (GFAT) that were maintained on a regular chow diet. Results: Saline-treated mice fed this HF diet for 1 week did not have an increase in adiposity, lean mass, or body mass while displaying early insulin resistance. Consistent with an HBP/Sp1 cholesterolgenic response, Sp1 displayed increased O-GlcNAcylation and binding to the HMGCR promoter that increased HMGCR expression in skeletal muscle from saline-treated HF-fed mice. Skeletal muscle from these saline-treated HF-fed mice also showed a resultant elevation of PM cholesterol with an accompanying loss of cortical filamentous actin (F-actin) that is essential for insulin-stimulated glucose transport. Treating these mice daily with MTM during the 1-week HF diet fully prevented the diet-induced Sp1 cholesterolgenic response, loss of cortical F-actin, and development of insulin resistance. Similarly, increases in HMGCR expression and cholesterol were measured in muscle from GFAT transgenic mice compared to age- and weight-match wildtype littermate control mice. In the GFAT Tg mice we found that these increases were alleviated by MTM. Conclusions: These data identify increased HBP/Sp1 activity as an early mechanism of diet-induced insulin resistance. Therapies targeting this mechanism may decelerate T2D development.

Introduction: The 21-gene assay provides prognostication for estrogen receptor positive, human epidermal growth factor receptor-2 negative (ER+/HER2-) early female breast cancer patients. This signature has not been validated in male breast cancer (MBC). Methods: A systematic review and meta-analysis was performed in accordance to the PRISMA guidelines. Retrospective cohort studies comparing 21-gene assay scores in female and MBC were included. Dichotomous variables were pooled as odds ratios (OR) and associated 95% confidence intervals (CI) using the Mantel–Haenszel method. Results: Six studies including 176,338 patients were included (mean age of 63.4 years, range: 33–88). Of these, 1.0% had MBC (1826/176,338) and 99.0% were female patients (174,512/176,338). MBC patients were more likely to have increased tumour stage, nodal involvement, and grade 3 disease (all P 30 (408/1822) versus 18.3% in female patients (31,852/174,500). In female patients, 52.0% had scores 30 (OR: 0.69, 95% CI: 0.45–1.07) as MBC patients. Conclusion: There are similar anticipated scores for female and MBC undergoing 21-gene expression assay testing for early stage, ER+/HER2-breast cancer. In the absence of stage matching, cautious interpretation of these results is required. Validation of the 21-gene assay in MBC is still required.

Purpose: Mammographic screening programmes have increased detection rates of non-palpable breast cancers. In these cases, wire-guided localization (WGL) is the most common approach used to guide breast conserving surgery (BCS). Several RCTs have compared WGL to a range of novel localization techniques. We aimed to perform a network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing methods of non-palpable breast cancer localization. Methods: A NMA was performed according to PRISMA-NMA guidelines. Analysis was performed using R packages and Shiny. Results: 24 RCTs assessing 9 tumour localization methods in 4236 breasts were included. Margin positivity and reoperation rates were 16.9% (714/4236) and 14.3% (409/2870) respectively. Cryo-assisted localization had the highest margin positivity (28.2%, 58/206) and reoperation (18.9%, 39/206) rates. Compared to WGL (n = 2045 from 24 RCTs) only ultrasound guided localization (USGL) (n = 316 from 3 RCTs) significantly lowered margin positivity (odds ratio (OR): 0.192, 95% confidence interval (CI): 0.079–0.450) and reoperation rates (OR: 0.182, 95%CI: 0.069–0.434). Anchor-guided localization (n = 52, 1 RCT) significantly lowered margin positivity (OR: 0.229, 95%CI: 0.050–0.938) and magnetic-marker localization improved patient satisfaction (OR: 0.021, 95%CI: 0.001–0.548). There was no difference in operation duration, overall complications, haematoma, seroma, surgical site infection rates, or specimen size/vol/wt between methods. Conclusion: USGL and AGL are non-inferior to WGL for the localization of non-palpable breast cancers. The reported data suggests that these techniques confer reduced margin positivity rates and requirement for re-operation. However, caution when interpreting results relating to RCTs with small sample sizes and further validation is required in larger prospective, randomized studies.

Electric vehicles are seen as a potential solution in reducing the fossil fuel dependence of the transport sector and could also serve as secondary storage for renewable energy. This study aims to clarify the role of EV in managing curtailment in electricity grid with high PV penetration. An energy balance analysis was conducted to assess the impact of various EV adoption rates and PV capacity growth rates on curtailment throughout a 10-year planning period. Results show that EV as mobile storage has a significant impact in reducing curtailment. In the case of Kyushu, Japan, the analysis showed that 20 GWh was sufficient by 2031. It will require 300,000 to 570,000 electric vehicles as mobile storage to reach this capacity, depending on the combinations of EV classes used. Additional capacity will only benefit spring and autumn, which does not merit an increased target due to the low capacity factor. Following the logistics growth model, the current adaption rate is insufficient to reach target volume, and external support will be necessary. EV as mobile storage can keep the curtailment to around 10%–15% but has less impact initially; thus, stalling the additional capacity until sufficient EV capacity is available might be necessary to keep the curtailment below 10%. Overall, EV as secondary storage is ideal for regions experiencing PV curtailment, and cars are only used for specific activities.

Purpose There is debate about the effectiveness and toxicity of pelvic lymph node (PLN) irradiation in addition to prostate bed radiotherapy when used to treat disease recurrence following radical prostatectomy. We compared toxicity from radiation therapy (RT) to the prostate bed and pelvic lymph nodes (PBPLN-RT) with prostatebed only radiation therapy (PBO-RT) following radical prostatectomy. Methods and Materials Patients with prostate cancer who underwent post-prostatectomy RT between 2010 and 2016 were identified by using the National Prostate Cancer Audit (NPCA) database. Follow-up data was available up to December 31, 2018. Validated outcome measures, based on a framework of procedural and diagnostic codes, were used to capture ≥Grade 2 gastrointestinal (GI) and genitourinary (GU) toxicity. An adjusted competing-risks regression analysis estimated subdistribution hazard ratios (sHR). A sHR > 1 indicated a higher incidence of toxicity with PBPLN-RT than with PBO-RT. Results 5-year cumulative incidences in the PBO-RT (n = 5,087) and PBPLNRT (n = 593) groups was 18.2% and 15.9% for GI toxicity, respectively. For GU toxicity it was 19.1% and 20.7%, respectively. There was no evidence of difference in GI or GU toxicity after adjustment between PBO-RT and PBPLN-RT (GI: adjusted sHR, 0.90, 95% CI, 0.67–1.19; P = 0.45); (GU: adjusted sHR, 1.19, 95% CI, 0.99–1.44; P = 0.09). Conclusions This national population-based study found that including PLNs in the radiation field following radical prostatectomy is not associated with a significant increase in rates of ≥Grade 2 GI or GU toxicity at 5 years.

Introduction: Alectinib was found to have superior efficacy to crizotinib in the phase 3 ALEX study and is a preferred initial treatment for patients with advanced ALK-positive NSCLC. To understand the efficacy of alectinib in U.S. clinical practice, we conducted a retrospective real-world comparative effectiveness analysis of first-line alectinib versus crizotinib. Methods: Adults with advanced ALK-positive NSCLC who received first-line alectinib (from December 11, 2015) or crizotinib (from January 1, 2014) were included from a real-world database. Propensity scores were applied to balance baseline characteristics. Real-world data (RWD), including real-world progression-free survival (rwPFS), real-world overall survival, real-world time to new central nervous system (CNS) metastases, and outcomes in patients with or without baseline CNS metastases were analyzed. The ALEX-like RWD cohort (filtered by ALEX laboratory eligibility criteria) was used to compare real-world comparative effectiveness with ALEX. Results: The RWD cohort comprised 364 patients (141 alectinib; 223 crizotinib); rwPFS (weighted hazard ratio [wHR] = 0.46, 95% confidence interval [CI]: 0.33–0.65) and real-world overall survival (wHR = 0.46, 95% CI: 0.31–0.69) were significantly improved with alectinib versus crizotinib. In patients with baseline brain scans, a substantial rwPFS benefit was found regardless of baseline CNS metastases. Real-world time to new CNS metastases was delayed with alectinib versus crizotinib in patients with (wHR = 0.28, 95% CI: 0.16–0.52) and without (wHR = 0.42, 95% CI: 0.24–0.76) baseline CNS metastases. The ALEX-like RWD cohort comprised 325 patients (120 alectinib; 205 crizotinib); alectinib was found to have similar rwPFS benefits with ALEX. Conclusions: Outcomes were significantly improved with first-line alectinib versus crizotinib in patients with advanced ALK-positive NSCLC in the U.S. real-world setting.