bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase Ib Study of the Immunocytokine Simlukafusp Alfa (FAP-IL2v) in Combination with Cetuximab in Patients with Head and Neck Squamous Cell Carcinoma
Authors: Hansen Aaron R. , Gomez-Roca Carlos A. , Robbrecht Debbie G. J. , Verlingue Loic , Italiano Antoine , Bauman Julie E. , Steeghs Neeltje , Prenen Hans , Fayette Jérôme , Spicer James , Niu Jiaxin , Habigt Christin , Schneider Meike , Evers Stefan , Sleiman Nassim , Dejardin David , Ardeshir Caroline , Schmid Daniela , Boetsch Christophe , Charo Jehad , Kraxner Anton , Teichgräber Volker , Keshelava Nino , Bonomi Marcelo R.
Published: October 2024

Purpose: This phase Ib trial evaluated fibroblast activation protein-α–targeted IL2 variant (FAP-IL2v), a novel immunocytokine engineered to minimize CD25-mediated toxicities, in combination with cetuximab, in patients with recurrent, unresectable, or metastatic head and neck squamous cell carcinoma (HNSCC).

Patients and Methods: Patients received FAP-IL2v either on a continuous weekly (QW) schedule or QW for 4 weeks and then every 2 weeks (Q2W). Cetuximab was dosed at QW or Q2W schedules. The primary objectives were to evaluate the safety and tolerability, maximum tolerated dose, pharmacokinetics, and clinical activity for the combination of FAP-IL2v with cetuximab. Exploratory objectives included pharmacodynamic analyses.

Results: A total of 58 patients were enrolled, 19 patients into the dose-escalation part, and 39 patients into the expansion part. The maximum tolerated dose of FAP-IL2v was defined as 10 mg (QW/Q2W) in combination with cetuximab (500 mg/m2, Q2W), which was further tested in the expansion part. The most common FAP-IL2v–related adverse events with a grade 3 or 4 severity were hypophosphatemia (19%), lymphopenia (16%), and infusion-related reaction (14%). The pharmacokinetics of FAP-IL2v in combination with cetuximab was similar to that after administration as monotherapy. Consistent with the proposed mode of action, FAP-IL2v preferentially expanded intratumoral NK and CD8 T cells. Four patients achieved a partial response, and the objective response rate was 7% (95% confidence interval, 3.2–14.7).

Conclusions: The safety profile of FAP-IL2v in combination with cetuximab was acceptable, and pharmacodynamic markers support the proposed mode of action of this combination, but the overall low antitumor activity does not warrant further clinical exploration in HNSCC. [Part C of Study BP29842 (NCT02627274).]
Abstract B016: Lactate uptake through MCT11 enforces dysfunction in terminally exhausted T cells
Authors: Peralta Ronal M. , Delgoffe Greg M.
Published: October 2024

CD8+ T cells are critical mediators of antitumor immunity but differentiate into a state of dysfunction, known as exhaustion, after experiencing persistent TCR stimulation and metabolic stress in the tumor microenvironment (TME). Exhausted T (Texh) cells are characterized by the sustained upregulation of co-inhibitory molecules and reduced stemness and polyfunctionality. The TME also creates an immunosuppressive metabolic environment via reduced levels of vital nutrients and oxygen combined with increased catabolic waste products. Additionally, highly glycolytic tumor and stromal cells secrete lactic acid, acidifying the extracellular space. How Texh cells survive and function in the face of this altered metabolite balance remains unclear. Recent studies have shown that lactate can be incorporated into the TCA cycle by CD8+ T cells and that it can be utilized in the TME as a fuel source by regulatory T cells and macrophages. We hypothesized that CD8+ tumor-infiltrating lymphocytes (TIL) may take also take up lactate as to meet their metabolic demands in the TME. Here, we show via RNAseq and flow cytometry staining that Texh cells upregulate a newly characterized monocarboxylate transporter, MCT11 (encoded by Slc16a11), enabling uptake of lactic acid which can drive their dysfunction in the TME. MCT11 expression requires both the core exhaustion program induced through chronic activation and metabolic stress signals, like hypoxia, originating within tissues. Overexpression of MCT11 in tumor- specific T cells decreased their polyfunctionality, while conditional deletion of MCT11 in T cells reduced lactic acid uptake in Texh cells and improved effector function and response to immunotherapy. Further, a monoclonal antibody targeting MCT11 reduced lactate uptake specifically in Texh cells, which, when used therapeutically in tumor- bearing mice, resulted in significantly reduced tumor growth, inducing complete regressions and immunologic memory in lactate-rich tumors. Our data support a model in which the exhaustion program upregulates MCT11, rendering exhausted T cells sensitive to toxic lactic acid present at high levels in the tumor microenvironment. MCT11 represents an attractive target to edit in therapeutic T cells or block using antibodies to render exhausted T cells impervious to lactic acid, allowing for tumor eradication.

Citation Format: Ronal M. Peralta, Greg M. Delgoffe. Lactate uptake through MCT11 enforces dysfunction in terminally exhausted T cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B016.
Abstract B018: CCL24+ monocytes drives resistance to anti-PD-L1 blockade in hepatocellular carcinoma
Authors: DENG HAIJING , Fu-Wan Sit Grace , Wing-Sum Cheu Jacinth , Zhang Yan , Liu Cindy Xinqi , Chen Yiling , Ooi Zher Yee , Wai-Hin Yuen Vincent , Oi-Lin Ng Irene , Chak-Lui Wong Carmen
Published: October 2024

Background: Immunotherapy has promising anti-tumor activity in patients with advanced Hepatocellular carcinoma (HCC). However, the objective response rate of PD-L1 blockade is limited. Therefore, there is an urgent need to explore resistance mechanisms in immunotherapy. Methods and Results: We used the anti-PD-L1 resistant trp53KO/c-mycOE mice to explore tumor immune microenvironment. Fresh isolated single cells were analysed by single-cell RNA sequencing (scRNA seq), TCR sequencing and Cytometry by Time-Of-Flight (CyTOF). Gene expression of the tumors samples was tested by bulk RNA sequencing. In vivo efficacy studies were executed in trp53KO/c-mycOE mice induced by hydrodynamic tail vein injection. The function of immune cells was evaluated by multiple flow cytometry. Results: We found although anti-PD-L1 treatment significantly improved T cells infiltration and TCR clonal expansion. These T cells exhibited highly exhausted status with highly exhausted markers (CD39, LAG3, PD-1) expression. Targeting the exhausted markers by specific antibodies cannot unleash the function of T cells, which suggested the persistent immunosuppressive microenvironment existed. Bulk RNA sequencing showed significantly activation of IFNG related pathway. scRNA seq exhibited increased monocytes ratio and the IFNG score prominently upregulated in monocytes after anti- PD-L1 treatment. Subclusters analysis showed that CCL24+ monocytes were increased remarkably after treatment. CCL24+ monocytes showed significant response to IFNG and these cells also significantly expressed IL10, VEGFA, ARG1 etc. Conclusion: Our data demonstrated anti-PD-L1 blockade induced IFNG related pathways and increased the CCL24+ monocytes infiltration. These cells maybe the potential targets mediating the resistant mechanisms for immunotherapy. Further exploration could facilitate the development of new combination therapies that synergistically enhance treatment efficacy for patients with HCC.

Citation Format: HAIJING DENG, Grace Fu-Wan Sit, Jacinth Wing-Sum Cheu, Yan Zhang, Cindy Xinqi Liu, Yiling Chen, Zher Yee Ooi, Vincent Wai-Hin Yuen, Irene Oi-Lin Ng, Carmen Chak-Lui Wong. CCL24+ monocytes drives resistance to anti-PD-L1 blockade in hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B018.
Abstract B044: Development of Tumour-specific CD146 CAR-T Cells for Targeted Cancer Immunotherapy of Solid Tumours
Authors: Uzuner Erez , Mole Holly , Beyza GURLER Sevim , Wong Chun Wai , Fernandez Carro Macarena Lucia , Leshem Rotem , Sefton Kieran , Tovey Helen , Picken Andrew , Blot-Chabaud Marcel , Hurlstone Adam
Published: October 2024

Background: In comparison to the success with hematologic cancers, CAR-T cells for solid cancers have been held back by significant “on-target/off-tumour” toxicities caused by the absence of specific target proteins. Although CD146 (aka MCAM) is a glycoprotein expressed on benign cells, including endothelial cells, pericytes and smooth muscle cells, a conformation has been identified enriched in tumours that we call tumour-specific (ts) CD146. Herein, we attempt to engender tumour specificity of CAR-T cells by targeting tsCD146 widely expressed in several solid tumours, notably melanoma and ovarian cancer. Methods: We assessed the CAR activity using flow cytometry by measuring CD69 expression on CAR-expressing Jurkat cells, an early activation marker, after co-culturing with CD146-positive and CD146-negative human melanoma and ovarian cancer cell lines. The effector functions of CAR-T cells have been evaluated both in vitro by the relative luciferase activity of target cells and ELISA for IFN-g and TNF-a secretion after co-culturing and in vivo by assessing the tumour growth by IVIS bioluminescent imaging. Results: Through multiple rounds of protein engineering, we have developed several CAR constructs to respond to a tumour-enriched CD146 isoform. Our CAR demonstrated antigen-dependent activation of Jurkat cells when co-cultured with CD146-positive human melanoma and ovarian cancer cell lines, comparable to a CAR targeting pan-CD146. CAR primary T cells co-cultured with these cell lines exhibited proportional killing activity and other effector functions. Upon assessment of anti-tumour activities of CAR-T cells in mice engrafted with WM266-4 cells, CAR-T-treated mice showed reduced tumour burden and prolonged survival compared to mice treated with untransduced T cells. Conclusions: We have successfully integrated the antigen-binding domain of an anti-tsCD146 antibody into a CAR scaffold. The ability of tsCD146 CAR primary T cells to target CD146-expressing cancerous cells provides a novel approach for targeted immunotherapy of solid tumours.

Citation Format: Erez Uzuner, Holly Mole, Sevim Beyza GURLER, Chun Wai Wong, Macarena Lucia Fernandez Carro, Rotem Leshem, Kieran Sefton, Helen Tovey, Andrew Picken, Marcel Blot-Chabaud, Adam Hurlstone. Development of Tumour-specific CD146 CAR-T Cells for Targeted Cancer Immunotherapy of Solid Tumours [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B044.
Abstract B048: Next Generation Binding: Measuring Cell Avidity to Fully Characterize Cell-Cell Interactions and Understand Mechanism of Action for Cellular Therapies
Authors: Hoang Song-My
Published: October 2024

While conventional assays such as affinity, cytokine secretion, and cytotoxicity provide valuable data at a molecular level, this information is insufficient to fully characterize and select the best cellular therapies. There is still a lack of understanding about cell-cell interactions that drive functional processes. Cell Avidity, the collective strength of interactions between an effector and its target, can help elucidate the mechanism of action for therapeutic candidates. Our highly flexible Cell Avidity platform, the z-Movi Cell Avidity Analyzer, combines fluorescence microscopy with acoustic force to distinguish cell binding in a physiological context. This provides a comprehensive view of cell binding characteristics to interrogate potency, safety, sensitivity, and binding kinetics. Cell avidity has been used to: 1) Engineer CAR-T cells secreting a T-cell engaging molecule to overcome a challenging tumor microenvironment in pancreatic adenocarcinoma. 2) Reveal critical neutrophil-tumor cell interactions in the tumor microenvironment. 3) Identify essential proteins involved in B-cell lymphoma binding to stromal cells in the tumor microenvironment. 4) Fine-tune the affinity/cell avidity of CAR-T cells to mitigate on-target off-tumor toxicity in renal cell carcinoma. 5) Format-tune in vivo-launched bispecific T cell engagers to enhance efficacy against renal cell carcinoma. 6) Characterize the mechanism of action to assess the function and efficacy of NK-cell cytotoxicity. Cell Avidity is an emerging biomarker that directly quantifies the strength of the physical interactions between target and effector cells. We developed a Cell Avidity platform that enables characterization and screening of molecular binders and cellular products, including antibodies, small molecules, and cell therapies.

Citation Format: Song-My Hoang. Next Generation Binding: Measuring Cell Avidity to Fully Characterize Cell-Cell Interactions and Understand Mechanism of Action for Cellular Therapies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B048.
Abstract PR-04: A TROP2/Claudin program mediates immune exclusion to impede checkpoint blockade in breast cancer
Authors: Wu Bogang , Thant Win , Bitman Elena , Liu Ting , Liu Jie , Paschalis Eleftherios I. , Xu Katherine H. , Nieman Linda T. , Ting David T. , Thimmiah Nayana , Sun Sheng , Abelman Rachel O. , Isakoff Steven J. , Spring Laura M. , Bardia Aditya , Ellisen Leif W.
Published: October 2024

Background: Antibody Drug Conjugates (ADCs) targeting Trophoblast Cell-Surface Antigen 2 (TROP2) are emerging as paradigm-changing drugs, but the therapeutically relevant mechanisms of TROP2 itself remain unknown. The goal of this project is to investigate the role of TROP2 in promoting breast cancer aggressiveness and provide insights into the mechanisms of action of TROP2-targeted ADCs. Methods: TROP2 loss-of-function studies were performed in multiple syngeneic mouse mammary tumor models. Truncated TROP2 mutants were reconstituted into CRISPR knockout cells to map essential domains that enable TROP2 tumor-promoting activity. Flow cytometry for tumor infiltrating lymphocytes, tissue histology and immunofluorescence were used to assess tumor microenvironment. Data from immune checkpoint-treated patients were used to test hypotheses from the preclinical findings. Results: We find that TROP2 mediates a mechanism of immune exclusion in Triple-Negative Breast Cancer (TNBC) through association with the essential tight junction protein Claudin 7. TROP2 expression is inversely correlated with T cell infiltration and strongly associated with outcomes in TNBC. Loss-of-function and reconstitution experiments demonstrate TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple claudins, enabling T cell infiltration. Employing a humanized TROP2 syngeneic TNBC model, we show that TROP2 targeting via Sacituzumab govitecan (SG) induces an anti-PD1 response associated with broad immune cell activation, and TROP2 is highly associated with lack of response to anti-PD1 therapy in human breast cancer. Conclusions: TROP2 mediates immune exclusion and may be targeted to enhance immunotherapy response.

Citation Format: Bogang Wu, Win Thant, Elena Bitman, Ting Liu, Jie Liu, Eleftherios I. Paschalis, Katherine H. Xu, Linda T. Nieman, David T. Ting, Nayana Thimmiah, Sheng Sun, Rachel O. Abelman, Steven J. Isakoff, Laura M. Spring, Aditya Bardia, Leif W. Ellisen. A TROP2/Claudin program mediates immune exclusion to impede checkpoint blockade in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr PR-04.
Abstract PR-05: Nous-209 off-the-shelf vaccine targets neoantigens mutations well represented both in primary and metachronous incident CRCs from Lynch syndrome patients
Authors: De Marco Lorenzo , Micarelli Elisa , Panula Joni , D'Alise Anna Morena , Leoni Guido , Hokkanen Kalle E. , Hämäläinen Eija , Mecklin Jukka-Pekka , Scarselli Elisa , Seppälä Toni
Published: October 2024

Lynch Syndrome (LS) is the most common hereditary cancer syndrome, caused by germline mutations in one of the four DNA mismatch repair (MMR) genes. LS patients have a high risk to develop microsatellite instable (MSI) colorectal cancers. Tumors developed by LS carriers display high levels of microsatellite instability, which leads to the accumulation of large numbers of mutations, among which frameshift insertion/deletions (indels) within microsatellite (MS) loci are very common and shared among different tumors. When indels occur in coding genes they give rise to frameshift peptides (FSPs) with a very high potential to act as safe and potent neoantigens for a vaccine. NOUS-209 is a genetic vaccine encoding 209 neoantigens, shared across sporadic and hereditary MSI tumors, developed for interception and treatment of MSI tumors. Phase 1b trial evaluating NOUS-209 monotherapy in healthy LS carriers showed the induction of a potent and broad immune response. Here, we characterize indels encoding FSPs in a cohort of 50 incident MSI CRC from LS patients detected during routine screening (38 primary tumors; 22 metachronous tumors) by whole Exomeseq NGS. Overall, primary and metachronous tumors have a similar number of indels in coding genes. The repertoire of detected indels is only partially shared (27%) between the two categories of tumors. The 209 indels selected for the NOUS-209 vaccine are instead highly shared (95%) between primary and metachronous tumors. Moreover, the analysis of 8 patients for which both the primary and the metachronous tumor were available confirmed the presence of the 209 mutations both in the first and the second tumor. Therefore, the NOUS 209 vaccine has the potential to prevent tumor occurrence both in previvors and survivors by inducing a broad T cell immune response against recurrent FSP.

Citation Format: Lorenzo De Marco, Elisa Micarelli, Joni Panula, Anna Morena D'Alise, Guido Leoni, Kalle E. Hokkanen, Eija Hämäläinen, Jukka-Pekka Mecklin, Elisa Scarselli, Toni Seppälä. Nous-209 off-the-shelf vaccine targets neoantigens mutations well represented both in primary and metachronous incident CRCs from Lynch syndrome patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr PR-05.
Figure S6 from Peripheral Blood IFN Responses to Toll-Like Receptor 1/2 Signaling Associate with Longer Survival in Men with Metastatic Prostate Cancer Treated with Sipuleucel-T
Authors: Brown Michael C. , D’Anniballe Vincent M. , Boczkowski David , Kandadi Harini , Sheikh Nadeem , Kornahrens William , Heath Elisabeth I. , Thakur Archana , Chen Wei , Lum Lawrence , Cackowski Frank C. , Boerner Julie , Gunn Michael D. , Armstrong Andrew J. , Nair Smita K.
Published: October 2024

Related to Figure 4
Figure 3 from Peripheral Blood IFN Responses to Toll-Like Receptor 1/2 Signaling Associate with Longer Survival in Men with Metastatic Prostate Cancer Treated with Sipuleucel-T
Authors: Brown Michael C. , D’Anniballe Vincent M. , Boczkowski David , Kandadi Harini , Sheikh Nadeem , Kornahrens William , Heath Elisabeth I. , Thakur Archana , Chen Wei , Lum Lawrence , Cackowski Frank C. , Boerner Julie , Gunn Michael D. , Armstrong Andrew J. , Nair Smita K.
Published: October 2024

IFN-β induction after TLR1/2 stimulation associates with PBMC ELISpot responses to Fluzone, PHA, and CEFT (cytomegalovirus, EBV, Fluzone, and Tetanus peptide pool). A, ELISpot SFU after each indicated stimulant (n = 77 CEFT, n = 79 Fluzone, n = 82 for others). B, Cell type–specific PBMC densities as a percentage of live single cells (bottom) separated by median IFN-β response after TLR1/2 stimulation (n = 106, PRIME study). A and B,P values are from unpaired t test; mean + SEM is shown. C, Correlation (Spearman r) of each indicated PBMC (ELISpot), serum (ELISA), or sip-T product metric (CD54 upreg and TNC) output with fold mock IFN-β values after TLR1/2 stimulation; (*) indicates FDR adjusted Q < 0.05. See Supplementary Figs. S4 and S5 for extended data and representative gating. SFU, spot forming units.
Cost-Effectiveness of a Shock Team Approach in Refractory Cardiogenic Shock
Authors: Taleb Iosif , Giannouchos Theodoros V. , Kyriakopoulos Christos P. , Clawson Antoine , Davis Erin S. , Sideris Konstantinos , Tseliou Eleni , Shah Kevin S. , Tonna Joseph E. , Dranow Elizabeth , Jones Tara L. , Carter Spencer J. , Fang James C. , Stehlik Josef , Ohsfeldt Robert L. , Selzman Craig H. , Hanff Thomas C. , Drakos Stavros G.
Published: October 2024

BACKGROUND:

Multidisciplinary Shock Teams have improved clinical outcomes for cardiogenic shock, but their implementation costs have not been studied. This study’s objective was to compare costs between patients treated with and without a Shock Team and determine if the team’s implementation is cost-effective compared with standard of care.

METHODS:

We examined patients with refractory cardiogenic shock treated with or without a Shock Team at a tertiary academic hospital from 2009 to 2018. Real-world hospital data were used to compare costs and outcomes, including survival at discharge, 1-year survival, and quality-adjusted life years gained at 1 year. Incremental cost-effectiveness ratios were calculated over a 1-year time horizon, with parameter uncertainty evaluated through probabilistic sensitivity analysis using 1000 second-order Monte Carlo simulations.

RESULTS:

The study involved 244 patients, with 123 treated by the Shock Team and 121 receiving standard of care. Patients were predominantly male (77.5%), with a mean age of 58 (18–92) years. The Shock Team approach improved survival rates at hospital discharge and 1-year follow-up (61.0% versus 47.9%;
P
=0.04 and 55.0% versus 40.5%;
P
=0.03, respectively). The incremental cost-effectiveness ratio for increases in survival probability at discharge for the multidisciplinary Shock Team compared with standard of care was $102 088. The incremental cost-effectiveness ratio for increases in survival probability at 1-year was estimated at $96 152 and at $127 862 per 1 quality-adjusted life year gained. Probabilistic sensitivity analysis estimates showed that the Shock Team was cost-effective in the majority of simulations using a willingness-to-pay threshold of $150 000, while it was also dominant in almost one-third of the simulations.

CONCLUSIONS:

The Shock Team approach for treating refractory cardiogenic shock may be a cost-effective alternative to traditional standard of care. These findings can help prioritize the implementation of Shock Team initiatives to further improve cardiogenic shock outcomes.
Three-Year Outcomes Following TAVR in Younger (<75 Years) Low-Surgical-Risk Severe Aortic Stenosis Patients
Authors: Modine Thomas , Tchétché Didier , Van Mieghem Nicolas M. , Deeb G. Michael , Chetcuti Stanley J. , Yakubov Steven J. , Sorajja Paul , Gada Hemal , Mumtaz Mubashir , Ramlawi Basel , Bajwa Tanvir , Crouch John , Teirstein Paul S. , Kleiman Neal S. , Iskander Ayman , Bagur Rodrigo , Chu Michael W.A. , Berthoumieu Pierre , Sudre Arnaud , Adrichem Rik , Ito Saki , Huang Jian , Popma Jeffrey J. , Forrest John K. , Reardon Michael J.
Published: October 2024

BACKGROUND:

Transcatheter aortic valve replacement (TAVR) is an alternative to surgery in patients with severe aortic stenosis, but data are limited on younger, low-risk patients. This analysis compares outcomes in low-surgical-risk patients aged <75 years receiving TAVR versus surgery.

METHODS:

The Evolut Low Risk Trial randomized 1414 low-risk patients to treatment with a supra-annular, self-expanding TAVR or surgery. We compared rates of all-cause mortality or disabling stroke, associated clinical outcomes, and bioprosthetic valve performance at 3 years between TAVR and surgery patients aged <75 years.

RESULTS:

In patients <75 years, 352 were randomized to TAVR and 351 to surgery. Mean age was 69.1±4.0 years (minimum 51 and maximum 74); Society of Thoracic Surgeons Predicted Risk of Mortality was 1.7±0.6%. At 3 years, all-cause mortality or disabling stroke for TAVR was 5.7% and 8.0% for surgery (
P
=0.241). Although there was no difference between TAVR and surgery in all-cause mortality, the incidence of disabling stroke was lower with TAVR (0.6%) than surgery (2.9%;
P
=0.019), while surgery was associated with a lower incidence of pacemaker implantation (7.1%) compared with TAVR (21.0%;
P
<0.001). Valve reintervention rates (TAVR 1.5%, surgery 1.5%,
P
=0.962) were low in both groups. Valve performance was significantly better with TAVR than surgery with lower mean aortic gradients (
P
<0.001) and lower rates of severe prosthesis-patient mismatch (
P
<0.001). Rates of valve thrombosis and endocarditis were similar between groups. There were no significant differences in rates of residual ≥moderate paravalvular regurgitation.

CONCLUSIONS:

Low-risk patients <75 years treated with supra-annular, self-expanding TAVR had comparable 3-year all-cause mortality and lower disabling stroke compared with patients treated with surgery. There was significantly better valve performance in patients treated with TAVR.

REGISTRATION:

URL:
https://clinicaltrials.gov
; Unique identifier: NCT02701283.
Is “Application” Everything about Studying for a University Degree? The Multiple Influences Shaping Undergraduates in Chinese Higher Education in Contemporary Times
Authors: ZHUANG Tengteng , XU Xiaoxuan
Published: October 2024

Based on the self-reflection of 22 undergraduate students at a renowned Chinese university regarding their journey towards obtaining a bachelor’s degree, this study reveals the discrepancy between the idealistic functions and missions of higher education as perceived by students and their actual implementations in the real world. It further explores the multifaceted logics exerted by the higher education environment on students during their educational journey. Data analysis shows that contemporary global neoliberalism, alongside traditional Chinese cultural ideologies such as Confucianism and Daoism, significantly impacts the educational philosophies of university students to varying extents. These diverse ideologies drive students to demonstrate varied learning states and behaviors, showcasing the complex interplay of global and local forces in shaping student experiences in higher education.
Caretaker of a collection
Authors: Koops Bert-Jaap
Published: October 2024

When re-assessing women’s roles in the art world, we should not neglect traditional, perhaps stereotypical, functions. Jo van Bilderbeek-Lamaison (1849–1951) exemplifies the importance of caretaking: after her husband’s death in 1918, she played a crucial role in caring for their art collection and bequeathing it to the state. She lived in a Dordrecht house museum (the Rijksmuseum Van Bilderbeek-Lamaison, not publicly accessible), carefully exercising her responsibility ‘in her husband’s spirit’ in house maintenance, loans of artworks, and art preservation – a challenge given the fuel crisis in the 1930s and 1940s.

This case study sheds light on women’s role in the art world around 1900 from the perspective of separate public/private spheres and the associated distinction between productive labour and reproductive/caring labour. The case suggests that caring labour is not be limited to care for people, but can include care for objects, such as an art collection in a house museum.
Quantitative Identification of Moisture Sources over the Tibetan Plateau: Spatial Distributions and Temporal Variabilities
Authors: Guo Xiaoyu , Wang Lei , Tian Lide , Zhang Lin , Zhao Wanglin
Published: October 2024

The imbalanced hydrological cycles and water resource instability over the Tibetan Plateau (TP) are a topic of wide concern. Moisture sources affected by large-scale circulations are the main controls of precipitation and water resource distributions; as such, the quantitative identification of moisture sources is the key to the changes in precipitation or water-related environments, further aids efficient water management over the TP and in downstream regions of Asia. In this study, we primarily identified the spatial distributions and temporal variabilities of TP’s varied moisture sources, using HYSPLIT modeling and spatially dense precipitation isotopes (δ18O). Results showed that 1) moistures from the westerlies (West), the western arm of Indian summer monsoon (ISM) (ISM1), the eastern arm of ISM (ISM2), and the inner TP are the TP’s main moisture sources, with highest proportional contributions being >70%, ∼40%, >80%, and ∼10%–20% at northwest, southwest, and southeast sectors of the study area and the central TP region; 2) each moisture has its own region where it predominates and shows specific trends during 1951–2020 (West-northwest sector-increase, ISM1-southwest sector-increase, ISM2-southeast sector-decrease, and TP-central TP region-increase); 3) each of the moisture proportions and their temporal trends varied with different days of back trajectories (days 02–04–06–08–10), while their spatial patterns are similar; and 4) when verifying the modeled moisture proportions, precipitation δ18O is positively correlated or covaries with dry sources such as the West or TP moisture and inversely for humid ISM (ISM1 or ISM2) moisture. This work will improve our understanding of moisture-related hydrological, meteorological, and ecological studies in the “Asian Water Tower” region.

Significance Statement

The Tibetan Plateau (TP) is undergoing imbalanced hydrological cycles and water resource instability in response to global climate change. As the TP supplies vast quantities of water to Asia’s huge population, the socioeconomic impact caused by these changes is considerable. This study aims to quantitatively identify the spatial distributions and temporal variabilities of varied moisture sources over the TP in recent decades, using high-resolution modeling and ground-based precipitation isotopes. Results show that each moisture has its own region where it predominates and shows specific trends during 1951–2020. These findings can help to explain precipitation patterns or water resource distributions and provide insights into efficient water management over the TP and in downstream regions of Asia.
Adaptive fault-tolerant control of uncertain systems with unknown actuator failures and input delay
Authors: Cai Jianping , Guo Dong , Wang Wei
Published: October 2024

Unknown failures and time delays of actuators which may degrade system performance seem inevitable in practical systems. However, the available results to compensate for unknown failures of time delay actuators based on adaptive approaches are very limited. In this paper, we address such a problem by considering controlling a class of second-order systems with unknown actuator failures and input delays. Firstly, the controlled system is transformed into a triangular structure model. Meanwhile, the input time delay is transformed into dynamics of the output signal. Then, an adaptive controller is developed using backstepping. Not only can the uncertainties due to actuator failure be compensated, but the unknown input delay has also been effectively restrained under the proposed control scheme. The upper bound condition of strength scalar [Formula: see text] is proposed. It is a sufficient condition for system stability. When the strength scalar satisfies this condition, the design parameters exist and the system is stable under the controlling of the proposed controller. Finally, the effectiveness of the proposed control scheme is verified through simulation results, including numerical simulation and actual system simulation. Through the comparative simulation, it can be seen that the control scheme proposed in this paper has faster convergence speed.
Domestic violence and depression among Chinese adolescents: The role of self-evaluation
Authors: Fu Wangqian , Zhang Shiqi , Zhu Yuehua , Liu Ruidong
Published: October 2024

Background:

Depression of adolescents seriously affects their mental health as well as the formation and development of sound personality. According to Family Systems Theory, individuals’ mental health is closely related with external (e.g. domestic violence) and internal factor (e.g. self-evaluation). The formation mechanism of depression needs deep investigation in order to provide better educational intervention for students and promote their healthy development.

Aim:

The study examined the relationship among domestic violence, depression, and self-evaluation.

Methods:

The data were collected from 1,011 Chinese adolescents ( Mage = 12.04 ± 1.71) by the questionnaire of Family Violence Scale, Depression Questionnaire, and Rosenberg Self Esteem Scale.

Results:

We found domestic violence and depression were significantly positively correlated ( r = .25, p < .001); self-evaluation was significantly negatively correlated with domestic violence ( r = −.26, p < .001) and depression ( r = −.50, p < .001). Moreover, domestic violence could directly and positively predict depressed psychology, and could also indirectly predict depressed psychology through the mediating effect of self-evaluation.

Conclusion:

The level of depression of adolescents was closely related with domestic violence and self-evaluation. And self-evaluation played a mediating role between domestic violence and self-evaluation.
Network analysis of correlations between suicide exposure, depression, and anxiety symptoms in adolescents
Authors: He Tianyu , Zou Huijing , Hou Hao , Yu Yijing , Wang Fan , Tian Chunfeng , Luo Dan , Zhou Yang , Zhao Jun , Yang Bing Xiang
Published: October 2024

Background:

Adolescents with a history of suicide exposure, defined as experiencing the suicide death of a family member, friend, or other acquaintances, are more likely to experience mental health issues such as depression or anxiety.

Aims:

This study aimed to explore prevalence rates and the network of adolescents’ suicide exposure, depression, and anxiety symptoms, and to clarify the correlations between suicide exposure and symptoms of depression and anxiety.

Method:

A total of 8,957 adolescents were included in this cross-sectional study. Data regarding general information, symptoms of depression and anxiety, and suicide exposure were collected from mid-September to early October 2021. Network analysis was employed to assess relationships between suicide exposure and individual symptoms of both depression and anxiety. Central symptoms were identified by strength; the flow network was visualized to identify symptoms directly related to suicide exposure.

Results:

The prevalence rates of suicide exposure, depression, and anxiety were 5.28%, 12.87%, and 10.48%. Results indicated that suicide exposure was associated with both depression and anxiety, and had the strongest positive association with suicidal ideation. Central symptoms of the network were sad mood, nervousness, fatigue, irritability, and uncontrollable worry. Bridge symptoms were suicidal ideation and irritability. Appetite changes, suicidal ideation, uncontrollable worry, sleep difficulties, and irritability were symptoms directly related to suicide exposure.

Conclusions:

There were significant inter-symptom associations between suicide exposure, depression, and anxiety in adolescents. It is recommended that future studies explore whether targeted interventions and long-term monitoring concerning these inter-symptom associations can protect adolescents with suicide exposure.
Asylum-seeker women: Coping strategies and mental wellbeing
Authors: Shishehgar Sara , Gholizadeh Leila , DiGiacomo Michelle , Davidson Patricia Mary
Published: October 2024

Background:

Asylum seekers in Australia are subjected to various punitive measures that can affect their psychological wellbeing. The capacity of asylum seekers to adapt and cultivate effective coping strategies can enhance their resilience, facilitate their settlement processes and promote their overall mental health.

Aim:

This study aims to explore the coping strategies employed by women who are asylum-seekersthat have the potential to enhance their resilience post migration.

Method:

A semi-structured qualitative study was conducted with asylum-seeker women from Iran. Data were analysed using an inductive thematic analysis.

Results:

Seventeen participants described their experiences of applying various strategies to enhance their coping ability, resilience and maintain their mental wellbeing when facing ongoing challenges. Problem-solving strategies included social engagement, adjusting life plans and seeking support from formal and informal resources. Emotion-focussed strategies were positive thinking and maintaining hope, avoidance and spirituality. While emotion-focussed strategies enabled the women to manage their stresses temporarily, problem-solving strategies allowed them to effectively address the challenges they faced after migration.

Conclusion:

Providing supportive resources for asylum seekers, removing stigma and developing community ties may assist individuals in improving their coping skills, resilience and mental wellbeing.
Slowdown of the Indian Economy During 2019–2020: Deconstructing the Anomaly
Authors: Gupta Poonam
Published: October 2024

In this paper, we analyse the deep and anomalous economic slowdown in 2019–2020, when the Indian economy grew at a rate of 4 per cent, the lowest in a decade. We argue that the slowdown was largely confined to one year, 2019–2020. The growth rate in the prior years averaged 7 per cent a year, and in none of the other years was it significantly below this average rate of growth. In contrast to some of the prevailing narratives, the slowdown did not permeate widely across sectors and activities. It was concentrated primarily in the manufacturing sector. The agriculture sector grew faster than before, and the services sector experienced only a mild deceleration, that too in the last two quarters of the year. On the demand side, the slowdown was reflected in a sharp contraction in exports; while the deceleration in consumption was milder, investment growth was flat and government expenditure grew at a faster pace than in the previous decade. The slowdown can be accounted for by three factors. First, about a 50 basis points worth of the slowdown was due to the COVID-induced lockdown in the last week of March 2020. Second, more than 100 basis points worth of the slowdown was due to the collapse in exports, attributed both to a large global slowdown in trade and to the fact that India lost ground to other countries in maintaining its market share in a slowing market. Finally, the credit collapse from banks, non-banking financial companies and housing finance companies impacted economic growth.

JEL Codes: E65, F40, O11, O47, O53
Hyoscyamus niger poisoning in Sudan: A case report
Authors: Hassan Ibrahim Nagmeldin
Published: October 2024

Hyoscyamus niger, commonly known as henbane, contains potent alkaloids that can cause anticholinergic toxicity when ingested. This case report describes a 35-year-old male gardener who presented with confusion, hallucinations, dry mouth, and dilated pupils after consuming parts of the plant. The patient was treated with rehydration, activated charcoal, and physostigmine, leading to rapid clinical improvement. This case highlights the importance of recognizing plant-based poisonings and the efficacy of physostigmine in managing anticholinergic syndrome. Public awareness and education on the dangers of unfamiliar plants are essential to prevent accidental ingestions.
Mindfulness meditation among South African psychologists: a pathway to ‘being’ amid existential suffering in contemporary South Africa
Authors: Korving Ciara , Munro Nicholas
Published: October 2024

Mindfulness is currently regarded as a life skill as well as part of an approach to life that can generate beneficial intrapersonal and relational outcomes. Given the centrality of intrapersonal and relational outcomes in psychotherapeutic encounters, it seems logical that the practice of mindfulness by psychologists would be relevant to explore, especially in contemporary South African contexts where high levels of trauma, interpersonal distress, and resultant existential and intrapsychic struggles prevail. The study seeks to address an identified gap in existing research concerning the experienced relevance of long-term mindfulness meditative practice for counselling psychology and therapeutic practice generally, particularly in the South African context. Located within an interpretivist paradigm and interpretative phenomenological analysis, this study explored the mindfulness and mindfulness meditation practices of 11 South African counselling psychologists and the ways in which these practices informed their being in both personal and psychotherapeutic settings. Each participant was invited to participate in a semi-structured interview and reflexive journalling task as part of the research process. The findings centralise the being capacities afforded to psychologists through a mindfulness practice and identify how the related elements of non-judgement, nonattachment, and (re)connection enable enhanced relational encounters with clients. The findings contribute to the limited literature related to the value of psychologists’ mindfulness practices in relation to the way in which they manage their own responses to clients, as well as the potential for mindfulness practices to help clients manage presenting trauma responses.
Artificial Intelligence and U.S. Military Cadets’ Attitudes About Future War
Authors: Lushenko Paul , Sparrow Robert
Published: October 2024

What shapes warfighters’ trust in military technologies augmented with Artificial Intelligence (AI)? Research often assumes that junior military personnel, including cadets training to become officers, will trust AI during future wars, and at higher levels than senior officers. We test these claims by fielding a survey experiment among a representative sample of cadets assigned to the Reserve Officers’ Training Corps (ROTC) program in the United States. Our analysis reveals that cadets are more trusting of AI-enhanced military technologies than senior officers, but that their trust is shaped by a more conservative understanding of the appropriate use and oversight of AI. We also find that cadets’ trust is shaped by a complex set of instrumental, normative, and operational considerations, including ongoing cognitive development, education, and professional enculturation. These results provide the first experimental evidence of cadets’ trust in AI-enhanced military technologies and have implications for future research, policy, and military modernization.
An approach of designing a child-height-assisted robot with semi-autonomous enhances social reciprocity for children with autism spectrum disorders
Authors: Cheng Yufang , Yao Kai-Chao , Qiu Li-xin , Cheng Li-hung
Published: October 2024

Individuals with autism spectrum disorder (ASD) often face significant challenges in social reciprocity, which involves the mutual exchange of social cues and interactions. This study investigates the potential of using a child-height assistive robot named Rudolf to enhance the social reciprocity skills of children with ASD. The research focused on two main questions: how the robot’s semi-autonomous functions influence the enhancement of social reciprocity and how its customizable features elicit and improve these skills. Rudolf was specifically designed to engage children with ASD in a structured, supportive environment, offering tailored interactions to practice social reciprocity. A multiple-probe design was employed over three months to evaluate the robot’s impact on the social skills of three participants with ASD. The study revealed significant improvements in the children’s social reciprocity, with participants demonstrating increased engagement, trust, and interaction within the robot-assisted environment. The customizable functionalities of Rudolf were particularly effective in eliciting and reinforcing interactive behaviors. This research highlights the potential of assistive robots, like Rudolf, in addressing the unique social challenges faced by individuals with ASD. The findings suggest that such robots, when designed with customizable, child-centered features, can significantly enhance social skills in this population. The study contributes to the development of tailored assistive technologies that improve social integration and overall quality of life for children with ASD.
Political liberalism, dualist democracy and the call to constituent power
Authors: Michelman Frank I.
Published: October 2024

Alessandro Ferrara’s argument in Sovereignty Across Generations takes shape within a broadly Rawlsian ‘political liberal’ framework of thought about moral underpinnings for a constitutional-democratic practice of politics. Where, exactly (I ask here), is the place within that thought for concern about occurrences in a country’s past of popular constituent power? If the country’s currently established constitutional regime is fully democratic (and is otherwise morally in order) by whatever operational measures you and I might think to apply, why should we or anyone care about how or by whose authority the regime got set up and running in the first place? By Ferrara’s Rawls-inspired teaching in Sovereignty Across Generations, the answer to that question will come from a certain conception of political legitimacy. But then a potent objection comes from those who press the question of how to reconcile a democratic conception of legitimacy with a subjection of current (say) deliberative-majoritarian rule to antecedently imposed terms of constraint. Under Rawlsian and Ferrarian stimulus, I look into the possible relevance here of H.L.A. Hart’s proposition of a complementarity or fusion, in our concept of law, of an ‘internal’ with an ‘external’ perspective that those involved may adopt toward the coercive social practice in question. Underlying the Rawlsian constitutional proposition on legitimacy, I end by suggesting, is the thought that, in order for a person to live in freedom under law, that person will have to sustain simultaneously an internal attitude of bonding to their society’s own ongoing project of legality and an external attitude of critical judgemental of that project as reasonably and rationally acceptable to free and equal citizens in conditions of reasonable pluralism.
Governing poverty and migration in European nation-states – keywords revisited: Postscript
Authors: Anderson Bridget
Published: October 2024

Taken together these essays reveal both synergies and contradictions between and within immigration and welfare policies. Several common themes emerge. Firstly, while access to the welfare state is an important signifier of membership, in practice claiming certain state benefits is accompanied by suspicion, surveillance and stigma. The good citizen is a worker citizen. Secondly, the importance of the welfare state in putting the nation into the nation-state: the normative national community imagined as the rightful subject of welfare states is racialised and classed. Thirdly, deservingness functions in both welfare states and immigration regimes to prioritise victimhood rather than rights and redistribution.