bluuebunny/crossref_metadata_2025_split huggingface dataset:
The EU project Real4Reg: unlocking real-world data with AI
Authors: Peltner Jonas , Becker Cornelia , Wicherski Julia , Wortberg Silja , Aborageh Mohamed , Costa Inês , Ehrenstein Vera , Fernandes Joana , Heß Steffen , Horváth-Puhó Erzsébet , Korcinska Handest Monika Roberta , Lentzen Manuel , Maguire Peggy , Meedom Niels Henrik , Moore Rebecca , Moore Vanessa , Nagy Dávid , McNamara Hillary , Paakinaho Anne , Pfeifer Kerstin , Pylkkänen Liisa , Rajamaki Blair , Reviers Evy , Röthlein Christoph , Russek Martin , Silva Célia , De Valck Dirk , Vo Thuan , Bräuner Elvira , Fröhlich Holger , Furtado Cláudia , Hartikainen Sirpa , Kallio Aleksi , Tolppanen Anna-Maija , Haenisch Britta 
Published: February 2025

Abstract

Background
The use of real-world data is established in post-authorization regulatory processes such as pharmacovigilance of drugs and medical devices, but is still frequently challenged in the pre-authorization phase of medicinal products. In addition, the use of real-world data, even in post-authorization steps, is constrained by the availability and heterogeneity of real-world data and by challenges in analysing data from different settings and sources. Moreover, there are emerging opportunities in the use of artificial intelligence in healthcare research, but also a lack of knowledge on its appropriate application to heterogeneous real-world data sources to increase evidentiary value in the regulatory decision-making and health technology assessment context.

Methods
The Real4Reg project aims to enable the use of real-world data by developing user-friendly solutions for the data analytical needs of health regulatory and health technology assessment bodies across the European Union. These include artificial intelligence algorithms for the effective analysis of real-world data in regulatory decision-making and health technology assessment. The project aims to investigate the value of real-world data from different sources to generate high-quality, accessible, population-based information relevant along the product life cycle. A total of four use cases are used to provide good practice examples for analyses of real-world data for the evaluation and pre-authorization stage, the improvement of methods for external validity in observational data, for post-authorization safety studies and comparative effectiveness using real-world data. This position paper introduces the objectives and structure of the Real4Reg project and discusses its important role in the context of existing European projects focussing on real-world data.

Discussion
Real4Reg focusses on the identification and description of benefits and risks of new and optimized methods in real-world data analysis including aspects of safety, effectiveness, interoperability, appropriateness, accessibility, comparative value creation and sustainability. The project’s results will support better decision-making about medicines and benefit patients’ health.

Trial registration Real4Reg is registered in the HMA-EMA Catalogues of real-world data sources and studies (EU PAS number EUPAS105544).
‘You constantly have to be switched on’: A qualitative interview study of parents of children with STXBP1-related disorders in the Netherlands
Authors: van Till Sietske A. L. , Sybesma Sybren , Bruining Hilgo , Verhage Matthijs , Bunnik Eline M. 
Published: February 2025

Abstract

Background
Disorder-related variants in the STXBP1 gene are increasingly detected in children with severe developmental disorders. It is commonly acknowledged that developmental disorders significantly impact family life, but little is known about the day-to-day experiences of caregivers living with children with STXBP1-related disorders (STXBP1-RD). This knowledge gap may hinder researchers and care professionals from aligning research activities, care, and support with the perspectives of parents.

Methods
We conducted a semi-structured interview study to gain a better understanding of the impact of having a child with STXBP1-RD on daily family life. Interviews were audio-recorded, transcribed, and analyzed thematically. We developed an ‘analytical framework based on verbs’, as verbs signify action, to present our results on the experiences of parents in everyday life.

Results
We conducted 16 interviews with 21 parents of children with STXBP1-RD (2 to 18 years old), living in the Netherlands. The respondents described their caregiving responsibilities as extremely intense and demanding. They reported being constantly occupied with caring for their child, and expressed a feeling of always being ‘switched on’. Parents’ experiences are described using the following five verbs: (1) caring for their child, (2) recognizing their child’s needs and having their child’s needs recognized, (3) searching for answers and suitable care, (4) balancing delivering care while preserving other domains of life, and (5) coping with emotional impacts.

Conclusions
This study shows how parenting a child with STXBP1-RD involves continuous engagement with both child-related care responsibilities and other activities, such as arranging suitable care and coping with emotional impacts. The accumulation of these responsibilities and challenges significantly impacts the everyday lives of the entire family. To support STXBP1 patient families, a broad approach is needed, focusing not only on developing new medical treatments, but also on improving other therapies (e.g., speech therapy or physiotherapy) and providing social support for the entire family, including emotional support, assistance with administrative tasks, and improved information provision after diagnosis.
Inferring protein from transcript abundances using convolutional neural networks
Authors: Schwehn Patrick Maximilian , Falter-Braun Pascal 
Published: February 2025

Abstract

Background
Although transcript abundance is often used as a proxy for protein abundance, it is an unreliable predictor. As proteins execute biological functions and their expression levels influence phenotypic outcomes, we developed a convolutional neural network (CNN) to predict protein abundances from mRNA abundances, protein sequence, and mRNA sequence in Homo sapiens (H. sapiens) and the reference plant Arabidopsis thaliana (A. thaliana).

Results
After hyperparameter optimization and initial data exploration, we implemented distinct training modules for value-based and sequence-based data. By analyzing the learned weights, we revealed common and organism-specific sequence features that influence protein-to-mRNA ratios (PTRs), including known and putative sequence motifs. Adding condition-specific protein interaction information identified genes correlated with many PTRs but did not improve predictions, likely due to insufficient data. The integrated model predicted protein abundance on unseen genes with a coefficient of determination (r2) of 0.30 in H. sapiens and 0.32 in A. thaliana.

Conclusions
For H. sapiens, our model improves prediction performance by nearly 50% compared to previous sequence-based approaches, and for A. thaliana it represents the first model of its kind. The model’s learned motifs recapitulate known regulatory elements, supporting its utility in systems-level and hypothesis-driven research approaches related to protein regulation.
Neuroinflammation and pathways that contribute to tourette syndrome
Authors: Wu Xinnan , Hao Juanjuan , Jiang Keyu , Wu Min , Zhao Xin , Zhang Xin 
Published: February 2025

Abstract
Tourette syndrome (TS), a neurological and psychological disease, typically exhibit motor and phonic tics. The pathophysiology of TS remains controversial. Currently, the recognized pathogenesis of TS is the imbalance of neurotransmitters, involving abnormality of the cortex-striatum-thalamus-cortex circuit. Recently, clinical researches demonstrate that triggers such as infection and allergic reaction could lead to the onset or exacerbation of tic symptoms. Current studies have also suggested that neural-immune crosstalk caused by inflammation is also associated with TS, potentially leading to the occurrence of tics by inducing neurotransmitter abnormalities. Herein, we review inflammation-related factors contributing to the occurrence of TS as well as the mechanisms by which immune-inflammatory pathways mediate the onset of TS. This aims to clarify the pathogenesis of TS and provide a theoretical basis for the treatment of TS.
Dedifferentiated fat cells-derived exosomes (DFATs-Exos) loaded in GelMA accelerated diabetic wound healing through Wnt/β-catenin pathway
Authors: Dong Miao , Ma Xuan , Li Facheng 
Published: February 2025

Abstract

Background
Diabetic foot ulcers pose significant challenges for clinicians worldwide. Cell-free exosome therapy holds great potential for wound healing. Dedifferentiated fat cells (DFATs) have been used in tissue engineering and regeneration, but there are no reports on the use of DFATs-derived exosomes in diabetic wound repair.

Objectives
This study aims to investigate whether DFATs-Exos accelerated diabetic wound healing and explore its potential mechanism.

Methods
In vitro, DFATs-Exos were harvested from adipose tissue and used to treat endothelial cells (ECs) and fibroblasts. XAV939 was used as a Wnt/β-catenin pathway inhibitor. The biocompatibility of gelatin methacryloyl (GelMA) hydrogel was assessed. In vivo, DFAT-derived exosomes were encapsulated in 10% GelMA hydrogel and applied to a diabetic wound model. Histological analysis and wound closure rates were evaluated.

Results
DFATs-Exos promoted angiogenesis in ECs and significantly alleviated the high glucose-induced inhibition of cell proliferation and migration by activating the Wnt/β-catenin pathway. In vivo, compared to DFAT-Exos or GelMA alone, the DFAT-Exos/GelMA combination accelerated wound closure and enhanced collagen maturity.

Conclusion
The DFAT-Exos/GelMA hydrogel significantly promoted wound healing in a diabetic animal model through activation of the Wnt/β-catenin signaling pathway.
The trajectory of sleep after critical illness: a 24-month follow-up study
Authors: Henríquez-Beltrán Mario , Benítez Iván D. , Vaca Rafaela , Santisteve Sally , Aguilà Maria , Vila Anna , Minguez Olga , Rodríguez-Muñoz Carlos , Galán-González Anna , Carvalho-Brugger Sulamita , González Paula , Rodríguez Paula , Caballero Jesús , Barberà Carme , Torres Gerard , Labarca Gonzalo , Malla-Banyeres Mar , Moncusí-Moix Anna , Torres Antoni , de Gonzalo-Calvo David , Barbé Ferran , González Jessica , Targa Adriano D. S. 
Published: February 2025

Abstract

Background
Survivors of critical illness endure long-lasting physical and mental challenges. Despite the persistence of poor sleep quality in a considerable proportion of patients at the 12-month follow-up, studies with assessments exceeding this period are limited. We aimed to investigate the trajectory of sleep over the 24 months following critical illness.

Methods
Observational, prospective study. Patients diagnosed with SARS-CoV-2 infection were recruited during the intensive care unit stay. Evaluations of sleep (Pittsburgh Sleep Quality Index [PSQI]), mental health (Hospital Anxiety and Depression Scale [HADS]), quality of life (12-item Short Form Survey [SF-12]), and other factors were performed in the short-term, and at 12 and 24 months after hospital discharge. Good sleep quality was defined as a PSQI score of ≤ 5. Minimal clinically important improvement (MCII) was defined as a decrease of ≥ 4 points in the PSQI score between the short-term assessment and the 24-month follow-up.

Results
The cohort included 196 patients (69.9% males), with a median [p25;p75] age of 62.0 [53.0;67.2] years. The global population showed a mean (95% CI) change of − 0.91 ( − 1.50 to − 0.31) points in the PSQI score from the short-term assessment to the 24-month follow-up. Based on PSQI score trajectories, three distinct groups of patients were identified: (i) the healthy group, consisting of patients with good sleep quality in the short-term that was maintained throughout the follow-up period; (ii) the MCII group, consisting of patients with poor sleep quality in the short-term, but with improvement over time, ultimately reaching levels comparable to the healthy group; (iii) the non-MCII group, consisting of those with consistently poor sleep quality across the entire follow-up. Further analyses revealed that PSQI score trajectories were closely aligned with those of the HADS and SF-12 mental scores.

Conclusions
Our findings reveal that a subset of critical illness survivors requires up to 24 months after the acute phase to fully restore their sleep quality, while a significant proportion does not experience a clinically significant improvement in sleep quality over this period. These distinct sleep trajectories are strongly correlated with mental health status, highlighting the importance of addressing sleep alongside mental health within the framework of post-intensive care syndrome.
Roux-en-Y gastric bypass-associated fecal tyramine promotes colon cancer risk via increased DNA damage, cell proliferation, and inflammation
Authors: Glymenaki Maria , Curio Sophie , Shrestha Smeeta , Zhong Qi , Rushton Laura , Barry Rachael , El-Bahrawy Mona , Marchesi Julian R. , Wang Yulan , Gooderham Nigel J. , Guerra Nadia , Li Jia V. 
Published: February 2025

Abstract

Background
Fecal abundances of Enterobacteriaceae and Enterococcaceae are elevated in patients following Roux-en-Y gastric bypass (RYGB) surgery. Concurrently, fecal concentrations of tyramine, derived from gut bacterial metabolism of tyrosine and/or food, increased post-RYGB. Furthermore, emerging evidence suggests that RYGB is associated with increased colorectal cancer (CRC) risk. However, the causal link between RYGB-associated microbial metabolites and CRC risk remains unclear. Hence, this study investigated the tyrosine metabolism of Enterobacteriaceae and Enterococcaceae strains isolated from patients post-RYGB and explored the causal effects of tyramine on the CRC risk and tumorigenesis using both human colonic cancer cell line (HCT 116) and wild-type and Apc

Min/+ mice.

Results
We isolated 31 bacterial isolates belonging to Enterobacteriaceae and Enterococcaceae families from the feces of patients with RYGB surgery. By culturing the isolates in tyrosine-supplemented medium, we found that Citrobacter produced phenol as a main product of tyrosine, whereas Enterobacter and Klebsiella produced 4-hydroxyphenylacetate, Escherichia produced 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate, and Enterococcus and two Klebsiella isolates produced tyramine. These observations suggested the gut bacterial contribution to increased fecal concentrations of tyramine post-RYGB. We subsequently evaluated the impact of tyramine on CRC risk and development. Tyramine induced necrosis and promoted cell proliferation and DNA damage of HCT 116 cells. Daily oral administration of tyramine for 49 days to wild-type mice resulted in visible adenomas in 5 out of 12 mice, accompanied by significantly enhanced DNA damage (γH2AX +) and an increased trend of cell proliferation (Ki67 +) in the ileum, along with an upregulated expression of the cell division cycle gene (Cdc34b) in the colon. To evaluate the impact of tyramine on intestinal tumor growth, we treated Apc

Min/+ mice with the same doses of tyramine and duration. These mice showed larger colonic tumor size and increased intestinal cell proliferation and inflammation (e.g., increased mRNA expression of IL-17A and higher number of Ly6G + neutrophils) compared to water-treated Apc

Min/+ control mice.

Conclusions
Our results collectively suggested that RYGB-associated fecal bacteria could contribute to tyramine production and tyramine increased CRC risk by increasing DNA damage, cell proliferation, and pro-inflammatory responses of the gut. Monitoring and modulating tyramine concentrations in high-risk individuals could aid CRC prognosis and management.
Antimicrobial resistance surveillance and trends in armed conflict, fragile, and non-conflict countries of the Eastern Mediterranean Region
Authors: Moghnieh Rima , Bizri Nazih , Abdallah Dania , Sayegh Mohamed H. 
Published: February 2025

Abstract

Background
The WHO Eastern Mediterranean Region (EMR) faces major social, economic, and demographic challenges, with nearly half of its countries affected by conflicts that severely disrupt health systems. This study compared antimicrobial resistance (AMR) rates and surveillance efforts in conflict-affected, fragile, and non-conflict countries, further subdivided by income.

Methods
Data on bacteriologically confirmed bloodstream infections (BC-BSIs) from 2017 to 2021 were extracted from the WHO GLASS database. Countries were classified as conflict-affected, fragile, or non-conflict (subdivided by income) using World Bank criteria. Descriptive statistics (mean ± SD) were calculated, and group comparisons were performed using unpaired t-tests with Welch’s correction. Mean differences (MD) and 95% confidence intervals (CI) were reported.

Results
Conflict-affected countries reported significantly fewer surveillance sites than non-conflict countries (MD: 0.60, 95% CI: 0.361 to 0.836, P < 0.001) and fewer BC-BSIs per million population (MD: 31.00, 95% CI: 17.210 to 44.790, P < 0.001). In conflict zones, Acinetobacter spp. and S. aureus represented a higher proportion of BSIs compared to non-conflict countries (Acinetobacter spp. MD: -11.86, 95% CI: − 27.130 to 3.399, P = 0.099; S. aureus MD: − 10.68, 95% CI: − 30.030 to 8.680, P = 0.203). Carbapenem resistance in Acinetobacter spp. exceeded 65% across the groups, peaking in fragile zones (83.38%). Third-generation cephalosporin-resistant E. coli (3GCREC) prevalence ranged from 47.99% to 76.34%, peaking in conflict zones (76.34%). Carbapenem-resistant E. coli (CREC) prevalence ranged from 2.31% to 15.95%, highest in non-conflict low-middle income countries (15.95%). Third-generation cephalosporin-resistant K. pneumoniae (3GCRKP) exceeded 50% in all groups, peaking in conflict zones (80.42%). The prevalence of carbapenem-resistant K. pneumoniae (CRKP) ranged from 14.49% to 45.70%, peaking in conflict zones and non-conflict low-middle income countries (45.70%). Methicillin-resistant S. aureus (MRSA) exceeded 30%, peaking in conflict zones (70.09%).

Conclusions
Conflict-affected countries have weaker AMR surveillance and lower BC-BSI detection but a higher burden of resistant pathogens, notably carbapenem-resistant Acinetobacter spp. and MRSA. Tailored strategies are essential to restore infrastructure, strengthen surveillance, and mitigate the long-term impact of AMR in these zones.

Graphical Abstract
Wearable devices for patient monitoring in the intensive care unit
Authors: Angelucci Alessandra , Greco Massimiliano , Cecconi Maurizio , Aliverti Andrea 
Published: February 2025

Abstract
Wearable devices (WDs), originally launched for fitness, are now increasingly recognized as valuable technologies in several clinical applications, including the intensive care unit (ICU). These devices allow for continuous, non-invasive monitoring of physiological parameters such as heart rate, respiratory rate, blood pressure, glucose levels, and posture and movement. WDs offer significant advantages in making monitoring less invasive and could help bridge gaps between ICUs and standard hospital wards, ensuring more effective transitioning to lower-level monitoring after discharge from the ICU. WDs are also promising tools in applications like delirium detection, vital signs monitoring in limited resource settings, and prevention of hospital-acquired pressure injuries. Despite the potential of WDs, challenges such as measurement accuracy, explainability of data processing algorithms, and actual integration into the clinical decision-making process persist. Further research is necessary to validate the effectiveness of WDs and to integrate them into clinical practice in critical care environments.
Take home messages

Wearable devices are revolutionizing patient monitoring in ICUs and step down units by providing continuous, non-invasive, and cost-effective solutions.

Validation of their accuracy and integration in the clinical decision-making process remain crucial for widespread clinical adoption.
Tumor ADC value predicts outcome and yields refined prognostication in uterine cervical cancer
Authors: Lura Njål , Wagner-Larsen Kari S. , Ryste Stian , Fasmer Kristine , Forsse David , Trovik Jone , Halle Mari K. , Bertelsen Bjørn I. , Riemer Frank , Salvesen Øyvind , Woie Kathrine , Krakstad Camilla , Haldorsen Ingfrid S. 
Published: February 2025

Abstract

Pelvic MRI is essential for evaluating local and regional tumor extent in uterine cervical cancer (CC). Tumor microstructure captured by diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) markers may be closely linked to prognosis in CC.

Purpose To explore whether primary tumor ADC markers predict survival in CC.

Material and methods CC patients (n = 179) diagnosed during 2009–2020 with MRI-assessed primary maximum tumorsize ≥ 2 cm were included in this retrospective single-center study. Two radiologists read all MRIs independently, measuring mean tumor ADC values in manually drawn regions of interest (ROIs) and mean tumor ADC (tumorADCmean) from five measurements for the two readers was used. ADC from ROIs in the myometrium (myometriumADC), cervical stroma (cervixADC), and bladder (bladderADC) were used to calculate ADC ratios. ADC markers were explored in relation to the International Federation of Gynecology and Obstetrics (FIGO) (2018) stage, disease-specific survival (DSS), and recurrence/progression-free survival (RPFS).

Results Inter-reader agreement for all ADC measurements was high (ICC:0.59–0.79). Low tumorADCmean predicted advanced FIGO stage (P = 0.04) and reduced DSS (hazard ratio (HR): 0.96, P < 0.001; AIC: 441). MyometriumADC/tumorADCmean yielded the best Cox regression fit (AIC = 430) among all tumor ADC markers. Patients with high myometriumADC/tumorADCmean had significantly reduced 5-year DSS for FIGO stage I, II, and III (P = 0.01, 0.004, and 0.02, respectively) and tended to the same for FIGO IV (P = 0.22).

Conclusion Low tumorADCmean predicted reduced DSS in CC. High myometriumADC/tumorADCmean was the strongest ADC predictor of poor DSS and a marker of high-risk phenotype independent of FIGO stage.