bluuebunny/crossref_metadata_2025_split huggingface dataset:
De novo and inherited variants in DDX39B cause a novel neurodevelopmental syndrome
Authors: Booth Kevin T A , Jangam Sharayu V , Chui Martin M C , Treat Kayla , Graziani Lorenzo , Soldano Alessia , Ruan Yao , Wan-Hei Hui Jeffrey , White Kerry , Christensen Celanie K , Lynnes Ty , Yamamoto Shinya , Kanca Oguz , Tsang Mandy H Y , Lynch Sally A , Mullegama Sureni V , Batista Julia , Iancu Daniela , Joss Shelagh K , Wong Sandra Y Y , Mak Christopher C Y , Kwong Anna K Y , Bellen Hugo J , Conboy Erin , Sanges Remo , Leung Anskar Yu-Hung , Wangler Michael F , Chung Brian H Y , Vetrini Francesco 
Published: January 2025

Abstract
DDX39B is a conserved member of the DEAD-box family of ATP-dependent RNA helicases, critical in mRNA metabolism across eukaryotes. DDX39B is also a core component of the TRanscription-EXport (TREX) super protein complex, which recent studies have highlighted the important role of its subunits in neurodevelopmental disorders. Here, we describe six individuals from five families, four harboring de novo missense variants in DDX39B, and one with an inherited splicing variant, presenting with variable developmental delay, congenital hypotonia, epilepsy, short stature, skeletal abnormalities, dysmorphic features and microcephaly in three patients.
3D molecular modeling predicts these variants would alter protein structure. In vitro studies using overexpression of HA-tagged human DDX39B protein in 293FT cells revealed variants p.(Gly92Asp) and c.433-1G&gt;T impaired interaction with DDX39B and other TREX complex members, while variants p.(Gly37Cys), p.(Ser44Arg), and p.(Arg123Gln) did not affect TREX complex assembly. Blood transcriptomics studies demonstrated significantly elevated aberrant splicing events in individuals carrying the p.(Gly37Cys), p.(Arg123Gln), and c.433-1G&gt;T variant, compared to controls, suggesting a mRNA signature of disrupted mRNA splicing and export. To understand variant effects in vivo, we generated Drosophila transgenic DDX39B-reference and variant flies. Human reference DDX39B when overexpressed ubiquitously led to lethality but the patient variants did not, suggesting that the mutants are loss-of-function alleles. Zebrafish anti-sense morpholino knockdown of DDX39B led to reduced head size and body length consistent with the patient phenotypes, and these effects were mitigated by synthesized mRNA, indicating a loss-of-function effect of DDX39B.
Collectively, our human genetic data, coupled with in silico, in vitro, and in vivo data supports that DDX39B is a novel candidate gene in a potential group of disorders called TREX-complex-related neurodevelopmental syndrome.
Intestinal epithelial PTPN23 is essential for gut barrier integrity and prevention of fatal bacterial translocation
Authors: Sanchez Alvarez Rocio , Montalban-Arques Ana , Morsy Yasser , Gottier Claudia , Häfliger Janine , Atrott Kirstin , Bircher Anna , Katkeviciute Egle , Pöhlmann Doris , Linzmeier Luise , Determann Madita , Mamie Céline , Niechcial Anna , Schwarzfischer Marlene , Zeissig Sebastian , Lang Silvia , Scharl Michael , Spalinger Marianne 
Published: January 2025

Abstract

Background and Aims
Protein tyrosine phosphatase nonreceptor type 23 (PTPN23) regulates the internalization of growth factor receptors such as the epithelial growth factor receptor (EGFR). Given the crucial function of such receptors in intestinal epithelial cells (IECs), we assessed the involvement of PTPN23 in intestinal homeostasis and epithelial proliferation.

Methods
We generated mouse models with constitutive (PTPN23fl/flVilCre+/−) or inducible (PTPN23fl/flVilCreERT+/−) deletion of PTPN23 in IEC. To elucidate the functional consequences of PTPN23 deletion in IEC, we performed barrier function studies, flow cytometry, RNAseq, and in vivo experiments applying EGFR inhibition, antibiotic treatment, or co-housing approaches to further delineate the observed phenotype.

Results
Deletion of PTPN23 in IECs resulted in a severe early-onset phenotype in both models. Mice were characterized by elongated colon, epithelial hyperproliferation, splenomegaly, and diarrhea leading to the death of the mice within 3 weeks of PTNP23 deletion. Compromised gut barrier integrity resulted in enhanced bacterial translocation accompanied by reduced IgA transcytosis in PTPN23fl/flVilCreERT+/− compared to wild-type mice. Although EGFR surface expression was increased upon PTPN23-deletion, inhibition of EGFR signaling did not prevent disease. In contrast, and in accordance with defective bacterial handling, antibiotic treatment, but not co-housing, fully rescued the phenotype.

Conclusions
The absence of PTPN23 in IECs leads to lethal dysregulation of intestinal homeostasis, triggered by bacterial infiltration due to defects in the intestinal epithelial barrier and impaired IgA transcytosis. Thus, we identify PTPN23 as a novel key player in preserving intestinal epithelial homeostasis, ultimately preventing bacterial overgrowth and excessive immune activation in the intestine.
Clinical derivation and data simulated validation of rule-out and rule-in algorithms for the Siemens Atellica IM high-sensitivity cardiac troponin I assay
Authors: Restan Ingar Ziad , Steiro Ole-Thomas , Pickering John W , Tjora Hilde L , Langørgen Jørund , Omland Torbjørn , Collinson Paul , Bjørneklett Rune , Vikenes Kjell , Steinsvik Trude , Skadberg Øyvind , Mjelva Øistein R , Larsen Alf Inge , Bonarjee Vernon V S , Aakre Kristin M 
Published: January 2025

Abstract

Background
This prospective, two-centre study derived and validated predictive algorithms for the Siemens Atellica IM high-sensitivity cardiac troponin I (hs-cTnI) assay in the emergency department (ED).

Methods
Algorithms for predicting 30-day myocardial infarction type 1 and 2 (MI) and death or non-ST-elevation myocardial infarction (NSTEMI, type 1 and 2) at index admission were developed from a derivation cohort of 1896 patients and validated using a synthetic dataset with nearly 1 million patient cases. Performance was compared to the European Society of Cardiology algorithms for hs-cTnT (Roche Diagnostics) and hs-cTnI (Abbott Diagnostics).

Results
An admission hs-cTnI concentration &lt; 5 ng/L had a negative predictive value (NPV) and sensitivity for 30-day MI or death of 99.5 - 99.7 and 98.1- 98.8%, respectively, in the derivation cohort and validation dataset. The NPV and sensitivity was ≥99.7% and ≥98.8% for ruling out index NSTEMI. A 0-1-hour algorithm with baseline hs-cTnI concentration &lt; 10 ng/L and Δ change &lt; 3 ng/L had NPV of ≥99.5% and sensitivity ≥97.3% for predicting 30-day MI or death, and a ≥99.5% sensitivity and NPV for index NSTEMI. Rule-in algorithms of either 0-hour hs-cTnI ≥ 120 ng/L or 0-1 h Δ change ≥ 12 ng/L had positive predictive value (PPV) ≥ 73% and specificity &gt;96% for 30-day MI or death and index NSTEMI. The results were comparable to established hs-cTn algorithms.

Conclusions
This study presents Siemens Atellica hs-cTnI algorithms for diagnosis and risk-prediction in the ED with performance comparable to established hs-cTnT (Roche) and hs-cTnI (Abbott) algorithms.
Impact of technical, patient and measurement variables on Serial HU-based quantitative coronary plaque analysis in CT: Time for a New Chapter
Authors: Calicchio Francesca , Epstein Elizabeth , Boussoussou Melinda , Vattay Borbála , van Rosendael Alexander , Newlander Shawn , Kolossváry Márton , Szilveszter Bálint , Maurovich-Horvat Pál , Marques Hugo , McVeigh Elliot , Wesbey George 
Published: January 2025

Abstract
This review article explores the challenges and controversies involved in accurately identifying and reliably quantifying coronary plaque over time through coronary computed tomography angiography (CCTA), particularly focusing on lipid-rich, low-attenuation plaques. It highlights significant variability in lipid-rich plaque measurements across studies, questioning their reliability for tracking biological plaque transformation in clinical practice. To address this issue, the review article proposes suggestions for serial CCTA plaque measurements, aiming for realistic goals for reproducible and meaningful serial plaque coronary CT angiography imaging. It also emphasizes the necessity of standardized, validated methods for quantitative plaque analysis and underscores the potential of phantom-based calibration to improve the reliability and consistency of serial plaque measurements in clinical practice.
How Dark Trading Harms Financial Markets
Authors: Halim Edward , Riyanto Yohanes E , Roy Nilanjan , Wang Yan 
Published: January 2025

Abstract
We design an experiment to analyse the consequences of dark trading in a financial market. The channel through which dark trading affects market efficiency depends critically on how information regarding fundamentals is distributed among investors. When information is concentrated in the hands of a few investors, possibly due to sparse investor connectedness or low media coverage, dark trading primarily impacts market efficiency by deteriorating the quality of asset prices. When information is diffused, dark trading no longer harms price discovery, but the unobserved liquidity entails welfare loss. Dark trading does not widen the earnings gap between informed and uninformed traders.
More than meets the eye: predicting adrenocortical carcinoma outcomes with pathomics
Authors: Kong Jianqiu , Luo Mingli , Huang Yi , Lin Ying , Tan Kaiwen , Zou Yitong , Yong Juanjuan , Fu Sha , Zhang Shaoling , Fan Xinxiang , Lin Tianxin 
Published: January 2025

Abstract

Background
Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with high recurrence rates and poor prognosis. Current prognostic models are inadequate, highlighting the need for innovative diagnostic tools. Pathomics, which utilizes computer algorithms to analyze whole-slide images, offers a promising approach to enhance prognostic models for ACC.

Methods
A retrospective cohort of 159 patients who underwent radical adrenalectomy between 2002 and 2019 was analyzed. Patients were divided into training (N = 111) and validation (N = 48) cohorts. Pathomics features were extracted using an unsupervised segmentation method. A pathomics signature (PSACC) was developed through LASSO-Cox regression, incorporating 5 specific pathomics features.

Results
The PSACC showed a strong correlation with ACC prognosis. In the training cohort, the hazard ratio was 3.380 (95% CI, 1.687-6.772, P &lt; .001), and in the validation cohort, it was 3.904 (95% CI, 1.039-14.669, P &lt; .001). A comprehensive nomogram integrating PSACC and M stage significantly outperformed the conventional clinicopathological model in prediction accuracy, with concordance indexes of 0.779 versus 0.668 in the training cohort (P = .002) and 0.752 versus 0.603 in the validation cohort (P = .003).

Conclusions
The development of a pathomics-based nomogram for ACC presents a superior prognostic tool, enhancing personalized clinical decision making. This study highlights the potential of pathomics in refining prognostic models for complex malignancies like ACC, with implications for improving prognosis prediction and guiding treatment strategies in clinical practice.
Near-universal prevalence of central adiposity in heart failure with preserved ejection fraction: the PARAGON-HF trial
Authors: Peikert Alexander , Vaduganathan Muthiah , Claggett Brian L , Kulac Ian J , Litwin Sheldon , Zile Michael , Desai Akshay S , Jhund Pardeep S , Butt Jawad H , Lam Carolyn S P , Martinez Felipe , Van Veldhuisen Dirk J , Zannad Faiez , Rouleau Jean , Lefkowitz Martin , McMurray John J V , Solomon Scott D , Packer Milton 
Published: January 2025

Abstract

Background and Aims
An expansion of fat mass is an integral feature of patients with heart failure and preserved ejection fraction (HFpEF). While body mass index (BMI) is the most common anthropometric measure, a measure of central adiposity—the waist-to-height ratio (WHtR)—focuses on body fat content and distribution; is not distorted by bone or muscle mass, sex, or ethnicity; and may be particularly relevant in HFpEF.

Methods
The PARAGON-HF trial randomized 4796 patients with heart failure and ejection fraction ≥45% to valsartan or sacubitril/valsartan. The current work characterizes the association of BMI and WHtR with clinical features, outcomes, and the response to neprilysin inhibition.

Results
About half (49%) of the participants were considered obese by BMI (≥30 kg/m2), but nearly every patient (96%) had central adiposity (WHtR ≥0.5). Among patients who were not obese (BMI &lt;30 kg/m2), 860 (37%) had marked central adiposity (WHtR ≥0.6). Higher BMI and WHtR were both associated with higher risk of total heart failure hospitalizations, but as compared with BMI, WHtR was linearly associated with heart failure outcomes and identified a higher proportion of patients who had a particularly elevated risk (i.e., 30% or greater). An obesity-survival paradox (i.e., improved outcomes in those with greater adiposity) was apparent with BMI in unadjusted analyses, but it was not observed with WHtR. Although neprilysin inhibition appeared to have greater effects on heart failure outcomes in patients with higher BMI and WHtR, analyses of interaction with obesity metrics did not show significant heterogeneity across the range of values for adiposity.

Conclusions
In PARAGON-HF, in contrast with BMI, nearly every patient with HFpEF had central adiposity (as assessed by WHtR), and the risks of adverse heart failure events were more robustly related to WHtR. These data challenge the current reliance on BMI as an appropriate metric of adiposity, and they suggest that—rather than obesity-related HFpEF being regarded as a select HFpEF subgroup—central adiposity is a ubiquitous feature of HFpEF.
Signatures of natural selection may indicate a genetic basis for the beneficial effects of oily fish intake in indigenous people from coastal Ecuador
Authors: Brandt Débora Y C , Del Brutto Oscar H , Nielsen Rasmus 
Published: January 2025

Abstract
Atahualpa is a rural village located in coastal Ecuador, a region that has been inhabited by people as early as 10,000 years ago. The traditional diet of their indigenous inhabitants is rich in oily fish and they have, therefore, served as a model for investigating the beneficial effects of such a diet. However, the genetic background of this population has not been studied. In this study, we sequenced the genomes of Atahualpa residents to look for variants under natural selection, which could mediate the effects of oily fish intake. DNA was extracted from 50 blood samples from randomly selected individuals recruited in the Atahualpa Project Cohort. After applying various filters, we calculated genome-wide genotype likelihoods from 33 samples, and combined data from those samples with data from other populations to investigate how the Atahualpa population is genetically related to these populations. Using selection scans, we identified signals of natural selection that may explain the above-mentioned dietary effects. The genetic ancestry in Atahualpa residents is 94.1% of indigenous American origin, but is substantially diverged from other indigenous populations in neighboring countries. Significant signatures of natural selection were found in the Atahualpa population, including a broad selection signal around the SUFU gene, which is a repressor of Hedgehog pathway signaling and associated with lipid metabolism, and another signal in the upstream region of LRP1B which encodes low-density lipoprotein (LDL) receptor related protein 1B. Our selection study reveals genes under selection in the Atahualpa population, which could mediate the beneficial effects of oily fish intake in this population.
Care Recipients’ Cognitive Trajectories and Caregivers’ Depressive Symptoms: The Mediating Role of Caregiving Burden
Authors: Lou Yifan , Gong Jiaowei , Zang Emma 
Published: January 2025

Abstract

Background and Objectives
The heterogeneity of population-based trajectories of care recipients’ (CRs) cognitive functioning and how they are associated with their caregivers’ mental health is less studied in the United States. Informed by the stress process model, this study examines the relationship between care recipients’ cognitive trajectories and caregivers’ depressive symptoms, and the mediating role of caregiving burden.

Research Design and Methods
Data were from the National Health and Aging Trends Study (2011-2020) for 1,086 care recipients and their 1,675 caregivers from the 2021 National Study of Caregiving. We applied Bayesian group-based trajectory modeling to identify distinct cognitive trajectory groups among care recipients. Hierarchical linear models were then used to examine the associations between these trajectory group memberships and caregivers’ depressive symptoms. Finally, Gelbach decomposition analysis was conducted to investigate the mediating role of physical, emotional, and financial caregiving burden.

Results
Five cognitive trajectories were identified among care recipients: “high start, stable” (11.81%), “medium-high start, slight decline” (31.83%), “medium start, slight decline” (27.72%), “medium-low start, sharp decline” (20.60%), and “low start, sharp decline” (8.04%). Worse cognitive trajectories (e.g., lower baselines and steeper slopes) were associated with increasing caregivers’ depressive symptoms; financial, emotional, and physical caregiving burdens jointly explained 63.5% of this association. Emotional caregiving difficulty is the most important contributing caregiving burden, explaining 49.6% of the observed association.

Discussion and Implications
When understanding caregiving experiences, it is critical to consider longitudinal cognitive course among care recipients. Interventions targeting multiple aspects of caregiving burden, especially emotional burden, should be prioritized.
What explains the growth in hospital assets from 2000 through 2019? A decomposition analysis
Authors: Teeple Stephanie , Andy Caroline , Schpero William L , Chatterjee Paula 
Published: January 2025

Abstract
Understanding disparities in hospital finances is essential for ensuring equitable systems of care. One understudied element is total assets, which include both financial and capital resources that hospitals acquire. We evaluated changes and drivers of variation in US hospital assets from 2000 through 2019 using data from the Centers for Medicare and Medicaid Services and American Hospital Association Annual Survey. We decomposed overall variation in total assets to determine the level (hospital, health system, or health care market) that contributed most to variation, and examined the extent to which asset growth was associated with changes in common inputs to hospital wealth vs changing relationships with these inputs or other unmeasured factors. Total assets held by US hospitals increased from $750 billion in 2000 to $1.6 trillion in 2019. Most variation occurred between hospitals, such that high-asset hospitals tended to remain high-asset and low-asset hospitals remained low-asset. Most of the increase in assets was due to unmeasured factors (ie, not patient revenue). We conclude that hospital wealth in the form of assets has grown substantially over time and accrued primarily to wealthy hospitals. Policymakers should consider broader measures of hospital wealth when targeting financial resources and efforts to strengthen data on hospital financing.
Use of wireless geographic locating system to improve medical equipment utilization and medical quality
Authors: Huang Tien-Lin , Lei Yi-Fang , Wang Pa-Chun 
Published: January 2025

Abstract
Hospitals require continuous process optimization to ensure uninterrupted care. This study investigates the integration of Real-Time Locating Systems (RTLS) with logistics and dispatch management in a metropolitan hospital. The system, which tracks circulating beds and medical equipment, improves resource allocation, reduces inefficiencies, and enhances task distribution using wearable devices and big data analytics. Results showed a 20.9% reduction in delivery time, 86.8% faster equipment search, and 91.2% staff satisfaction with zero adverse event recurrence. The findings underscore RTLS’s potential to enhance medical quality, efficiency, and patient safety through digital technology adoption.
Correlation between rrs gene mutations and amikacin resistance in Mycobacterium abscessus: implications for fitness cost and clinical prevalence
Authors: Ding Jie , Hameed H M Adnan , Long Lihua , Zhang Jingran , Fang Cuiting , Tian Xirong , Zhang Han , Li Lijie , Li Chunyu , Yang Ruhao , Gao Yamin , Wang Shuai , Zhang Tianyu 
Published: January 2025

Abstract

Objectives
Amikacin is crucial for treating Mycobacterium abscessus (Mab) infections, with resistance primarily attributed to rrs gene mutations. The correlation between specific mutations and amikacin susceptibility, along with the associated fitness cost, requires further investigation.

Methods
We isolated spontaneous amikacin-resistant mutants in vitro and identified their mutation sites in the rrs gene via Sanger sequencing, which were then compared with existing reports. Using CRISPR/Cas12a-assisted recombineering, we engineered Mab strains with specific rrs mutations. The growth rate and fitness costs in vitro were evaluated, in conjunction with drug susceptibility testing to determine the relationship between rrs mutations and amikacin resistance.

Results
The mutation frequency of Mab for amikacin resistance ranged from 4.68 × 10⁻⁷ to 9.38 × 10⁻⁹. Three rrs mutation sites (A1375G, C1376T, G1458T) were identified, with A1375G being the most prevalent. Two additional sites, T1373A and T1465A, have been reported previously but not detected in this study. The five gene-edited strains demonstrated resistance to amikacin and cross-resistance to other aminoglycosides, and all exhibited slower in vitro growth rates than the wild-type Mab. Competitive experiments revealed that T1373A and T1465A have high fitness costs, while C1376T and G1458T have weak fitness costs and A1375G shows no fitness costs.

Conclusions
Our findings confirm that rrs mutations confer high-level amikacin resistance, with the limited mutation spectrum in clinical isolates possibly linked to higher spontaneous mutation frequency and lower fitness costs.
Sulfate-reducing bacteria block cadmium and lead uptake in rice by regulating sulfur metabolism
Authors: Fang Li-Rong , Ren Jing-Yu , Sun Kai , Zhang Wei , He Wei , Dai Chuan-Chao 
Published: January 2025

Abstract

Aim
This study was dedicated to investigating the role of sulfur metabolic processes in sulfate-reducing bacteria in plant resistance to heavy metal contamination.

Methods and results
We constructed sulfate-reducing bacterial communities based on the functional properties of sulfate-reducing strains and then screened out the most effective sulfate-reducing bacterial community SYN1, that prevented Cd and Pb uptake in rice through a hydroponic experiment. This community lowered Cd levels in the roots and upper roots by 36.60% and 39.88%, respectively, and Pb levels by 35.96% and 51.54%. We also compared two treatment groups, inoculated with SYN1 and exogenously added GSH, and found that both enhanced the antioxidant response of the plants, increased the lignin and GSH contents and the expression of genes related to the phenylpropane biosynthesis pathway (OsCAD, Os4CL, OsCOMT, OsPOD, OsC3H, and OsPAL), and decreased the expression of heavy metal transporter genes (OsHMA2, OsIRT1) expression. There were no significant differences between the two treatments.

Conclusions
Sulfate-reducing bacteria produce GSH through the sulfur assimilation pathway, and GSH can directly chelate heavy metals or enhance plant antioxidant enzyme activities and regulate processes such as the uptake and translocation of heavy metals, thus enhancing plant resistance to heavy metal toxicity.