bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and characterisation of band-shaped tail lesions in Holstein cows
Authors: Volhøj Tobias , Nielsen Cecilie Kirstine , Schjermer Ditte Marie , Jensen Natascha Schou , Jørgensen Benjamin Meyer , Nielsen Søren Saxmose , Jensen Henrik Elvang
Published: May 2024

The aim of the study was to characterise and determine the prevalence of band-shaped tail lesions in Holstein cows. Lesions were present either as wounds or by epithelised granulation/connective tissue formations. Both types were characterised by a median localisation 7 cm from the tip of the tail, and they occurred on the dorsal aspect of the tail. From here they encircled the tail either completely or in varying degrees, and they were often present as isolated lesions (93%). The prevalence of band-shaped tail lesions was found to be 25% among 2099 cows examined in 16 Danish Holstein herds with a variation from 18 to 40% between herds. In the herds, the wound lesions and the connective tissue formations accounted for 22% and 78% of all band-shaped tail lesions, respectively. Among 458 Holstein cows examined at an abattoir the prevalence of band-shaped tail lesions was 23%, i.e. similar to the prevalence within the herds. At the abattoir the share of band-shaped wound lesions was 67% and the band-shaped connective tissue formation 33%. Associations between the occurrence of band-shaped tail lesions and parity and lack of the tail tip were observed.
The infectivity of AAV9 is influenced by the specific location and extent of chemically modified capsid residues
Authors: Milagros Sergio , de Erenchun Pablo Ramírez-Ruiz , Guembe Maite , Carte Beatriz , Méndez Miriam , Uribarri Ander , Aldabe Rafael
Published: May 2024

Background

Several treatments for genetic diseases utilizing recombinant adeno-associated viruses (AAVs) have recently gained approval. However, the development of a greater number of therapeutic AAVs is constrained by certain limitations. While extensive efforts have concentrated on screening AAV genetic libraries, an alternative strategy involves modifying the AAV capsid by attaching various moieties. The capsid of AAV plays a pivotal role in transducing target cells and evading immune responses, making modifications a key avenue for engineering improved variants.

Results

In our study, we replaced specific AAV9 capsid residues with an unnatural amino acid bearing a bioorthogonal group, identifying four positions with no adverse impact on production. Utilizing click chemistry, we attached varying proportions of Cy5.5 to these positions, allowing us to assess the impact of these modifications on AAV9 infectivity in cultured cells. Our findings reveal that both the position and degree of capsid modification significantly affect AAV transduction. While higher amounts of attached molecules lead to an increased number of AAV genomes within cells, this does not positively impact transgene expression. Conversely, a negative impact on transgene expression is observed when the AAV capsid is highly modified, with the degree of this effect associated with the modified residue.

Conclusion

Careful control of both the degree and specific position of capsid modifications is crucial for optimizing transduction efficiency and minimizing undesired effects on transgene expression. These results underscore the importance of precision in AAV capsid modification to achieve optimal transduction efficiency while mitigating potential drawbacks on transgene expression.
PSMD9 promotes the malignant progression of hepatocellular carcinoma by interacting with c-Cbl to activate EGFR signaling and recycling
Authors: Su Yuting , Meng Lili , Ge Chao , Liu Yuqi , Zhang Chi , Yang Yue , Tian Wei , Tian Hua
Published: May 2024

Background

Mounting evidences shows that the ubiquitin‒proteasome pathway plays a pivotal role in tumor progression. The expression of 26S proteasome non-ATPase regulatory subunit 9 (PSMD9) is correlated with recurrence and radiotherapy resistance in several tumor types. However, the role and mechanism of PSMD9 in hepatocellular carcinoma (HCC) progression remain largely unclear.

Methods

PSMD9 was identified as a prognosis-related biomarker for HCC based on analysis of clinical characteristics and RNA-seq data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and the JP Project of the International Cancer Genome Consortium (ICGC-LIRI-JP). PSMD9 expression was analyzed in cancer tissues and adjacent noncancerous tissues via immunohistochemistry and Western blotting. Multiple in vivo and in vitro experimental techniques (such as CCK-8, colony formation, EdU, and Transwell assays; flow cytometry; Western blotting; quantitative RT-PCR; Coimmunoprecipitation assay and immunofluorescence confocal imaging) were used to assess the functions of PSMD9 in the pathogenesis of HCC.

Results

We found that the expression of PSMD9 was upregulated and associated with a poor prognosis in HCC patients. PSMD9 promoted HCC cell proliferation, migration, invasion and metastasis. Knockdown of PSMD9 significantly inhibited HCC cell proliferation by inducing G1/S cell cycle arrest and apoptosis. Mechanistically, we demonstrated that PSMD9 promoted HCC cell proliferation and metastasis via direct interaction with the E3 ubiquitin ligase c-Cbl, suppresses EGFR ubiquitination, influenced EGFR endosomal trafficking and degradation and subsequently activated ERK1/2 and Akt signaling. In addition, we showed that PSMD9 knockdown sensitized HCC cells to the tyrosine kinase inhibitor erlotinib in vitro and in vivo.

Conclusions

Collectively, our results indicate that PSMD9 drives HCC progression and erlotinib resistance by suppressing c-Cbl mediated EGFR ubiquitination and therefore can be a potential therapeutic target for HCC.
Proto-oncogene c-Myb potentiates cisplatin resistance of ovarian cancer cells by downregulating lncRNA NKILA and modulating cancer stemness and LIN28A-let7 axis
Authors: Zhang Xue-Yan , Zhu Bo-Chi , He Miao , Dong Shan-Shan
Published: May 2024

Ovarian cancer is a major gynecological cancer that has poor prognosis associated mainly to its late diagnosis. Cisplatin is an FDA approved ovarian cancer therapy and even though the therapy is initially promising, the patients mostly progress to resistance against cisplatin. The underlying mechanisms are complex and not very clearly understood. Using two different paired cell lines representing cisplatin-sensitive and the cisplatin-resistant ovarian cancer cells, the ES2 and the A2780 parental and cisplatin-resistant cells, we show an elevated proto-oncogene c-Myb in resistant cells. We further show down-regulated lncRNA NKILA in resistant cells with its de-repression in resistant cells when c-Myb is silenced. NKILA negatively correlates with cancer cell and invasion but has no effect on cellular proliferation or cell cycle. C-Myb activates NF-κB signaling which is inhibited by NKILA. The cisplatin resistant cells are also marked by upregulated stem cell markers, particularly LIN28A and OCT4, and downregulated LIN28A-targeted let-7 family miRNAs. Whereas LIN28A and downregulated let-7s individually de-repress c-Myb-mediated cisplatin resistance, the ectopic expression of let-7s attenuates LIN28A effects, thus underlying a c-Myb-NKILA-LIN28A-let-7 axis in cisplatin resistance of ovarian cancer cells that needs to be further explored for therapeutic intervention.
Causes and attributable fraction of death from ARDS in inflammatory phenotypes of sepsis
Authors: Evrard Bruno , Sinha Pratik , Delucchi Kevin , Hendrickson Carolyn M. , Kangelaris Kirsten N. , Liu Kathleen D. , Willmore Andrew , Wu Nelson , Neyton Lucile , Schmiege Emma , Gomez Antonio , Kerchberger V. Eric , Zalucky Ann , Matthay Michael A. , Ware Lorraine B. , Calfee Carolyn S.
Published: May 2024

Background

Hypoinflammatory and hyperinflammatory phenotypes have been identified in both Acute Respiratory Distress Syndrome (ARDS) and sepsis. Attributable mortality of ARDS in each phenotype of sepsis is yet to be determined. We aimed to estimate the population attributable fraction of death from ARDS (PAFARDS) in hypoinflammatory and hyperinflammatory sepsis, and to determine the primary cause of death within each phenotype.

Methods

We studied 1737 patients with sepsis from two prospective cohorts. Patients were previously assigned to the hyperinflammatory or hypoinflammatory phenotype using latent class analysis. The PAFARDS in patients with sepsis was estimated separately in the hypo and hyperinflammatory phenotypes. Organ dysfunction, severe comorbidities, and withdrawal of life support were abstracted from the medical record in a subset of patients from the EARLI cohort who died (n = 130/179). Primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support.

Results

The PAFARDS was 19% (95%CI 10,28%) in hypoinflammatory sepsis and, 14% (95%CI 6,20%) in hyperinflammatory sepsis. Cause of death differed between the two phenotypes (p < 0.001). Respiratory failure was the most common cause of death in hypoinflammatory sepsis, whereas circulatory shock was the most common cause in hyperinflammatory sepsis. Death with severe underlying comorbidities was more frequent in hypoinflammatory sepsis (81% vs. 67%, p = 0.004).

Conclusions

The PAFARDS is modest in both phenotypes whereas primary cause of death among patients with sepsis differed substantially by phenotype. This study identifies challenges in powering future clinical trials to detect changes in mortality outcomes among patients with sepsis and ARDS.
Enhancing pathological complete response prediction in breast cancer: the role of dynamic characterization of DCE-MRI and its association with tumor heterogeneity
Authors: Zhang Xinyu , Teng Xinzhi , Zhang Jiang , Lai Qingpei , Cai Jing
Published: May 2024

Background

Early prediction of pathological complete response (pCR) is important for deciding appropriate treatment strategies for patients. In this study, we aimed to quantify the dynamic characteristics of dynamic contrast-enhanced magnetic resonance images (DCE-MRI) and investigate its value to improve pCR prediction as well as its association with tumor heterogeneity in breast cancer patients.

Methods

The DCE-MRI, clinicopathologic record, and full transcriptomic data of 785 breast cancer patients receiving neoadjuvant chemotherapy were retrospectively included from a public dataset. Dynamic features of DCE-MRI were computed from extracted phase-varying radiomic feature series using 22 CAnonical Time-sereis CHaracteristics. Dynamic model and radiomic model were developed by logistic regression using dynamic features and traditional radiomic features respectively. Various combined models with clinical factors were also developed to find the optimal combination and the significance of each components was evaluated. All the models were evaluated in independent test set in terms of area under receiver operating characteristic curve (AUC). To explore the potential underlying biological mechanisms, radiogenomic analysis was implemented on patient subgroups stratified by dynamic model to identify differentially expressed genes (DEGs) and enriched pathways.

Results

A 10-feature dynamic model and a 4-feature radiomic model were developed (AUC = 0.688, 95%CI: 0.635–0.741 and AUC = 0.650, 95%CI: 0.595–0.705) and tested (AUC = 0.686, 95%CI: 0.594–0.778 and AUC = 0.626, 95%CI: 0.529–0.722), with the dynamic model showing slightly higher AUC (train p = 0.181, test p = 0.222). The combined model of clinical, radiomic, and dynamic achieved the highest AUC in pCR prediction (train: 0.769, 95%CI: 0.722–0.816 and test: 0.762, 95%CI: 0.679–0.845). Compared with clinical-radiomic combined model (train AUC = 0.716, 95%CI: 0.665–0.767 and test AUC = 0.695, 95%CI: 0.656–0.714), adding the dynamic component brought significant improvement in model performance (train p < 0.001 and test p = 0.005). Radiogenomic analysis identified 297 DEGs, including CXCL9, CCL18, and HLA-DPB1 which are known to be associated with breast cancer prognosis or angiogenesis. Gene set enrichment analysis further revealed enrichment of gene ontology terms and pathways related to immune system.

Conclusion

Dynamic characteristics of DCE-MRI were quantified and used to develop dynamic model for improving pCR prediction in breast cancer patients. The dynamic model was associated with tumor heterogeniety in prognostic-related gene expression and immune-related pathways.
The left atrial appendage closure by surgery 2 trial: statistical analysis plan for a randomized multicenter trial exploring if the closure of the left atrial appendage during open-heart surgery reduces stroke irrespective of patients’ stroke risk and preoperative atrial fibrillation status
Authors: Madsen Christoffer L. , Park-Hansen Jesper , Hadad Rakin , Greve Anders M. , Domínguez Helena
Published: May 2024

Background

Surgical left atrial appendage (LAA) closure concomitant to open-heart surgery prevents thromboembolism in high-risk patients. Nevertheless, high-level evidence does not exist for LAA closure performed in patients with any CHA2DS2-VASc score and preoperative atrial fibrillation or flutter (AF) status—the current trial attempts to provide such evidence.

Methods

The study is designed as a randomized, open-label, blinded outcome assessor, multicenter trial of adult patients undergoing first-time elective open-heart surgery. Patients with and without AF and any CHA2DS2-VASc score will be enrolled. The primary exclusion criteria are planned LAA closure, planned AF ablation, or ongoing endocarditis. Before randomization, a three-step stratification process will sort patients by site, surgery type, and preoperative or expected oral anticoagulation treatment. Patients will undergo balanced randomization (1:1) to LAA closure on top of the planned cardiac surgery or standard care. Block sizes vary from 8 to 16. Neurologists blinded to randomization will adjudicate the primary outcome of stroke, including transient ischemic attack (TIA). The secondary outcomes include a composite outcome of stroke, including TIA, and silent cerebral infarcts, an outcome of ischemic stroke, including TIA, and a composite outcome of stroke and all-cause mortality. LAA closure is expected to provide a 60% relative risk reduction. In total, 1500 patients will be randomized and followed for 2 years.

Discussion

The trial is expected to help form future guidelines within surgical LAA closure. This statistical analysis plan ensures transparency of analyses and limits potential reporting biases.

Trial registration

Clinicaltrials.gov, NCT03724318. Registered 26 October 2018, https://clinicaltrials.gov/study/NCT03724318.

Protocol version

https://doi.org/10.1016/j.ahj.2023.06.003.
Evaluation of lived experience Peer Support intervention for mental health service consumers in Primary Care (PS-PC): study protocol for a stepped-wedge cluster randomised controlled trial
Authors: Lawn Sharon , Shelby-James Tania , Manger Sam , Byrne Louise , Fuss Belinda , Isaac Vivian , Kaambwa Billingsley , Ullah Shahid , Rattray Megan , Gye Bill , Kaine Christine , Phegan Caroline , Harris Geoff , Worley Paul
Published: May 2024

Background

The demand for mental health services in Australia is substantial and has grown beyond the capacity of the current workforce. As a result, it is currently difficult for many to access secondary healthcare providers. Within the secondary healthcare sector, however, peer workers who have lived experience of managing mental health conditions have been increasingly employed to intentionally use their journey of recovery in supporting others living with mental health conditions and their communities. Currently, the presence of peer workers in primary care has been limited, despite the potential benefits of providing supports in conjunction with GPs and secondary healthcare providers.

Methods

This stepped-wedge cluster randomised controlled trial (RCT) aims to evaluate a lived experience peer support intervention for accessing mental health care in primary care (PS-PC). Four medical practices across Australia will be randomly allocated to switch from control to intervention, until all practices are delivering the PS-PC intervention. The study will enrol 66 patients at each practice (total sample size of 264). Over a period of 3–4 months, 12 h of practical and emotional support provided by lived experience peer workers will be available to participants. Scale-based questionnaires will inform intervention efficacy in terms of mental health outcomes (e.g., self-efficacy) and other health outcomes (e.g., healthcare-related costs) over four time points. Other perspectives will be explored through scales completed by approximately 150 family members or carers (carer burden) and 16 peer workers (self-efficacy) pre- and post-intervention, and 20 medical practice staff members (attitudes toward peer workers) at the end of each study site’s involvement in the intervention. Interviews (n = 60) and six focus groups held toward the end of each study site’s involvement will further explore the views of participants, family members or carers, peer workers, and practice staff to better understand the efficacy and acceptability of the intervention.

Discussion

This mixed-methods, multi-centre, stepped-wedge controlled study will be the first to evaluate the implementation of peer workers in the primary care mental health care sector.

Trial registration

Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12623001189617. Registered on 17 November 2023,https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386715
A novel dance intervention program for children and adolescents with developmental disabilities: a pilot randomized control trial
Authors: Anderson Jeffrey T. , Toolan Christina , Coker Emily , Singer Hannah , Pham Derek , Jackson Nicholas , Lord Catherine , Wilson Rujuta B.
Published: May 2024

Background

Organized physical activity programs have been shown to provide wide benefits to participants, though there are relatively few studies examining the impact of these programs for individuals with developmental disabilities. This pilot study was conducted to determine the feasibility and impact of an undergraduate-led dance intervention program for children and adolescents with developmental disabilities. We evaluated the impact of the dance program on motor ability and social skills.

Methods

The study design was a waitlist control clinical trial in which participants were randomized to active and control groups. Eligible participants included male and female children and adolescents between the ages of 4 and 17 years with neurodevelopmental disabilities. The Motor Assessment Battery for Children Checklist and the Social Responsiveness Scale were used to assess change in motor and social skills, respectively. After gathering baseline data, the active group completed 1 h of online dance classes per week for 10 weeks, while the control group entered a 10-week waiting period. All participants then returned for a follow-up visit. Pre- and post-intervention data were analyzed using linear mixed-effects modeling adjusting for age and class attendance with subject random intercept.

Results

We recruited and randomized 43 participants with neurodevelopmental disabilities (mean age = 8.63, SD = 2.98), of which 30 participated in dance classes. The attendance rate was 82.6% for the active group and 61.7% for the control group. The active group demonstrated a significant improvement in motor skills in an unpredictable environment, as indicated on the Motor Assessment Battery for Children Checklist (n = 21, p = 0.05). We also observed positive trends in social skills that did not reach significance.

Conclusions

Our results indicate that it is feasible to develop and implement a fully digital dance intervention program for individuals with developmental disabilities. Further, we find that change in motor skills can be detected after just 10 h of low-intensity participation. However, a lack of significant change in social skills coupled with limitations in study implementation suggests further research is needed to determine the full impact of this dance program.

Trial Registration

ClinicalTrials.gov Protocol Registration System: Protocol ID 20-001680-AM-00005, registered 17/2/2021 – Retrospectively Registered, https://clinicaltrials.gov/study/NCT04762290.
Cancer awareness and its related factors among junior high and high school teachers in Japan: a cross-sectional survey
Authors: Suzuki Kumi , Hayashi Naoko , Yamanaka Masako , Minamiguchi Yoko , Yamauchi Eiko , Fukawa Akiko , Tsuda Yasuhiro , Fujisaka Yasuhito , Doi Tomoki , Tomari Yuko
Published: May 2024

Background

The early detection and prevention of many cancers is possible. Therefore, public awareness about cancer risk factors and warning signs must be increased to ensure early diagnosis. Although Japan has implemented mandatory cancer education in junior high and high schools, few studies have evaluated teachers’ cancer awareness. This study aimed to determine Japanese junior high and high school teachers’ awareness of cancer and related factors.

Methods

This cross-sectional study obtained data through an online questionnaire survey using questions from the Cancer Awareness Measure (CAM) developed by Cancer Research UK. Thirty items were selected from three CAM modules: cancer risk factors, cancer warning signs, and barriers to seeking help. Descriptive statistics were used for socio-demografic data and CAM module questions. The χ2 test was performed on the relationship between cancer awareness and socio-demographic data. Multiple logistic regression analysis was used to identify factors influencing cancer awareness.

Results

Respondents included 316 junior high school and 463 high school teachers (541 men; 238 women; average age = 48.2 years; average teaching experience = 23.5 years). An average of 5.41 out of 11 cancer risk factors were recognized. More than 70% of teachers recognized smoking, exposure to another person’s cigarette smoke, and having a close relative with cancer as risk factors. On average, 4.52 out of 9 cancer warning signs were recognized. More than 50% of teachers recognized the warning signs of unexplained lump or swelling, unexplained weight loss, and unexplained bleeding. Barriers to seeking help had a low average score of 4.51 out of 20. However, the most commonly recognized “barriers to seeking help” were “too busy to make time,” “difficult to make an appointment,” “worried about what the doctor might find,” and “too scared.” Moreover, the common factors that affected awareness of cancer risk factors and cancer warning signs were gender and cancer experience of relatives. Factors that affected awareness of “barriers to seeking help” were “participation in cancer-related workshops,” age, gender, and cancer experience of relatives.

Conclusions

Cancer awareness education should consider interventions that can improve knowledge of the symptoms and signs related to cancer without increasing the awareness of barriers to seeking help.
Assessment of spongy moth infestation impacts on forest productivity and carbon loss using the Sentinel-2 satellite remote sensing and eddy covariance flux data
Authors: Hussain Nur , Gonsamo Alemu , Wang Shusen , Arain M. Altaf
Published: May 2024

Background

Deciduous forests in eastern North America experienced a widespread and intense spongy moth (Lymantria dispar) infestation in 2021. This study quantified the impact of this spongy moth infestation on carbon (C) cycle in forests across the Great Lakes region in Canada, utilizing high-resolution (10 × 10 m2) Sentinel-2 satellite remote sensing images and eddy covariance (EC) flux data. Study results showed a significant reduction in leaf area index (LAI) and gross primary productivity (GPP) values in deciduous and mixed forests in the region in 2021.

Results

Remote sensing derived, growing season mean LAI values of deciduous (mixed) forests were 3.66 (3.18), 2.74 (2.64), and 3.53 (2.94) m2 m−2in 2020, 2021 and 2022, respectively, indicating about 24 (14)% reduction in LAI, as compared to pre- and post-infestation years. Similarly, growing season GPP values in deciduous (mixed) forests were 1338 (1208), 868 (932), and 1367 (1175) g C m−2, respectively in 2020, 2021 and 2022, showing about 35 (22)% reduction in GPP in 2021 as compared to pre- and post-infestation years. This infestation induced reduction in GPP of deciduous and mixed forests, when upscaled to whole study area (178,000 km2), resulted in 21.1 (21.4) Mt of C loss as compared to 2020 (2022), respectively. It shows the large scale of C losses caused by this infestation in Canadian Great Lakes region.

Conclusions

The methods developed in this study offer valuable tools to assess and quantify natural disturbance impacts on the regional C balance of forest ecosystems by integrating field observations, high-resolution remote sensing data and models. Study results will also help in developing sustainable forest management practices to achieve net-zero C emission goals through nature-based climate change solutions.
Uncovering the social impact of digital steganalysis tools applied to cybercrime investigations: a European Union perspective
Authors: Nicolás-Sánchez Alejandro , Castro-Toledo Francisco J.
Published: May 2024

Background

European Union (EU) research on cybersecurity is actively developing more efficient digital steganalysis techniques aimed at uncovering hidden online illegal content in apparently legitimate multimedia files. Beyond issues such as the design, effectiveness and functionality of the technology, this paper addresses the recently raised concern of societal impact, which refers to the influence, consequences, or effects, whether expected or not, that a particular action, policy, or technological advance has on society as a whole or on different segments of society. These impacts can be broad and multifaceted, encompassing economic, social, cultural, environmental and ethical dimensions, amongst others.

Aim

The aim of this article is to take an exploratory look at the societal challenges and benefits associated with the use of digital steganalysis tools in cybercrime investigations in EU member states, adopting a dual mixed-methods perspective.

Methods

First, a systematic review of the scientific literature published within 2017–2023, focusing on the societal dimension of steganalysis tools, including peer reviewed journal and conference papers on steganalysis and crime (N = 55) was carried out. For the second part of the paper, two nominal group discussions were conducted with experts from Law Enforcement Agencies (LEAs): the first on societal benefits (N = 7), the second on societal challenges (N = 6). These consensus-building discussions aimed to identify, quantitatively assess and rank the various challenges and potential social benefits associated with the use of digital steganalysis tools in police investigations.

Results

Findings reveal a widespread oversight in addressing the social impact dimension by tool designers on academic papers, especially regarding societal acceptance issues. The expert-citizens argued for stakeholders and public awareness of both risks and benefits of steganalysis tools.

Conclusions

This study highlights the current need to consider not only the technological aspects, but also the profound social dimension arising from the use of these tools, such as public awareness of cybercrime and the ethical design and use of digital crime investigation tools. Understanding and evaluating societal impacts is essential for making informed decisions, shaping policies, and addressing the needs and concerns of diverse stakeholders in various domains. This multidisciplinary approach is crucial to achieving a more balanced and comprehensive understanding of the impact of digital steganalysis tools in the field of digital criminal investigation.
Cognitive training via mobile app for addressing eating disorders’ cognitions in adolescents: a randomized control trial protocol
Authors: Corberán Marta , Arnáez Sandra , Saman Yuliya , Pascual-Vera Belén , García-Soriano Gemma , Roncero María
Published: May 2024

During adolescence, individuals are particularly vulnerable to developing eating disorders (EDs). To address the dysfunctional beliefs linked to these disorders, a new mobile app has been developed. This app, called GG eating disorders-Adolescents (GGED-AD), was created based on CBT to help adolescents work on their self-dialogue related to the core beliefs of eating disorders. The objective is to present the protocol for a randomized controlled trial to explore the efficacy of GGED-AD.

Methods The study will be carried out in adolescents aged 13 to 16 from an educational center in the Valencian Community. The participants will be randomized into two groups: the experimental group will use the GGED-AD app during 14 consecutive days for approximately 5 min each day; and the control group will use a neutral app (GGNEUTRAL) during the same time. Both groups will complete instruments that assess dysfunctional beliefs related to eating disorders, eating symptoms, symptoms of depression and anxiety, body satisfaction and self-esteem before and after the intervention. A follow-up will be conducted one month later.

Results A decrease in the degree of ascription to dysfunctional beliefs associated with eating disorders and eating symptomatology is expected, as well as an increase in body satisfaction and the self-esteem of the participants of the experimental group.

Discussion The app in this study could help tackle and prevent ED-related symptoms in adolescents.

Trial registration NCT06039514.
Effects of local reduction of endogenous α-synuclein using antisense oligonucleotides on the fibril-induced propagation of pathology through the neural network in wild-type mice
Authors: Sano Tatsuhiko , Nagata Tetsuya , Ebihara Satoe , Yoshida-Tanaka Kie , Nakamura Ayako , Sasaki Asuka , Shimozawa Aki , Mochizuki Hideki , Uchihara Toshiki , Hasegawa Masato , Yokota Takanori
Published: May 2024

In Parkinson's disease and other synucleinopathies, fibrillar forms of α-synuclein (aSyn) are hypothesized to structurally convert and pathologize endogenous aSyn, which then propagates through the neural connections, forming Lewy pathologies and ultimately causing neurodegeneration. Inoculation of mouse-derived aSyn preformed fibrils (PFFs) into the unilateral striatum of wild-type mice causes widespread aSyn pathologies in the brain through the neural network. Here, we used the local injection of antisense oligonucleotides (ASOs) against Snca mRNA to confine the area of endogenous aSyn protein reduction and not to affect the PFFs properties in this model. We then varied the timing and location of ASOs injection to examine their impact on the initiation and propagation of aSyn pathologies in the whole brain and the therapeutic effect using abnormally-phosphorylated aSyn (pSyn) as an indicator. By injecting ASOs before or 0–14 days after the PFFs were inoculated into the same site in the left striatum, the reduction in endogenous aSyn in the striatum leads to the prevention and inhibition of the regional spread of pSyn pathologies to the whole brain including the contralateral right hemisphere. ASO post-injection inhibited extension from neuritic pathologies to somatic ones. Moreover, injection of ASOs into the right striatum prevented the remote regional spread of pSyn pathologies from the left striatum where PFFs were inoculated and no ASO treatment was conducted. This indicated that the reduction in endogenous aSyn protein levels at the propagation destination site can attenuate pSyn pathologies, even if those at the propagation initiation site are not inhibited, which is consistent with the original concept of prion-like propagation that endogenous aSyn is indispensable for this regional spread. Our results demonstrate the importance of recruiting endogenous aSyn in this neural network propagation model and indicate a possible potential for ASO treatment in synucleinopathies.
Social spaces: from Georg Simmel to Erving Goffman
Authors: Liu Sida
Published: May 2024

Focusing on the concept of social space in the writings of three sociologists, Georg Simmel, Robert E. Park, and Erving Goffman, this article examines the classic theoretical formulations of social spaces in the tradition of the Chicago School of Sociology. For Simmel and the Chicago School, the foundation of social spaces lies in the social interactions among actors, and social entities and structures emerge from these interaction processes. This theoretical tradition emphasizes the interdependence of physical space and social space, highlighting two featured assumptions about social space: endogeneity and temporality. It also focuses on the relationship between spaces and human emotions.
Can on-line gait training improve clinical practice? Study protocol for feasibility randomised controlled trial of an on-line educational intervention to improve clinician’s gait-related decision-making in ambulant children and young people with cerebral palsy
Authors: Hebda-Boon Anna , Shortland Adam P. , Birn-Jeffery Aleksandra , Morrissey Dylan
Published: May 2024

Background

Instrumented gait analysis (IGA) is an assessment and research tool with proven impacts on clinical decision-making for the management of ambulant children and young people with cerebral palsy (CYPwCP) but is underused and variably understood by relevant clinicians. Clinicians’ difficulties in gaining expertise and confidence in using IGA are multifactorial and related to access for clinical decision-making, limited training opportunities and inability to translate this training into clinical practice.

Methods

The primary aim of this study is to test the feasibility of an educational intervention to advance clinicians’ application of gait analysis in CYPwCP, to inform a definitive trial. The secondary aim is to measure the effect that appropriate IGA training has on physiotherapists’ knowledge, skills, confidence and behaviours. This will be a two-arm feasibility randomised controlled trial with an experimental and control group. The 6-week on-line intervention uses a multicomponent approach grounded in behavioural change techniques. A repeated measures design will be adopted, whereby participants will complete outcome measures at baseline, immediately after the intervention and at 4 months. The primary outcome measures (trial feasibility-related outcomes) are recruitment and engagement. The secondary outcome measures (trial research-related outcomes) are knowledge, skills, confidence and practice change. Outcome measures will be collected via online questionnaires and during observed skill assessments. Analysis of data will use descriptive statistics, two-way mixed ANOVA model and qualitative content analysis.

Discussion

This study will determine feasibility of the definitive randomised control trial of educational intervention delivered to advance clinicians’ application of gait analysis in CYPwCP. This study offers the shift in emphasis from regarding IGA as a tool to a focus on clinicians’ requirements for access, training and a well-defined role to optimise utilisation of IGA. The impact of this should be better engagement with IGA and clinical practice change. This study will contribute to a body of educational research into clinical education of healthcare professionals and IGA training offering insight into high levels of evaluation evidence including clinical behaviour change.

Trial registration

Protocol has been registered with the Open Science Framework (osf.io/nweq6) in June 2023.
Insights into the structural and functional analysis of impact of the missense mutations on α-synuclein: an in silico study
Authors: Sharma Abhishek , Mahur Pragati , Singh Amit Kumar , Muthukumaran Jayaraman , Jain Monika
Published: May 2024

Background

Alpha synuclein (α-synuclein) is coded by SNCA gene and found in a helical form with phospholipids or in an unfolded arrangement in the cytosol and belongs to the synuclein family other than beta synuclein and gamma synuclein. It is a short protein made of 140 amino acids with three domains: an N-terminal lipid binding helix, a non-amyloid-ß component (NAC), and an acidic tail at the C-terminus. α-Synuclein is present in aggregated and fibrillar form in Lewy bodies and its association has been related to multiple system atrophy (MSA), Parkinson’s disease (PD), and Dementia with Lewy bodies (DLB). Our objective is to investigate and prioritise the possible nsSNPs in the α-synuclein protein that have been potentially connected to human neurodegenerative diseases.

Results

We used the series of computational tools to predict the mutation's harmful effect on three-dimensional structure of α-synuclein based on consensus approach. Our findings pointed to a significant computational blueprint for discovering nsSNPs connected to neurodegenerative illnesses from a large SNP data set while also minimising the expenses of experimentally showing harmful nsSNPs.

Conclusions

The prioritised G25S (rs1433622151), V66E (rs1261243630), and V77D (rs745815563) mutations can be employed in additional experimental studies to assess the α-synuclein protein mutation in relation to neurodegenerative illnesses and develop a therapeutics against them.

Graphical Abstract
Effectiveness of lime kiln dust on swelling of subgrade expansive soil
Authors: Eid Mennat-allah , Gomaa Youssef , Galal Sameh
Published: May 2024

Background

The structure of flexible or rigid pavement built on expansive subgrade soil that has a volumetric change is vulnerable to many problems that might cause failure. Pavement and construction became more durable and economical by enhancing the quality of subgrade expansive soil. Solid waste recycling has become very popular recently as a means of attaining sustainable waste management, so using lime kiln dust (LKD), which is a by-product of quick lime production, to treat expansive soil in pavement subgrades. This research describes the effect of LKD on the chemical composition, strength, and swelling of high and low-plastic clay that were extracted from two sites. The minimum LKD required for treating expansive soils was determined by using the Eades and Grim pH test. From tests, it was found that the addition of LKD increased the shrinkage limit by a range (250–500)% and decreased the plasticity and swelling potential by between (50 and 100)% of expansive subgrade soils. The strength according to CBR, increased approximately by 150% for CL soil and 800% for CH soil.

Results

The optimal percentage of LKD for CH soil is 6%, and for CL soil, it is 2%. The plastic limit increased by 50% for CH soil at 6% LKD. On the other hand, CL soil became non-plastic at 4% LKD. With an increase in the percentage of LKD, it led an the increase in the shrinkage limit by 500% in CH soil and 250% in CL soil. The free swell decreased by 50% in CH soil and 100% in CL soil. The swelling pressure decreased by 50% for two expansive soils. CBR increased by 800% in CH soil and by 150% in CL soil.

Conclusion

This work found that the addition of LKD improves the physical, chemical, and mechanical properties of expansive subgrade soil.
Interplay between endocannabinoids and dopamine in the basal ganglia: implications for pain in Parkinson’s disease
Authors: Mancini Maria , Calculli Alessandra , Di Martino Deborah , Pisani Antonio
Published: May 2024

Pain is a complex phenomenon, and basal ganglia circuitry integrates many aspects of pain including motor, emotional, autonomic, and cognitive responses. Perturbations in dopamine (DA) signaling are implicated in the pathogenesis of chronic pain due to its involvement in both pain perception and relief. Several lines of evidence support the role of endocannabinoids (eCBs) in the regulation of many electrical and chemical aspects of DAergic neuron function including excitability, synaptic transmission, integration, and plasticity. However, eCBs play an even more intricate and intimate relationship with DA, as indicated by the adaptive changes in the eCB system following DA depletion. Although the precise mechanisms underlying DA control on pain are not fully understood, given the high correlation of eCB and DAergic system, it is conceivable that eCBs may be part of these mechanisms.

In this brief survey, we describe the reciprocal regulation of eCB-DA neurotransmission with a particular emphasis on the actions of eCBs on ionic and synaptic signaling in DAergic neurons mediated by CB receptors or independent on them. Furthermore, we analyze the eCB-DA imbalance which characterizes pain condition and report the implications of reduced DA levels for pain in Parkinson’s disease. Lastly, we discuss the potential of the eCB-DA system in the development of future therapeutic strategies for the treatment of pain.
Evolution of the Innovative Therapies for Children With Cancer Consortium Trial Portfolio for Drug Development for Children With Cancer
Authors: Bautista Francisco , Verdú-Amorós Jaime , Geoerger Birgit , Rubio-San-Simón Alba , Paoletti Xavier , Zwaan C. Michel , Casanova Michela , Marshall Lynley V. , Carceller Fernando , Doz Francois , Lecinse Carole , Vassal Gilles , Pearson Andrew D.J. , Kearns Pamela , Moreno Lucas ,   on behalf of the Innovative Therapies For Children With Cancer Consortium
Published: May 2024

PURPOSE

The aim of the Innovative Therapies for Children with Cancer (ITCC) consortium is to improve access to novel therapies for children and adolescents with cancer. The evolution of the ITCC clinical trial portfolio since 2003 was reviewed.

METHODS

All ITCC-labeled phase I/II trials opened between January 1, 2003 and February 3, 2018 were analyzed in two periods (2003-2010 and 2011-2018), and data were extracted from the ITCC database, regulatory agencies' registries, and publications.

RESULTS

Sixty-one trials (62% industry-sponsored) enrolled 3,198 patients. The number of trials in the second period increased by almost 300% (16 v 45). All biomarker-driven trials (n = 14) were conducted in the second period. The use of rolling six and model-based designs increased (1 of 9, 11% v 21 of 31, 68%), and that of 3 + 3 designs decreased (5 of 9, 55% v 5 of 31, 16%; P = .014). The proportion of studies evaluating chemotherapeutics only decreased (5 of 16, 31% v 4 of 45, 9%), the proportion of single-agent targeted therapies did not change (9 of 16, 56.2% v 24 of 45, 53.3%), the proportion of combination targeted therapies trials increased (2 of 16, 12%, v 17 of 45, 38%), the proportion of randomized phase II trials increased (1 of 7, 14% v 8 of 14, 57%). More trials were part of a pediatric investigation plan in the second period (4 of 16, 25% v 21 of 45, 46%). The median time for Ethics Committees' approvals was 1.7 times longer for academic compared with industry-sponsored trials.

CONCLUSION

This study reports a shift in the paradigm of early drug development for childhood cancers, with more biologically relevant targets evaluated in biomarker-driven trials or in combination with other therapies and with more model-based or randomized designs and a greater focus on fulfilling regulatory requirements. Improvement of trial setup and recruitment could increase the number of patients benefiting from novel agents.
Sleep Quality Moderates the Associations between Cardiorespiratory Fitness and Hippocampal and Entorhinal Volume in Middle-Aged and Older Adults
Authors: CALLOW DANIEL D. , SPIRA ADAM P. , BAKKER ARNOLD , SMITH J. CARSON
Published: May 2024

Introduction/Purpose

As individuals age, the entorhinal cortex (ERC) and hippocampus—crucial structures for memory—tend to atrophy, with related cognitive decline. Simultaneously, lifestyle factors that can be modified, such as exercise and sleep, have been separately linked to slowing of brain atrophy and functional decline. However, the synergistic impact of fitness and sleep on susceptible brain structures in aging adults remains uncertain.

Methods

We examined both independent and interactive associations of fitness and subjective sleep quality with regard to ERC thickness and hippocampal volume in 598 middle-aged and older adults from the Human Connectome Lifespan Aging Project. Cardiorespiratory fitness was assessed using the 2-min walk test, whereas subjective sleep quality was measured with the continuous Pittsburgh Sleep Quality Index global score. High-resolution structural magnetic resonance imaging was used to examine mean ERC thickness and bilateral hippocampal volume. Through multiple linear regression analyses, we investigated the moderating effects of subjective sleep quality on the association between fitness and brain structure, accounting for age, sex, education, body mass index, gait speed, and subjective physical activity.

Results

We found that greater cardiorespiratory fitness, but not subjective sleep quality, was positively associated with bilateral hippocampal volume and ERC thickness. Notably, significant interaction effects suggest that poor subjective sleep quality was associated with a weaker association between fitness and both hippocampal volume and ERC thickness.

Conclusions

Findings suggest the potential importance of both cardiorespiratory fitness and subjective sleep quality in preserving critical, age-vulnerable brain structures. Interventions targeting brain health should consider potential combined effects of sleep and fitness on brain health.
Η επίδραση της μισθολογικής ανισότητα των φύλων στην οικονομική μεγέθυνση
Authors: Γκρίνγουδ Ελένη
Published: May 2024

Η παρούσα διδακτορική διατριβή εξετάζει βιβλιογραφικά και εμπειρικά την επίδραση της μισθολογικής ανισότητας μεταξύ των φύλων στην οικονομική μεγέθυνση στην Ευρώπη. Στην ανάλυση παλινδρόμησης το δείγμα αποτελείται από 31 ευρωπαϊκές χώρες, 28 κράτη-μέλη της ΕΕ και τρία κράτη-μέλη της EFTA, καλύπτοντας μια περίοδο 30 ετών, από το 1991 ως το 2020. Η μισθολογική ανισότητα μεταξύ των φύλων αντιπροσωπεύεται από το μισθολογικό χάσμα των φύλων, του οποίου τα δεδομένα προέρχονται από τη στατιστική βάση δεδομένων της UNECE (United Nations Economic Commission for Europe), και αναφέρονται στο έμφυλο χάσμα ωριαίων απολαβών από εργασία. Ο ρυθμός μεγέθυνσης του κατά κεφαλήν ΑΕΠ λειτουργεί ως η πλέον αποδεκτή μεταβλητή προσέγγισης για την οικονομική πρόοδο των χωρών. Η κύρια ανεξάρτητη μεταβλητή του υποδείγματος μεγέθυνσης είναι το μισθολογικό χάσμα των φύλων, ενώ εντάσσονται στην ανάλυση παλινδρόμησης και άλλες ανεξάρτητες μεταβλητές οι οποίες έχουν επίδραση στη μεγέθυνση με βάση τη βιβλιογραφία, όπως το αρχικό επίπεδο εισοδήματος, το ανθρώπινο κεφάλαιο, οι επενδύσεις, οι άμεσες ξένες επενδύσεις, οι κρατικές δαπάνες και ο πληθωρισμός. Η ανάλυση παλινδρόμησης γίνεται χρησιμοποιώντας μέσους όρους πενταετίας για όλες τις μεταβλητές, ώστε να αφαιρεθούν οι επιδράσεις των βραχυχρόνιων επιχειρηματικών κύκλων και για λόγους συγκρισιμότητας με τις προηγούμενες έρευνες. Η Μέθοδος Ελαχίστων Τετραγώνων (OLS), το Υπόδειγμα Σταθερών Επιδράσεων (FE) και η Γενικευμένη Μέθοδος Ροπών (GMM) χρησιμοποιούνται ως μέθοδοι ανάλυσης παλινδρόμησης. Τα αποτελέσματα της GMM ανάλυσης λογίζονται από τη βιβλιογραφία ως τα περισσότερο εύρωστα, καθώς οι πρώτες διαφορές αφαιρούν την επίδραση των μη παρατηρήσιμων, σταθερών στο χρόνο, επιδράσεων, οι οποίες διαφέρουν μεταξύ των χωρών, και η χρήση εσωτερικών βοηθητικών μεταβλητών ελέγχει το πρόβλημα της ενδογένειας. Η μέθοδος GMM αποκαλύπτει μια θετική και στατιστικά σημαντική επίδραση της μισθολογικής ανισότητας των φύλων στη μεγέθυνση. Τα αποτελέσματα ερμηνεύονται με βάση τη θεωρητική βιβλιογραφία που υποστηρίζει τη θετική σχέση μεταξύ του έμφυλου μισθολογικού χάσματος των φύλων και της μεγέθυνσης. Πιο συγκεκριμένα, το μισθολογικό χάσμα των φύλων συρρικνώνει το συνολικό εισόδημα της εργασίας, με αποτέλεσμα να αυξάνεται το εισόδημα του κεφαλαίου. Το επιπλέον εισόδημα του κεφαλαίου επενδύεται, η παραγωγή αυξάνεται και η οικονομία μεγεθύνεται. Έτσι, η διανομή εισοδήματος μεταξύ κεφαλαίου και εργασίας και οι επενδύσεις λειτουργούν ως κανάλια διαμεσολάβησης της υπό εξέτασης σχέσης.