bluuebunny/crossref_metadata_2025 huggingface dataset:
Nivolumab in Patients with Metastatic Castration-Resistant Prostate Cancer with and without DNA Repair Defects
Authors: Isaacsson Velho Pedro , Bastos Diogo Assed , Saint’ana Pedro Tofani , Rigatti Brenda , da Costa Emily Tonin , Muniz David Q.B. , Andreis Felipe , Ferreira Rafael Dal Ponte , Giongo Pedrotti Luana , Maistro Simone , Katayama Maria Lucia Hirata , Folgueira Maria Aparecida Azevedo Koike , Morelle Alessandra , Leal Alessandro , de Castro Gilberto
Published: September 2024

Purpose:

Despite the success of immune checkpoint inhibitors (ICI) across various cancers, their efficacy in metastatic castration-resistant prostate cancer (mCRPC) is modest, except for a subset of patients who experience significant, yet unpredictable, benefits. DNA repair defects (DRD) are associated with higher neoantigen load, which may predict response. Our study explored the potential of DRD for enhanced responsiveness to the ICI nivolumab.

Patients and Methods:

We conducted a phase II, multicenter, single-arm trial evaluating nivolumab in patients with mCRPC with prior docetaxel therapy. The DRD were assessed using ctDNA. The primary endpoint was PSA50 response. Secondary endpoints included the objective response rate, radiographic progression-free survival (rPFS), and overall survival. Also, exploratory comprehensive genomic profiling was performed via whole-exome sequencing of tumor samples and matched normal tissues, alongside PD-L1 expression evaluation.

Results:

Among the 38 enrolled patients, DRD was identifiable in 30.5% (11/36) through ctDNA and/or whole-exome sequencing analyses. The overall PSA50 response rate was 10.5% (4/38). The PSA50 and objective response rates did not significantly differ between patients with and without DRD (18.2% vs. 8%; P = 0.57 and 50% vs. 17.6%; P = 0.27, respectively). The median PSA-PFS (1.9 vs. 2.8 months; P = 0.52) and rPFS (3.4 vs. 5.5 months; P = 0.7) were not statistically different between patients with and without DRD. Grade ≥ 3 adverse events were reported in 47.3% of participants.

Conclusions:

Nivolumab has clinical activity in a subset of patients with mCRPC; however, DRD does not predict response. These results highlight the necessity of identifying new biomarkers to more accurately determine patients with mCRPC who might respond to ICIs.
Supplementary Figure 4 from Generation, Transcriptomic States, and Clinical Relevance of CX3CR1+ CD8 T Cells in Melanoma
Authors: Ishigaki Hirohito , Yamauchi Takayoshi , Long Mark D. , Hoki Toshifumi , Yamamoto Yuta , Oba Takaaki , Ito Fumito
Published: September 2024

Single-cell profiling of melanoma-infiltrating cells from patients treated with immune checkpoint inhibitor therapy in the Sade-Feldman et al. data
Supplementary Table 3 from SREBP-Dependent Regulation of Lipid Homeostasis Is Required for Progression and Growth of Pancreatic Ductal Adenocarcinoma
Authors: Ishida Chiaki T. , Myers Stephanie L. , Kubota Casie S. , Shao Wei , McGuire Meredith R. , Liu Chune , Ewachiw Theodore E. , Mukhopadhyay Debaditya , Ke Suqi , Wang Hao , Rasheed Zeshaan A. , Anders Robert A. , Espenshade Peter J.
Published: September 2024

Table S3. Detailed cause of death and observed lesions in KPC mouse cohorts
Supplementary Table S3 from mTORC1-Driven Protein Translation Correlates with Clinical Benefit of Capivasertib within a Genetically Preselected Cohort of PIK3CA-Altered Tumors
Authors: Sobsey Constance A. , Froehlich Bjoern C. , Mitsa Georgia , Ibrahim Sahar , Popp Robert , Zahedi Rene P. , de Bruin Elza C. , Borchers Christoph H. , Batist Gerald
Published: September 2024

Detailed results of pathway mapping by Qiagen IPA
Supplementary Materials and Methods from SREBP-Dependent Regulation of Lipid Homeostasis Is Required for Progression and Growth of Pancreatic Ductal Adenocarcinoma
Authors: Ishida Chiaki T. , Myers Stephanie L. , Kubota Casie S. , Shao Wei , McGuire Meredith R. , Liu Chune , Ewachiw Theodore E. , Mukhopadhyay Debaditya , Ke Suqi , Wang Hao , Rasheed Zeshaan A. , Anders Robert A. , Espenshade Peter J.
Published: September 2024

SUPPLEMENTARY MATERIALS AND METHODS
Supplementary Methods S1 from mTORC1-Driven Protein Translation Correlates with Clinical Benefit of Capivasertib within a Genetically Preselected Cohort of PIK3CA-Altered Tumors
Authors: Sobsey Constance A. , Froehlich Bjoern C. , Mitsa Georgia , Ibrahim Sahar , Popp Robert , Zahedi Rene P. , de Bruin Elza C. , Borchers Christoph H. , Batist Gerald
Published: September 2024

Supplemental Materials and Methods concerning patient samples, cell lines, tissue culture, iMALDI-MS, Nano-LC-Orbitrap-MS, LC-MRM-MS
Supplementary Figure S2 from mTORC1-Driven Protein Translation Correlates with Clinical Benefit of Capivasertib within a Genetically Preselected Cohort of PIK3CA-Altered Tumors
Authors: Sobsey Constance A. , Froehlich Bjoern C. , Mitsa Georgia , Ibrahim Sahar , Popp Robert , Zahedi Rene P. , de Bruin Elza C. , Borchers Christoph H. , Batist Gerald
Published: September 2024

Individual protein concentrations measured by iMALDI-MS for PTEN vs. IHC H-score
Allostatic Load as a Mediator and Perceived Chronic Stress as a Moderator in the Association between Maternal Mental Health and Preterm Birth: A Prospective Cohort Study of Pregnant Women in Pakistan
Authors: Premji Shahirose Sadrudin , Lalani Sharifa , Ghani Farooq , Nausheen Sidrah , Forcheh Ntonghanwah , Omuse Geoffrey , Letourneau Nicole , Babar Neelofur , Sulaiman Salima , Wangira Musana , Ali Shahnaz Shahid , Islam Nazneen , Dosani Aliyah , Yim Ilona S ,   on behalf of Maternal-infant Global Health Team – Collaborators in Research
Published: September 2024

Introduction: The complex biopsychosocial pathways linking maternal mental health with preterm birth (PTB) are not well understood. This study aimed to explore allostatic load (AL) as a mediator and perceived chronic stress as a moderator in the pathway linking maternal mental health and PTB. Methods: A cohort study of pregnant women (n = 1,567) recruited at clinic visits within 10–19 weeks of gestation was assessed for maternal mental health (i.e., pregnancy-related anxiety, state anxiety, depressive symptoms) and perceived chronic stress. Blood pressure and levels of cortisol, total cholesterol, C-reactive protein, and glycosylated hemoglobin were used to create a composite measure of AL. Results: AL had the most significant effect on PTB (odds ratio (OR) = 1.84, 95% CI = 1.26–12.67, p = 0.001), while systolic blood pressure emerged as the only significant individual marker using variable selection (OR = 22%, 95% CI = 1.06–1.40, p < 0.001) in multiple logistic regression analysis. A mediation analysis revealed that maternal mental health did not have a significant direct effect on PTB (p = 0.824), but its indirect effect mediated by AL was significant (z = 2.33, p < 0.020). Low and high levels of perceived chronic stress, relative to the mean, moderated this indirect effect (z = 3.66, p < 0.001). Conclusions: AL has a significant direct influence on PTB and mediates the effect of maternal mental health on PTB; however, the indirect effect of AL is indistinguishable between women with higher or lower levels of perceived chronic stress than normal.
Two Cases of Intraocular Undifferentiated Pleomorphic Sarcoma
Authors: Khatab Sodaba , Colijn Johanna Maria , Naus Nicole , Verdijk Robert M. , Hötte Gijsbert
Published: September 2024

Introduction: Undifferentiated pleomorphic sarcoma (UPS), formerly known as malignant fibrous histiocytoma, is a high-grade soft tissue sarcoma arising from mesenchymal stem cells. UPSs are rare and account for about 5% of all soft tissue sarcoma. UPSs arising in the head and neck are especially rare, comprising 1–3% of all UPSs. Case Presentation: In this report, we describe 2 cases of intraocular UPS. Both cases concern 68-year-old males: one developing a UPS in an eviscerated socket after a chronic fibrinous inflammation and the other years after ocular trauma. Conclusion: Our cases may support the hypothesis of chronic inflammation playing a role in sarcoma formation as they are characterized by a longstanding history of (surgical) trauma with signs of chronic inflammation and phthisis bulbi.
Evaluation of Cardiac Function Recovery in Patients with Paroxysmal Atrial Fibrillation after Catheter Radiofrequency Ablation Using Two-Dimensional Speckle Tracking Imaging and Real-Time Three-Dimensional Echocardiography
Authors: Han Rui , Mei Ying-Chen , Li Hai-Wei , Li Rong-Juan , He Yi-Hua , Wang Ze-Feng , Wu Yong-Quan
Published: September 2024

Introduction: The aim of this study was to evaluate the utility of 2D-STI and real-time three-dimensional echocardiography (RT-3DE) in assessing changes in left atrial (LA) structure and function in patients with paroxysmal atrial fibrillation (PAF) post-radiofrequency catheter ablation (RFCA). Methods: A retrospective analysis was conducted on 44 PAF patients who underwent RFCA at BA Hospital from March 2022 to March 2023. An age- and gender-matched control group of 32 healthy individuals was also included. Comprehensive echocardiographic parameters including LA dimensions (LAAPD, LALRD), volumes (LAVmin, LAVmax), ejection fraction (LAEF), and tissue velocities (a’, Ar) were compared between groups. Post-RFCA changes in these parameters were also assessed at 1, 3, and 6 months. Results: Pre-RFCA, PAF patients demonstrated larger LA dimensions and volumes with reduced LAEF and tissue velocities compared to controls. Post-RFCA, there was a significant improvement in LAEF and left ventricular ejection fraction at 1, 3, and 6 months, with the most pronounced changes observed at 6 months. LA dimensions increased initially but then decreased from 1 to 6 months post-RFCA. Notably, strain rate (SRS, SRE, SRA) measurements in various LA segments improved progressively, with the most significant enhancements at 6 months, suggesting improved atrial mechanics. Conclusion: The application of 2D-STI and RT-3DE provides a quantitative means to evaluate the structural and functional changes in the LA of PAF patients following RFCA. The progressive improvements in LA dimensions, volumes, and strain measurements up to 6-month post-RFCA indicate the potential of these techniques in monitoring treatment efficacy and patient recovery.
From Knowability to Conjecturability, and Back Again
Authors: Heylen Jan , Grigoryan Kristine
Published: September 2024

Chiffi and Pietarinen (2020) argue that the knowability paradox disappears if we adopt the concept of conjecturability instead of knowability within the framework of Peirce’s theory of science. They make two main claims: first, conjecturability plays an all-important role in scientific inquiry and it explains better scientific progress than knowability; second, conjecturability does not produce aparadox akin to the knowability paradox. However, based on our reading of Peirce, we contend that knowability plays an important role in scientific inquiry and progress. Moreover, we show that there is a conjecturability paradox with an analogous conclusion as the knowability paradox, which is rooted in their modal analysis of conjecturability.
What Is Shiʿi Writing?
Authors: Warner George
Published: September 2024

This article examines three Būyid-era adab compendia by Shiʿi authors—al-Ābī’s Nathr al-durr, al-Sharīf al-Murtaḍā’s Ghurar al-fawāʾid and al-Sharīf al-Raḍī’s Nahj al-balāgha—analysing how these works express Shiʿi ideas and sentiments, and how these expressions are calibrated to take account of a presumed majority-non-Shiʿi readership. It is argued that this process is not simply one of dilution, rather the three works exhibit specific shared strategies that allow them to accommodate powerful assertions of Shiʿism without ceasing to be intelligible to non-Shiʿis. The article shows the complex relationships between these works, adab literature and Shiʿi legal and theological literature, inviting a reconsideration of how particular kinds of writing are deemed central or peripheral to Shiʿi thought and experience. In addition, these analyses supply important historical context for the composition of Nahj al-balāgha, a work that has long possessed immense status in multiple Muslim traditions as well as in Arabic literature.
The Samaritans as an Islamicate Minority, c. 750–950
Authors: Wood Philip
Published: September 2024

This article examines the testimony of the Arabic Samaritan Chronicle to examine the lachrymose account of the decline of the community. It compares this narrative to those of contemporary Christian sources and argues that the impression of crisis is appreciable worse than for most Christian populations. This rests in part on the small size of the Samaritan population, which made it vulnerable to natural disasters, and its separation from a wider Mediterranean diaspora, which might have allowed the community in Samaria to generate resources. It further argues that the strict exclusion of non-Samaritans made collaboration with Muslim authorities very hard for Samaritan leaders, which reduced its flexibility in dealing with authoritarian structures that might change rapidly.
Late Cretaceous rapid exhumation of the Central Tibetan Plateau: Insights from low-temperature thermochronology
Authors: LI SI-QI , SUN GAO-YUAN , YOU TIAN-NAN , HU XIU-MIAN
Published: September 2024

The uplift history of the Tibetan Plateau is a hot topic for the geological study. The Lhasa terrane, situated on the southern edge of Eurasian plate, records the tectonic evolution of the Tibetan Plateau preceding the collision between the Indian and Eurasian continental plates. This paper employs low-temperature thermochronological methods, including zircon and apatite (U-Th)/He dating, as well as apatite fission track (AFT) analysis, to investigate the Bange pluton in the northern Lhasa terrane. The research results indicate that the zircon and apatite helium (ZHe and AHe) ages from the plutons range from 90 to 78 Ma and 83 to 63 Ma, respectively, while the AFT ages span from 65 to 46 Ma. Thermal history reveals that the Bange pluton experienced a rapid cooling phase during the Late Cretaceous (from ~94 to 70 Ma), with a cooling rate of ~4.2 °C/Ma, subsequently followed by a slow cooling rate with ~1.1 °C/Ma. These results suggest that the Bange pluton has underwent rapid uplift during the Late Cretaceous to Paleocene. This Late Cretaceous rapid cooling event is also observed in other regions of the Lhasa terrane, indicating a widespread period of rapid cooling and exhumation. Since the Cenozoic, the cooling rate of the Bange pluton has significantly decreased, which would suggest that the tectonic uplift of the central Tibetan Plateau may not be related to the India-Asia continental collision. Considering the regional tectonic context, the collision between the Lhasa terrane and the Qiangtang terrane during the Late Jurassic to Early Cretaceous may have initiated the exhumation of the Lhasa terrane in the Late Cretaceous.
An Early Cretaceous radiolarian assemblage from the strata south to the Zhongba microterrane in the Zhongba area, southern Tibet
Authors: HE ZHI-HAO , LI XIN , LI YA-LIN , CHENG JIAN-BO
Published: September 2024

The presence of the Zhongba microterrane causes the Yarlung–Tsangpo suture zone to be bifurcated into two parts in its western segment: the Northern Ophiolitic Belt and Southern Ophiolitic Belt. This indicates that the evolution of the Neo-Tethys Ocean in the western segment is more complex than previous interpretation. Between the Southern Ophiolitic Belt and the Zhongba microterrane, there exists a successive stratigraphic sequence. In this study, a total of 15 genera belonging to 20 species of radiolarians were identified from the siliceous strata of the Dangxin Formation within this sequence, constraining the age of the Dangxin Formation to the Barremian, Early Cretaceous. Additionally, a stratigraphic column was constructed based on the basic understanding of this stratigraphic sequence from regional geological surveys, and it was compared with deep-water sediments in the Tethyan Himalaya. The results show that this sequence can be correlated with the Rilang, Duobeng, Chuangde, and Zongzhuo formations, which were deposited on the passive margin of the Indian plate.
Atmospheric geographies of (counter)terrorism
Authors: Fregonese Sara , Simpson Paul , Masson Damien , Runkel Simon , Benjamin Carrie Ann , Berlin Samuel , Ciax Katharina , Drongiti Angeliki
Published: September 2024

How are terror threats and counterterrorism measures experienced in everyday urban spaces? We argue that thinking atmospherically about the spaces of urban encounters with (counter)terrorism is important, firstly, to identify and question feelings and dispositions shaped by discourses, practices, and infrastructures of (counter)terrorism; secondly, to contribute spatial perspectives of felt experience to literatures on security and (counter)terrorism in geography and beyond; thirdly, to connect official understandings of (counter)terrorism with its everyday felt experiences and materialities. We highlight two conceptual and empirical arenas – the crowd and the question of difference – where atmospheric approaches to urban (counter)terrorism can be developed.
Salinity and Temperature Effects on the Release of Benzalkonium Chloride from Hydrogel Material
Authors: Smith M.J. , Flowers T.H. , Parr A.C.S. , Cowling M.J. , Hodgkiess T.
Published: September 2024

The effects of salinity and temperature on the release of the quaternary ammonium compound, benzalkonium chloride (BAC), from a poly (2-hydroxyethyl methacrylate) (PHEMA) hydrogel were studied. Previous research had shown that such a combination produced a transparent coating, which demonstrated reduced biofouling properties in a marine environment. Release was monitored at two salinities, low (4 parts per thousand) and normal (35ppt) which is the approximate salinity of natural seawater, as well as at four temperatures 5°C, 10°C, 15°C and 35°C. Quantitative analysis was carried out using high performance liquid chromatography. The diffusion coefficients for each parameter were evaluated and these demonstrated that at the low salinity the release was approximately 4 times faster than at the higher salinity. At both salinities increasing the temperature increased the diffusion coefficient. It is thought that salinity influences the diffusion coefficient and the passage of BAC through the pores within the hydrogel by its effect on the degree of micelle formation.
Moving Targets and Missed Opportunities: Being Honest With Teachers and Ourselves
Authors: Farmer Thomas W.
Published: September 2024

This article provides a conceptual commentary on the special series on potential burnout of teachers of students with emotional and behavioral difficulties (EBD). The issue of teacher burnout is considered through a dynamic, ecological systems theory framework to summarize the complexities of working with students with EBD and to highlight the importance of addressing their needs from a whole child in context perspective. Current limits of eividence-based practices, service delivery structures, and research approaches are also considered and possible steps forward are discussed.
Modelling of auto-ignition to flame propagation transition for Dual-Fuel combustion
Authors: Tarot Maxime , Jay Stéphane , Michel Jean-Baptiste , Colin Olivier
Published: September 2024

Dual-Fuel (DF) combustion engines are a promising alternative to conventional technologies in terms of efficiency and emissions in particular for heavy duty vehicles or marine engines. DF engines involve the injection of a high reactivity pilot spray as a source of ignition for a lean and low reactivity premixed main charge. As a result, auto-ignition (AI) spots emerging from pilot spray generate premixed flame (PF) combustion of the main charge. Nevertheless, transition from AI to PF is not fully understood and thus challenging in terms of modelling. The main goal of this work is to propose a predictive model valid for both AI and PF regime, including transition phenomena, in a Large-Eddy Simulation (LES) context. Firstly, a set of one-dimensional study is conducted. The limitations of two classical approaches for describing auto-ignition (AI), premixed flame (PF) propagation, and regime transitions are identified. The analysis reveals that transition from AI to PF is rather progressive, and starts with hot flame ignition (HFI). Thickened Flame Model (TFM), including detailed resolution of chemistry, and reveals that standard formulation is unable to represent AI, as thickening factor dramatically increases AI delays. A modelling approach involving a thickening factor relaxation time is proposed for LES of DF engines applications, and appears capable of representing transition from AI to PF phenomena in reactivity stratified situations typically encountered in DF applications. The potential of this approach, its accuracy and its limitations are assessed by comparing the model behaviour against 1D reference test cases, and measurements on an optical test bench.
Severe thrombocytopaenia caused by trastuzumab emtansine in a patient with breast cancer: A case report
Authors: Nakatani Kaori , Momo Kenji , Kin Masaoki , Sasaki Tadanori , Akashi-Tanaka Sadako
Published: September 2024

We present the case of a 48-year-old woman with human epidermal growth factor receptor 2- and hormone receptor-positive left early breast cancer who developed severe thrombocytopaenia and moderate liver dysfunction after administration of trastuzumab emtansine as an adjuvant therapy. Briefly, she experienced grade 2 subcutaneous bleeding, decreased platelet count (18,000/µL), and elevated aspartate aminotransferase/alanine aminotransferase levels (254/193 IU), resulting in admission to the emergency room. Although thrombocytopaenia is a well-known adverse event associated with trastuzumab emtansine, we observed it immediately after trastuzumab emtansine administration in our patient. Based on the literature survey, we hypothesised that trastuzumab emtansine may have affected mature platelets in our patient. In addition, moderate hepatotoxicity may be partially explained based on the pharmacological mechanisms of trastuzumab emtansine action involving microtubule disorganisation in hepatocytes via cytoskeleton-associated protein 5 on the cell surface by emtansine. We discuss the mechanism of the development of thrombocytopaenia and liver dysfunction.
The cognitive and language development of young Flemish foster children
Authors: West Delphine , Gypen Laura , Stas Lara , Van Holen Frank , Vanderfaeillie Johan
Published: September 2024

Foster children often experienced adversities, putting them at risk for problematic outcomes ( Dozier & Rutter, 2016 ). To our knowledge, there is no research regarding the cognitive and language development of young Flemish foster children. In this study, we describe a study conducted longitudinal research over a one year period into the development of 53 young foster children (12–20 months old at T1). The cognitive and language development of the children was measured using the Bayley Scales of Infant and Toddler Development-Third-Edition (Bayley-III-NL). First, scaled scores of the Bayley subscales cognitive functioning, receptive language and expressive language, both at T1 and T2, were compared to the mean norm-scores. Second, the associated variables with the children’s functioning on cognitive and language scales were explored using Multilevel Modelling. For all subscales except receptive language at T2, the results did not significantly differ from the mean normative scores. The scores of the foster children in this study were significantly lower on receptive language at T2. When we looked at individual scores, most children (66%–83%) had scores that did not differ more than one standard deviation from the normative mean. Children in kinship foster care had lower scores in multiple developmental domains. There were also negative associations between both language subscales and insecure attachment behavior. For most subscales, the results did not significantly differ from the mean normative scores, which is promising.
Tetraspanin 3 promotes NSCLC cell proliferation via regulation of β1 integrin intracellular recycling
Authors: Zhang Yao , Wang Chenglong , Xu Yitong , Su Hongbo
Published: September 2024

Background

The involvement of tetraspanins in cancer development has been widely implicated. In this study, the function and molecular mechanisms of tetraspanin 3 (TSPAN3) in non-small cell lung cancer (NSCLC) cells were explored.

Methods

Tissue samples from patients diagnosed with NSCLC were analyzed by immunohistochemistry, western blotting, and real-time polymerase chain reaction (PCR) to indicate the involvement of TSPAN3 in cancer progression. In the meantime, we also performed exhaustive mechanistic studies using A549 and H460 cells in vitro through a variety of methods including western blotting, real-time PCR, immunofluorescent staining, coimmunoprecipitation, cell proliferation assay, and nocodazole (NZ) washout assay. Proper statistical analysis was implemented wherever necessary in this study.

Results

TSPAN3 was found to be highly expressed in lung cancer cells and tissues. Moreover, high levels of TSPAN3 positively correlated with poor differentiation, lymph node involvement, advanced pathological tumor-node-metastasis stage, and poor prognosis in patients with NSCLC. TSPAN3 showed potential to promote the proliferation of NSCLC cells in vitro and in vivo. Specifically, TSPAN3 was found to interact with β1 integrin via the LEL domain, thereby facilitating the sorting of β1 integrin into Rab11a endosomes and promoting β1 integrin recycling and upregulation.

Conclusions

Our findings reveal TSPAN3 may represent a potentially valuable therapeutic target for NSCLC.
The oncogenic ADAMTS1–VCAN–EGFR cyclic axis drives anoikis resistance and invasion in renal cell carcinoma
Authors: Wen Yu-Ching , Lin Yung-Wei , Ho Kuo-Hao , Yang Yi-Chieh , Lai Feng-Ru , Chu Chih-Ying , Chen Ji-Qing , Lee Wei-Jiunn , Chien Ming-Hsien
Published: September 2024

Background

Metastasis, the leading cause of renal cell carcinoma (RCC) mortality, involves cancer cells resisting anoikis and invading. Until now, the role of the matrix metalloproteinase (MMP)-related enzyme, A disintegrin and metalloprotease with thrombospondin motifs 1 (ADAMTS1), in RCC anoikis regulation remains unclear.

Methods

The clinical significance of ADAMTS1 and its associated molecules in patients with RCC was investigated using data from the Gene Expression Omnibus (GEO) and TCGA datasets. Human phosphoreceptor tyrosine kinase (RTK) array, luciferase reporter assays, immunoprecipitation (IP) assays, western blotting, and real-time reverse-transcription quantitative polymerase chain reaction (RT–qPCR) were used to elucidate the underlying mechanisms of ADAMTS1. Functional assays, including anoikis resistance assays, invasion assays, and a Zebrafish xenotransplantation model, were conducted to assess the roles of ADAMTS1 in conferring resistance to anoikis in RCC.

Results

This study found elevated ADAMTS1 transcripts in RCC tissues that were correlated with a poor prognosis. ADAMTS1 manipulation significantly affected cell anoikis through the mitochondrial pathway in RCC cells. Human receptor tyrosine kinase (RTK) array screening identified that epidermal growth factor receptor (EGFR) activation was responsible for ADAMTS1-induced anoikis resistance and invasion. Further investigations revealed that enzymatically active ADAMTS1-induced versican V1 (VCAN V1) proteolysis led to EGFR transactivation, which in turn, through positive feedback, regulated ADAMTS1. Additionally, ADAMTS1 can form a complex with p53 to influence EGFR signaling. In vivo, VCAN or EGFR knockdown reversed ADAMTS1-induced prometastatic characteristics of RCC. A clinical analysis revealed a positive correlation between ADAMTS1 and VCAN or the EGFR and patients with RCC with high ADAMTS1 and VCAN expression had the worst prognoses.

Conclusions

Our results collectively uncover a novel cyclic axis involving ADAMTS1–VCAN–EGFR, which significantly contributes to RCC invasion and resistance to anoikis, thus presenting a promising therapeutic target for RCC metastasis.
Characteristics and outcomes of emergency department patients across health care systems: an international multicenter cohort study
Authors: de Groot Bas , Meijs Nicoline T. C. , Moscova Michelle , Raven Wouter , Gaakeer Menno I. , Thijssen Wendy A. M. H. , Lameijer Heleen , Shetty Amith , Lassen Annmarie T.
Published: September 2024

Background

A wide variation of emergency medical system configurations across countries has limited the value of comparison of quality and performance measures in the past. Furthermore, lack of quantitative data on EDs prevents definition of the problems and possibilities for data driven improvement of quality of care. Therefore, the objective is to describe and compare Emergency Department (ED) populations and characteristics, and their outcomes in the Netherlands, Denmark and Australia, using a recently developed template for uniform reporting of standardized measuring and describing of care provided in the ED (structure, staffing and governance, population, process times and outcomes).

Methods

This international multicenter cohort included all consecutive ED visits from National Quality Registries or Databases from participating sites from three countries. Patient and ED characteristics (using the template for uniform reporting) and relevant clinical outcomes were described and compared per country.

Results

We included 212,515 ED visits in the Netherlands, 408,673 in Denmark and 556,652 in Australia. Patient characteristics differed markedly, with Australian ED patients being younger, less often triaged as “immediate”, and less often triaged with the high-risk chief complaints “feeling unwell” compared to Danish and Dutch patients. ED characteristics mainly differed with respect to the mean annual census per ED (Netherlands 26,738 (SD 2630), Denmark 36,675 (SD 12974), Australia 50,712 (4884)), median (IQR) lengths of stay of patients discharged home (Netherlands 2.1 (1.4–3.1); Denmark 2.8 (1.7–5.0); Australia 3.3 (2.0–5.0) hrs) and proportion of hospitalizations (ranging from 30.6 to 39.8%).

In-hospital mortality was 4.0% in Australia, higher compared to the Netherlands and Denmark (both 1.6%). Not all indicators of the framework were available in all registries.

Conclusions

Patient and ED characteristics and outcomes varied largely across countries. Meaningful interpretation of outcome differences across countries could be improved if quality registries would more consistently register the measures of the recently developed template for uniform reporting.
Usability and acceptability of self-testing for hepatitis C virus exposure in a high-prevalence urban informal settlement in Karachi, Pakistan
Authors: Mazzilli Sara , Aslam Muhammad K. , Akhtar Javed , Miazek Marta , Wailly Yves , Hamid Saeed , Shilton Sonjelle , Donchuk Dimitri , de Glanville William A. , Isaakidis Petros
Published: September 2024

Background

Hepatitis C virus (HCV) antibody self-testing (HCVST) may help expand screening access and support HCV elimination efforts. Despite potential benefits, HCVST is not currently implemented in Pakistan. This study aimed to assess the usability and acceptability of HCVST in a high HCV prevalence informal settlement in Karachi, Pakistan.

Methods

We performed a cross-sectional study in a hepatitis C clinic from April through June 2023. Participants were invited to perform a saliva-based HCVST (OraSure Technologies, USA) while following pictorial instructions. A study member evaluated test performance using a standardized checklist and provided verbal support if a step could not be completed. Perceived usability and acceptability were assessed using a semi-structured questionnaire. The HCVST was considered successful if the participant was able to complete all steps and correctly interpret test results. Overall concordance and positive and negative agreement were estimated in comparison with the HCVST result read by the study member (inter-reader concordance and agreement) and result of a second rapid HCV test (Abbott Diagnostics Korea Inc, South Korea) performed by a trained user (inter-operator concordance and agreement).

Results

The study included 295 participants of which 97 (32%) were illiterate. In total, 280 (95%, 95% CI 92–97%) HCVSTs were successful. Overall, 38 (13%) people performed the HCVST without verbal assistance, 67 (23%) needed verbal assistance in one step, 190 (64%) in two or more. Assistance was most often needed in managing the test buffer and test reading times. The inter-reader concordance was 96% and inter-operator concordance 93%. Inter-reader and inter-operator positive percent agreement were 84 and 70%, respectively. All participants reported they would use HCVST again and would recommend it to friends and family.

Conclusion

Saliva-based HCVST was very well accepted in this clinic-based setting. However, many people requested verbal support in several steps, highlighting the need for clear instructions for use and test devices that are simple to use, particularly in low literacy settings. Moderately low positive percent agreement with the results of a rapid test performed by a trained user highlights potential uncertainty in the accuracy of HCVST in the hands of lay users.
The fuzzy system ensembles entomological, epidemiological, demographic and environmental data to unravel the dengue transmission risk in an endemic city
Authors: de Souza Leandro André , de Oliveira Felipe , Lopes Renata Defante , Rivas Açucena Veleh , Martins Caroline Amaral , Silva Isaac , Villela Daniel A. M. , Teixeira Marcello Goulart , Xavier Samanta Cristina das Chagas , Maciel-de-Freitas Rafael
Published: September 2024

Background

The effectiveness of dengue control interventions depends on an effective integrated surveillance system that involves analysis of multiple variables associated with the natural history and transmission dynamics of this arbovirus. Entomological indicators associated with other biotic and abiotic parameters can assertively characterize the spatiotemporal trends related to dengue transmission risk. However, the unpredictability of the non-linear nature of the data, as well as the uncertainty and subjectivity inherent in biological data are often neglected in conventional models.

Methods

As an alternative for analyzing dengue-related data, we devised a fuzzy-logic approach to test ensembles of these indicators across categories, which align with the concept of degrees of truth to characterize the success of dengue transmission by Aedes aegypti mosquitoes in an endemic city in Brazil. We used locally gathered entomological, demographic, environmental and epidemiological data as input sources using freely available data on digital platforms. The outcome variable, risk of transmission, was aggregated into three categories: low, medium, and high. Spatial data was georeferenced and the defuzzified values were interpolated to create a map, translating our findings to local public health managers and decision-makers to direct further vector control interventions.

Results

The classification of low, medium, and high transmission risk areas followed a seasonal trend expected for dengue occurrence in the region. The fuzzy approach captured the 2020 outbreak, when only 14.06% of the areas were classified as low risk. The classification of transmission risk based on the fuzzy system revealed effective in predicting an increase in dengue transmission, since more than 75% of high-risk areas had an increase in dengue incidence within the following 15 days.

Conclusions

Our study demonstrated the ability of fuzzy logic to characterize the city’s spatiotemporal heterogeneity in relation to areas at high risk of dengue transmission, suggesting it can be considered as part of an integrated surveillance system to support timely decision-making.
The effect of parental pain, disability benefits and education on risk of long-term sick leave due to musculoskeletal disorders and the modifying effect of sleep and physical activity: the HUNT study
Authors: Moe Karoline , Skarpsno Eivind Schjelderup , Nilsen Tom Ivar Lund , Mork Paul Jarle , Aasdahl Lene
Published: September 2024

Background

Family factors, sleep, and physical activity have previously been associated with risk of sick leave and disability benefits due to musculoskeletal disorders. However, how these factors act during adolescence and young adulthood is unclear. The aim of this study was to (i) examine if chronic pain, disability benefits and education in parents influence the risk of long-term sick leave due to musculoskeletal disorders in young adulthood, and (ii) to explore if offspring sleep problems and physical activity modify these effects.

Methods

A population-based prospective study of 18,552 adolescents and young adults (≤ 30 years) in the Norwegian HUNT Study. Survey data was linked to national registry data on sick leave, disability benefits, family relations and educational attainment. We used Cox regression to estimate hazard ratio (HR) with 95% confidence interval (CI) for long-term (≥ 31 days) sick leave due to a musculoskeletal disorder in offspring associated with parental factors and the joint effect of parental factors and offspring lifestyle factors.

Results

Parental chronic pain (HR 1.36, 95% CI 1.27–1.45), disability benefits (HR 1.41, 95% CI 1.33–1.48) and low educational attainment (HR 1.78, 95% CI 1.67–1.90) increased the risk of long-term sick leave due to musculoskeletal disorders among offspring. There was no strong evidence that sleep and physical activity modified these effects.

Conclusion

Chronic pain, disability benefit and low education in parents increased the risk of long-term sick leave due to musculoskeletal disorders among offspring, but these effects were not modified by offspring sleep problems or physical activity level. The findings suggest that efforts beyond individual lifestyle factors might be important as preventive measures.
Analytical validation of the LungLB test: a 4-color fluorescence in-situ hybridization assay for the evaluation of indeterminate pulmonary nodules
Authors: Lutman Michelle L. , Gramajo-Leventon Daniel , Tahvilian Shahram , Baden Lara , Gilbert Courtney L. , Trejo Michael , Vail Eric , Donovan Michael J. , Katchman Benjamin A. , Pagano Paul C.
Published: September 2024

Background

Evaluation of indeterminate pulmonary nodules (IPNs) often creates a diagnostic conundrum which may delay the early detection of lung cancer. Rare circulating genetically abnormal cells (CGAC) have previously demonstrated utility as a biomarker for discriminating benign from malignant small IPNs in the LungLB assay. CGAC are identified using a unique 4-color fluorescence in-situ hybridization (FISH) assay and are thought to reflect early cell-based events in lung cancer pathogenesis and the anti-tumor immune response. LungLB is a prognostic tool that combines the CGAC biomarker and clinical features to aid in IPN evaluation by improving the stratification of patient risk of malignancy.

Methods

Herein we describe the analytical performance of the LungLB blood test. Analytical validation was performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines with adaptations for rare cell-based assays. Multiple operators, reagent lots, and assay runs were tested to examine accuracy, precision, reproducibility, and interfering factors.

Results

The FISH probes used in the LungLB assay demonstrate 100% sensitivity and specificity for their intended chromosomal loci (3q29, 3p22.1, 10q22.3 and 10cen). LungLB demonstrates analytical sensitivity of 10 CGAC per 10,000 lymphocytes analyzed, 100% analytical specificity, and high linearity (R2 = 0.9971). Within run measurements across 100 samples demonstrated 96% reproducibility. Interfering factors normally found in blood (lipemia, biotin) and exposure to adverse temperatures (-20ºC or 37ºC) did not interfere with results. Sample stability was validated to 96 hours.

Conclusion

The analytical performance of LungLB in this validation study successfully demonstrates it is robust and suitable for everyday clinical use.
Augmented reality visualization for ultrasound-guided interventions: a pilot randomized crossover trial to assess trainee performance and cognitive load
Authors: Liao Shu-Chen , Shao Shih-Chieh , Gao Shi-Ying , Lai Edward Chia-Cheng
Published: September 2024

Background

Augmented reality (AR) technology involving head-mounted displays (HMD) represents a significant innovation in medical education, particularly for training in guided invasive procedures. Novice physicians often face challenges in simultaneously identifying anatomical landmarks and performing procedures when learning point-of-care ultrasound (POCUS). Our primary objective was to determine the effectiveness of AR in enhancing physician training for ultrasound-guided interventions using AR visual overlays. The secondary objective was to compare cognitive load between traditional ultrasound training settings and AR-assisted training settings.

Methods

This randomized crossover study, conducted from 2021 to 2022, compared performance and cognitive load of trainees attempting accurate central venous catheter (CVC) placement using an AR-HMD to display ultrasound images (AR-US), compared with standard ultrasound without visual overlay (S-US). We enrolled 47 trainees, including 22 final-year undergraduate medical students and 25 postgraduate physicians (years 1–4) from three hospitals in Taiwan. All participants had basic training in US-guided CVC placement but lacked AR-US experience. Performance and cognitive load were assessed using time measurements and NASA Task Load Index (NASA-TLX), covering the dimensions of Mental-, Physical- and Temporal Demand, and Performance, Effort and Frustration.

Results

We found AR technology reduced the time required for critical steps in CVC placement, while minimizing users’ neck strain. Female and junior trainees using AR-US identified anatomy and localized veins faster than those using S-US. Using AR-US, female trainees significantly outperformed males in anatomical identification [mean difference (MD): -10.79 s (95% CI: -2.37 to -19.21)]. The NASA-TLX cognitive load assessment showed mental workload trending lower in all dimensions except performance while using AR-US, compared to S-US. Similarly, junior trainees’ effort- and frustration scores were lower [MD: -2.73 (95% CI: -5.04 to -0.41) and -2.41 (95% CI: -4.51 to -0.31), respectively], as were female trainees’ effort scores [MD: -3.07 (95% CI: -6.10 to -0.03)] when using AR-US, compared to S-US, whereby these differences were statistically significant.

Conclusions

AR technology helped improve trainee performance and reduced cognitive load during ultrasound-guided CVC placement. These findings support the application of AR technology to enhance physician training in ultrasound-guided interventional procedures, suggesting that AR-HMDs could be a valuable tool in medical education.

Trial registration

The trial was registered with Clinicaltrials.gov on 20/09/2023 as a clinical trial, under the identifier NCT 06055400.
Workplace learning: the bidirectional relationship between stress and self-regulated learning in undergraduates
Authors: Marsch Stephan , Yanagida Takuya , Steinberg Evelyn
Published: September 2024

The present study focused on the relationships between various aspects of self-regulated learning (SRL) and stress among undergraduate health science students in workplace settings. Although both constructs are associated with academic achievement it is still unclear how they influence each other. Employing a longitudinal diary design, the aim of the present study was to examine whether perceived stress in the previous week impacts SRL-aspects in the current week and, conversely, whether SRL-aspects in the previous week impacts stress in the current week. Subjects were 192 undergraduate health sciences students in their workplace placements. SRL-aspects and stress were assessed using scales and previously tested single-item measures. The 21 SRL-aspects used in this study included cognition (learning strategies), motivation, emotion, perception of the learning environment, and regulation of these areas on a metalevel (monitoring and control). Data collected over 15 weeks were analyzed using multilevel vector autoregressive models, with the data nested within weeks and one model dedicated to each SRL-aspect and its relationship with stress. Among the 21 path estimates assessing the impact of prior stress on individual SRL-aspects, 10 were statistically significant. For individual SRL-aspects impacting stress, 7 out of 21 paths were statistically significant (p < .05). Notably, no model showed statistical significance of effects in both directions. Except for two results, cross-lagged relationships were negative, indicating that better SRL-aspects from the previous week resulted in reduced stress in the current week and vice versa. The effects for the cross-lagged paths from SRL-aspects to stress were predominantly of medium size, whereas the influence of stress on individual SRL-aspects was predominantly small. The present study highlights a potentially causal and mostly negative relationship between stress and various aspects of SRL, but also that the individual relationships require differentiated consideration. The results can be used to develop targeted interventions in the practical part of the training of health science students to reduce stress and improve specific aspects of SRL. Furthermore, these findings underscore assumptions regarding connections between anxiety and increased stress, negative relationships between stress and motivation, and the importance of effective time management strategies for stress reduction.
Development and evaluation of an emergency department serious game for undergraduate medical students
Authors: Aster Alexandra , Hütt Christopher , Morton Caroline , Flitton Maxwell , Laupichler Matthias Carl , Raupach Tobias
Published: September 2024

Background

Serious games are risk-free environments training various medical competencies, such as clinical reasoning, without endangering patients’ safety. Furthermore, serious games provide a context for training situations with unpredictable outcomes. Training these competencies is particularly important for healthcare professionals in emergency medicine.

Methods

Based on these considerations, we designed, implemented, and evaluated a serious game in form of an emergency department, containing the features of a virtual patient generator, a chatbot for medical history taking with self-formulated questions, artificially generated faces based on an artificial intelligence algorithm, and feedback for students. The development process was based on an already existing framework resulting in an iterative procedure between development and evaluation. The serious game was evaluated using the System Usability Scale and the User Experience Questionnaire.

Results

The System Usability Scale provided a substantial result for the usability. In terms of the user experience, four scales yielded positive results, whereas two scales yielded neutral results.

Conclusion

The evaluation of both usability and user experience yielded overall positive results, while simultaneously identifying potential areas for improvement. Further studies will address the implementation of additional game design elements, and testing student learning outcome.