bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of early changes in lung ultrasound aeration scores and mortality in invasively ventilated patients: a post hoc analysis
Authors: Sinnige Jante S. , Filippini Daan F. L. , Hagens Laura A. , Heijnen Nanon F. L. , Schnabel Ronny M. , Schultz Marcus J. , Bergmans Dennis C. J. J. , Bos Lieuwe D. J. , Smit Marry R. 
Published: July 2024

Abstract
Background
Lung ultrasound (LUS) in an emerging technique used in the intensive care unit (ICU). The derivative LUS aeration score has been shown to have associations with mortality in invasively ventilated patients. This study assessed the predictive value of baseline and early changes in LUS aeration scores in critically ill invasively ventilated patients with and without ARDS (Acute Respiratory Distress Syndrome) on 30- and 90-day mortality.

Methods
This is a post hoc analysis of a multicenter prospective observational cohort study, which included patients admitted to the ICU with an expected duration of ventilation for at least 24 h. We restricted participation to patients who underwent a 12-region LUS exam at baseline and had the primary endpoint (30-day mortality) available. Logistic regression was used to analyze the primary and secondary endpoints. The analysis was performed for the complete patient cohort and for predefined subgroups (ARDS and no ARDS).

Results
A total of 442 patients were included, of whom 245 had a second LUS exam. The baseline LUS aeration score was not associated with mortality (1.02 (95% CI: 0.99 – 1.06), p = 0.143). This finding was not different in patients with and in patients without ARDS. Early deterioration of the LUS score was associated with mortality (2.09 (95% CI: 1.01 – 4.3), p = 0.046) in patients without ARDS, but not in patients with ARDS or in the complete patient cohort.

Conclusion
In this cohort of critically ill invasively ventilated patients, the baseline LUS aeration score was not associated with 30- and 90-day mortality. An early change in the LUS aeration score was associated with mortality, but only in patients without ARDS.

Trial registration
ClinicalTrials.gov, ID NCT04482621.
Genome-scale metabolic network of human carotid plaque reveals the pivotal role of glutamine/glutamate metabolism in macrophage modulating plaque inflammation and vulnerability
Authors: Jin Han , Zhang Cheng , Nagenborg Jan , Juhasz Peter , Ruder Adele V. , Sikkink Cornelis J. J. M. , Mees Barend M. E. , Waring Olivia , Sluimer Judith C. , Neumann Dietbert , Goossens Pieter , Donners Marjo M. P. C. , Mardinoglu Adil , Biessen Erik A. L. 
Published: July 2024

Abstract
Background
Metabolism is increasingly recognized as a key regulator of the function and phenotype of the primary cellular constituents of the atherosclerotic vascular wall, including endothelial cells, smooth muscle cells, and inflammatory cells. However, a comprehensive analysis of metabolic changes associated with the transition of plaque from a stable to a hemorrhaged phenotype is lacking.

Methods
In this study, we integrated two large mRNA expression and protein abundance datasets (BIKE, n = 126; MaasHPS, n = 43) from human atherosclerotic carotid artery plaque to reconstruct a genome-scale metabolic network (GEM). Next, the GEM findings were linked to metabolomics data from MaasHPS, providing a comprehensive overview of metabolic changes in human plaque.

Results
Our study identified significant changes in lipid, cholesterol, and inositol metabolism, along with altered lysosomal lytic activity and increased inflammatory activity, in unstable plaques with intraplaque hemorrhage (IPH+) compared to non-hemorrhaged (IPH−) plaques. Moreover, topological analysis of this network model revealed that the conversion of glutamine to glutamate and their flux between the cytoplasm and mitochondria were notably compromised in hemorrhaged plaques, with a significant reduction in overall glutamate levels in IPH+ plaques. Additionally, reduced glutamate availability was associated with an increased presence of macrophages and a pro-inflammatory phenotype in IPH+ plaques, suggesting an inflammation-prone microenvironment.

Conclusions
This study is the first to establish a robust and comprehensive GEM for atherosclerotic plaque, providing a valuable resource for understanding plaque metabolism. The utility of this GEM was illustrated by its ability to reliably predict dysregulation in the cholesterol hydroxylation, inositol metabolism, and the glutamine/glutamate pathway in rupture-prone hemorrhaged plaques, a finding that may pave the way to new diagnostic or therapeutic measures.
ProtecT-2-D trial protocol: cardiovascular protection in patients with type 2 diabetes and established heart and/or vascular disease at a cardio-metabolic clinic—a randomized controlled trial
Authors: Overgaard Katrine Schultz , Mohamed Roda Abdulkadir , Andersen Thomas Rueskov , Lambrechtsen Jess , Egstrup Kenneth , Auscher Søren 
Published: July 2024

Abstract
Background
Cardiovascular disease remains the primary cause of morbidity and mortality despite advancements in the treatment of patients with type 2 diabetes. Effective diabetes management extends beyond blood glucose control and includes cardiovascular prevention and treatment. However, the conventional healthcare model often emphasizes single-disease-specific management, leading to fragmented care. We aim to establish an affordable Cardio-Metabolic Clinic (CMC) that can provide comprehensive assessment and specialized care with a focus on cardiovascular protection.

Methods
The ProtecT-2-D study is a prospective, randomized control trial at the Cardiovascular Research Unit, Odense University Hospital Svendborg, Denmark. In this study, 1500 participants with type 2 diabetes and cardiovascular disease will be randomly assigned in a 2:1 ratio to receive either the intervention: treatment in the CMC, or the control: standard of care. The Cardio-Metabolic Clinic applies a decision-making algorithm coded with the latest guidelines to evaluate lifestyle factors and manage medical treatment. Health examinations are conducted at baseline and after three years, and clinical events will be assessed through registry and journal audits after five and ten years. The primary outcome is the time to the first occurrence of a composite of cardiovascular deaths, non-fatal acute myocardial infarctions, non-fatal stroke, or hospitalization due to heart failure at a time frame of five years.

Discussion
The Cardio-Metabolic Clinic represents a pioneering approach to diabetes management that aims to improve patient outcomes by reducing the cardiovascular disease burden. This study could transform diabetes care and offer a multidisciplinary, cost-effective, and specialized treatment. We need to establish the efficacy and feasibility of a CMC to integrate comparable clinics into broader healthcare systems, and potentially enhance cardiovascular health in patients with type 2 diabetes.

Trial registration number
ClinicalTrials.gov NCT06203860.

Graphical Abstract
Measures of overnight oxygen saturation to characterize sleep apnea severity and predict postoperative respiratory depression
Authors: Assadi Atousa , Chung Frances , Yadollahi Azadeh 
Published: July 2024

Abstract
Background
Sleep apnea syndrome, characterized by recurrent cessation (apnea) or reduction (hypopnea) of breathing during sleep, is a major risk factor for postoperative respiratory depression. Challenges in sleep apnea assessment have led to the proposal of alternative metrics derived from oxyhemoglobin saturation (SpO2), such as oxygen desaturation index (ODI) and percentage of cumulative sleep time spent with SpO2 below 90% (CT90), as predictors of postoperative respiratory depression. However, their performance has been limited with area under the curve of 0.60 for ODI and 0.59 for CT90. Our objective was to propose novel features from preoperative overnight SpO2 which are correlated with sleep apnea severity and predictive of postoperative respiratory depression.

Methods
Preoperative SpO2 signals from 235 surgical patients were retrospectively analyzed to derive seven features to characterize the sleep apnea severity. The features included entropy and standard deviation of SpO2 signal; below average burden characterizing the area under the average SpO2; average, standard deviation, and entropy of desaturation burdens; and overall nocturnal desaturation burden. The association between the extracted features and sleep apnea severity was assessed using Pearson correlation analysis. Logistic regression was employed to evaluate the predictive performance of the features in identifying postoperative respiratory depression.

Results
Our findings indicated a similar performance of the proposed features to the conventional apnea–hypopnea index (AHI) for assessing sleep apnea severity, with average area under the curve ranging from 0.77 to 0.81. Notably, entropy and standard deviation of overnight SpO2 signal and below average burden showed comparable predictive capability to AHI but with minimal computational requirements and individuals’ burden, making them promising for screening purposes. Our sex-based analysis revealed that compared to entropy and standard deviation, below average burden exhibited higher sensitivity in detecting respiratory depression in women than men.

Conclusion
This study underscores the potential of preoperative SpO2 features as alternative metrics to AHI in predicting postoperative respiratory.
Reactive oxygen species/glutathione dual sensitive nanoparticles with encapsulation of miR155 and curcumin for synergized cancer immunotherapy
Authors: Li Kangkang , Wang Juan , Xie Yi , Lu Ziyao , Sun Wen , Wang Kaixuan , Liang Jinxin , Chen Xuehong 
Published: July 2024

AbstractConsiderable attention has been directed towards exploring the potential efficacy of miR-155 in the realm of cancer immunotherapy. Elevated levels of miR-155 in dendritic cells (DCs) have been shown to enhance their maturation, migration, cytokine secretion, and their ability to promote T cell activation. In addition, overexpression of mir155 in M2 macrophages boost the polarization towards the M1 phenotype. Conversely, miR-155 has the propensity to induce the accumulation of immunosuppressive cells like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor tissue. To account for this discrepancy, it is imperative to get help from a drug that could deal with immunosuppressive effect. Curcumin (CUR) exhibits the capacity to prompt Tregs converse into T helper 1 cells, fostering the polarization of M2 tumor-associated macrophage towards the M1 phenotype, and impeding the recruitment and aggregation of MDSCs within the tumor microenvironment. Nonetheless, CUR is known to exert an immunosuppressive impact on DCs by hindering the expression of maturation markers, cytokines, and chemokines, thereby prevent DCs response to immunostimulatory agents. Hence, a reactive oxygen species/glutathione dual responsive drug conveyance platform (CUR/miR155@DssD-Hb NPs) was devised to co-deliver CUR and miR155, with the aim of exploring their synergistic potential in bolstering a sustained and robust anti-tumor immune response. In vitro and in vivo results have suggested that CUR/miR155@DssD-Hb NPs can effectively inhibit the viability of 4T1 and B16F10 tumor cells, trigger the release of damage associated molecular patterns, stimulate DCs maturation, subsequent activation of CD8+ T cells, diminish immunosuppressive cell populations (MDSCs, Tregs, M2 TAMs and exhausted T cells), promote the formation of long-term immunity and lessen the formation of metastatic nodules in the lungs. In summary, the co-delivery system integrating CUR and miR155 (CUR/miR155@DssD-Hb NPs) demonstrates promise as a promising strategy for the immunotherapy of melanoma and triple negative breast cancer.
Graphical abstract
The role of playgrounds in promoting children’s health – a scoping review
Authors: Schipperijn Jasper , Madsen Cathrine Damsbo , Toftager Mette , Johansen Danielle Nørager , Lousen Ida , Amholt Thea Toft , Pawlowski Charlotte Skau 
Published: July 2024

Abstract
Background
Active outdoor play is important for children’s health and development, and playgrounds provide good places for play. However, the importance of playground use for health and well-being is unclear. Our scoping review aims to create an overview of all research on playground use and health benefits for children.

Methods
Scopus, Web of Science, SportDiscus, and PsycInfo were searched using two search blocks, focusing on 'playground' and 'children' respectively, for publications from 2000 to November 2023. The primary inclusion criterion was examining the relationship between playground use and positive physical, mental, or social health outcomes. Only papers published in English were reviewed. For each publication, we synthesized and condensed the results, categorizing them by playground setting, reported health outcome, participant age group, study design, methodologies, publication's country, year, and ‘stage of evidence’.

Results
Data from 247 studies were extracted and nearly 80% of these publications were descriptive or exploratory studies. Fifty-two were intervention studies. Adding playground markings to schoolyards led to increased physical activity. Greening schoolyards had mainly positive effects on social and mental health. In Early Childhood Education and Care, renewing play structures had a positive effect on physical activity in three publications. All Public Open Space interventions we found were different, with mixed effects on health outcomes.

Conclusions
The existing evidence provides good arguments for policy makers, city planners and school-leaders to invest in adding playground markings in schoolyards as this will likely result in more physical activity. The evidence for the health benefits of investing in new play structures indicated that tailoring the playground to local needs is important as ‘one size does not fit all’ and playgrounds need to be designed as engaging and interesting places for children’s play if they are to generate health benefits. Investing in ‘greening’ playgrounds is likely to result in social and mental health benefits for children, but does not always result in more physical activity.
The research field needs more efficacy and effectiveness studies, and in particular replication and scale-up studies to demonstrate which type of playground interventions are successful.

Protocol
The review protocol was registered at Open Science Framework (https://doi.org/10.17605/OSF.IO/UYN2V).
Combined expert-in-the-loop—random forest multiclass segmentation U-net based artificial intelligence model: evaluation of non-small cell lung cancer in fibrotic and non-fibrotic microenvironments
Authors: Saqi Anjali , Liu Yucheng , Politis Michelle Garlin , Salvatore Mary , Jambawalikar Sachin 
Published: July 2024

Abstract
Background
The tumor microenvironment (TME) plays a key role in lung cancer initiation, proliferation, invasion, and metastasis. Artificial intelligence (AI) methods could potentially accelerate TME analysis. The aims of this study were to (1) assess the feasibility of using hematoxylin and eosin (H&E)-stained whole slide images (WSI) to develop an AI model for evaluating the TME and (2) to characterize the TME of adenocarcinoma (ADCA) and squamous cell carcinoma (SCCA) in fibrotic and non-fibrotic lung.

Methods
The cohort was derived from chest CT scans of patients presenting with lung neoplasms, with and without background fibrosis. WSI images were generated from slides of all 76 available pathology cases with ADCA (n = 53) or SCCA (n = 23) in fibrotic (n = 47) or non-fibrotic (n = 29) lung. Detailed ground-truth annotations, including of stroma (i.e., fibrosis, vessels, inflammation), necrosis and background, were performed on WSI and optimized via an expert-in-the-loop (EITL) iterative procedure using a lightweight [random forest (RF)] classifier. A convolution neural network (CNN)-based model was used to achieve tissue-level multiclass segmentation. The model was trained on 25 annotated WSI from 13 cases of ADCA and SCCA within and without fibrosis and then applied to the 76-case cohort. The TME analysis included tumor stroma ratio (TSR), tumor fibrosis ratio (TFR), tumor inflammation ratio (TIR), tumor vessel ratio (TVR), tumor necrosis ratio (TNR), and tumor background ratio (TBR).

Results
The model’s overall classification for precision, sensitivity, and F1-score were 94%, 90%, and 91%, respectively. Statistically significant differences were noted in TSR (p = 0.041) and TFR (p = 0.001) between fibrotic and non-fibrotic ADCA. Within fibrotic lung, statistically significant differences were present in TFR (p = 0.039), TIR (p = 0.003), TVR (p = 0.041), TNR (p = 0.0003), and TBR (p = 0.020) between ADCA and SCCA.

Conclusion
The combined EITL—RF CNN model using only H&E WSI can facilitate multiclass evaluation and quantification of the TME. There are significant differences in the TME of ADCA and SCCA present within or without background fibrosis. Future studies are needed to determine the significance of TME on prognosis and treatment.
Application prospects of the 2BS cell-adapted China fixed rabies virus vaccine strain 2aG4-B40
Authors: Xu Ying , Weng Lin , Wang Xuan , Li Ming , Guo Wanping , Liu Yiqing , Li Xiang , Wang Zhenping , Liu Xinyu , Xu Shengnan , He Feide , Hou Qianqian , Li Tengzhou , Du Wenke , Zhang Yabo , Chang Shumin , Zhang Liwen , Zhang Yuntao 
Published: July 2024

Abstract
Background
Rabies is a fatal zoonotic disease whose pathogenesis has not been fully elucidated, and vaccination is the only effective method for protecting against rabies virus infection. Most inactivated vaccines are produced using Vero cells, which are African green monkey kidney cells, to achieve large-scale production. However, there is a potential carcinogenic risk due to nonhuman DNA contamination. Thus, replacing Vero cells with human diploid cells may be a safer strategy. In this study, we developed a novel 2BS cell-adapted rabies virus strain and analysed its sequence, virulence and immunogenicity to determine its application potential as a human diploid cell inactivated vaccine.

Methods and results
The 2BS cell-adapted rabies virus strain 2aG4-B40 was established by passage for 40 generations and selection of plaques in 2BS cells. RNA sequence analysis revealed that mutations in 2BS cell-adapted strains were not located at key sites that regulate the production of neutralizing antibodies or virulence in the aG strain (GQ412744.1). The gradual increase in virulence (remaining above 7.0 logLD50/ml from the 40th to 55th generation) and antigen further indicated that these mutations may increase the affinity of the adapted strains for human diploid cells. Identification tests revealed that the 2BS cell-adapted virus strain was neutralized by anti-rabies serum, with a neutralization index of 19,952. PrEP and PEP vaccination and the NIH test further indicated that the vaccine prepared with the 2aG4-B40 strain had high neutralizing antibody levels (2.24 to 46.67 IU/ml), immunogenicity (protection index 270) and potency (average 11.6 IU/ml).

Conclusions
In this study, a 2BS cell-adapted strain of the 2aG4 rabies virus was obtained by passage for 40 generations. The results of sequencing analysis and titre determination of the adapted strain showed that the mutations in the adaptive process are not located at key sequence regions of the virus, and these mutations may enhance the affinity of the adapted strain for human diploid cells. Moreover, vaccines made from the adapted strain 2aG4-B40 had high potency and immunogenicity and could be an ideal candidate rabies virus strain for inactivated vaccine preparation.
Development and validation of an automated Tomotherapy planning method for cervical cancer
Authors: Han Feiru , Xue Yi , Huang Sheng , Lu Tong , Yang Yining , Cao Yuanjie , Chen Jie , Hou Hailing , Sun Yao , Wang Wei , Yuan Zhiyong , Tao Zhen , Jiang Shengpeng 
Published: July 2024

Abstract
Purpose
This study aimed to develop an automated Tomotherapy (TOMO) planning method for cervical cancer treatment, and to validate its feasibility and effectiveness.

Materials and methods
The study enrolled 30 cervical cancer patients treated with TOMO at our center. Utilizing scripting and Python environment within the RayStation (RaySearch Labs, Sweden) treatment planning system (TPS), we developed automated planning methods for TOMO and volumetric modulated arc therapy (VMAT) techniques. The clinical manual TOMO (M-TOMO) plans for the 30 patients were re-optimized using automated planning scripts for both TOMO and VMAT, creating automated TOMO (A-TOMO) and automated VMAT (A-VMAT) plans. We compared A-TOMO with M-TOMO and A-VMAT plans. The primary evaluated relevant dosimetric parameters and treatment plan efficiency were assessed using the two-sided Wilcoxon signed-rank test for statistical analysis, with a P-value < 0.05 indicating statistical significance.

Results
A-TOMO plans maintained similar target dose uniformity compared to M-TOMO plans, with improvements in target conformity and faster dose drop-off outside the target, and demonstrated significant statistical differences (P+ < 0.01). A-TOMO plans also significantly outperformed M-TOMO plans in reducing V50Gy, V40Gy and Dmean for the bladder and rectum, as well as Dmean for the bowel bag, femoral heads, and kidneys (all P+ < 0.05). Additionally, A-TOMO plans demonstrated better consistency in plan quality. Furthermore, the quality of A-TOMO plans was comparable to or superior than A-VMAT plans. In terms of efficiency, A-TOMO significantly reduced the time required for treatment planning to approximately 20 min.

Conclusion
We have successfully developed an A-TOMO planning method for cervical cancer. Compared to M-TOMO plans, A-TOMO plans improved target conformity and reduced radiation dose to OARs. Additionally, the quality of A-TOMO plans was on par with or surpasses that of A-VMAT plans. The A-TOMO planning method significantly improved the efficiency of treatment planning.