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.

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.

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).

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.

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.

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.

Engineering strategies to optimise adoptive cell therapy in ovarian cancer.

Ovarian cancer is amongst the ten most common cancer types in women, and it is one of the leading causes of death. Despite the promising results of targeted therapies, including anti-angiogenic agents and poly (ADP-ribose) polymerase inhibitors (PARPi), the majority of patients will relapse and develop treatment resistance, implying that novel therapeutic strategies are required. Adoptive cell therapy (ACT) refers to the process by which autologous immune cells are used to eliminate cancer. Examples include tumour infiltrating lymphocytes (TILs), T cells genetically engineered with T cell receptors (TCR), or chimeric antigen receptor (CAR)-T cells. Recently, ACT has revealed promising results in the treatment of haematological malignancies, however, its application to solid tumours is still limited due to lack of functionality and persistence of T cells, prevalence of an exhausted phenotype and impaired trafficking towards the tumour microenvironment (TME). In this review we explore the potential of ACT for the treatment of ovarian cancer and strategies to overcome its principal limitations.

Relationship Between Community-Level Distress and Cardiac Rehabilitation Participation, Facility Access, and Clinical Outcomes After Inpatient Coronary Revascularization.

BACKGROUND: Although disparities in cardiac rehabilitation (CR) participation are well documented, the role of community-level distress is poorly understood. This study evaluated the relationship between community-level distress and CR participation, access to CR facilities, and clinical outcomes. METHODS: A retrospective cohort study was conducted on a 100% sample of Medicare beneficiaries undergoing inpatient coronary revascularization between July 2016 and December 2018. Community-level distress was defined using the Distressed Community Index quintile at the beneficiary zip code level, with the first and fifth quintiles representing prosperous and distressed communities, respectively. Outpatient claims were used to identify any CR use within 1 year of discharge. Beneficiary and CR facility zip codes were used to describe access to CR facilities. Adjusted logistic regression models evaluated the association between Distressed Community Index quintiles, CR use, and clinical outcomes, including one-year mortality, all-cause hospitalization, and acute myocardial infarction hospitalization. RESULTS: A total of 414 730 beneficiaries were identified, with 96 929 (23.4%) located in the first and 67 900 (16.4%) in the fifth quintiles, respectively. Any CR use was lower for beneficiaries in distressed compared with prosperous communities (26.0% versus 46.1%, P<0.001), which was significant after multivariable adjustment (odds ratio, 0.41 [95% CI, 0.40-0.42]). A total of 98 458 (23.7%) beneficiaries had a CR facility within their zip code, which increased from 16.3% in prosperous communities to 26.6% in distressed communities. Any CR use was associated with absolute reductions in mortality (-6.8% [95% CI, -7.0% to -6.7%]), all-cause hospitalization (-5.9% [95% CI, -6.3% to -5.6%]), and acute myocardial infarction hospitalization (-1.3% [95% CI, -1.5% to -1.1%]), which were similar across each Distressed Community Index quintiles. CONCLUSIONS: Although community-level distress was associated with lower CR participation, the clinical benefits were universally received. Addressing barriers to CR in distressed communities should be considered a significant priority to improve survival after coronary revascularization and reduce disparities.

del Nido versus blood cardioplegia in cardiac surgery: A multicenter analysis of over 40,000 patients.

OBJECTIVES: The use of del Nido cardioplegia in adult cardiac surgery is rising in popularity. The objective of this large multicenter study was to evaluate the use and associated outcomes of del Nido versus blood cardioplegia in adult cardiac surgery. METHODS: Patients undergoing coronary artery bypass grafting (CABG) and/or valve (mitral, aortic), and/or nondescending thoracic aortic surgery (July 2014 to March 2022) across 39 centers were extracted from the Perfusion Measures and Outcomes registry. Patients were stratified by cardioplegia type for unadjusted analysis and multivariable mixed-effects models were used for risk adjustment. RESULTS: Of 44,175 patients, 42.5% used del Nido, with use increasing 48% over time. Overall, the del Nido group had shorter median crossclamp time (74 minutes vs 87 minutes, P < .001) and lower median peak intraoperative glucose levels (161 mg/dL vs 180 mg/dL, P < .001). Use of del Nido was not associated with operative mortality (adjusted odds ratio [ORadj], 1.16; P = .075) nor major morbidity (ORadj, 1.05; P = .25). Findings for valve cases were similar, except crossclamp time differences were variable by type of valve procedure. Within the CABG subgroup there was a trend toward increased operative mortality with del Nido (ORadj, 1.24; P = .069), whereas the risk of renal failure approaches statistical significance in the aortic subgroup (ORadj, 1.54; P = .056). CONCLUSIONS: In this large, multicenter study, the use of del Nido was associated with variable crossclamp time differences, lower intraoperative glucose levels, and no significant difference in major morbidity or mortality. Efficiency benefits of del Nido may be limited in valve cases, whereas outcomes in CABG and aortic cases warrant further study.

Determinants and Outcomes Associated With Skilled Nursing Facility Use After Coronary Artery Bypass Grafting: A Statewide Experience.

BACKGROUND: Skilled nursing facility (SNF) care is frequently used after cardiac surgery, but the patterns and determinants of use have not been well understood. The objective of this study was to evaluate determinants and outcomes associated with SNF use after isolated coronary artery bypass grafting. METHODS: A retrospective analysis of Medicare Fee-For-Service claims linked to the Society of Thoracic Surgeons clinical data was conducted on isolated coronary artery bypass grafting patients without prior SNF use in Michigan between 2011 and 2019. Descriptive analysis evaluated the frequency, trends, and variation in SNF use across 33 Michigan hospitals. Multivariable mixed-effects regression was used to evaluate patient-level demographic and clinical determinants of SNF use and its effect on short- and long-term outcomes. RESULTS: In our sample of 8614 patients, the average age was 73.3 years, 70.5% were male, and 7.7% were listed as non-White race. An SNF was utilized by 1920 (22.3%) patients within 90 days of discharge and varied from 3.2% to 58.3% across the 33 hospitals. Patients using SNFs were more likely to be female, older, non-White, with more comorbidities, worse cardiovascular function, a perioperative morbidity, and longer hospital lengths of stay. Outcomes were significantly worse for SNF users, including more frequent 90-day readmissions and emergency department visits and less use of home health and rehabilitation services. SNF users had higher risk-adjusted hazard of mortality (hazard ratio, 1.41 [95% CI, 1.26-1.57]; P<0.001) compared with non-SNF users and had 2.7-percentage point higher 5-year mortality rate in a propensity-matched cohort of patients (18.1% versus 15.4%; P<0.001). CONCLUSIONS: The use of SNF care after isolated coronary artery bypass grafting was frequent and variable across Michigan hospitals and associated with worse risk-adjusted outcomes. Standardization of criteria for SNF use may reduce variability among hospitals and ensure appropriateness of use.

Evidence of clinical efficacy of a first generation CD19 CAR T cell in B cell malignancies.

The persistence and reactivity of CAR T cells were enhanced by adding co-stimulatory domains, which is the basis of currently approved CAR-T cell therapies. However, this comes at the expense of increasing toxicities from the strong cytokine release effect. This is the first report from anti-CD19 CAR-T cell therapy with a single activation domain to show a favourable safety profile and clinical efficacy with two patients who achieved durable responses up to 28 months in a cohort with heavily pretreated B cell malignancies.

Flexible social inference facilitates targeted social learning when rewards are not observable.

Groups coordinate more effectively when individuals are able to learn from others' successes. But acquiring such knowledge is not always easy, especially in real-world environments where success is hidden from public view. We suggest that social inference capacities may help bridge this gap, allowing individuals to update their beliefs about others' underlying knowledge and success from observable trajectories of behaviour. We compared our social inference model against simpler heuristics in three studies of human behaviour in a collective-sensing task. Experiment 1 demonstrated that average performance improved as a function of group size at a rate greater than predicted by heuristic models. Experiment 2 introduced artificial agents to evaluate how individuals selectively rely on social information. Experiment 3 generalized these findings to a more complex reward landscape. Taken together, our findings provide insight into the relationship between individual social cognition and the flexibility of collective behaviour.