bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association between patent foramen ovale and unexplained syncope in pediatric patients
Authors: Zou Runmei , Wang Shuo , Liu Ping , Chen Donghai , Yan Jun , Cai Hong , Wang Yuwen , Wang Cheng 
Published: January 2024

Abstract
Background
Patent foramen ovale (PFO) is associated with transient ischemia attack (TIA) or stroke, paradoxical embolism, and migraines. PFO closure decreases the recurrent incidence of cerebral ischemic events and reduces the incidence of syncope in adults. However, whether PFO is associated with syncope in pediatric patients has not been investigated.

Methods
1001 pediatric patients (aged 4 to 17 years, mean age 10.31 ± 2.61 years, 519 males) who complained of unexplained syncope, palpitation, headache, dizziness and chest pain and were hospitalized in the Syncope Ward, The Second Xiangya Hospital, Central South University between January 2013 and April 2022 were recruited. Children with definite etiology of syncope, neurological, cardiogenic, psychological and other system diseases were excluded. PFO was measured by transthoracic echocardiography and right-heart contrast echocardiography was performed to identify the presence of right-to-left shunting. The demographic data and medical records were retrospectively reviewed and analyzed.

Results
276 cases were included in the simple syncope group, 379 cases in the headache/dizziness group, 265 cases in the chest pain group, and 81 cases in the palpitation group. The incidence of PFO between the four groups was insignificant (4.71%, 4.74%, 4.15%, 6.17%, respectively, P = 0.903). Multivariate Logistic regression demonstrated that PFO is not associated with the increased risk of syncope (P = 0.081).

Conclusion
PFO may not increase the risk of syncope in pediatric patients. Further study may include a large and multicenter sample to investigate the association between PFO and unexplained syncope.
Modeling methyl-sensitive transcription factor motifs with an expanded epigenetic alphabet
Authors: Viner Coby , Ishak Charles A. , Johnson James , Walker Nicolas J. , Shi Hui , Sjöberg-Herrera Marcela K. , Shen Shu Yi , Lardo Santana M. , Adams David J. , Ferguson-Smith Anne C. , De Carvalho Daniel D. , Hainer Sarah J. , Bailey Timothy L. , Hoffman Michael M. 
Published: January 2024

Abstract
Background
Transcription factors bind DNA in specific sequence contexts. In addition to distinguishing one nucleobase from another, some transcription factors can distinguish between unmodified and modified bases. Current models of transcription factor binding tend not to take DNA modifications into account, while the recent few that do often have limitations. This makes a comprehensive and accurate profiling of transcription factor affinities difficult.

Results
Here, we develop methods to identify transcription factor binding sites in modified DNA. Our models expand the standard /// DNA alphabet to include cytosine modifications. We develop Cytomod to create modified genomic sequences and we also enhance the MEME Suite, adding the capacity to handle custom alphabets. We adapt the well-established position weight matrix (PWM) model of transcription factor binding affinity to this expanded DNA alphabet. Using these methods, we identify modification-sensitive transcription factor binding motifs. We confirm established binding preferences, such as the preference of ZFP57 and C/EBPβ for methylated motifs and the preference of c-Myc for unmethylated E-box motifs.

Conclusions
Using known binding preferences to tune model parameters, we discover novel modified motifs for a wide array of transcription factors. Finally, we validate our binding preference predictions for OCT4 using cleavage under targets and release using nuclease (CUT&RUN) experiments across conventional, methylation-, and hydroxymethylation-enriched sequences. Our approach readily extends to other DNA modifications. As more genome-wide single-base resolution modification data becomes available, we expect that our method will yield insights into altered transcription factor binding affinities across many different modifications.
Upregulation of PD-1/PD-L1 and downregulation of immune signaling pathways lead to more severe visceral leishmaniasis in undernutrition mice
Authors: He Jinlei , Zhang Jianhui , Liao Xuechun , Xiao Yuying , Li Jiao , Zheng Zhiwan , Chen Dali , Chen Jianping 
Published: January 2024

Abstract
Background
Leishmaniasis is mainly prevalent in tropical and subtropical developing countries, where chronic undernutrition often co-exists. Undernutrition is reported to promote the progression of leishmaniasis, but its immune mechanisms have not been fully elucidated.

Methods
To simulate chronic undernutrition of patients in epidemic areas and explore the immune mechanism of undernutrition promoting leishmaniasis, BALB/c mouse models with different nutritional imbalances were established, including undernutrition 75%, undernutrition 65% and obesity mouse models. After infection with Leishmania donovani in these model mice, we focused on evaluating the progress of leishmaniasis in the spleen and liver, the expression of important immunosuppressive and immunoactivation molecules, and changes of spleen transcriptome. The immune signaling pathways enriched by differentially expressed genes and hub genes were analyzed.

Results
The results showed that among the mouse infection models, undernutrition 75% + infection group had the highest parasite load in the spleen and liver at the 8th week post-infection, possibly due to the continuous increase of PD-1, PD-L1 and TCR. Spleen RNA-seq results suggested that some immune signaling pathways were downregulated in undernutrition 75% + infection group, including neutrophil extracellular trap formation, IL-17 signaling pathway, natural killer cell-mediated cytotoxicity, etc. Among them, neutrophil extracellular trap formation pathway had the largest number of downregulated genes. This also explained why undernutrition 75% + infection group had the highest parasite load. Through PPI network analysis, hub genes such as Lcn2, Ltf, Mpo, Dnaja1, Hspa1a, Hspa1b and Hsph1 were screened out and might play important roles in the process of undernutrition promoting leishmaniasis.

Conclusions
Undernutrition upregulated PD-1 and PD-L1 expression and downregulated immune signaling pathways in mice with visceral leishmaniasis. The signaling pathways and hub genes may serve as drug targets or intervention targets for the treatment of leishmaniasis patients with undernutrition.

Graphical Abstract
A novel detection method based on MIRA-CRISPR/Cas13a-LFD targeting the repeated DNA sequence of Trichomonas vaginalis
Authors: Yang Zhenke , Wang Jinghui , Qi Yiming , Shi Yiping , Li Fakun , Wang Weijuan , Tian Xiaowei , Mei Xuefang , Zhang Zhenchao , Wang Shuai 
Published: January 2024

Abstract
Background
Trichomonas vaginalis is a protozoan parasite, widely recognized as the most prevalent non-viral sexually transmitted infection (STI) globally. This infection is linked to various complications, including pelvic inflammatory disease, adverse pregnancy outcomes, and an increased risk of acquiring HIV. Current molecular detection methods for T. vaginalis are often costly and technically challenging.

Methods
We developed a novel detection method for T. vaginalis using a multi-enzyme isothermal rapid amplification–clustered regularly interspaced short palindromic repeats (MIRA-CRISPR)/Cas13a-lateral flow device (LFD). This assay targets the repeated DNA sequence (GenBank: L23861.1) of T. vaginalis and is performed at a constant temperature of 37 °C for approximately 1 hour.

Results
The detection limit of genomic DNA (gDNA) using our protocol was 1 × 10–4 ng/μl. Specificity was confirmed by the absence of cross-reaction with gDNA from various other microorganisms such as Staphylococcus aureus, Lactobacillus taiwanensis, Escherichia coli, Monilia albicans, Giardia lamblia, or Toxoplasma gondii. Among 30 clinical samples tested, the positive rates of T. vaginalis detection were 33.33% (10/30) by wet mount microscopy, 40% (12/30) by nested polymerase chain reaction (PCR), 40% (12/30) by MIRA-CRISPR/Cas13a-LFD, and 40% (12/30) by the culture method. Compared with the culture method, the gold standard for diagnosing trichomoniasis, wet mount microscopy showed a sensitivity of 83.3% and moderate diagnostic agreement (kappa value = 0.87). Both nested PCR and MIRA-CRISPR/Cas13a-LFD exhibited 100% sensitivity and excellent diagnostic agreement (kappa value = 1).

Conclusions
The MIRA-CRISPR/Cas13a-LFD method is a convenient, rapid, stable, and accurate diagnostic tool for detecting T. vaginalis. This method has the potential to enhance the diagnosis and management of vaginitis, offering a significant improvement over existing diagnostic techniques.

Graphical Abstract
Development and validation of a predictive model based on clinical and MpMRI findings to reduce additional systematic prostate biopsy
Authors: Cheng Xueqing , Chen Yuntian , Xu Jinshun , Cai Diming , Liu Zhenhua , Zeng Hao , Yao Jin , Song Bin 
Published: January 2024

Abstract
Objectives
To develop and validate a predictive model based on clinical features and multiparametric magnetic resonance imaging (mpMRI) to reduce unnecessary systematic biopsies (SBs) in biopsy-naïve patients with suspected prostate cancer (PCa).

Methods
A total of 274 patients who underwent combined cognitive MRI-targeted biopsy (MRTB) with SB were retrospectively enrolled and temporally split into development (n = 201) and validation (n = 73) cohorts. Multivariable logistic regression analyses were used to determine independent predictors of clinically significant PCa (csPCa) on cognitive MRTB, and the clinical, MRI, and combined models were established respectively. Area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analyses were assessed.

Results
Prostate imaging data and reporting system (PI-RADS) score, index lesion (IL) on the peripheral zone, age, and prostate-specific antigen density (PSAD) were independent predictors and included in the combined model. The combined model achieved the best discrimination (AUC 0.88) as compared to both the MRI model incorporated by PI-RADS score, IL level, and zone (AUC 0.86) and the clinical model incorporated by age and PSAD (AUC 0.70). The combined model also showed good calibration and enabled great net benefit. Applying the combined model as a reference for performing MRTB alone with a cutoff of 60% would reduce 43.8% of additional SB, while missing 2.9% csPCa.

Conclusions
The combined model based on clinical and mpMRI findings improved csPCa prediction and might be useful in making a decision about which patient could safely avoid unnecessary SB in addition to MRTB in biopsy-naïve patients.

Critical relevance statement
The combined model based on clinical and mpMRI findings improved csPCa prediction and might be useful in making a decision about which patient could safely avoid unnecessary SB in addition to MRTB in biopsy-naïve patients.

Key points
• Age, PSAD, PI-RADS score, and peripheral index lesion were independent predictors of csPCa.
• Risk models were used to predict the probability of detecting csPCa on cognitive MRTB.
• The combined model might reduce 43.8% of unnecessary SBs, while missing 2.9% csPCa.

Graphical Abstract
Impact of point-of-care clinical decision support on referrer behavior, imaging volume, patient radiation dose exposure, and sustainability
Authors: Schranz Amy L. , Ryan Dave T. , David Raegan , McNeill Graeme , Killeen Ronan P. 
Published: January 2024

Abstract
Objectives
When referring patients to radiology, it is important that the most appropriate test is chosen to avoid inappropriate imaging that may lead to delayed diagnosis, unnecessary radiation dose, worse patient outcome, and poor patient experience. The current radiology appropriateness guidance standard at our institution is via access to a standalone web-based clinical decision support tool (CDST). A point-of-care (POC) CDST that incorporates guidance directly into the physician workflow was implemented within a subset of head and neck cancer specialist referrers. The purpose of this audit was to evaluate the imaging pathway, pre- and post-implementation to assess changes in referral behavior.

Methods
CT and MRI neck data were collected retrospectively to examine the relationship between imaging referrals pre- and post-POC CDST implementation. Effective radiation dose and estimated carbon emissions were also compared.

Results
There was an overall reduction in absolute advanced imaging volume by 8.2%, and a reduction in duplicate CT and MRI imaging by 61%, p < 0.0001. There was also a shift in ordering behavior in favor of MRI (OR [95% CI] = 1.50 [1.02–2.22], p = 0.049). These changes resulted in an effective radiation dose reduction of 0.27 mSv per patient, or 13 equivalent chest x-rays saved per patient, p < 0.0001. Additionally, the reduction in unnecessary duplicate imaging led to a 13.5% reduction in carbon emissions, p = 0.0002.

Conclusions
Implementation of the POC CDST resulted in a significant impact on advanced imaging volume, saved effective dose, and reduction in carbon emissions.

Critical relevance statement
The implementation of a point-of-care clinical decision support tool may reduce multimodality ordering and advanced imaging volume, manifesting in reduced effective dose per patient and reduced estimated carbon emissions. Widespread utilization of the point-of-care clinical decision support tool has the potential to reduce imaging wait times.

Key points
• Implementation of the point-of-care clinical decision support tool reduced the number of patients who simultaneously had a CT and MRI ordered for the same clinical indication compared to a standalone web-based clinical decision support tool.
• The point-of-care clinical decision support tool reduced the absolute number of CT/MRI scans requested compared to the standalone web-based clinical decision support tool.
• Utilization of the point-of-care clinical decision support tool led to a significant reduction in the effective dose per patient compared to the standalone web-based clinical decision support tool.

Graphical Abstract
Economic evaluation of percutaneous cryoablation vs conventional surgery in extra-abdominal desmoid tumours in the Spanish healthcare system
Authors: Narvaez José Antonio , Bernabeu Daniel , Muntaner Lorenzo , Gomez Fernando , Martel José , Castellano María del Mar , García-Marcos Raúl , Britel Reda , Oyagüez Itziar , Tejado Nerea , Ortiz-Cruz Eduardo 
Published: January 2024

Abstract
Background
Desmoid tumours (DTs) or deep fibromatosis are benign soft-tissue tumours, sometimes locally aggressive, requiring intervention on some cases. Surgery has been the gold standard, but new less invasive techniques such as percutaneous cryoablation have proved their effectiveness, reducing health resources and complications. The study aimed to compare the total cost of percutaneous cryoablation and conventional surgery for patients with extra-abdominal and/or abdominal wall DTs, candidates for local ablative treatment in Spain.

Methods
A cost-analysis model was developed. An expert panel provided data about resource consumption for the percutaneous cryoablation technique and validated the epidemiology used for target population estimation. Unitary resources cost (€ 2022) derived from local cost databases. A retrospective analysis of 54 surgical cases in 3 Spanish hospitals was performed to estimate the cost of conventional surgery based on the cost of the Diagnosis-Related group (DRG) codes identified on this patient sample, weighted by each DRG proportion. The total cost for each alternative included intervention cost and complications cost, considering debridement required in 4.5% of cases with percutaneous cryoablation and minor surgery for surgical site infection in 18.0% for conventional surgery.

Results
The total cost for percutaneous cryoablation (€ 5774.78/patient-year) was lower than the total cost for conventional surgery (€ 6780.98/patient-year), yielding cost savings up to € 80,002 in 1 year for the entire cohort of 80 patients with DTs eligible for intervention estimated in Spain. One-way sensitivity analyses confirmed the results’ robustness.

Conclusion
Percutaneous cryoablation versus conventional surgery would yield cost savings for the management of DT patients in Spain.

Critical relevance statement
This manuscript provides insight into the economic impact derived from the savings related to the use of percutaneous cryoablation for desmoid-type tumours from the perspective of the Spanish National Healthcare System, providing useful information for the health decision-making process.

Key points
• Desmoid tumours are locally aggressive and may require local therapy.
• Percutaneous cryoablation procedure is less invasive than the conventional surgery.
• Cost comparison shows savings associated to percutaneous cryoablation use.

Graphical Abstract
Uncovering impaired mitochondrial and lysosomal function in adipose-derived stem cells from obese individuals with altered biological activity
Authors: Wang Bo , Zhang Ge , Hu Yuwen , Mohsin Ali , Chen Zhimin , Hao Weijie , Li Zhanxia , Gao Wei-Qiang , Guo Meijin , Xu Huiming 
Published: January 2024

Abstract
Background
Adipose-derived stem cells (ADSCs) have been extensively used in preclinical and clinical trials for treating various diseases. However, the differences between ADSCs from lean individuals (L-ADSCs) and those from obese individuals (O-ADSCs) have not been thoroughly investigated, particularly regarding their mitochondrial and lysosomal functions. Therefore, this study aims to evaluate the differences between L-ADSCs and O-ADSCs in terms of cell biological activity, mitochondria, and lysosomes.

Methods
We first isolated and cultured L-ADSCs and O-ADSCs. We then compared the differences between the two groups in terms of biological activity, including cell proliferation, differentiation potential, and their effect on the polarization of macrophages. Additionally, we observed the mitochondrial and lysosomal morphology of ADSCs using an electronic microscope, MitoTracker Red, and lysotracker Red dyes. We assessed mitochondrial function by examining mitochondrial membrane potential and membrane fluidity, antioxidative ability, and cell energy metabolism. Lysosomal function was evaluated by measuring autophagy and phagocytosis. Finally, we performed transcriptome analysis of the ADSCs using RNA sequencing.

Results
The biological activities of O-ADSCs were decreased, including cell immunophenotypic profiles, cell proliferation, and differentiation potential. Furthermore, compared to L-ADSCs, O-ADSCs promoted M1-type macrophage polarization and inhibited M2-type macrophage polarization. Additionally, the mitochondrial morphology of O-ADSCs was altered, with the size of the cells becoming smaller and mitochondrial fragments increasing. O-ADSCs also exhibited decreased mitochondrial membrane potential and membrane fluidity, antioxidative ability, and energy metabolism. With respect to lysosomes, O-ADSCs contained ungraded materials in their lysosomes, enhanced lysosomal permeability, and reduced autophagy and phagocytosis ability. RNA sequence analysis indicated that the signalling pathways related to cell senescence, cancer, and inflammation were upregulated, whereas the signalling pathways associated with stemness, cell differentiation, metabolism, and response to stress and stimuli were downregulated.

Conclusions
This study indicates that ADSCs from individuals (BMI > 30 kg/m2) exhibit impaired mitochondrial and lysosomal function with decreased biological activity.
Good manufacturing practice production of human corneal limbus-derived stromal stem cells and in vitro quality screening for therapeutic inhibition of corneal scarring
Authors: Santra Mithun , Geary Moira L. , Rubin Elizabeth , Hsu Michael Y. S. , Funderburgh Martha L. , Chandran Christine , Du Yiqin , Dhaliwal Deepinder K. , Jhanji Vishal , Yam Gary Hin-Fai 
Published: January 2024

Abstract
Background
Mesenchymal stem cells in the adult corneal stroma (named corneal stromal stem cells, CSSCs) inhibit corneal inflammation and scarring and restore corneal clarity in pre-clinical corneal injury models. This cell therapy could alleviate the heavy reliance on donor materials for corneal transplantation to treat corneal opacities. Herein, we established Good Manufacturing Practice (GMP) protocols for CSSC isolation, propagation, and cryostorage, and developed in vitro quality control (QC) metric for in vivo anti-scarring potency of CSSCs in treating corneal opacities.

Methods
A total of 24 donor corneal rims with informed consent were used—18 were processed for the GMP optimization of CSSC culture and QC assay development, while CSSCs from the remaining 6 were raised under GMP-optimized conditions and used for QC validation. The cell viability, growth, substrate adhesion, stem cell phenotypes, and differentiation into stromal keratocytes were assayed by monitoring the electric impedance changes using xCELLigence real-time cell analyzer, quantitative PCR, and immunofluorescence. CSSC’s conditioned media were tested for the anti-inflammatory activity using an osteoclastogenesis assay with mouse macrophage RAW264.7 cells. In vivo scar inhibitory outcomes were verified using a mouse model of anterior stromal injury caused by mechanical ablation using an Algerbrush burring.

Results
By comparatively assessing various GMP-compliant reagents with the corresponding non-GMP research-grade chemicals used in the laboratory-based protocols, we finalized GMP protocols covering donor limbal stromal tissue processing, enzymatic digestion, primary CSSC culture, and cryopreservation. In establishing the in vitro QC metric, two parameters—stemness stability of ABCG2 and nestin and anti-inflammatory ability (rate of inflammation)—were factored into a novel formula to calculate a Scarring Index (SI) for each CSSC batch. Correlating with the in vivo scar inhibitory outcomes, the CSSC batches with SI < 10 had a predicted 50% scar reduction potency, whereas cells with SI > 10 were ineffective to inhibit scarring.

Conclusions
We established a full GMP-compliant protocol for donor CSSC cultivation, which is essential toward clinical-grade cell manufacturing. A novel in vitro QC–in vivo potency correlation was developed to predict the anti-scarring efficacy of donor CSSCs in treating corneal opacities. This method is applicable to other cell-based therapies and pharmacological treatments.