bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Genomic Analysis and Clinical Outcomes ofBRAF-mutated Advanced Biliary Tract Cancers
Authors: Tang Tin-Yun , Nichetti Federico , Kaplan Ben , Lonardi Sara , Pietrantonio Filippo , Salvatore Lisa , Vivaldi Caterina , Rimassa Lorenza , de Braud Filippo , Rizzato Mario Domenico , Pavlick Dean , Chu Randy , Danner De Armas Anaemy , Sharaf Radwa , Sokol Ethan , Rodon Ahnert Jordi , Ross Jeffrey S. , Javle Milind , Niger Monica
Published: September 2023

Purpose:

BRAF mutations are rare in biliary tract cancers (BTC), but are of interest given the recent developments in targeted therapy for BTC. We investigated the clinical outcomes in a cohort of BRAF-mutant advanced BTC treated with first-line chemotherapy. Furthermore, we investigated the genomic landscape of BRAF class I, II, and III mutations in the intrahepatic cholangiocarcinoma (iCCA) subgroup of BTC.

Experimental Design:

We analyzed two nonoverlapping cohorts. We examined the genomic landscape of BRAF-mutated iCCA in a “genomic cohort” [187 class I, 82 class II, 113 class III BRAF mutants and 8,026 wildtype (WT)]. We also analyzed median progression-free survival (PFS) and overall survival (OS) on first-line chemotherapy in a separate multi-institutional “clinical cohort” of patients with BTC (including iCCA and extrahepatic cholangiocarcinoma (eCCA) and gallbladder cancer; 41 class I, 32 class II+III BRAF mutants and 1,042 WT).

Results:

In the entire BTC clinical cohort, the median PFS was shorter for class I [HR, 2.11 (P < 0.001)] and class II+III [HR, 1.72 (P = 0.007)] as compared with BRAF WT. OS was also shorter in class I [HR, 2.04 (P = 0.011)] and class II+III [HR, 1.86 (P = 0.002)] as compared with BRAF WT. In the iCCA subgroup, class I alterations were mutually exclusive with FGFR2, IDH1/2, ERBB2, and KRAS mutations. Class II+III mutations appear to be mutually exclusive with FGFR2 and KRAS.

Conclusions:

In BTC, all classes of BRAF mutations are associated with a worse prognosis. BRAF mutations occur in 5% of iCCA subgroup and may be mutually exclusive with other targetable mutations.
An Eye-Tracking Study on Viewer Compliance with the Gestalt Closure Principle: Analyzing the Impact of Gap Size and the Golden Ratio
Authors: Hu Xinran
Published: September 2023

The Gestalt principle of closure refers to brain activity filling in missing information to perceive objects as complete, even when partially hidden. Designers leverage this principle to imply shapes without explicitly showing them. However, evaluating viewer responses poses challenges. The author conducted a comprehensive eye-tracking experiment to determine when viewers mentally completed a gap in a circle and explored the potential influence of the golden ratio on the closure principle. The golden ratio, approximately 1.618, is associated with visual harmony and is used in art and design to create pleasing proportions. Findings showed that viewers tend to mentally close gaps up to 135° but avoid closure beyond 150°. This suggests the golden ratio’s relevance in applying the closure principle to design.
Testing Causal Effects of Empathy on Children’s Prosociality in Politeness Dilemmas - An Intervention Study
Authors: Thiede Noemi , Stengelin Roman , Seibold Astrid , Haun Daniel B. M.
Published: September 2023

Empathy is commonly considered a driver of prosociality in child ontogeny, but causal assumptions regarding this effect mostly rely on correlational research designs. Here, 96 urban German children (5–8 years; 48 girls; predominantly White; from mid-to-high socioeconomic backgrounds) participated in an empathy intervention or a control condition before prosocial behaviors (polite lie-telling: rating the drawing as good; prosocial encouragement: utterances interpreted as cheering up the artist) were assessed in an art-rating task. Contrasting children’s empathy at baseline with their empathy after the intervention indicated promoted empathy compared to the control group. Despite the intervention’s effect on children’s empathy, there were no simultaneous changes in prosocial behaviors. At the same time, children’s empathy at baseline was associated with their prosocial encouragement. These results indicate conceptual associations between children’s empathy and prosociality. However, they do not support strict causal claims regarding this association in middle childhood. Further applications of the novel short-time intervention to address causal effects of empathy on prosociality and other developmental outcomes are discussed.
Everything is Infinite: Children’s Beliefs About Endless Space, Time, and Number
Authors: Sullivan Jessica , Cramer-Benjamin Sophie , Alvarez Joseph , Barner David
Published: September 2023

How do children form beliefs about the infinity of space, time, and number? We asked whether children held similar beliefs about infinity across domains, and whether beliefs in infinity for domains like space and time might be scaffolded upon numerical knowledge (e.g., knowledge successors within the count list). To test these questions, 112 U.S. children (aged 4;0–7;11) completed an interview regarding their beliefs about infinite space, time, and number. We also measured their knowledge of counting, and other factors that might impact performance on linguistic assessments of infinity belief (e.g., working memory, ability to respond to hypothetical questions). We found that beliefs about infinity were very high across all three domains, suggesting that infinity beliefs may arise early in development for space, time, and number. Second, we found that—across all three domains—children were more likely to believe that it is always possible to add a unit than to believe that the domain is endless. Finally, we found that understanding the rules underlying counting predicted children’s belief that it is always possible to add 1 to any number, but did not predict any of the other elements of infinity belief.
Kanon und Klassiker der Frühen Neuzeit?
Authors: Bach Oliver
Published: September 2023

The aim of this article is to outline several aspects of a canon of early modern German literature as they had been discussed by a volume Klassiker der Frühen Neuzeit (ed. Regina Toepfer) in 2022. In the light of recent criticism of any conception of canon as an outcome of hegemonial thinking as well as considering the increasing disregard of early modern literature even in universities, it is foremost the Early Modern Literature Studies who are urged to discuss the question of whether there are sufficient reasons for upholding a literary canon at least to a certain degree and whether texts of the early modern period can or must be part of such a canon.
Religious School Education in Brazilian Supreme Federal Court Voting
Authors: Montero Paula
Published: September 2023

This article examines the arguments made by the eleven Justices of the Supreme Federal Court who, in 2017, decided on the constitutionality of offering confessional education in public schools. We will explore how long-term disputed ethical and legal values are rearticulated in these votes concerning the notion of belief, almost 40 years after defining Religious Education as a fundamental human right by the Constitution. It is not a matter of harking back to the topic of secularism, as a social process or as a legal norm or political doctrine. The discursive analysis of the ministers’ votes formulations aims, on the contrary, to unveil the different religious constructions implied in their uses of the terms religion and rights and to understand how they operate when putting forward an idea of citizenship and/or the nation. The aim is to clarify, from this systematic examination of the votes, the configuration of common legal sense when issuing value judgments about religion and its protection. Therefore, our primary focus will be to circumscribe what counts as religion in these legal narratives.
Commentary on Urban Secularism: Negotiating Religious Diversity in Europe by Julia Martínez-Ariño
Authors: Barras Amélie
Published: September 2023

This article offers critical and complementary commentary on the new book Urban Secularism: Negotiating Religious Diversity in Europe by Julia Martínez-Ariño.
The Devil is in the Details
Authors: Hjelm Titus
Published: September 2023

This article offers critical and complementary commentary on the new book Urban Secularism: Negotiating Religious Diversity in Europe by Julia Martínez-Ariño.
Historical Analogies
Authors: Keulen Sjoerd
Published: September 2023

Historical analogies are amongst the most important tools in applied history. On the one hand, they are applauded as decision-making tools, on the other hand they are criticised by the historical discipline. In the discipline of applied history, historical analogies remain deconceptualised. This article defines and classifies the various forms of historical analogy. Classification is based on people and events, on how history is learned and on the depth of the lessons learned from historical analogies. The functions of historical analogies in policymaking and decision-making are discussed and clarified by means of historical examples. The article then reflects on the limitations of historical analogies and, to conclude, suggests ways to encourage the correct use of historical analogies.
Nadir Shah Afshar’s Policy towards the Armenian Community
Authors: Gozalova Nigar R.
Published: September 2023

Based on the primary sources, the article examined the position and status of the Christian population during the reign of Nadir Shah Afshar (1688–1747). Special attention is paid to the question of privileges and patronage of the Armenian community. it is argued that the supportive policy of Nadir Shah towards representatives of Christian churches and monasteries was expressed in numerous decrees and firmans of the Afshar ruler. Thanks to the patronage of Nadir Shah, the possessions of the diocese of Uch-Kilsa (Echmiadzin) were exempted from taxes; they were allowed not only to rebuild churches, but even to build new ones. Nadir Shah also patronized the resettlement of the Armenian population from the neighboring Ottoman Empire, etc. An analysis of the sources helps to examine religious freedom in the Afshar’s state, including its tax policy in relation to Christian churches and monasteries.
The Emergence of a New Identity
Authors: Yengimolki Ahmad
Published: September 2023

This present study aims to challenge simplistic views of division and boundaries between Muslims and Christians. It delves into the cultural and artistic relationship between the Safavid ruling elite and the newly arrived Armenians in seventeenth-century Isfahan. The primary goal is to understand how the Armenian population merged with the predominantly Muslim community of Isfahan. An insightful perspective is gained by examining the Armenian architecture in Isfahan, where Armenians adapted and appropriated local architectural elements, creating a sense of belonging and shared identity. To gain a comprehensive understanding, the study delves into the wider cultural and political context of Isfahan during that time, drawing from a diverse array of European, Persian, and Armenian sources. By adopting this inclusive approach, the study explores the complex interplay of Christian and Muslim, as well as Safavid and Armenian elements within Isfahani society, thereby shedding light on the multifaceted identities at play.
Do personal relationships boost academic performance more for women than for men?
Authors: Dokuka Sofia , Mikhaylova Oxana
Published: September 2023

Social integration is known to be positively related to academic performance. It is also well-known to play a different role for (self-identified) men and women. In this paper, we examine the differences seen in the correlations between academic performance and social integration for men and women. Gender was determined on the basis of self-identification. Utilizing the data from the Russian representative panel of late adolescents ( N = 4,400), we demonstrate a positive relationship between the core discussion network size as a measure of social integration. Using moderation analysis, we demonstrate that the role of social integration for women is more pronounced than for men. Our findings show the importance of social integration and support for girls and women and suggest possible policy implications.
Prevalence and impact of diabetes on survival of patients with multiple myeloma in different racial groups
Authors: Shah Urvi A. , Moshier Erin , Derkach Andriy , Huang Yuanhui , Mailankody Sham , Tan Carlyn R. , Maclachlan Kylee , Hultcrantz Malin , Korde Neha , Hassoun Hani , Thibaud Santiago , Sanchez Larysa , Rodriguez Cesar , Richard Shambavi , Richter Joshua , Rossi Adriana , Cho Hearn Jay , Lesokhin Alexander , Chari Ajai , Usmani Saad Z. , Jagannath Sundar , Parekh Samir , Gallagher Emily J.
Published: September 2023

Multiple myeloma (MM) is twice as common in Black individuals compared with in White individuals, and diabetes mellitus (DM) disproportionately affects Black patients. Although numerous studies have shown a correlation between DM and MM, this has not been studied in the context of race and in vivo mechanisms. We conducted a retrospective clinical study of 5383 patients with MM of which 15% had DM (White, 12% and Black, 25%). Multivariable Cox models showed reduced overall survival (OS) for patients with DM (hazard ratio, 1.27; 95% confidence interval, 1.11-1.47; P < .001). This appeared to be driven by a marked difference in OS between White patients with and without DM but not in Black patients. In contrast, obesity was associated with better OS in Black patients but not in White patients. To complement this analysis, we assessed MM growth in a genetically engineered immunocompromised nonobese diabetic (Rag1−/−/muscle creatinine kinase promoter expression of a human IGF1R [M] with a lysine [K] to arginine [R] point mutation) mouse model to evaluate the mechanisms linking DM and MM. MM.1S xenografts grew in more Rag1−/−/MKR mice and grew more rapidly in the Rag1−/−/MKR mice compared with in controls. Western blot analysis found that MM1.S xenografts from Rag1−/−/MKR mice had higher phosphorylated S6 ribosomal protein (Ser235/236) levels, indicating greater activation of the mammalian target of rapamycin pathway. Our study is, to our knowledge, the first to evaluate racial differences in DM prevalence and survival in MM, as well as the effect of DM on tumor growth in mouse models. Our results suggest that DM may contribute to the higher incidence of MM in Black patients; and to improve survival in MM, DM management cannot be ignored.
A large-scale targeted proteomics of serum and tissue shows the utility of classifying high grade and low grade meningioma tumors
Authors: Halder Ankit , Biswas Deeptarup , Chauhan Aparna , Saha Adrita , Auromahima Shreeman , Yadav Deeksha , Nissa Mehar Un , Iyer Gayatri , Parihari Shashwati , Sharma Gautam , Epari Sridhar , Shetty Prakash , Moiyadi Aliasgar , Ball Graham Roy , Srivastava Sanjeeva
Published: September 2023

Background

Meningiomas are the most prevalent primary brain tumors. Due to their increasing burden on healthcare, meningiomas have become a pivot of translational research globally. Despite many studies in the field of discovery proteomics, the identification of grade-specific markers for meningioma is still a paradox and requires thorough investigation. The potential of the reported markers in different studies needs further verification in large and independent sample cohorts to identify the best set of markers with a better clinical perspective.

Methods

A total of 53 fresh frozen tumor tissue and 51 serum samples were acquired from meningioma patients respectively along with healthy controls, to validate the prospect of reported differentially expressed proteins and claimed markers of Meningioma mined from numerous manuscripts and knowledgebases. A small subset of Glioma/Glioblastoma samples were also included to investigate inter-tumor segregation. Furthermore, a simple Machine Learning (ML) based analysis was performed to evaluate the classification accuracy of the list of proteins.

Results

A list of 15 proteins from tissue and 12 proteins from serum were found to be the best segregator using a feature selection-based machine learning strategy with an accuracy of around 80% in predicting low grade (WHO grade I) and high grade (WHO grade II and WHO grade III) meningiomas. In addition, the discriminant analysis could also unveil the complexity of meningioma grading from a segregation pattern, which leads to the understanding of transition phases between the grades.

Conclusions

The identified list of validated markers could play an instrumental role in the classification of meningioma as well as provide novel clinical perspectives in regard to prognosis and therapeutic targets.
Work-related outcomes in individuals with and without lower limb osteoarthritis: an online survey
Authors: Alyousef Yousef S. , Johnston Venerina , Smith Michelle D.
Published: September 2023

Objective

While osteoarthritis (OA) affects people who are still participating in the workforce, there is limited data about the impact of OA on work. The aim of this study was to compare work participation in individuals with and without lower limb OA.

Methods

This cross-sectional study included workers with (n = 124) and without (n = 106) lower limb OA. Work participation was assessed as work status (full/part time work), work ability (Work Ability Index (WAI)), absenteeism and presenteeism (World Health Organization’s Health and Work Performance Questionnaire (WHO-HPQ)), and perceived difficulties meeting work demands (Work Role Functioning Questionnaire (WRFQ)). The data were analyzed using an analysis of covariance with age, body mass index and physical job demands included as covariates.

Results

Work ability was poorer (p < 0.001) and loss of work performance (p < 0.001) was higher among workers with OA than healthy controls. There was no statistical difference in absenteeism or overall ability to meet work demands between participants with and without lower limb OA. However, workers with lower limb OA had more difficulty with work scheduling demands (p = 0.05) and physical demands (p = 0.003) than healthy workers.

Conclusion

Lower limb OA was associated with poorer work ability, loss of work performance and difficulty in meeting physical and work scheduling demands. Health professionals and employers should consider these challenges when managing individuals with lower limb OA and supporting them to remain in the workforce.
Real-world data emulating randomized controlled trials of non-vitamin K antagonist oral anticoagulants in patients with venous thromboembolism
Authors: Yoon Dongwon , Jeong Han Eol , Park Sohee , You Seng Chan , Bang Soo-Mee , Shin Ju-Young
Published: September 2023

Background

Emulating randomized controlled trials (RCTs) by real-world evidence (RWE) studies would benefit future clinical and regulatory decision-making by balancing the limitations of RCT. We aimed to evaluate whether the findings from RWE studies can support regulatory decisions derived from RCTs of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with venous thromboembolism (VTE).

Methods

Five landmark trials (AMPLIFY, RE-COVER II, Hokusai-VTE, EINSTEIN-DVT, and EINSTEIN-PE) of NOACs were emulated using the South Korean nationwide claims database (January 2012 to August 2020). We applied an active comparator and new-user design to include patients who initiated oral anticoagulants within 28 days from their VTE diagnoses. The prespecified eligibility criteria, exposure (each NOAC, such as apixaban, rivaroxaban, dabigatran, and edoxaban), comparator (conventional therapy, defined as subcutaneous heparin followed by warfarin), and the definition of outcomes from RCTs were emulated as closely as possible in each separate emulation cohort. The primary outcome was identical to each trial, which was defined as recurrent VTE or VTE-related death. The safety outcome was major bleeding. Propensity score matching was conducted to balance 69 covariates between the exposure groups. Effect estimates for outcomes were estimated using the Mantel–Haenszel method and Cox proportional hazards model and subsequently compared with the corresponding RCT estimates.

Results

Compared to trial populations, real-world study populations were older (range: 63–69 years [RWE] vs. 54–59 years [RCT]), with more females (55–60.5% vs. 39–48.3%) and had a higher prevalence of active cancer (4.2–15.4% vs. 2.5–9.5%). The emulated estimates for effectiveness outcomes showed superior effectiveness of NOAC (AMPLIFY: relative risk 0.81, 95% confidence interval 0.70–0.94; RE-COVER II: hazard ratio [HR] 0.60, 0.37–0.96; Hokusai-VTE: 0.49, 0.31–0.78; EINSTEIN-DVT: 0.54, 0.33–0.89; EINSTEIN-PE: 0.50, 0.34–0.74), when contrasted with trials that showed non-inferiority. For safety outcomes, all emulations except for AMPLIFY and EINSTEIN-DVT yielded results consistent with their corresponding RCTs.

Conclusions

This study revealed the feasibility of complementing RCTs with RWE studies by using claims data in patients with VTE. Future studies to consider the different demographic characteristics between RCT and RWE populations are needed.
Multimodal non-invasive non-pharmacological therapies for chronic pain: mechanisms and progress
Authors: Shi Yu , Wu Wen
Published: September 2023

Background

Chronic pain conditions impose significant burdens worldwide. Pharmacological treatments like opioids have limitations. Non-invasive non-pharmacological therapies (NINPT) encompass diverse interventions including physical, psychological, complementary and alternative approaches, and other innovative techniques that provide analgesic options for chronic pain without medications.

Main body

This review elucidates the mechanisms of major NINPT modalities and synthesizes evidence for their clinical potential across chronic pain populations. NINPT leverages peripheral, spinal, and supraspinal mechanisms to restore normal pain processing and limit central sensitization. However, heterogeneity in treatment protocols and individual responses warrants optimization through precision medicine approaches.

Conclusion

Future adoption of NINPT requires addressing limitations in standardization and accessibility as well as synergistic combination with emerging therapies. Overall, this review highlights the promise of NINPT as a valuable complementary option ready for integration into contemporary pain medicine paradigms to improve patient care and outcomes.
Association of cardio-renal biomarkers and mortality in the U.S.: a prospective cohort study
Authors: Yang Fan , Wang Mingsi , Chen Yuzhu , Wu Jianjun , Li Yilan
Published: September 2023

Objective

Diabetes poses a significant threat to human health. There is a lack of large-scale cohort studies to explore the association between mortality risk and indicators beyond blood glucose monitoring in diabetic populations.

Methods

Multivariable Cox proportional hazards regression models were performed to investigate the association of 13 blood biomarkers with mortality risk in the National Health and Nutrition Examination Survey (NHANES) and biomarker levels were log-transformed and correlated with mortality.

Results

During a median follow-up of 7.42 years, 1783 diabetic patients were enrolled. Compared to traditional risk factors, the addition of hs-cTnT, hs-cTnI, NT-proBNP, creatinine, cystatin C, and β-2 microglobulin biomarkers increased the predictive ability for all-cause mortality by 56.4%, 29.5%, 38.1%, 18.8%, 35.7%, and 41.3%, respectively. However, the inclusion of blood glucose monitoring had no impact on the prediction of all-cause mortality. Compared with the 1st quartiles of creatinine and Cystatin C, the risk of diabetes mortality were higher in the highest quartiles (HR: 5.16, 95% CI: 1.87–14.22; HR: 10.06, 95% CI: 4.20-24.13).

Conclusions

In the diabetic population, elevated plasma levels of hs-cTnT, hs-cTnI, NT-proBNP, creatinine, cystatin C, and β-2 microglobulin serve as robust and straightforward predictors of long-term mortality compared to blood glucose levels and HbA1c values. Creatinine and cystatin C stand out as more precise markers for predicting diabetes mortality prior to blood glucose monitoring.
Item response theory-based psychometric analysis of the Short Warwick-Edinburgh Mental Well-Being Scale (SWEMWBS) among adolescents in the UK
Authors: Hanzlová Radka , Lynn Peter
Published: September 2023

Background

Middle and late adolescence is the period in a person's life that is most vulnerable to mental health problems. To enable an evidence base that can support policies to prevent such problems, it is crucial to have good quality, reliable, and accurate measurement tools for mental well-being. One of them is the Short Warwick-Edinburgh Mental Well-Being Scale (SWEMWBS). This study aimed to test the psychometric properties of the SWEMWBS on a large sample of adolescents aged 16 to 19 from the United Kingdom (UK) (N = 8,090). Data were from four waves of the longitudinal panel study Understanding Society.

Methods

The analysis was conducted using Item Response Theory (IRT), which is the most appropriate method for testing psychometric properties. The Graded Response Model (GRM) was applied to the data. The reliability and criterion validity of the SWEMWBS were also examined.

Results

The presented results confirm the very good psychometric properties of the SWEMWBS amongst adolescents aged 16 to 19 years. The assumptions for the use (unidimensionality, local non-independence, monotonicity) of IRT were met. The results of GRM showed very high discriminant power for all items. The five-category response scale performed optimally; however, differences were found between points on the response scale both between and within items. In general, the scale as a whole showed very good functioning, but particularly in the negative values of mental well-being.

Conclusions

The SWEMWBS was confirmed as a concise, reliable, and valid instrument for measuring mental well-being among older UK adolescents.
Constructing founder sets under allelic and non-allelic homologous recombination
Authors: Bonnet Konstantinn , Marschall Tobias , Doerr Daniel
Published: September 2023

Homologous recombination between the maternal and paternal copies of a chromosome is a key mechanism for human inheritance and shapes population genetic properties of our species. However, a similar mechanism can also act between different copies of the same sequence, then callednon-allelic homologous recombination (NAHR). This process can result in genomic rearrangements—including deletion, duplication, and inversion—and is underlying many genomic disorders. Despite its importance for genome evolution and disease, there is a lack of computational models to study genomic loci prone to NAHR. In this work, we propose such a computational model, providing a unified framework for both (allelic) homologous recombination and NAHR. Our model represents a set of genomes as a graph, where haplotypes correspond to walks through this graph. We formulate two founder set problems under our recombination model, provide flow-based algorithms for their solution, describe exact methods to characterize the number of recombinations, and demonstrate scalability to problem instances arising in practice.
Do women with high-risk HPV E6/E7 mRNA test positivity and NILM cytology need colposcopy?
Authors: Liu Ying , Jin Xiu , Gong Yingying , Ma Yingying , Du Beibei , Yang Linqing , Wang Yunfei , Zhu Weipei
Published: September 2023

Purpose

This study aimed to assess the value of an HPV E6/E7 mRNA assay and HPV 16 18/45 genotype assay combined with age stratification for triaging women negative for intraepithelial lesions or malignancy (NILM) cytology.

Methods

From January 2017 to December 2021, a total of 162,309 eligible women underwent cervical cancer screening at the Affiliated Hospital of Jining Medical University, China. Excluding those with negative HPV E6/E7 mRNA, abnormal and unsatisfactory cytology, and those who failed to undergo colposcopy, 6,845 women were ultimately included in our study. We analysed the triage guidance for different subtypes of HPV in the presence of NILM cytology.

Results

Among 162,309 women, 19,834 (12.2%) were positive for HPV E6/E7 mRNA. Of the 6,845 women included in the study, 1,941 (28.4%), 561 (8.2%), 55 (0.8%) and 4,288 (62.6%) tested positive for HPV 16, HPV 18/45, HPV16/18/45 or other HR-HPV genotypes, respectively. The proportions of LSIL+ (including LSIL, HSIL and ICC) and HSIL+ (including HSIL and ICC) pathological results in the HPV 16/18/45 + group were 57% and 34.1%, respectively, higher than 36.3% and 11% in the other HR-HPV + group (χ2 = 653.214, P < 0.001). The percentages of LSIL + and HSIL + in the HPV16 + group (61.3% and 42.8%, respectively) and HPV16+/18/45 + group (76.3% and 41.9%, respectively) were much higher than those in the HPV18 + group (40.6% and 13.1%, respectively) (P < 0.001). However, there was no significant difference in the percentage of histopathological results between the HPV16 + group and HPV16+/18/45 + groups (P > 0.05). The above results were consistent after stratification according to age.

Conclusion

The rate of histopathological abnormalities was still high for the other HR-HPV subtypes with NILM cytology, although the rate of histopathological abnormalities was much higher for the HPV 16/18/45 positive subtypes. Therefore, colposcopy should be performed in women with HPV E6/E7 mRNA positivity and NILM cytology, regardless of age and HPV genotype.
Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction
Authors: Jakobsson Gabriel , Papareddy Praveen , Andersson Henrik , Mulholland Megan , Bhongir Ravi , Ljungcrantz Irena , Engelbertsen Daniel , Björkbacka Harry , Nilsson Jan , Manea Adrian , Herwald Heiko , Ruiz-Meana Marisol , Rodríguez-Sinovas Antonio , Chew Michelle , Schiopu Alexandru
Published: September 2023

Background and Aims

The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD.

Methods

The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9−/− mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice.

Results

In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9−/− mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9−/− mice, confirming target specificity.

Conclusion

Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis.

Graphical Abstract
Core and penumbra estimation using deep learning-based AIF in association with clinical measures in computed tomography perfusion (CTP)
Authors: Bal Sukhdeep Singh , Yang Fan-pei Gloria , Chi Nai-Fang , Yin Jiu Haw , Wang Tao-Jung , Peng Giia Sheun , Chen Ke , Hsu Ching-Chi , Chen Chang-I
Published: September 2023

Objectives

To investigate whether utilizing a convolutional neural network (CNN)-based arterial input function (AIF) improves the volumetric estimation of core and penumbra in association with clinical measures in stroke patients.

Methods

The study included 160 acute ischemic stroke patients (male = 87, female = 73, median age = 73 years) with approval from the institutional review board. The patients had undergone CTP imaging, NIHSS and ASPECTS grading. convolutional neural network (CNN) model was trained to fit a raw AIF curve to a gamma variate function. CNN AIF was utilized to estimate the core and penumbra volumes which were further validated with clinical scores.

Results

Penumbra estimated by CNN AIF correlated positively with the NIHSS score (r = 0.69; p < 0.001) and negatively with the ASPECTS (r =  − 0.43; p < 0.001). The CNN AIF estimated penumbra and core volume matching the patient symptoms, typically in patients with higher NIHSS (> 20) and lower ASPECT score (< 5). In group analysis, the median CBF < 20%, CBF < 30%, rCBF < 38%, Tmax > 10 s, Tmax > 10 s volumes were statistically significantly higher (p < .05).

Conclusions

With inclusion of the CNN AIF in perfusion imaging pipeline, penumbra and core estimations are more reliable as they correlate with scores representing neurological deficits in stroke.

Critical relevance statement

With CNN AIF perfusion imaging pipeline, penumbra and core estimations are more reliable as they correlate with scores representing neurological deficits in stroke.

Graphic abstract
Stable isotope labeling and ultra-high-resolution NanoSIMS imaging reveal alpha-synuclein-induced changes in neuronal metabolism in vivo
Authors: Spataro Sofia , Maco Bohumil , Escrig Stéphane , Jensen Louise , Polerecky Lubos , Knott Graham , Meibom Anders , Schneider Bernard L.
Published: September 2023

In Parkinson’s disease, pathogenic factors such as the intraneuronal accumulation of the protein α-synuclein affect key metabolic processes. New approaches are required to understand how metabolic dysregulations cause degeneration of vulnerable subtypes of neurons in the brain. Here, we apply correlative electron microscopy and NanoSIMS isotopic imaging to map and quantify 13C enrichments in dopaminergic neurons at the subcellular level after pulse-chase administration of 13C-labeled glucose. To model a condition leading to neurodegeneration in Parkinson’s disease, human α-synuclein was unilaterally overexpressed in the substantia nigra of one brain hemisphere in rats. When comparing neurons overexpressing α-synuclein to those located in the control hemisphere, the carbon anabolism and turnover rates revealed metabolic anomalies in specific neuronal compartments and organelles. Overexpression of α-synuclein enhanced the overall carbon turnover in nigral neurons, despite a lower relative incorporation of carbon inside the nucleus. Furthermore, mitochondria and Golgi apparatus showed metabolic defects consistent with the effects of α-synuclein on inter-organellar communication. By revealing changes in the kinetics of carbon anabolism and turnover at the subcellular level, this approach can be used to explore how neurodegeneration unfolds in specific subpopulations of neurons.
Increased paclitaxel recovery from Taxus baccata vascular stem cells using novel in situ product recovery approaches
Authors: Santoyo-Garcia Jorge H. , Valdivia-Cabrera Marissa , Ochoa-Villarreal Marisol , Casasola-Zamora Samuel , Ripoll Magdalena , Escrich Ainoa , Moyano Elisabeth , Betancor Lorena , Halliday Karen J. , Loake Gary J. , Rios-Solis Leonardo
Published: September 2023

In this study, several approaches were tested to optimise the production and recovery of the widely used anticancer drug Taxol® (paclitaxel) from culturable vascular stem cells (VSCs) of Taxus baccata, which is currently used as a successful cell line for paclitaxel production. An in situ product recovery (ISPR) technique was employed, which involved combining three commercial macro-porous resin beads (HP-20, XAD7HP and HP-2MG) with batch and semi-continuous cultivations of the T. baccata VSCs after adding methyl jasmonate (Me-JA) as an elicitor. The optimal resin combination resulted in 234 ± 23 mg of paclitaxel per kg of fresh-weight cells, indicating a 13-fold improved yield compared to the control (with no resins) in batch cultivation. This resin treatment was further studied to evaluate the resins’ removal capacity of reactive oxygen species (ROS), which can cause poor cell growth or reduce product synthesis. It was observed that the ISPR cultivations had fourfold less intracellular ROS concentration than that of the control; thus, a reduced ROS concentration established by the resin contributed to increased paclitaxel yield, contrary to previous studies. These paclitaxel yields are the highest reported to date using VSCs, and this scalable production method could be applied for a diverse range of similar compounds utilising plant cell culture.

Graphical Abstract
S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis
Authors: Koning T. , Cordova F. , Aguilar G. , Sarmiento J. , Mardones G. A. , Boric M. , Varas-Godoy M. , Lladser A. , Duran W. N. , Ehrenfeld P. , Sanchez F. A.
Published: September 2023

Background

Nitric oxide is produced by different nitric oxide synthases isoforms. NO activates two signaling pathways, one dependent on soluble guanylate cyclase and protein kinase G, and other where NO post-translationally modifies proteins through S-nitrosylation, which is the modification induced by NO in free-thiol cysteines in proteins to form S-nitrosothiols. High levels of NO have been detected in blood of breast cancer patients and increased NOS activity has been detected in invasive breast tumors compared to benign or normal breast tissue, suggesting a positive correlation between NO biosynthesis, degree of malignancy and metastasis. During metastasis, the endothelium plays a key role allowing the adhesion of tumor cells, which is the first step in the extravasation process leading to metastasis. This step shares similarities with leukocyte adhesion to the endothelium, and it is plausible that it may also share some regulatory elements. The vascular cell adhesion molecule-1 (VCAM-1) expressed on the endothelial cell surface promotes interactions between the endothelium and tumor cells, as well as leukocytes. Data show that breast tumor cells adhere to areas in the vasculature where NO production is increased, however, the mechanisms involved are unknown.

Results

We report that the stimulation of endothelial cells with interleukin-8, and conditioned medium from breast tumor cells activates the S-nitrosylation pathway in the endothelium to induce leukocyte adhesion and tumor cell extravasation by a mechanism that involves an increased VCAM-1 cell surface expression in endothelial cells. We identified VCAM-1 as an S-nitrosylation target during this process. The inhibition of NO signaling and S-nitrosylation blocked the transmigration of tumor cells through endothelial monolayers. Using an in vivo model, the number of lung metastases was inhibited in the presence of the S-nitrosylation inhibitor N-acetylcysteine (NAC), which was correlated with lower levels of S-nitrosylated VCAM-1 in the metastases.

Conclusions

S-Nitrosylation in the endothelium activates pathways that enhance VCAM-1 surface localization to promote binding of leukocytes and extravasation of tumor cells leading to metastasis. NAC is positioned as an important tool that might be tested as a co-therapy against breast cancer metastasis.
Product Variety, the Cost of Living, and Welfare across Countries
Authors: Cavallo Alberto , Feenstra Robert C. , Inklaar Robert
Published: September 2023

We use the structure of the Melitz (2003) model to compute the cost of living and welfare across 47 countries, and compare these to conventional measures of prices and real consumption from the International Comparisons Project (ICP). The cost of living is inferred without directly using ICP prices of traded goods and instead relying on output prices, openness, domestic trade costs, and product variety measured by the counts of barcodes or firms. We find that welfare relative to the United States is lower than indicated by real consumption for most countries, but similar in China and Japan and similar or higher in some European countries. (JEL E21, E23, E31, O11)
Perfil clínico dos pacientes internados por Covid-19 na unidade de terapia intensiva
Authors: Durães Renata Ribeiro , Ladeia Elias Daniel Santos , Coelho Geisiany De Souza Santos , Fagundes Paulo Tadeu Morais
Published: September 2023

Objetivo: identificar o perfil clínico dos pacientes internados por COVID-19 na Unidade de Terapia Intensiva (UTI) de um hospital privado. Métodos: trata-se deum estudo de caráter descritivo, documental, retrospectivo, de corte transversal e análise quantitativa, conduzido em um hospital, no município de Montes Claros, MG, por meio da análise de prontuários de 142 pacientes da UTI com diagnóstico de COVID-19 no período de janeiro de 2020 a abril de 2021. Resultados: dos 142 indivíduos, a média de idadefoi de 64,1 anos, com 58,5% do sexo masculino. Das comorbidades prévias, as que tiveram maior prevalência foram a hipertensão arterial sistêmica com 26,8% e diabetes mellitus com 9,2%. Destes, 133 indivíduos utilizaram ventilação mecânica, com a prevalência de 47,9% no modo ventilação com volume controlado. O tempo médio de internação foi de 6 dias, sendo que 93,7% dos indivíduos foram a óbito, 4,9% receberam alta e 1,4% transferidos para outro hospital. Conclusão: evidenciou-se predominância do sexo masculino, com média de idade de 64,1 anos, o modo ventilatório mais utilizado foi o controlado o volume, com tempo de uso médio de uso 7,9 dias, ou seja, pouco tempo, fato que pode ser justificado pelo alto índice de óbitos na amostra estudada.
XRD analysis of nanoparticles synthesized using aqueous and
alcoholic extracts of Cuscuta reflexa
Authors: Ranjan Rakesh , Prasad Sinha Manoranjan
Published: September 2023

Plants are one of the most abundant sources of biomolecules on the planet. Researchers and academics have become more interested in the antibacterial and therapeutic characteristics of plants over the last decade. The introduction and combination of nanotechnology and phytochemistry brought up new possibilities. The synthesis of metallic nanoparticles mediated by plant extracts developed quickly and has been extensively researched. In this paper, we describe the manufacture of silver nanoparticles from Cuscuta reflexa aqueous and alcoholic extracts. For
characterisation, the nanoparticles were subjected to X-ray diffraction (XRD) examination. XRD analysis offers concrete information about the structure and crystalline size of nanoparticles, and it can play an important role in nanoparticle characterisation. The observation includes findings for matched phases, search-match, selection criteria, peak list, crystallite size estimation, crystallinity analysis, diffraction pattern graphics, and so on. The nano size of the crystals was disclosed by XRD
examination, which proved to be 38.55 nm and 66.27 nm in the case of nanoparticles synthesised using aqueous and alcoholic extracts of Cuscuta reflexa, respectively. The crystal system was reported to be cubic with side length of 0.4 nm, the calculated density of silver in nanoparticles was calculated to be 10.506 g/cm3 which corresponds with the density of silver element, i.e., 10.49 g/cm3
Museums, immigration, identity
Authors: Τσιοτινού Αγγελική
Published: September 2023

Η διατριβή μου αντλεί από τον θεωρητικό προβληματισμό για την ερμηνεία του υλικού και άυλου πολιτισμού στα μουσεία εστιάζοντας στην αναπαράσταση της μεταναστευτικής εμπειρίας κοινοτήτων και πρωτίστως στον τρόπο που η διαχείριση των υλικών καταλοίπων σε αυτά διαμορφώνει ταυτότητες. Επικεντρώνεται στα ελληνοαμερικανικά μουσεία των Η.Π.Α., στα οποία εκτίθενται τα υλικά τεκμήρια των Ελλήνων μεταναστών των αρχών του 20ου αιώνα στις Η.Π.Α. και των απογόνων τους στη σύγχρονη εποχή της πολυπολιτισμικότητας και της διεθνικότητας. Συγκεκριμένα αναλύεται η “ποιητική” και η “πολιτική” των μόνιμων εκθέσεων σε τρία μουσεία-μελέτες περίπτωσης, δηλαδή οι τρόποι με τους οποίους τα εκθεσιακά αφηγήματα παράγουν νόημα μέσα από την χρήση, την πλαισιοθέτηση, και την ερμηνεία, του υλικού και άυλου πολιτισμού (τη λεγόμενη, δηλαδή, ποιητική του νοήματος), καθώς και οι τρόποι που τα εκθεσιακά αφηγήματα παράγουν μια ιστορικά, πολιτισμικά, και ιδεολογικά προσδιορισμένη μορφή γνώσης ή λόγου για τους αποδέκτες τους, η οποία εμπλέκεται σε σχέσεις εξουσίας, δηλαδή αναπαράγει πολιτισμικές και φυλετικές ιεραρχίες, διαμορφώνει απόψεις, και πλάθει ταυτότητες (δηλαδή τη λεγόμενη πολιτική του νοήματος). Μέσα από την ανάλυση τριών ελληνοαμερικανικών μουσειακών εκθέσεων ως μελετών περίπτωσης, εντοπίζω την ύπαρξη διαφορετικών ερμηνειών για την ελληνοαμερικανική εμπειρία στον μουσειακό χώρο που θα μπορούσαν να συνοψιστούν ως α. η εθνική/επίσημη, β. η λαϊκή και γ. η εθνογραφική. Αναλύω τα χαρακτηριστικά της κάθε ερμηνευτικής προσέγγισης όπως αυτά προκύπτουν από το επιστημολογικό, θεσμικό και ιδεολογικό πλαίσιο δημιουργίας της κάθε έκθεσης ούτως ώστε να εξηγήσω τα διαφορετικά αφηγήματα των εκθέσεων. Συζητώ, επίσης, τους στόχους και τις σκοπιμότητες που εξυπηρετεί κάθε μια ερμηνευτική προσέγγιση, αναδεικνύοντας την ύπαρξη πολλαπλών -έως και αντιμαχόμενων- ελληνοαμερικανικών ταυτοτήτων που η εκάστοτε ομάδα δημιουργών της έκθεσης επιχειρεί να καθιερώσει μέσα από το εγχείρημά της. Η διατριβή μου, έτσι, συμβάλλει στη βαθύτερη κατανόηση της μουσειακής συνθήκης σήμερα, όσον αφορά την αναπαράσταση εθνοτικών κοινοτήτων και ταυτοτήτων. Η κατανόηση αυτή είναι σημαντική για να αποφύγουμε μια ουσιοκρατική προσέγγιση των μουσειακών εκθέσεων και των ταυτοτήτων γενικότερα, δηλαδή μια προσέγγιση που παίρνει ως δεδομένη μια αναπαράσταση και μια κοινωνική ή εθνοτική ταυτότητα, αντί να αναδείξει το πλαίσιο κατασκευής τους. Έτσι, μέσα από την ανάλυση και την ερμηνεία των παραπάνω μουσειακών αναπαραστάσεων, η έρευνά μου συμβάλλει στη βαθύτερη κατανόηση των ελληνοαμερικανικών ταυτοτήτων, και της κατασκευής τους σε συγκεκριμένα ιστορικά, κοινωνικά και πολιτικά πλαίσια, κατανόηση η οποία είναι κρίσιμη και αναγκαία για κάθε εγχείρημα προσέγγισης των Ελλήνων της διασποράς στην Αμερική.