Shared functional specialization in transformer-based language models and the human brain.

When processing language, the brain is thought to deploy specialized computations to construct meaning from complex linguistic structures. Recently, artificial neural networks based on the Transformer architecture have revolutionized the field of natural language processing. Transformers integrate contextual information across words via structured circuit computations. Prior work has focused on the internal representations ("embeddings") generated by these circuits. In this paper, we instead analyze the circuit computations directly: we deconstruct these computations into the functionally-specialized "transformations" that integrate contextual information across words. Using functional MRI data acquired while participants listened to naturalistic stories, we first verify that the transformations account for considerable variance in brain activity across the cortical language network. We then demonstrate that the emergent computations performed by individual, functionally-specialized "attention heads" differentially predict brain activity in specific cortical regions. These heads fall along gradients corresponding to different layers and context lengths in a low-dimensional cortical space.

Interaction structure constrains the emergence of conventions in group communication.

Real-world communication frequently requires language producers to address more than one comprehender at once, yet most psycholinguistic research focuses on one-on-one communication. As the audience size grows, interlocutors face new challenges that do not arise in dyads. They must consider multiple perspectives and weigh multiple sources of feedback to build shared understanding. Here, we ask which properties of the group's interaction structure facilitate successful communication. We used a repeated reference game paradigm in which directors instructed between one and five matchers to choose specific targets out of a set of abstract figures. Across 313 games (N = 1,319 participants), we manipulated several key constraints on the group's interaction, including the amount of feedback that matchers could give to directors and the availability of peer interaction between matchers. Across groups of different sizes and interaction constraints, describers produced increasingly efficient utterances and matchers made increasingly accurate selections. Critically, however, we found that smaller groups and groups with less-constrained interaction structures ("thick channels") showed stronger convergence to group-specific conventions than large groups with constrained interaction structures ("thin channels"), which struggled with convention formation. Overall, these results shed light on the core structural factors that enable communication to thrive in larger groups.

Increasing Adoption of Left Atrial Appendage Occlusion in Isolated Coronary Artery Bypass Grafting.

BACKGROUND: Recent randomized trial data showed fewer strokes with left atrial appendage occlusion (LAAO) following cardiac surgery in patients with atrial fibrillation. We developed a quality initiative to increase LAAO adoption. METHODS: Among 11,099 patients undergoing isolated CABG between January 2019-March 2021 at 33 hospitals in Michigan, those with atrial fibrillation undergoing first-time, on-pump CABG were eligible (n=1,241). A goal LAAO rate of 75% was selected as a quality improvement target through a statewide collaborative. An interrupted time series analysis evaluated the change in LAAO rate before (January-December 2019) versus after (January 2020-March 2021) implementation. RESULTS: Implementation of the quality metric improved LAAO rate from 61% (357/581) before to 79% (520/660) after implementation (p<0.001). Compared to patients not undergoing concomitant LAAO, LAAO patients (71%, 877/1,241) were older, more frequently male, and had a lower STS-PROM (2.9±3.5% vs. 3.7±5.7%, p=0.003), while other baseline characteristics including CHA2DS2-VASc scores were similar. Mean bypass and cross-clamp times were 7 and 6 minutes longer, respectively, in the LAAO group among those who did not undergo concomitant ablation. Operative mortality, major morbidity, blood product administration, and thromboembolic events were similar between groups. Interrupted time series analysis showed a significant increase in LAAO rate after implementation (p=0.009). CONCLUSIONS: LAAO in patients with atrial fibrillation undergoing isolated CABG did not add operative risk versus isolated CABG without LAAO. A statewide quality improvement initiative was successful in increasing the rate of concomitant LAAO and could be further evaluated as a potential quality metric in cardiac surgery.

Original Research: Nurses' Knowledge and Attitudes Regarding the Sustainable Development Goals: A Global Study.

BACKGROUND: Nurses have a critical role to play in achieving the United Nations' 17 Sustainable Development Goals (SDGs). While Goal 3 (good health and well-being) is of particular importance to nursing, every SDG contributes to the advancement of universal health and well-being. Yet many nurses are unfamiliar with the SDGs and how they relate to everyday nursing practices. PURPOSE: The purpose of this study was to examine RNs' knowledge of and attitudes toward the SDGs. METHODS: This study used a descriptive correlational cross-sectional design. A convenience sample of RNs from multiple countries completed an anonymous online survey that included eight demographic items and 25 items exploring participants' knowledge of and attitudes toward the SDGs. Descriptive, parametric, and nonparametric statistics were used to analyze the data. RESULTS: The majority of nurses in this study perceived themselves as lacking knowledge of the SDGs. Most wanted to know more, including how they could take action to help achieve the goals. Overall, participants agreed that the SDGs are relevant to nursing practice and that nurses are integral to their advancement. Participants who were younger than age 50, those living in the United States, and those who practiced primarily in a clinical or community setting were more likely than others to self-report lower SDG knowledge scores. CONCLUSIONS: The study findings contribute to our collective understanding of RNs' knowledge and attitudes regarding the SDGs. They can assist nurse educators and leaders worldwide in developing targeted strategies to better inform nurses and prepare them for actions that will advance these goals. Increasing nurses' knowledge of the SDGs, especially as these goals relate to daily clinical practice, may lead to greater nursing engagement and impact.

The Association of Oxygen Delivery and Transfusion on Cardiopulmonary Bypass with Acute Kidney Injury.

OBJECTIVES: To estimate whether the association of transfusion and acute kidney injury (AKI) has a threshold of oxygen delivery below which transfusion is beneficial but above which it is harmful. DESIGN: Retrospective study SETTING: Cardiovascular operating room and intensive care unit PARTICIPANTS: Patients undergoing cardiac surgery with continuous oxygen delivery monitoring during cardiopulmonary bypass INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Logistic regression was used to estimate the associations between oxygen delivery (mean, cumulative deficit, and bands of oxygen delivery), transfusion, and their interaction and AKI. A subgroup analysis of transfused and nontransfused patients with exact matching on cumulative oxygen deficit and time on bypass with adjustment for propensity to receive a transfusion using logistic regression. Nine hundred ninety-one of 4,203 patients developed AKI within 7 days. After adjustment for confounders, lower mean oxygen delivery (odds ratio [OR], 0.968; 95% confidence interval [CI], 0.949-0.988; p = 0.002) and transfusions (OR, 1.442; 95% CI, 1.077, 1.932; p = 0.014) were associated with increased odds of AKI by 7 days. As oxygen delivery decreased, the risk of AKI increased, with the slope of the OR steeper at <160 mL/m2/min. In the subgroup analysis, matched transfused patients were more likely than matched nontransfused patients to develop AKI (45% [n = 145] v 31% [n = 101]; p < 0.001). However, after propensity score adjustment, the difference was nonsignificant (OR, 1.181; 95% CI, 0.796-1.752; p = 0.406). CONCLUSIONS: We found a nonlinear relationship between oxygen delivery and AKI. We found no level of oxygen delivery at which transfusion was associated with a decreased risk of AKI.

Single-neuron analysis of aging-associated changes in learning reveals impairments in transcriptional plasticity.

The molecular mechanisms underlying age-related declines in learning and long-term memory are still not fully understood. To address this gap, our study focused on investigating the transcriptional landscape of a singularly identified motor neuron L7 in Aplysia, which is pivotal in a specific type of nonassociative learning known as sensitization of the siphon-withdraw reflex. Employing total RNAseq analysis on a single isolated L7 motor neuron after short-term or long-term sensitization (LTS) training of Aplysia at 8, 10, and 12 months (representing mature, late mature, and senescent stages), we uncovered aberrant changes in transcriptional plasticity during the aging process. Our findings specifically highlight changes in the expression of messenger RNAs (mRNAs) that encode transcription factors, translation regulators, RNA methylation participants, and contributors to cytoskeletal rearrangements during learning and long noncoding RNAs (lncRNAs). Furthermore, our comparative gene expression analysis identified distinct transcriptional alterations in two other neurons, namely the motor neuron L11 and the giant cholinergic neuron R2, whose roles in LTS are not yet fully elucidated. Taken together, our analyses underscore cell type-specific impairments in the expression of key components related to learning and memory within the transcriptome as organisms age, shedding light on the complex molecular mechanisms driving cognitive decline during aging.

Evaluation of sex differences in the receipt of concomitant atrial fibrillation procedures during nonmitral cardiac surgery.

OBJECTIVE: Women are less likely to receive guideline-recommended cardiovascular care, but evaluation of sex-based disparities in cardiac surgical procedures is limited. Receipt of concomitant atrial fibrillation (AF) procedures during nonmitral cardiac surgery was compared by sex for patients with preoperative AF. METHODS: Patients with preoperative AF undergoing coronary artery bypass grafting and/or aortic valve replacement at any of the 33 hospitals in Michigan from 2014 to 2022 were included. Patients with prior cardiac surgery, transcatheter AF procedure, or emergency/salvage status were excluded. Hierarchical logistic regression identified predictors of concomitant AF procedures, account for hospital and surgeon as random effects. RESULTS: Of 5460 patients with preoperative AF undergoing nonmitral cardiac surgery, 24% (n = 1291) were women with a mean age of 71 years. Women were more likely to have paroxysmal (vs persistent) AF than men (80% vs 72%; P < .001) and had a higher mean predicted risk of mortality (5% vs 3%; P < .001). The unadjusted rate of concomitant AF procedure was 59% for women and 67% for men (P < .001). After risk adjustment, women had 26% lower adjusted odds of concomitant AF procedure than men (adjusted odds ratio, 0.74; 95% CI, 0.64-0.86; P < .001). Female sex was the risk factor associated with the lowest odds of concomitant AF procedure. CONCLUSIONS: Women are less likely to receive guideline recommended concomitant AF procedure during nonmitral surgery. Identification of barriers to concomitant AF procedure in women may improve treatment of AF.

Risk of Pacemaker Implantation After Degenerative Mitral and Concomitant Tricuspid Valve Surgery.

BACKGROUND: A recent multicenter trial showed a reduction in tricuspid regurgitation (TR) progression when tricuspid annuloplasty was performed at the time of surgery for degenerative mitral regurgitation (MR), but with a 14% pacemaker (PPM) rate. We present real-world outcomes at a high-volume center for degenerative MR surgery with/without tricuspid annuloplasty. METHODS: Patients undergoing first-time degenerative mitral surgery between 2011-2021 were identified (n=1,738). After excluding patients undergoing aortic, aortic valve, or tricuspid replacement procedures, patients were stratified into mitral surgery alone (n=1,068) versus mitral surgery plus tricuspid annuloplasty (n=417). Outcomes including operative mortality, new PPM implantation, and postoperative length of stay as well as risk-adjusted overall mortality were compared. RESULTS: Among 1,485 patients in this study, 98% underwent mitral repair. Compared to concomitant tricuspid annuloplasty patients, those undergoing mitral surgery alone were 6 years younger and had lower median STS PROM. Among concomitant tricuspid repair patients, 85% (355/417) had moderate or less preoperative TR, while 15% (61/417) had severe TR. Operative mortality was 1.4%. The incidence of new PPM implantation was 0.7% (7/1,068) in the mitral only group and 5.5% (23/417) in the concomitant tricuspid group (p<0.001). Although unadjusted cumulative survival was lower in the concomitant tricuspid group, after risk adjustment, concomitant tricuspid surgery was not associated with worse overall mortality (HR 0.80 [95% CI, 0.53-1.19], p=0.27). CONCLUSIONS: Concomitant tricuspid annuloplasty is safe, with no difference in mortality and a less than 6% PPM rate at a high-volume mitral center. These data provide real-world context for concomitant tricuspid annuloplasty.

Sex-Based Differences in Concomitant Tricuspid Repair During Degenerative Mitral Surgery.

BACKGROUND: Women with mitral valve disease have higher rates of tricuspid regurgitation (TR) than men. Although tricuspid valve repair (TVr) decreases the progression of TR, we hypothesize that there may be sex-based differences in concomitant TVr at the time of mitral valve operations. METHODS: Adults undergoing mitral valve operation for degenerative disease with moderate or worse preoperative TR at a high-volume center from 2014 to 2023 were identified. Patients with a previous tricuspid intervention were excluded. A multivariable logistic regression identified predictors of concomitant TVr. To evaluate the clinical impact of not performing TVr, a competing risk model compared development of severe TR or valve-related reoperation by sex among patients without TVr. RESULTS: Most included patients were women (55% [n = 214 of 388]), and the median age was 73 years (quartile 1-quartile 3, 65-79 years). There was no difference in the rate of severe TR by sex (female, 28%; male, 26%; P = .63). The unadjusted rate of concomitant TVr was 57% for women and 73% for men (P < .001). Overall, women had 52% lower adjusted odds of TVr (adjusted odds ratio, 0.48; 95% CI, 0.29-0.81; P = .006), including a lower adjusted rate for moderate TR (47% [95% CI, 45%-49%] vs 66% [95% CI, 64%-69%]) and for severe TR (83% [95% CI, 81%-86] vs 92% [95% CI, 90%-93%]) Among those without TVr, 12% of women and 0% of men had severe TR or required a valve-related reoperation at 4 years (P < .001). CONCLUSIONS: Women with moderate or severe TR undergoing mitral valve operation for degenerative disease were less likely to receive concomitant TVr, severe TR was more likely to develop, or they would more likely need a valve-related reoperation. Evaluation of sex-based treatment differences is imperative to improve outcomes for women.

Extracellular vesicles incorporating retrovirus-like capsids for the enhanced packaging and systemic delivery of mRNA into neurons.

The blood-brain barrier (BBB) restricts the systemic delivery of messenger RNAs (mRNAs) into diseased neurons. Although leucocyte-derived extracellular vesicles (EVs) can cross the BBB at inflammatory sites, it is difficult to efficiently load long mRNAs into the EVs and to enhance their neuronal uptake. Here we show that the packaging of mRNA into leucocyte-derived EVs and the endocytosis of the EVs by neurons can be enhanced by engineering leucocytes to produce EVs that incorporate retrovirus-like mRNA-packaging capsids. We transfected immortalized and primary bone-marrow-derived leucocytes with DNA or RNA encoding the capsid-forming activity-regulated cytoskeleton-associated (Arc) protein as well as capsid-stabilizing Arc 5'-untranslated-region RNA elements. These engineered EVs inherit endothelial adhesion molecules from donor leukocytes, recruit endogenous enveloping proteins to their surface, cross the BBB, and enter the neurons in neuro-inflammatory sites. Produced from self-derived donor leukocytes, the EVs are immunologically inert, and enhanced the neuronal uptake of the packaged mRNA in a mouse model of low-grade chronic neuro-inflammation.

Hospital Variation in Skilled Nursing Facility Use After Coronary Artery Bypass Graft Surgery.

BACKGROUND: Over 20% of patients are discharged to a skilled nursing facility (SNF) after coronary artery bypass graft surgery, but little is known about specific drivers for postdischarge SNF use. The purpose of this study was to evaluate hospital variation in SNF use and its association with postoperative outcomes after coronary artery bypass graft. METHODS AND RESULTS: A retrospective study design utilizing Medicare Provider Analysis and Review files was used to evaluate SNF use among 70 509 beneficiaries undergoing coronary artery bypass graft, with or without valve procedures, between 2016 and 2018. A total of 17 328 (24.6%) were discharged to a SNF, ranging from 0% to 88% across 871 hospitals. Multilevel logistic regression models identified significant patient-level predictors of discharge to SNF including increasing age, comorbidities, female sex, Black race, dual eligibility, and postoperative complications. After adjusting for patient and hospital factors, 15.6% of the variation in hospital SNF use was attributed to the discharging hospital. Compared with the lower quartile of hospital SNF use, hospitals in the top quartile of SNF use had lower risk-adjusted 1-year mortality (12.5% versus 8.6%, P<0.001) and readmission (59.9% versus 49.8%, P<0.001) rates for patients discharged to a SNF. CONCLUSIONS: There is high variability in SNF use among hospitals that is only partially explained by patient characteristics. Hospitals with higher SNF utilization had lower risk-adjusted 1-year mortality and readmission rates for patients discharged to a SNF. More work is needed to better understand underlying provider and hospital-level factors contributing to SNF use variability.

Impact of Frailty in Patients Undergoing Minimally Invasive Mitral Valve Surgery.

OBJECTIVE: Psoas muscle size is a reliable marker of sarcopenia and frailty that correlates with adverse outcomes after cardiac surgery. However, its use in mitral and minimally invasive cardiac surgery is lacking. We sought to determine whether frailty, as measured by psoas muscle index, increases surgical risk for minimally invasive mitral valve surgery. METHODS: Patients undergoing isolated minimally invasive mitral surgery via right minithoracotomy were identified. Patients who underwent maze, tricuspid intervention, and those who were emergent were excluded. Total psoas muscle area was calculated using the average cross-sectional area at the L3 vertebra on computed tomography scan and indexed to body surface area. Sarcopenia was defined as <25th gender-specific percentile. Patients were stratified by sarcopenia status and outcomes compared. RESULTS: Of 287 total patients, 192 patients met inclusion criteria. Sarcopenic patients were 6 years older (66 vs 60 years, P = 0.01), had lower preoperative albumin levels (4.0 vs 4.3 g/dL, P < 0.001), and had higher Society of Thoracic Surgeons risk of morbidity/mortality (13.1% vs 9.0%, P = 0.003). Operative major morbidity or mortality was 6.4% versus 5.5% (P = 0.824), while the 1-year mortality rate was 2.1% versus 0% (P = 0.08). After risk adjustment, psoas index did not predict operative morbidity or mortality. However, sarcopenia was associated with higher odds of readmission (odds ratio = 0.74, P = 0.02). CONCLUSIONS: Contrary to other cardiac operations, for patients undergoing isolated minimally invasive mitral valve surgery, sarcopenia was not associated with increased perioperative risk except for higher readmission rates. Minimally invasive surgical approaches should be strongly considered as the approach of choice in frail patients.

The Emergence of Specialized Roles Within Groups.

Humans routinely form groups to achieve goals that no individual can accomplish alone. Group coordination often brings to mind synchrony and alignment, where all individuals do the same thing (e.g., driving on the right side of the road, marching in lockstep, or playing musical instruments on a regular beat). Yet, effective coordination also typically involves differentiation, where specialized roles emerge for different members (e.g., prep stations in a kitchen or positions on an athletic team). Role specialization poses a challenge for computational models of group coordination, which have largely focused on achieving synchrony. Here, we present the CARMI framework, which characterizes role specialization processes in terms of five core features that we hope will help guide future model development: Communication, Adaptation to feedback, Repulsion, Multi-level planning, and Intention modeling. Although there are many paths to role formation, we suggest that roles emerge when each agent in a group dynamically allocates their behavior toward a shared goal to complement what they expect others to do. In other words, coordination concerns beliefs (who will do what) rather than simple actions. We describe three related experimental paradigms-"Group Binary Search," "Battles of the Exes," and "Find the Unicorn"-that we have used to study differentiation processes in the lab, each emphasizing different aspects of the CARMI framework.

Reconciling truthfulness and relevance as epistemic and decision-theoretic utility.

People use language to influence others' beliefs and actions. Yet models of communication have diverged along these lines, formalizing the speaker's objective in terms of either the listener's beliefs or actions. We argue that this divergence lies at the root of a longstanding controversy over the Gricean maxims of truthfulness and relevance. We first bridge the divide by introducing a speaker model which considers both the listener's beliefs (epistemic utility) and their actions (decision-theoretic utility). We show that formalizing truthfulness as an epistemic utility and relevance as a decision-theoretic utility reconciles the tension between them, readily explaining puzzles such as context-dependent standards of truthfulness. We then test a set of novel predictions generated by our model. We introduce a new signaling game which decouples utterances' truthfulness and relevance, then use it to conduct a pair of experiments. Our first experiment demonstrates that participants jointly maximize epistemic and decision-theoretic utility, rather than either alone. Our second experiment shows that when the two conflict, participants make a graded tradeoff rather than prioritizing one over the other. These results demonstrate that human communication cannot be reduced to influencing beliefs or actions alone. Taken together, our work provides a new foundation for grounding rational communication not only in what we believe, but in what those beliefs lead us to do. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Endothelial to mesenchymal transition in the interleukin-1 pathway during aortic aneurysm formation.

OBJECTIVE: Endothelial to mesenchymal transition may represent a key link between inflammatory stress and endothelial dysfunction seen in aortic aneurysm disease. Endothelial to mesenchymal transition is regulated by interleukin-1ß, and previous work has demonstrated an essential role of interleukin-1 signaling in experimental aortic aneurysm models. We hypothesize that endothelial to mesenchymal transition is present in murine aortic aneurysms, and loss of interleukin-1 signaling attenuates this process. METHODS: Murine aortic aneurysms were created in novel CDH5-Cre lineage tracking mice by treating the intact aorta with peri-adventitial elastase. Endothelial to mesenchymal transition transcription factors as well as endothelial and mesenchymal cell markers were analyzed via immunohistochemistry and immunofluorescence (n = 10/group). To determine the role of interleukin-1 signaling, endothelial-specific interleukin-1 receptor 1 knockout and wild-type mice (n = 10/group) were treated with elastase. Additionally, C57/BL6 mice were treated with the interleukin-1 receptor 1 antagonist Anakinra (n = 7) or vehicle (n = 8). RESULTS: Elastase treatment yielded greater aortic dilation compared with controls (elastase 97.0% ± 34.0%; control 5.3% ± 4.8%; P < .001). Genetic deletion of interleukin-1 receptor 1 attenuated aortic dilation (control 126.7% ± 38.7%; interleukin-1 receptor 1 knockout 35.2% ± 14.7%; P < .001), as did pharmacologic inhibition of interleukin-1 receptor 1 with Anakinra (vehicle 146.3% ± 30.1%; Anakinra 63.5% ± 23.3%; P < .001). Elastase treatment resulted in upregulation of endothelial to mesenchymal transition transcription factors (Snail, Slug, Twist, ZNF) and mesenchymal cell markers (S100, alpha smooth muscle actin) and loss of endothelial cell markers (vascular endothelial cadherin, endothelial nitric oxide synthase, von Willebrand factor). These changes were attenuated by interleukin-1 receptor 1 knockout and Anakinra treatment. CONCLUSIONS: Endothelial to mesenchymal transition occurs in aortic aneurysm disease and is attenuated by loss of interleukin-1 signaling. Endothelial dysfunction through endothelial to mesenchymal transition represents a new and novel pathway in understanding aortic aneurysm disease and may be a potential target for future treatment.

Modeling and estimating a threshold effect: An application to improving cardiac surgery practices.

Estimating thresholds when a threshold effect exists has important applications in biomedical research. However, models/methods commonly used in the biomedical literature may lead to a biased estimate. For patients undergoing coronary artery bypass grafting (CABG), it is thought that exposure to low oxygen delivery (DO2) contributes to an increased risk of avoidable acute kidney injury. This research is motivated by estimating the threshold of nadir DO2 for CABG patients to help develop an evidence-based guideline for improving cardiac surgery practices. We review several models (sudden-jump model, broken-stick model, and the constrained broken-stick model) that can be adopted to estimate the threshold and discuss modeling assumptions, scientific plausibility, and implications in estimating the threshold. Under each model, various estimation methods are studied and compared. In particular, under a constrained broken-stick model, a modified two-step Newton-Raphson algorithm is introduced. Through comprehensive simulation studies and an application to data on CABG patients from the University of Michigan, we show that the constrained broken-stick model is flexible, more robust, and able to incorporate scientific knowledge to improve efficiency. The two-step Newton-Raphson algorithm has good computational performances relative to existing methods.

Use of the Rasch Model for Fit Statistics and Rating Scale Diagnosis for the Student Perception Appraisal-Revised.

Background and Purpose: Nursing student retention is essential to meet workforce demands. Jeffrey's Nursing Student Retention Student Perception Appraisal-Revised (SPA-R1) has been used extensively to understand factors that impact retention. Psychometric testing of the SPA-R1 contributes to greater confidence in the instrument's reliability and validity. Methods: Item response theory and specifically, the single parameter polytomous Rasch model was used as a framework for fit statistic testing and rating scale diagnostics of the SPA-R1. This was a secondary analysis of a convenience sample of undergraduate prelicensure nursing students. The setting for the previous study was virtual, and the study period was 2022. Results: The model item characteristic curves for the 27 items of the SPA-R1 have similar shapes and are clustered in proximity. Overall, there are three clusters of items evident in the Rasch standardized residual contrast. The Rasch scale diagnostics indicated that the scale appropriately monotonically increases. However, there is a greater than 5 logit distance between does not apply and severely restricts, between severely restricts and moderately restricts, and between does not restrict or support and moderately supports. These large threshold distances indicate that additional steps in the scale may be warranted. The items cover the mid-range of the amount of retention perceptions; however, there are no items that represent the highest magnitude of the perceived amount of influence on retention. Conclusions: This study contributes further evidence to support the validity and reliability of the SPA-R1. We recommend adding steps to the scale, removing the does not apply response option, and considering scoring by three domains or clusters.

Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes.

Transfer of autologous tumor infiltrating lymphocytes (TIL) to patients with refractory melanoma has shown clinical efficacy in a number of trials. However, extending the clinical benefit to patients with other cancers poses a challenge. Inefficient costimulation in the tumor microenvironment can lead to T cell anergy and exhaustion resulting in poor anti-tumor activity. Here, we describe a chimeric costimulatory antigen receptor (CoStAR) comprised of FRα-specific scFv linked to CD28 and CD40 intracellular signaling domains. CoStAR signaling alone does not activate T cells, while the combination of TCR and CoStAR signaling enhances T cell activity resulting in less differentiated T cells, and augmentation of T cell effector functions, including cytokine secretion and cytotoxicity. CoStAR activity resulted in superior T cell proliferation, even in the absence of exogenous IL-2. Using an in vivo transplantable tumor model, CoStAR was shown to improve T cell survival after transfer, enhanced control of tumor growth, and improved host survival. CoStAR could be reliably engineered into TIL from multiple tumor indications and augmented TIL activity against autologous tumor targets both in vitro and in vivo. CoStAR thus represents a general approach to improving TIL therapy with synthetic costimulation.