bluuebunny/crossref_metadata_2025_split huggingface dataset:
Remodeling of the Tumor Microenvironment Through PAK4 Inhibition Sensitizes Tumors to Immune Checkpoint Blockade
Authors: Abril-Rodriguez Gabriel , Torrejon Davis Y. , Karin Daniel , Campbell Katie M. , Medina Egmidio , Saco Justin D. , Galvez Mildred , Champhekar Ameya S. , Perez-Garcilazo Ivan , Baselga-Carretero Ignacio , Singh Jas , Comin-Anduix Begoña , Puig-Saus Cristina , Ribas Antoni 
Published: September 2022

PAK4 inhibition can sensitize tumors to immune checkpoint blockade (ICB) therapy; however, the underlying mechanisms remain unclear. We report that PAK4 inhibition reverses immune cell exclusion by increasing the infiltration of CD8 T cells and CD103+ dendritic cells (DC), a specific type of DCs that excel at cross-presenting tumor antigens and constitute a source of CXCL10. Interestingly, in melanoma clinical datasets, PAK4 expression levels negatively correlate with the presence of CCL21, the ligand for CCR7 expressed in CD103+ DCs. Furthermore, we extensively characterized the transcriptome of PAK4 knockout (KO) tumors, in vitro and in vivo, and established the importance of PAK4 expression in the regulation of the extracellular matrix, which can facilitate immune cell infiltration. Comparison between PAK4 wild type and KO anti-PD-1 treated tumors revealed how PAK4 deletion sensitizes tumors to ICB from a transcriptomic perspective. In addition, we validated genetically and pharmacologically that inhibition of PAK4 kinase activity is sufficient to improve antitumor efficacy of anti-PD-1 blockade in multiple melanoma mouse models. Therefore, this study provides novel insights into the mechanism of action of PAK4 inhibition and provides the foundation for a new treatment strategy that aims to overcome resistance to PD-1 blockade by combining anti-PD-1 with a small-molecule PAK4 kinase inhibitor.Significance:Our findings provide new insights into PAK4 inhibition mechanism of action as well as the scientific foundation for specifically blocking PAK4 kinase activity using a novel and specific PAK4 kinase inhibitor to overcome resistance to PD-1 blockade.
Sex Differences and Utility of Treadmill Testing in Long‐QT Syndrome
Authors: Yee Lauren A. , Han Hui‐Chen , Davies Brianna , Pearman Charles M. , Laksman Zachary W. M. , Roberts Jason D. , Steinberg Christian , Tadros Rafik , Cadrin‐Tourigny Julia , Simpson Christopher S. , Gardner Martin , MacIntyre Ciorsti , Arbour Laura , Leather Richard , Fournier Anne , Green Martin S. , Kimber Shane , Angaran Paul , Sanatani Shubhayan , Joza Jacqueline , Khan Habib , Healey Jeffrey S. , Atallah Joseph , Seifer Colette , Krahn Andrew D. 
Published: September 2022

Background
Diagnosis of congenital long‐QT syndrome (LQTS) is complicated by phenotypic ambiguity, with a frequent normal‐to‐borderline resting QT interval. A 3‐step algorithm based on exercise response of the corrected QT interval (QTc) was previously developed to diagnose patients with LQTS and predict subtype. This study evaluated the 3‐step algorithm in a population that is more representative of the general population with LQTS with milder phenotypes and establishes sex‐specific cutoffs beyond the resting QTc.

Methods and Results

We identified 208 LQTS likely pathogenic or pathogenic
KCNQ1
or
KCNH2
variant carriers in the Canadian NLQTS (National Long‐QT Syndrome) Registry and 215 unaffected controls from the HiRO (Hearts in Rhythm Organization) Registry. Exercise treadmill tests were analyzed across the 5 stages of the Bruce protocol. The predictive value of exercise ECG characteristics was analyzed using receiver operating characteristic curve analysis to identify optimal cutoff values. A total of 78% of male carriers and 74% of female carriers had a resting QTc value in the normal‐to‐borderline range. The 4‐minute recovery QTc demonstrated the best predictive value for carrier status in both sexes, with better LQTS ascertainment in female patients (area under the curve, 0.90 versus 0.82), with greater sensitivity and specificity. The optimal cutoff value for the 4‐minute recovery period was 440 milliseconds for male patients and 450 milliseconds for female patients. The 1‐minute recovery QTc had the best predictive value in female patients for differentiating LQTS1 versus LQTS2 (area under the curve, 0.82), and the peak exercise QTc had a marginally better predictive value in male patients for subtype with (area under the curve, 0.71). The optimal cutoff value for the 1‐minute recovery period was 435 milliseconds for male patients and 455 milliseconds for femal patients.

Conclusions
The 3‐step QT exercise algorithm is a valid tool for the diagnosis of LQTS in a general population with more frequent ambiguity in phenotype. The algorithm is a simple and reliable method for the identification and prediction of the 2 major genotypes of LQTS.
Rates of Elective Percutaneous Coronary Intervention in England and Wales: Impact of COURAGE and ORBITA Trials
Authors: Rashid Muhammad , Stevens Chris , Wijeysundera Harindra C. , Curzen Nick , Khoo Chee Wah , Mohamed Mohamed Osama , Aktaa Suleman , Wu Jianhua , Ludman Peter F. , Mamas Mamas A. 
Published: September 2022

Background
There are limited data about how COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) and ORBITA (Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) trials have impacted percutaneous coronary intervention (PCI) practices at regional or national level. We evaluated temporal trends in elective PCI rates for stable angina and, specifically, examined the impact of the COURAGE and ORBITA trials on PCI practices in England and Wales.

Methods and Results
We used national PCI data comprising >1.2 million patients undergoing PCI between January 2006 and December 2019. Patient demographics, procedural details, and clinical outcomes were analyzed, and temporal trends in PCI rates for stable angina were compared before and after the publication of the COURAGE and ORBITA trials. Of 1 245 802 PCI procedures, 430 248 (34.5%) were performed for stable angina. Over the study period, the number of elective PCI procedures per year (30 823 in 2006 to 34 103 in 2019) and per 100 000 population estimates (50.7 in 2006 to 58.4 in 2019) remained stable. The proportion of patients undergoing elective PCI without angina symptoms almost doubled from 5.1% to 9.7%. The incidence rate of elective PCI volume after the COURAGE trial, published in 2007, was not different from before the trial was published (incidence rate ratio, 1.06 [95% CI, 0.69–1.62]). It also remained stable after the publication of the ORBITA trial in 2017 (incidence rate ratio, 0.96 [95% CI, 0.74–1.23]).

Conclusions
In this nationwide analysis, rates of elective PCI for stable angina remained stable over 14 years. Publication of the COURAGE and ORBITA trials had no impact on elective PCI activity.
Race, Interleukin‐6,
TMPRSS6
Genotype, and Cardiovascular Disease in Patients With Chronic Kidney Disease
Authors: Barrows Ian R. , Devalaraja Matt , Kakkar Rahul , Chen Jing , Gupta Jayanta , Rosas Sylvia E. , Saraf Santosh , He Jiang , Go Alan , Raj Dominic S. , Amdur Richard L. , Unruh Mark L. , Shah Vallabh O. , Rao Panduranga S. , Rahman Mahboob , Nelson Robert G. , Lash James P. , Feldman Harold I. , Cohen Debbie , Appel Lawrence J. 
Published: September 2022

Background
Differences in death rate and cardiovascular disease (CVD) between Black and White patients with chronic kidney disease is attributed to sociocultural factors, comorbidities, genetics, and inflammation.

Methods and Results

We examined the interaction of race, plasma IL‐6 (interleukin‐6), and
TMPRSS6
genotype as determinants of CVD and mortality in 3031 Chronic Renal Insufficiency Cohort study participants. The primary outcomes were all‐cause mortality and a composite of incident myocardial infarction, peripheral artery disease, stroke, and heart failure. During the median follow‐up of 10 years, Black patients with chronic kidney disease experienced a significantly higher mortality (34% versus 26%) and CVD composite (41% versus 28%) compared with White patients. After adjustment,
TMPRSS6
genotype did not associate with the outcomes. The adjusted hazard ratio for mortality (4.11 [2.48–6.80],
P
<0.001) and CVD composite (2.52 [1.96–3.24],
P
<0.001) were higher for the highest versus lowest IL‐6 quintile. The adjusted hazards for death per 1‐quintile increase in IL‐6 in White and Black individuals were 1.53 (1.42–1.64) versus 1.29 (1.20–1.38) (
P
<0.001), respectively. For CVD composite they were 1.61 (1.50–1.74) versus 1.30 (1.22–1.39) (
P
<0.001), respectively. In Cox proportional hazard models that included IL‐6, there was no longer a racial disparity for death (1.01 [0.87–1.16],
P
=0.92), but significant unexplained mediation remained for CVD (1.24 [1.07–1.43];
P
=0.004). Path models that included IL‐6, diabetes, and urine albumin to creatinine ratio were able to identify variables responsible for racial disparity in mortality and CVD.

Conclusions
Racial differences in mortality and CVD among patients with chronic kidney disease could be explained by good‐fitting path models that include selected mediator variables including diabetes and plasma IL‐6.
Outcomes Following Acute Coronary Syndrome in Patients With and Without Rheumatic Immune‐Mediated Inflammatory Diseases
Authors: Wassif Heba , Saad Marwan , Desai Rajul , Hajj‐Ali Rula A. , Menon Venu , Chaudhury Pulkit , Nakhla Michael , Puri Rishi , Prasada Sameer , Reed Grant W. , Ziada Khaled , Kapadia Samir , Desai Milind , Mentias Amgad 
Published: September 2022

Background
Rheumatic immune mediated inflammatory diseases (IMIDs) are associated with high risk of acute coronary syndrome. The long‐term prognosis of acute coronary syndrome in patients with rheumatic IMIDs is not well studied.

Methods and Results

We identified Medicare beneficiaries admitted with a primary diagnosis of myocardial infarction (MI) from 2014 to 2019. Outcomes of patients with MI and concomitant rheumatic IMIDs including systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, dermatomyositis, or psoriasis were compared with propensity matched control patients without rheumatic IMIDs. One‐to‐three propensity‐score matching was done for exact age, sex, race, ST‐segment–elevation MI, and non–ST‐segment–elevation MI variables and greedy approach on other comorbidities. The study primary outcome was all‐cause mortality. The study cohort included 1 654 862 patients with 3.6% prevalence of rheumatic IMIDs, the most common of which was rheumatoid arthritis, followed by systemic lupus erythematosus. Patients with rheumatic IMIDs were younger, more likely to be women, and more likely to present with non–ST‐segment–elevation MI. Patients with rheumatic IMIDs were less likely to undergo coronary angiography, percutaneous coronary intervention or coronary artery bypass grafting. After propensity‐score matching, at median follow up of 24 months (interquartile range 9–45), the risk of mortality (adjusted hazard ratio [HR], 1.15 [95% CI, 1.14–1.17]), heart failure (HR, 1.12 [95% CI 1.09–1.14]), recurrent MI (HR, 1.08 [95% CI 1.06–1.11]), and coronary reintervention (HR, 1.06 [95% CI, 1.01–1.13]) (
P
<0.05 for all) was higher in patients with versus without rheumatic IMIDs.

Conclusions
Patients with MI and rheumatic IMIDs have higher risk of mortality, heart failure, recurrent MI, and need for coronary reintervention during follow‐up compared with patients without rheumatic IMIDs.
Social Infrastructures, Military Entrepreneurship, and the Making of the Sultan’s Court in Fifteenth-Century Cairo
Authors: Van Steenbergen Jo , Termonia Maya 
Published: September 2022

Abstract
This paper engages with the organization of the leadership of the Syro-Egyptian sultanate in the long ninth/fifteenth century, focusing particularly on the case of the court position of ‘the Chief Head of the [sultan’s] Guards’ (raʾs nawbat al-nuwab). It explores narrative source reports to identify the sultanate’s sixty ‘Chief Heads’ and to reconsider what they did in this capacity. Through the analytical categories of the court, social infrastructures and military entrepreneurialism, this paper furthers understandings of how these military leaders were all constitutive participants in the era’s complex processes of resource accumulation, violence-wielding, courtly reconfiguration, and state formation.
European-native vocalizing: sex and age-class acoustic variation in the Central European red deer (Cervus elaphus)
Authors: Volodin Ilya A. , Karaseva Kseniya D. , Volodina Elena V. , Tari Tamás , Náhlik András 
Published: September 2022

Abstract
Within-population acoustic variation of European red deer Cervus elaphus follows two empirically established common rules: Rule 1: suggesting similar-pitched stag and hind calls because of potential prevalence of natural over sexual selection on call pitch; and Rule 2: predicting lower-pitched calls in adults, because larger vocal folds normally produce lower-pitched calls in mammals. We found that both rules were supported for native Pannonian red deer from Central Europe. All fundamental frequency () parameter values of hind contact calls (for the exclusion of the beginning ) were indistinguishable from those of stag rutting roars. These results agree with published data on vocalization of male and female American and Asian wapiti Cervus canadensis. Calls of adults of either sex were lower in frequency than calf calls. These results disagree with data collected from adult and young American wapiti producing same-frequency calls, probably because of a distinctive mechanism of sound production (whistling).
Explaining Epistemic Intuitions: From Intuitionist Particularism to Intuitionist Explanationism
Authors: McCain Kevin 
Published: September 2022

Abstract
In Radical Skepticism & Epistemic Intuition Michael Bergmann attempts to overcome the threat of radical skepticism as it arises in several different forms. The key to Bergmann’s response to skepticism is his method of intuitionist particularism wherein we give our intuitions about particular beliefs being justified more weight than we do intuitions about the premises of arguments for skepticism. There are two general problems for Bergmann’s response to skepticism. First, he fails to accurately portray the key principle of the skeptical argument. As a result, much of the apparent motivation for looking to intuitionist particularism as opposed to other responses to skepticism is merely apparent. Second, intuitionist particularism faces significant problems when it comes to the Problem of the Criterion and the resolution of conflicting intuitions. However, a related intuitionist method, one incorporating explanationism, may be able to deliver what intuitionist particularism promises while avoiding its problems.
Umorismo come strumento di critica all’Occidentalizzazione nel romanzo vietnamita Số Đỏ (Vũ Trọng Phụng, Hanoi, 1936)
Authors: Le Thuy Hien 
Published: September 2022

Abstract
Based on the study of humour and its classical categories (superiority, relief, incongruity), as well as its denunciation function, this paper is going to explore different humour techniques in Số Đỏ (Vũ Trọng Phụng 1936), a masterpiece of contemporary Vietnamese literature. Written during the most intense period of socioeconomic and political changes in colonial Indochina, this novel immediately stood out for its bitter humour, which laid bare the effects of modernization in northern Vietnam during late French colonization. Focusing on ridiculous members of the emergent Francophile bourgeoisie, the mocking of their uncritical imitation of the behaviors and customs of the Western culture, and the ironic description of absurd and incongruous situations, Vũ Trọng Phụng successfully revealed the socioeconomic crisis, the pressure of cultural changes, and the clash—both material and ideological—between East and West, tradition and modernity, which took place in Hanoi in the 1930s. Because of its controversial content, Số Đỏ, together with other works of Vũ Trọng Phụng, was the subject of intense literary and political debates in the ‘30s, during the French protectorate, and in the ‘60s was banned from communist-ruled Vietnam, until its rehabilitation in the late ‘80s. This case represents a rare example of criticism of Westernization seen through the sceptical eyes and humorous tone of a colonized author, and confirms once more the important political and social role of humour, its ability to represent reality, the dual existence of comic and tragic.
Technical Education in Nara Japan: Text and Context of the Yōshi kangoshō (ca. 720)
Authors: Manieri Antonio 
Published: September 2022

Abstract
The Yōshi kangoshō (Notes on Chinese Words by Master Yako, ca. 720) is a bilingual Sinitic-Japanese dictionary, now lost and surviving only in indirect transmission thanks to quotations in the Wamyōruijushō (Categorized Notes on Japanese Nouns, ca. 934) by Minamoto no Shitagō (911–983).
The lexical domains covered by the Yōshi kangoshō deal with technical knowledge, such as terminology for anatomy and medicine, archery, constructions, shipping and shipbuilding, the textile sector (clothes, belts, shoes, sewing, weaving, sericulture, dyeing, etc.), hippology and stock-breeding, agriculture, cooking, carpentry, sea and earth products, kinship.
In this paper, I propose a reconstruction of the Yōshi kangoshō, furnishing the complete list of its quotations. I would therefore like to propose that the Yōshi kangoshō should be reconsidered as an educational tool for learning terminologies, and that it was particularly useful for the technical education of clerks.
Kangdiz in Pahlavi Literature
Authors: Agostini Domenico 
Published: September 2022

Abstract
Though Kandiz seems to be depicted in the early Avestan sources, only in Zoroastrian Pahlavi literature does this fortress-city receive a rich and detailed description. Kangdiz becomes a significant and essential place, strongly connected to the legend of Zoroaster and the eschatological events of the final times. In its geographical, architectural, and religious transformation Kangdiz is often enriched with features belonging to other special Iranian places, such as the shelter of Jam. The fame and the narrative model of this city survives the first centuries of the Islamic conquest. This article presents the architecture and the geography of Kangdiz as found in Pahlavi sources and to define its eschatological role in the context of the Zoroastrian myth and religion.
“Climbing the Same Mountain”
Authors: Vine Bernadette , Holmes Janet , Marra Meredith 
Published: September 2022

Abstract
The enactment of biculturalism in Aotearoa New Zealand has varied greatly over the time since colonial settlement, and it is still a debated and evolving concept. In this article we examine practices adopted by one Māori Chief Executive Officer in two different workplaces at two different points in time to illustrate this process in action. Our analysis examines the way he opens meetings of his senior management teams, demonstrating the way he adopts flexible and context-sensitive approaches, taking account of exactly where each organisation and each individual, whatever their ethnicity and varied cultural experience, is located along the pathway to biculturalism. His introduction of Māori tikanga (ways of doing things) and practices into both workplaces sends the message that Māori culture and language are valued, while the differences between the two organisations, including a greater focus on bilingualism as part of biculturalism more recently, reflects shifting attitudes in wider society.
Tangent-Linear and Adjoint Models for the Transfer of Polarized Radiation
Authors: Ding Jiachen , Yang Ping 
Published: September 2022

Abstract
This study reports the development of tangent-linear and adjoint models for a vector radiative transfer model called TAMU-VRTM. This vector radiative transfer model is further validated in the case of the atmosphere–ocean coupled system, although previous validation was conducted for single and multiple layers. The TAMU-VRTM and tangent-linear and adjoint models can be applied to remote sensing and data assimilation based on spaceborne and airborne polarimetric observations. The tangent-linear and adjoint models accurately and efficiently compute the derivatives of output Stokes parameters with respect to input variables of the TAMU-VRTM. An inversion algorithm can straightforwardly compute the Jacobian matrix from the derivatives of Stokes parameters using the chain rule. We validate the tangent-linear and adjoint models by comparing them with the finite-difference method, and show that the finite-difference results converge to the tangent-linear and adjoint results. Furthermore, the adjoint model can efficiently compute the derivatives of observables with respect to the scattering phase matrix elements. This capability can be used to evaluate the scattering phase matrix assumed in an inversion algorithm and has potential for applications to inferring scattering phase matrix elements of cloud, aerosol, and hydrosol particles.
Explainability does not improve biochemistry staff trust in artificial intelligence-based decision support
Authors: Lancaster Farrell Christopher-John 
Published: September 2022

Background Explainability, the aspect of artificial intelligence-based decision support (ADS) systems that allows users to understand why predictions are made, offers many potential benefits. One common claim is that explainability increases user trust, yet this has not been established in healthcare contexts. For advanced algorithms such as artificial neural networks, the generation of explanations is not trivial, but requires the use of a second algorithm. The assumption of improved user trust should therefore be investigated to determine if it justifies the additional complexity. Methods Biochemistry staff completed a wrong blood in tube (WBIT) error identification task with the help of an ADS system. One-half of the volunteers were provided with both ADS predictions and explanations for those predictions, while the other half received predictions alone. The two groups were compared in terms of their rate of agreement with ADS predictions, as an index of user trust, and WBIT error detection performance. Since the AI model used to generate predictions was known to out-perform laboratory staff, increased trust was expected to improve user performance. Results Volunteers reviewed 1590 sets of results. The volunteers provided with explanations demonstrated no difference in their rate of agreement with the ADS system compared to volunteers receiving predictions alone (83.3% versus 81.8%, p = 0.46). The two volunteer groups were also equivalent in accuracy, sensitivity and specificity for WBIT error identification ( p-values >0.78). Conclusions For a WBIT error identification task, there was no evidence to justify the additional complexity of explainability on the grounds of increased user trust.