bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Combined Resistance to Meloidogyne enterolobii and M. incognita in Sweet Potato Genotypes
Authors: Galo David , Rezende Josielle Santos , La Bonte Don R. , Watson Tristan T.
Published: June 2024

Root-knot nematodes, genus Meloidogyne, are the most damaging nematodes of sweet potato, causing yield reduction and aesthetic damage of the marketable product. Several sweet potato cultivars currently grown in the Unites States have intermediate-to-high resistance to Meloidogyne incognita; however, many of these cultivars are susceptible to M. enterolobii. Therefore, the response of 69 sweet potato genotypes to M. enterolobii and M. incognita was evaluated under greenhouse conditions to identify potential sources of resistance. The cultivars ‘Beauregard’ and ‘Jewel’ were used as controls. Results showed that sweet potato genotypes were either highly resistant or highly susceptible to M. enterolobii, whereas they showed a wide-spectrum response to M. incognita, ranging from highly susceptible to highly resistant. Twenty-six genotypes were resistant to M. enterolobii and 11 genotypes were resistant to M. incognita. Combined resistance to M. enterolobii and M. incognita was observed in three sweet potato genotypes. Selected genotypes from this study will be used to incorporate the observed resistance into a commercially viable sweet potato cultivar.
Plastic Surgery Outreach Clinics Expand Access to Cleft and Craniofacial Care in Mississippi
Authors: Hopper Samuel J. , Hecox Emily E. , Brown Kathryn W. , Fernstrum Colton J. , Hoppe Ian C. , Humphries Laura S.
Published: June 2024

Accessing treatment at ACPA (American Cleft Palate-Craniofacial Association)–approved centers is challenging for individuals in rural communities. This study aims to assess how pediatric plastic surgery outreach clinics impact access for patients with orofacial cleft and craniosynostosis in Mississippi. An isochrone map was used to determine mean travel times from Mississippi counties to the sole pediatric hospital and the only ACPA-approved team in the state. This analysis was done before and after the establishment of two outreach clinics to assess differences in travel times and cost of travel to specialized plastic surgery care. Two sample t-tests were used for analysis.

The addition of outreach clinics in North and South Mississippi led to a significant reduction in mean travel times for patients with cleft and craniofacial diagnoses across the state's counties (1.81 hours vs 1.46 hours, P < 0.001). Noteworthy travel cost savings were observed after the introduction of outreach clinics when considering both the pandemic gas prices ($15.27 vs $9.80, P < 0.001) and post-pandemic prices ($36.52 vs $23.43, P < 0.001).

The addition of outreach clinics in Mississippi has expanded access to specialized healthcare for patients with cleft and craniofacial differences resulting in reduced travel time and cost savings for these patients. Establishing specialty outreach clinics in other rural states across the United States may contribute significantly to reducing burden of care for patients with clefts and craniofacial differences. Future studies can further investigate whether the inclusion of outreach clinics improves follow-up rates and surgical outcomes for these patients.
Barriers to Remote Burn Care Delivery
Authors: Edwards Shelley R. , Chamoun Gabrielle , Hecox Emily E. , Arnold Peter B. , Humphries Laura S.
Published: June 2024

Mounting evidence supports the use of telehealth to improve burn care access and efficiency. However, barriers to telehealth use remain throughout the United States and may disproportionately affect specific populations, such as rural and non-English-speaking patients. This study analyzes the association between physical proximity to burn care and determinants of telehealth access.

The relationship between telehealth-associated measures and proximity to burn care was analyzed with linear regression analysis. County-level data was sourced from the Agency for Healthcare Research and Quality's Social Determinants of Health Database (2020) and the American Community Survey (2021). County-level distances to the nearest American Burn Association (ABA)-verified burn center were calculated based on verified centers listed in the ABA burn center directory (n = 59). A subsequent analysis was performed on income-stratified datasets available for subset counties.

Distance was negatively correlated with access to a smartphone (P < 0.0001), broadband internet (P < 0.0001), and cellular data plan (P < 0.0001) and positively correlated with the percent of households with no computing device (P < 0.0001) and no internet access (P < 0.0001). Analysis of income-stratified data revealed similar results. The percent population not speaking English well (P < 0.0001) at all (P = 0.0009) and the proportion of limited English-speaking households (P = 0.0001) decreased as a function of distance.

People living furthest from an ABA-verified burn center in the United States are less likely to have adequate access to critical telehealth infrastructure compared to their counterparts living closer to a burn center. However, income impacts overall access and the degree to which access changes with proximity. Conversely, language-associated barriers decrease as distance increases.
Locoregional Flap Reconstruction of the Distal Third of the Leg – What Role Does it Have in a Modern Reconstructive Algorithm?
Authors: Galarza Laura , Talbot Hannah Grace , Bryant Gidarell C. , Davis Jared M.
Published: June 2024

Reconstruction of traumatic defects of the lower third of the leg poses a challenge due to limited locoregional options. Failed coverage can be associated with prolonged hospital stay, infection, loss of function, and unplanned return to surgery. Over the last few decades, free tissue transfer has dominated reconstructive algorithms for such defects; however, locoregional flaps may provide equally effective coverage in select patients. In the wake of the CODID-19 pandemic, locoregional flaps gained more consideration due to limited resources. We present a literature review and discussion of locoregional flaps, with emphasis on the quality and efficacy of these reconstructive modalities compared with free tissue transfer and surgical indications.

Soleus flaps, reverse sural flaps, and cutaneous perforator-based flaps are workhorses for small to medium size defects of the distal third of the leg, even in the setting of concomitant orthopedic trauma and exposed vital structures. It is important to consider such alternatives an integral part of the reconstructive algorithm as they can provide durable coverage with a favorable complication profile with less resource utilization. Appropriate patient selection requires consideration of the character of the defect, smoking status, preexisting vascular disease, and the zone of injury.
School-based caries prevention using silver diamine fluoride: A pragmatic randomized trial in low-income rural children
Authors: Ruff Ryan Richard , Niederman Richard
Published: June 2024

Background

Dental caries is the world’s most prevalent noncommunicable disease, disproportionately affecting children from low-income families and rural geographic areas.

Methods

The CariedAway 3.0 study was a cluster-randomized pragmatic non-inferiority trial comparing silver diamine fluoride (SDF) to sealants and atraumatic restorations (ART) for the prevention and control of dental caries. All participants also received fluoride varnish. Analysis consisted of mixed-effects logistic regression for caries prevalence and weighted least squares and mixed-effects negative binomial regression for caries incidence. A non-inferiority margin of 10% for the difference between groups was used. Dental caries was defined as an ICDAS score of four or greater.

Results

A total of 3345 children were enrolled across 35 schools; however there was a large proportion of children who were noncompliant and received external dental care over the course of the trial. In adjusted analyses of compliant participants (n=1083; 543 in the SDF group and 540 in the sealant and ART group), there was no difference in the weighted risk difference between treatment groups (B=0.003, 95% CI = -0.0001, 0.0008). The odds of caries prevalence was elevated in the SDF group in longitudinal analyses (OR = 1.35, 95% CI = 0.86, 2.11) but was not significant and was below the non-inferiority margin. There were no significant differences between groups for caries incidence in adjusted models (IRR = 1.19, 95% CI = 0.81, 1.74). Results for intent to treat analyses were similar to that of per-protocol.

Discussion

In this school-based clinical trial, the prevalence of dental caries in children treated with SDF and fluoride varnish was non-inferior compared to those treated with sealants, ART, and fluoride varnish, although the overall risk was slightly higher. Unfortunately, a high rate of dropout and participant noncompliance was observed, likely due to the impacts of COVID-19 on study procedures. As a result, observed effects may be unreliable beyond the short-term.

Trial Registration:NCT03448107
Reversible kink instability drives ultrafast jumping in nematodes and soft robots
Authors: Kumar Sunny , Tiwari Ishant , Ortega-Jimenez Victor M. , Dillman Adler R. , He Dongjing , Hu Yuhang , Bhamla M. Saad
Published: June 2024

Entomopathogenic nematodes (EPNs) exhibit a bending-elastic instability, or kink, before becoming airborne, a feature hypothesized but not proven to enhance jumping performance. Here, we provide the evidence that this kink is crucial for improving launch performance. We demonstrate that EPNs actively modulate their aspect ratio, forming a liquid-latched closed loop over a slow timescaleO(1 s), then rapidly open itO(10 µs), achieving heights of 20 body lengths (BL) and generating ∼ 104W/Kg of power. Using jumping nematodes, a bio-inspired Soft Jumping Model (SoftJM), and computational simulations, we explore the mechanisms and implications of this kink. EPNs control their takeoff direction by adjusting their head position and center of mass, a mechanism verified through phase maps of jump directions in simulations and SoftJM experiments. Our findings reveal that the reversible kink instability at the point of highest curvature on the ventral side enhances energy storage using the nematode’s limited muscular force. We investigated the impact of aspect ratio on kink instability and jumping performance using SoftJM, and quantified EPN cuticle stiffness with AFM, comparing it withC. elegans. This led to a stiffness-modified SoftJM design with a carbon fiber backbone, achieving jumps of ∼25 BL. Our study reveals how harnessing kink instabilities, a typical failure mode, enables bidirectional jumps in soft robots on complex substrates like sand, offering a novel approach for designing limbless robots for controlled jumping, locomotion, and even planetary exploration.
Development of a novel microphysiological system for neurotoxicity prediction using human iPSC-derived neurons with morphological deep learning
Authors: Han Xiaobo , Matsuda Naoki , Yamanaka Makoto , Suzuki Ikuro
Published: June 2024

Microphysiological system (MPS) is an in vitro culture technology that reproduces the physiological microenvironment and functionality of humans, and is expected to be applied for drug screening. In this study, we developed a MPS for structured culture of human iPSC-derived neurons, then predict drug-induced neurotoxicity by morphological deep learning. For human iPSC-derived cortical neurons, after administration of three different amyloid β (Aβ) peptides, neurotoxicity effects were evaluated by a deep learning image analysis, training two artificial intelligence (AI) models on neurites and PSD-95 images. The combined results indicated that Aβ 1-42 and 1-40, but not 1-28, induced synaptic degeneration, which is close to clinical reports. For human iPSC-derived sensory neurons, after administration of representative CIPN-related anti-cancer drugs, the toxic effects on soma and axons were evaluated by AI model using neurites images. Significant toxicity was detected in positive drugs and could be classified by different effects on soma or axon, suggesting that the current method provides an effective evaluation of chemotherapy-induced peripheral neuropathy. Taken together, it suggests that the present MPS combined with morphological deep learning is a useful platform for in vitro neurotoxicity assessment.
The role of service recovery in omnichannel integration services success model
Authors: Tseng Shu-Mei
Published: June 2024

Purpose

This study basically develops an omnichannel integration services (OIS) success model and further uses perceived value and stickiness to measure the actual net benefits. Furthermore, this study explores the role of service recovery in OIS success model.

Design/methodology/approach

A quantitative online survey study was mainly being conducted to statistically test these relationships among the customer experience, satisfaction, perceived value, stickiness and service recovery. The statistical data collected from 371 respondents were taken for analysis through partial least squares.

Findings

The findings revealed that the online and offline customer experiences have a significant influence on their level of online and offline satisfaction, respectively. Both online and offline satisfaction are major factors which are enhancing the perceived value and stickiness. Service recovery also has a significant effect on online and offline satisfaction.

Research limitations/implications

The results of the hypotheses presented in the OIS success model may usually vary from one cultural context to another. Hence, additional studies should access the current research model, especially those that are culturally different from Taiwan.

Practical implications

The service failures are always inevitable and the recovery of such encounters represent to have a significant challenge for OIS. Thus, practitioners should allocate more such resources to enhance on customer experience of OIS, which in turn promotes to enhance customer satisfaction. Moreover, OIS practitioners seem to be more concerned with a thought on how to avoid service failures and provide satisfied customer experience than developing service recovery strategies.

Originality/value

Although the past studies on multichannel retail have yielded insights into the factors affecting consumers' channel preferences, there is a dearth of research that sheds bright light on the intense factors affect the success of OIS; hence, a conceptual framework of OIS success model, referenced to the model of updated information systems success (ISS), thus is used to act as the basis of this study. Furthermore, this study explores the role of service recovery in OIS success model.
Cash waqf innovation in Islamic financial institutions and its governance issues, case studies: Indonesia, Malaysia, Türkiye
Authors: Nofianti Leny , Mukhlisin Murniati , Irfan Andi
Published: June 2024

Purpose

This study aims to examine the potential for waqf innovation to be developed as products and services by Islamic financial institutions, identify the barriers and facilitators to the implementation of cash waqf governance in Indonesia, Türkiye and Malaysia, and to explore how pandemics have influenced the role of cash waqf practices in the three countries.

Design/methodology/approach

This study adopts a qualitative approach with an interpretative perspective, drawing on ecology theory and Ibn Khaldun’s thought. The research method includes conducting literature reviews and interviews to explore the concept and significance of cash waqf, the offerings of Islamic financial institutions and the mechanisms for good governance of cash waqf to bolster the proposed model.

Findings

The finding shows that a model of cash waqf governance that outlines the relationships and interactions with the goal of advancing cash waqf. The use of technology, specifically computer technology, further strengthens these interactions.

Research limitations/implications

This study suffers from several limitations, such as the number of countries in the sampling. Thus, future research opportunities include exploring similar initiatives in other countries and examining the connections between different sub-fields within the global cash waqf practice.

Originality/value

The contribution of this study serves as a guide for cash waqf organizations to promote professional, responsible and accountable management practices; reduce the risks faced by waqf managers and support them in making improvements to enhance the role of waqf in Indonesia and elsewhere; as well as provide a reference for the government and waqf agencies in promoting the importance of cash waqf governance in the country.
Is warmth more critical than competence? Understanding how destination gender affects destination identification and destination advocacy
Authors: Hamdy Ahmed , Zhang Jian , Eid Riyad , Agag Gomaa
Published: June 2024

Purpose

This paper aims to examine a new approach to understanding the interrelationships between destination brand gender, stereotypes, destination brand identification and brand advocacy, as well as the mediating role of destination warmth (vs. competence) in the connections between destination brand femininity (vs. masculinity) and destination brand identification.

Design/methodology/approach

A qualitative study and literature review were conducted to revisit and refine the items on the scale. Preliminary item reduction was qualitatively grounded in focus groups, a panel of experts, and a pilot study. A follow-up quantitative evaluation of two studies (N1 = 705 and N2 = 472) was conducted to test seven hypotheses using exploratory factor analysis and confirmatory factor analysis with structural equation modeling.

Findings

The findings provide robust evidence for the interrelationships among destination brand gender, stereotypes, destination identification and destination advocacy. The outcomes also reveal that warmth is more important than competence for destination identification. Finally, the results indicated that only destination warmth serves as a partial mediator in the association between destination brand masculinity and femininity, on the one hand, and destination identification, on the other hand.

Originality/value

This article adds to the destination branding literature by using social role theory and the stereotype content model to explore novel connections among destination brand gender, stereotypes, destination brand identification and brand advocacy.
Limited variation in microbial communities across populations of Macrosteles leafhoppers (Hemiptera: Cicadellidae)
Authors: Mulio Sandra Åhlén , Zwolińska Agnieszka , Klejdysz Tomasz , Prus‐Frankowska Monika , Michalik Anna , Kolasa Michał , Łukasik Piotr
Published: June 2024

Microbial symbionts play crucial roles in insect biology, yet their diversity, distribution, and temporal dynamics across host populations remain poorly understood. In this study, we investigated the spatio‐temporal distribution of bacterial symbionts within the widely distributed and economically significant leafhopper genus Macrosteles, with a focus on Macrosteles laevis. Using host and symbiont marker gene amplicon sequencing, we explored the intricate relationships between these insects and their microbial partners. Our analysis of the cytochrome oxidase subunit I (COI) gene data revealed several intriguing findings. First, there was no strong genetic differentiation across M. laevis populations, suggesting gene flow among them. Second, we observed significant levels of heteroplasmy, indicating the presence of multiple mitochondrial haplotypes within individuals. Third, parasitoid infections were prevalent, highlighting the complex ecological interactions involving leafhoppers. The 16S rRNA data confirmed the universal presence of ancient nutritional endosymbionts—Sulcia and Nasuia—in M. laevis. Additionally, we found a high prevalence of Arsenophonus, another common symbiont. Interestingly, unlike most previously studied species, M. laevis exhibited only occasional cases of infection with known facultative endosymbionts and other bacteria. Notably, there was no significant variation in symbiont prevalence across different populations or among sampling years within the same population. Comparatively, facultative endosymbionts such as Rickettsia, Wolbachia, Cardinium and Lariskella were more common in other Macrosteles species. These findings underscore the importance of considering both host and symbiont dynamics when studying microbial associations. By simultaneously characterizing host and symbiont marker gene amplicons in large insect collections, we gain valuable insights into the intricate interplay between insects and their microbial partners. Understanding these dynamics contributes to our broader comprehension of host–microbe interactions in natural ecosystems.
Airway epithelial overexpressed cathepsin K induces airway remodelling through epithelial–mesenchymal trophic unit activation in asthma
Authors: Qin Ling , Yao Ye , Wang Weijie , Qin Qingwu , Liu Jingjing , Liu Huijun , Yuan Lin , Yuan Yunchang , Du Xizi , Zhao Bingrong , Wu Xinyu , Qing Bei , Huang Leng , Wang Gang , Xiang Yang , Qu Xiangping , Zhang Xuewei , Yang Ming , Xia Zhenkun , Liu Chi
Published: June 2024

Background and Purpose

Airway epithelial cells (AECs) regulate the activation of epithelial–mesenchymal trophic units (EMTUs) during airway remodelling through secretion of signalling mediators. However, the major trigger and the intrinsic pathogenesis of airway remodelling is still obscure.

Experimental Approach

The differing expressed genes in airway epithelia related to airway remodelling were screened and verified by RNA‐sequencing and signalling pathway analysis. Then, the effects of increased cathepsin K (CTSK) in airway epithelia on airway remodelling and EMTU activation were identified both in vitro and in vivo, and the molecular mechanism was elucidated in the EMTU model. The potential of CTSK as an an effective biomarker of airway remodelling was analysed in an asthma cohort of differing severity. Finally, an inhibitor of CTSK was administered for potential therapeutic intervention for airway remodelling in asthma.

Key Results

The expression of CTSK in airway epithelia increased significantly along with the development of airway remodelling in a house dust mite (HDM)‐stressed asthma model. Increased secretion of CTSK from airway epithelia induced the activation of EMTUs by activation of the PAR2‐mediated pathway. Blockade of CTSK inhibited EMTU activation and alleviated airway remodelling as an effective intervention target of airway remodelling.

Conclusion and Implications

Increased expression of CTSK in airway epithelia is involved in the development of airway remodelling in asthma through EMTU activation, mediated partly through the PAR2‐mediated signalling pathway. CTSK is a potential biomarker for airway remodelling, and may also be a useful intervention target for airway remodelling in asthma patients.
Umfassende Analyse des Einflusses der Body Composition auf die Wirksamkeit und das Nebenwirkungsprofil einer Systemtherapie mit Tyrosinkinaseinhibitoren bei Melanompatienten
Authors: Mengoni Miriam , Braun Andreas Dominik , Hinnerichs Mattes Simon , Aghayev Anar , Tüting Thomas , Surov Alexey
Published: June 2024

Hintergrund

Die Einführung von Tyrosinkinaseinhibitoren (TKI) hat die Behandlung von Patienten mit metastasiertem Melanom erheblich verbessert. Aktuelle Studien haben einen Zusammenhang zwischen dem Body‐Mass‐Index (BMI) und dem klinischen Verlauf von Patienten mit metastasiertem Melanom gezeigt. Weitere Studien mit kontroversen Ergebnissen haben jedoch die Interpretation dieser Ergebnisse erschwert. In der aktuellen Arbeit haben wir Parameter der Körperzusammensetzung (Body Composition) von Melanompatienten, die mit TKI behandelt wurden, analysiert, um deren Stellenwert als Biomarker zu evaluieren.

Patienten und Methodik

In einer retrospektiven Kohorte bestehend aus 57 Patienten wurden Parameter der Body Composition anhand von CT‐Scans untersucht und deren Einfluss auf das Therapieansprechen und das Auftreten unerwünschter Ereignisse analysiert. Die Studienkohorte umfasste alle Patienten mit metastasiertem, nicht resektablem Melanom im Stadium III/IV, die in unserer Abteilung eine Erstlinientherapie mit TKI erhalten hatten.

Ergebnisse

Mittels uni‐ und multivariater Analysen stellten wir einen Zusammenhang zwischen dem Gauge‐Index des viszeralen Fettgewebes (VATGI) und dem Überleben fest. Darüber hinaus untersuchten wir weitere Parameter der Body Composition, darunter die Sarkopenie, die ebenfalls mit einem kürzeren Gesamtüberleben assoziiert war. Weiterhin konnten wir nachweisen, dass Patienten mit niedrigem VATGI anteilsweise häufiger eine Fatigue aufwiesen.

Schlussfolgerungen

Unsere Studie ist die erste explorative Studie, die Parameter der Body Composition als Biomarker für Melanompatienten, die mit TKI behandelt werden, untersucht. Unsere Daten deuten darauf hin, dass der VATGI als Biomarker zur Vorhersage des Therapieerfolges verwendet werden könnte.
Repräsentation von Hautkarzinomen im öffentlichen Bewusstsein – Aufmerksamkeit weltweit und in Deutschland
Authors: Meinzenbach Anne , Kaatz Martin , Springer Steffen , Zieger Michael
Published: June 2024

Hintergrund und Zielsetzung

In den letzten Jahren ist eine Zunahme von Hauttumoren zu verzeichnen. Ziel dieser Studie war es daher, die Repräsentation von Hautkrebs im öffentlichen Bewusstsein weltweit und in Deutschland zu untersuchen und festzustellen, ob der Skin Cancer Awareness Month in den Suchinteressen der internetnutzenden Bevölkerung in gleicher Weise wie der Breast Cancer Awareness Month weltweit repräsentiert ist.

Daten und Methodik

In dieser Studie wurden die Daten von Google Trends verwendet, um den Grad der öffentlichen Aufmerksamkeit für verschiedene Tumorentitäten und Hautkrebsarten weltweit und in Deutschland zu ermitteln.

Ergebnisse

Die Ergebnisse dieser Analyse zeigten deutlich ein hohes Niveau für das relative öffentliche Suchinteresse am Thema Brustkrebs weltweit im Sensibilisierungsmonat Oktober. Weltweit und in Deutschland war ein gewisser Anstieg des Suchinteresses beziehungsweise ein gewisser saisonaler Effekt um den Sensibilisierungsmonat Mai für Hautkrebs festzustellen. So zeigte die Analyse beispielsweise ein Suchinteresse im Mai und während der Sommermonate in Deutschland.

Schlussfolgerungen

Es ist wahrscheinlich, dass die Bevölkerung, zum Beispiel in Deutschland, weiterhin von einer noch stärkeren Betonung des Themas Hautkrebs profitieren könnte.
Diagnoseverzögerung bei Hidradenitis suppurativa untersucht mit Daten von sozialen Medien und gesetzlichen Krankenversicherungen
Authors: Kirschner Uwe , Kahn Maria , Papukchieva Steffeni , Stosio Karolina , Keis Andreas , Biermann Mona H. C. , Häusser‐Fruh Gisela , Sturm Lisa , Eberl Markus , Friedrich Benjamin , Kurzen Hjalmar
Published: June 2024

Hintergrund

Die chronisch‐entzündliche Hauterkrankung Hidradenitis suppurativa (HS) führt bei Betroffenen zu ausgeprägten Schmerzen und verminderter Lebensqualität. Trotzdem vergehen oft mehrere Jahre bis zur korrekten Diagnosestellung. In dieser Analyse sollten krankheitsbedingte Erfahrungen und Wege der Patienten mit HS untersucht und der ärztlichen Sicht gegenübergestellt werden.

Patienten und Methodik

Für die Studie wurden Ergebnisse einer Befragung von Dermatologen und deren Patienten zur Versorgungsrealität bei HS in Deutschland sowie öffentliche Beiträge auf Internet‐Foren und in sozialen Medien analysiert. Zusätzlich wurden Abrechnungsdaten deutscher Krankenkassen ausgewertet.

Ergebnisse

Patienten mit HS haben eine um 43,3% reduzierte Arbeitsfähigkeit. Die Dermatologie (26,5%) war der am häufigsten konsultierte Fachbereich, die Diagnose HS wurde dabei überwiegend im stationären Bereich (43,8%) gestellt. Als häufigste alternative Diagnose bei HS‐Patienten wurden Abszesse angegeben (53,2%). Die Analyse von Wechseln zu anderen Behandlern ergab, dass diese in der Dermatologie (34,1%) und der Chirurgie (42,4%) vorwiegend innerhalb des Fachbereiches erfolgen. Überweisungen erhielt die Dermatologie mehrheitlich aus dem hausärztlichen Bereich (67,1%) allerdings nur 12,1% von Chirurgen.

Schlussfolgerungen

Die Diagnoseverzögerung und die dadurch verlängerte Krankheitsbelastung von Patienten mit HS muss dringend reduziert werden. Dazu sollte, möglichst schon als Teil des Medizinstudiums, ein über die Dermatologie hinaus reichendes Bewusstsein für die Erkrankung, ihre Erkennung und Behandlung gefördert werden.
Decoding changes in tumor‐infiltrating leukocytes through dynamic experimental models and single‐cell technologies
Authors: Lee Colin YC , Clatworthy Menna R , Withers David R
Published: June 2024

The ability to characterize immune cells and explore the molecular interactions that govern their functions has never been greater, fueled in recent years by the revolutionary advance of single‐cell analysis platforms. However, precisely how immune cells respond to different stimuli and where differentiation processes and effector functions operate remain incompletely understood. Inferring cellular fate within single‐cell transcriptomic analyses is now omnipresent, despite the assumptions typically required in such analyses. Recently developed experimental models support dynamic analyses of the immune response, providing insights into the temporal changes that occur within cells and the tissues in which such transitions occur. Here we will review these approaches and discuss how these can be combined with single‐cell technologies to develop a deeper understanding of the immune responses that should support the development of better therapeutic options for patients.
Enhancing Surgical Robotics: A Dynamic Model and Optimized Control Strategy for Cable-Driven Continuum Robots
Authors: Ghoul A. , Djeffal S. , Wang H. , Kara K. , Hadjili M. L.
Published: June 2024

This paper tackles the challenges encountered in surgical continuum robotics by introducing a dynamic model tailored for a cable-driven continuum robot. The intricacies of dynamic modeling and control frequently lead to suboptimal outcomes. Prior studies have often lacked comprehensive descriptions of individual robot component movements, thereby impeding control processes, especially in the presence of external disturbances. Although machine learning-based models show promise across different domains, they face hurdles in continuum robotics due to the complexity of the systems involved. Traditional mathematical models, in contrast, offer explicit equations, providing better interpretability, unlike machine learning models that may struggle with generalization, especially in highly nonlinear systems like continuum robots. The developed model adeptly captures the kinematic and dynamic constraints of various robot segments, serving as the foundation for a robust optimized control strategy. This strategy, which integrates computed torque control and particle swarm optimization, enables real-time computation of joint torques based on feedback, ensuring precise and stable task execution even amidst external perturbations. Comparative analysis with an optimized proportional-integral-derivative controller unequivocally demonstrates the superiority of the optimized computed torque controller in settling time, overshoot, and robustness against disturbances. This advancement represents a noteworthy contribution to robotics, with the potential to significantly enhance continuum robot performance in surgical and inspection applications, thereby fostering innovative advancements across various fields.
Uncertainty components in profile likelihood fits
Authors: Pinto Andrés , Wu Zhibo , Balli Fabrice , Berger Nicolas , Boonekamp Maarten , Chapon Émilien , Kawamoto Tatsuo , Malaescu Bogdan
Published: June 2024

When a measurement of a physical quantity is reported, the total uncertainty is usually decomposed into statistical and systematic uncertainties. This decomposition is not only useful for understanding the contributions to the total uncertainty, but is also required to propagate these contributions in subsequent analyses, such as combinations or interpretation fits including results from other measurements or experiments. In profile likelihood fits, widely applied in high-energy physics analyses, contributions of systematic uncertainties are routinely quantified using “impacts,” which are not adequate for such applications. We discuss the difference between impacts and actual uncertainty components, and establish methods to determine the latter in a wide range of statistical models.
Self-similar collapse in Painlevé–Gullstrand coordinates
Authors: Chakrabarti Soumya , Singha Chiranjeeb
Published: June 2024

We report a family of self-similar exact solutions in General Relativity. The solutions are found in a Painleve-Gullstrand coordinate system but can also be transformed smoothly into a diagonal form. The solutions represent a gravitational collapse leading to three possible outcomes, depending on the parameter space: (i) a collapse followed by a bounce and dispersal of the clustered matter distribution, (ii) a rapid collapse followed by a bounce and an eventual re-collapse, and (iii) a standard collapse leading to zero proper volume. Profiles of the energy conditions are studied for all of the scenarios, and it is noted that a bounce is usually associated with a violation of the Null Energy Condition. It is found that more than one null surfaces (apparent horizons) can develop during the collapse. We also discuss that for a general metric tensor having a conformal symmetry, some regions of the parameter space allows a formation of null throat, much like a wormhole. Matching the metric with a Schwarzschild metric in Painleve–Gullstrand form leads to the geodesic equation for a zero energy falling particle in the exterior.
ARDST: An Adversarial‐Resilient Deep Symbolic Tree for Adversarial Learning
Authors: Zhuo Sheng Da , Wu Di , Hu Xin , Wang Yu
Published: June 2024

The advancement of intelligent systems, particularly in domains such as natural language processing and autonomous driving, has been primarily driven by deep neural networks (DNNs). However, these systems exhibit vulnerability to adversarial attacks that can be both subtle and imperceptible to humans, resulting in arbitrary and erroneous decisions. This susceptibility arises from the hierarchical layer‐by‐layer learning structure of DNNs, where small distortions can be exponentially amplified. While several defense methods have been proposed, they often necessitate prior knowledge of adversarial attacks to design specific defense strategies. This requirement is often unfeasible in real‐world attack scenarios. In this paper, we introduce a novel learning model, termed “immune” learning, known as adversarial‐resilient deep symbolic tree (ARDST), from a neurosymbolic perspective. The ARDST model is semiparametric and takes the form of a tree, with logic operators serving as nodes and learned parameters as weights of edges. This model provides a transparent reasoning path for decision‐making, offering fine granularity, and has the capacity to withstand various types of adversarial attacks, all while maintaining a significantly smaller parameter space compared to DNNs. Our extensive experiments, conducted on three benchmark datasets, reveal that ARDST exhibits a representation learning capability similar to DNNs in perceptual tasks and demonstrates resilience against state‐of‐the‐art adversarial attacks.
Anti‐Helicobacter pylori Effects of Thymus caramanicus Jalas Essential Oils: A New Antimicrobial Approach
Authors: Asadi Sepehr , Rahimi Ebrahim , Shakerian Amir
Published: June 2024

Background. Helicobacter pylori are the principal causative factor in the etiological factors of chronic, active, or type B gastritis; peptic and duodenal ulcers; stomach carcinoma; and epithelial tissue lymphoid malignancies. It infects more than half of the population worldwide. To reduce H. pylori production, pharmacological therapy of H. pylori diseases typically involves using threefold treatment methods. However, as a result of such therapy, antimicrobial resistance is commonly developed. Alternative therapeutics for H. pylori diseases are thus of particular interest. Methods. Thyme essential oils (EOs) obtained from T. caramanicus Jalas plants in Iran were tested for antibacterial activity against H. pylori obtained from 320 poultry specimens in this investigation. Antibacterial activity was measured using inhibition zones, minimum inhibitory concentrations (MICs), and minimum bactericidal concentrations (MBCs). The impact of T. caramanicus Jalas essential oils on H. pylori isolate cagA, vacA, and babA2 gene expression was evaluated using a quantitative real‐time PCR method (p < 0.05). Results. The chemical content of these EOs varied significantly according to chromatographic examination. Thymol, carvacrol, and terpinene‐4‐ol are the most abundant components in these EOs. H. pylori was recognized as a Helicobacter species with a 175‐bp PCR product of 16S rRNA in 20/20 (100%). According to PCR results, all 20 (100%) isolates belonged to H. pylori. The EOs inhibited H. pylori in a dose‐dependent manner, with T. caramanicus Jalas being the most effective, followed by pterygium EOs in decreasing order. At 8 mg/mL of T. caramanicus Jalas EOs, IZs against H. pylori were 27.4 ± 0.42 mm, and at 8 mg/mL of pterygium, IZs against H. pylori were 1 ± 0.02. T. caramanicus Jalas essential oils were used to treat all bacteria, and the findings showed that T. caramanicus Jalas had a substantial inhibitory impact on the expression of cagA, vacA, and babA2 virulence‐related genes (p < 0.05). Conclusions. In a dose‐dependent manner, the EOs of T. caramanicus Jalas EO demonstrated a high degree of antimicrobial property against H. pylori bacteria. The most efficient EOs were those from T. caramanicus Jalas with relative concentrations of thymol and carvacrol, followed by the coumarin‐dominated pterygium EO with reduced antibacterial activity.
Abstract A003: Unwinding the complexities of helicases as compelling drug targets in oncology
Authors: Mamane Yael , Caple Zoe , Chapman Katie , Henderson Ian , Jordan Allan , Lyne Vanessa , Okoye Cynthia , Rigoreau Laurent , Kadamur Ganesh , Thomson Stuart , Tomlinson Chris , Wolf Jana
Published: June 2024

In recent years, helicases have moved to the forefront of research as novel drug targets for a variety of human diseases, including cancer. As critical components of the cell cycle and DNA repair, these enzymes offer an attractive point of therapeutic intervention. Recent bioinformatic endeavours such as the Cancer DepMap have further highlighted the essentiality of these proteins in the progression of numerous cancers. Inhibitors of Werner helicase (WRN) entered Phase I evaluation in 2023, after studies highlighted its role in tumours with microsatellite instability (MSI) and impaired mismatch repair (MMR). Building on these advances, helicases now represent a significant drug target class and are the subject of intense research. However, these targets present significant complexities in their prosecution. Hit finding and robust validation of these putative active compounds remains challenging, with high attrition rates and significant sensitivity to false positives. Resultant hits require thorough biological characterisation via both biochemical and biophysical methods, alongside determination of selectivity against other closely related family members, to increase confidence in their provenance before commencing a detailed drug discovery project. To exemplify these approaches, we have profiled three commercially available WRN inhibitors from two chemical series through a selection of biochemical and biophysical assays. The three compounds exhibit excellent selectivity against 6 distinct helicase/translocase targets. In Michaelis-Menten mechanism of Inhibition studies, we defined contrasting mechanisms of inhibition for the two series and were also able to identify time dependent inhibition with one compound series. Analysing binding interactions of the compounds against protein and protein:substrate complexes, via a fluorescent thermal shift assay (FTSA) and microscale thermophoresis (MST), enabled us to further understand and interrogate the mechanism of inhibition. Herein, we describe some of our experiences, learnings and best practices when prosecuting these compelling, but challenging, targets.

Citation Format: Yael Mamane, Zoe Caple, Katie Chapman, Ian Henderson, Allan Jordan, Vanessa Lyne, Cynthia Okoye, Laurent Rigoreau, Ganesh Kadamur, Stuart Thomson, Chris Tomlinson, Jana Wolf. Unwinding the complexities of helicases as compelling drug targets in oncology [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr A003.
Abstract B001: Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal cancers
Authors: Arnoldus Tim , van Vliet Alex , de Groot Adriaan F.H. , Blomberg Niek , Bleijerveld Onno B. , van Hal-van Veen Susan E. , Grootemaat Anita E. , Harkes Rolf , van der Wel Nicole N. , Altelaar Maarten , Giera Martin , Peeper Daniel S.
Published: June 2024

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR009) of the Conference Program/Proceedings.

Citation Format: Tim Arnoldus, Alex van Vliet, Adriaan F.H. de Groot, Niek Blomberg, Onno B. Bleijerveld, Susan E. van Hal-van Veen, Anita E. Grootemaat, Rolf Harkes, Nicole N. van der Wel, Maarten Altelaar, Martin Giera, Daniel S. Peeper. Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B001.
Abstract B007: Unexpected synthetic lethality mechanisms in eIF4A-targeted therapy
Authors: Zhao Na , Kabotyanski Elena , Saltzman Alexander , Rosen Jeffrey
Published: June 2024

BACKGROUND Dysregulation of mRNA translation, which is prevalent in cancer, presents an underexplored therapeutic vulnerability. The eukaryotic translation initiation factor 4A (eIF4A) promotes protein synthesis by unwinding secondary structures in the 5’-untranslated region of mRNAs to facilitate translation initiation. While perturbation of eIF4A minimally affects the health normal cells, it is crucial for the translation of many oncogenes and is considered essential in most cancer cell lines. Zotatifin, a first-in-class eIF4A inhibitor, is currently under evaluation in a Phase I/II clinical trial for KRAS-mutant tumors and ER+ breast cancers. In addition to the tumor-intrinsic effect, our recent publication in the Journal of Clinical Investigation revealed that pharmacological targeting of eIF4A not only affects tumor cells but also improves the tumor immune microenvironment. This results in tumor inhibition, heightened sensitivity to immune checkpoint blockade, and remarkable synergism with platinum in various preclinical triple-negative breast cancer mouse models. OBJECTIVES To investigate the mechanism underlying the synergy between eIF4A-targeted therapy and platinum. UNPUBLISHED RESULT Mass spectrometry proteomic analysis coupled with ELISA and qPCR analysis unveiled that eIF4A-targeted therapy promotes type I interferon (IFN) secretion and induces a robust type I IFN response both in vivo and in vitro. This suggests a tumor cell-autonomous effect of IFN induction by eIF4A inhibition. Combining platinum with eIF4A-targeted therapy further heightens the type I IFN response in vivo, leading to T cell-and macrophage-dependent synergistic tumor regression. Interestingly, this synergy was not observed in vitro, indicating the involvement of the host immune system in the efficacy of combination therapy. It is possible that platinum may stimulate certain immune populations to secrete IFN, which acts on tumor cells to upregulate their IFN response. CONCLUSION Activation of the type I IFN response by eIF4A inhibition combined with platinum in vivo can lead to synthetic lethality of tumor cells. These studies not only offer novel insights into eIF4A biology but also provide valuable guidance for ongoing and future clinical trials.

Citation Format: Na Zhao, Elena Kabotyanski, Alexander Saltzman, Jeffrey Rosen. Unexpected synthetic lethality mechanisms in eIF4A-targeted therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B007.
Abstract B017: Loss of UXS1 selectively kills KEAP1 mutant cancer cell lines by depleting pyrimidines and inducing replication stress
Authors: Hoffman Timothy , Gebru Melat , Boudreau Aaron , Han Fei , Foster-Duke Kelly , Gajda Jessica , Vu Ngoc , Bennett Bryson , Kort Michael , Shotwell Brad , Hickson Jonathan , Wilsomn Noel , Stokoe David
Published: June 2024

Kelch-like ECH Associated-Protein 1 (KEAP1) is the third most mutated gene in non-small cell lung cancer and is associated with poor prognosis. KEAP1 targets nuclear factor erythroid 2-related factor 2 (Nrf2) for degradation, hence KEAP1-mutated tumors have elevated Nrf2 levels and constitutive expression of its transcriptional targets. To identify potential therapeutic targets for KEAP1 mutated tumors, we interrogated the cancer Dependency Map (DepMap) database and identified UDP Xylose Synthase 1 (UXS1) as a synthetic lethal interaction gene in KEAP1 mutated cancer cell lines. UXS1 is a critical protein for the glycosaminoglycan (GAG) synthesis on proteoglycans, converting UDP-glucuronic acid (UDPGA) to UDP-xylose. UDP glucose dehydrogenase (UGDH) is a transcriptional target of Nrf2 highly expressed in KEAP1-mutant tumors, which converts UDP-glucose to UDPGA. Upon UXS1 knock-down, depletion of UDP-xylose is seen in both KEAP1-mutant and wildtype cells, as expected, whereas rapid accumulation of UDPGA is only seen in the KEAP1-mutant setting. This metabolic roadblock causes a shortage of available UDP and other pyrimidines, resulting in slowed S-phase progression, stalled DNA replication fork marks, subsequent DNA damage, and significant loss in cell viability. Notably, dependency on UXS1 can be rescued by either knocking out UGDH to prevent UDPGA accumulation or by supplementation of cells with uridine or cytidine to restore the pyrimidine nucleotide pools by boosting pyrimidine salvage pathway. Finally, we show that DNA replication stress in UXS1-depleted cells renders them sensitive to clinical cell-cycle checkpoint inhibitors, opening a further window of therapeutically exploitable vulnerability.

Citation Format: Timothy Hoffman, Melat Gebru, Aaron Boudreau, Fei Han, Kelly Foster-Duke, Jessica Gajda, Ngoc Vu, Bryson Bennett, Michael Kort, Brad Shotwell, Jonathan Hickson, Noel Wilsomn, David Stokoe. Loss of UXS1 selectively kills KEAP1 mutant cancer cell lines by depleting pyrimidines and inducing replication stress [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B017.