bluuebunny/crossref_metadata_2025 huggingface dataset:
Unlocking the Potential of the HEART Pathway: Predicting MACE and Facilitating Nurse–Physician Collaboration in Chest Pain Unit
Authors: Behpour Zahra , Amirsardari Zahra , Aghakhani Haniye , Zanganehfar Mohammadesmaeil , Khaleghparast Shiva , Shabani Fidan , Bakhshandeh Hooman , Sadeghipour Parham
Published: February 2025

Background and Objective:

The HEART pathway serves as a tool for predicting major adverse cardiac events (MACE) among patients presenting with acute chest pain, aiding in the early discharge of low-risk patients and reducing unnecessary cardiac investigations. This study aimed to evaluate physician–nurse reliability of the HEART pathway and investigate the efficacy of HEART pathway to predict 3-month MACE in patients with acute chest pain.

Methods:

We conducted a prospective study on 97 patients experiencing acute chest pain. A team of 3 professionals, a nurse, a cardiology resident, and a cardiology attending physician, performed risk stratification. We assessed interrater reliability among the raters as well as explored 3-month MACE outcomes.

Results:

Excellent pairwise agreements were found between the raters. Overall agreement among raters was excellent, with an intraclass correlation coefficient of 0.84 (95% confidence interval: 0.73–0.97). The HEART pathway score exhibited strong predictive power (area under curve: 0.85) for 3-month MACE. At a cutoff score of 4, sensitivity, specificity, and negative predictive values were 87.5%, 58.9%, and 95.8%, respectively.

Conclusions:

The HEART pathway score effectively predicts 3-month MACE in patients with acute nontraumatic chest pain. Moreover, the high agreement among the attending physician, the resident physician, and the nurse suggests that nurses could use this tool, potentially reducing the workload on physicians.
A Case of Uveal Melanoma Masquerading as Choroidal Lymphoma
Authors: Sahal H Saleh , Rima Stepanian , Joseph D Juliano , Robert Folberg , Lau-Sickon Laurie , Lisa J Faia , Adam J Weiner
Published: February 2025

Purpose:

To present a case of uveal melanoma masquerading as choroidal lymphoma.

Methods:

A retrospective case report in which medical and imaging records, including fundus photography, optical coherence tomography, fundus autofluorescence, fluorescein angiography, and ultrasonography were reviewed.

Results:

A 77-year-old woman presented with decreased vision was found to have a diffuse, shallow, yellow choroidal mass associated with RPE pigmentary changes and exudative detachment in her right eye. Multi-modal imaging demonstrated thickened choroid with a “lumpy-bumpy” appearance on OCT, “leopard-spotting” on fundus autofluorescence, and a shallow “table-top” configuration on B scan. Systemic workup was unremarkable. The patient elected to undergo treatment with low-dose external beam radiation for presumed choroidal lymphoma. There was no response to radiation prompting retinochoroidal biopsy, which revealed spindle-cell uveal melanoma and resulted in enucleation.

Conclusion:

We present a case of uveal melanoma masquerading as choroidal lymphoma. This case highlights that uveal melanoma can rarely masquerade as other entities, including uveal lymphoma.
Phoenix Sepsis Criteria in Critically Ill Children: Retrospective Validation Using a United States Nine-Center Dataset, 2012–2018
Authors: Sanchez-Pinto L. Nelson , Daniels Latasha A. , Atreya Mihir , Faustino E. Vincent S. , Farris Reid W. D. , Geva Alon , Khemani Robinder G. , Rogerson Colin , Shah Sareen S. , Weiss Scott L. , Bennett Tellen D.
Published: February 2025

Objectives:

To perform: 1) external validation of the Phoenix Sepsis Score and Phoenix sepsis criteria in a multicenter cohort of critically ill children with infection and a comparison with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria; 2) a study of Phoenix sepsis criteria performance in patient subgroups based on age and comorbidities; 3) an assessment of microbiological profile of children with Phoenix sepsis; and 4) a study of the performance of the Phoenix-8 score.

Design:

Secondary, retrospective analysis of a multicenter cohort study from 2012 to 2018.

Setting:

Nine PICUs in the United States.

Patients:

PICU admissions with suspected infection.

Interventions:

None.

Measurements and Main Results:

Among 25,680 encounters of children with suspected or confirmed infection on PICU admission (4.6% in-hospital mortality), 11,168 (43%) met Phoenix criteria for sepsis or septic shock (9% in-hospital mortality). The Phoenix criteria generally outperformed the IPSCC criteria at discriminating mortality in all critically ill children with infections and across all subgroup analyses, including age group, malignancy, or technology dependence. Of 11,168 patients who met Phoenix criteria, 28% were negative for IPSCC criteria for sepsis and these had higher in-hospital mortality than those who met IPSCC sepsis criteria but not Phoenix criteria (4.7% vs.1.7%; p < 0.001), which was similar to the mortality of patients without sepsis (1.3%). Sepsis was associated with respiratory or bloodstream infection, most commonly Pseudomonas aeruginosa or Staphylococcus aureus. The Phoenix-8 score had good discrimination of mortality in children with infections, comparable to or better than validated and widely used severity of illness and organ dysfunction scores.

Conclusions:

In 2012–2018, among U.S. patients with suspected or confirmed infection admitted to nine PICUs, those with the highest risk of mortality can be identified using the Phoenix sepsis criteria, including in children of different age groups and those with major comorbidities.
Kidney organ injury scaling: 2025 update
Authors: Keihani Sorena , Tominaga Gail T. , Matta Rano , Gross Joel A. , Cribari Chris , Kaups Krista L. , Crandall Marie , Kozar Rosemary A. , Werner Nicole L. , Zarzaur Ben L. , Coburn Michael , Myers Jeremy B.
Published: February 2025

The American Association for the Surgery of Trauma initially published the organ injury scaling for the kidney in 1989, which was subsequently updated in 2018. This current American Association for the Surgery of Trauma kidney organ injury scaling update incorporates the latest evidence in diagnosis and management of renal trauma and is based upon a multidisciplinary consensus. These changes reflect the near universal use of computed tomography for renal trauma evaluation and the widespread adoption of conservative management across all grades of renal trauma.
Anticoagulant vs. antiviral therapy, recovery and neurodamage in Long COVID: a real-world prospective cohort study
Authors: Jamoulle Marc , Mignolet Margaux , Meyts Isabelle , Ladang Aurélie , Nicaise Charles , Van Weyenbergh Johan
Published: February 2025

Recent estimates consider that Long COVID affects 400 million people worldwide, of which <10% recover after two years. Predictive biomarkers and effective therapies are urgently needed for the clinical management of Long COVID. Neurological manifestations (poor memory, brain fog) are frequent, while neurodamage and neuroinflammatory markers UCHL1, GFAP and NFL were found to be increased in some but not all Long COVID cohorts. However, a direct link between two major Long COVID disease mechanisms, viral persistence and coagulation defects, and CNS damage is unclear. Therefore, we investigated the effect of combined anticoagulant (Asaflow + Clopidogrel) vs. antiviral (Paxlovid) treatment upon clinical outcome and neurodamage markers in Long COVID patients. Using multivariate logistic regression, we found that second-line antiviral treatment is the single best predictor of clinical recovery in a real-world Long COVID cohort (n=106) with long-term (220 person-years) follow-up. Our results support a putative role for viral persistence in Long COVID pathogenesis but also indicate a large therapeutic window for Paxlovid and other antivirals. A rapid decline in neurodamage markers (GFAP/NFL) upon antiviral treatment suggests CNS damage in Long COVID might be therapeutically targeted and should be considered in ongoing and future clinical trials.
panHiTE: a comprehensive and accurate pipeline for TE detection in large-scale population genomes
Authors: Hu Kang , Xu Minghua , Wang Jianxin
Published: February 2025

Transposable elements (TEs) are key drivers of genomic variation and species evolution. Advances in high-throughput sequencing have enabled whole-genome sequencing of individuals or subspecies, facilitating the identification of population-specific variations. Detecting population-specific TE insertions at scale is crucial for understanding species-specific phenotypic traits. However, tools for constructing comprehensive pan-TE databases remain limited. To address this gap, we develop panHiTE, a population-scale TE detection and annotation tool with several core innovations. panHiTE features a deep learning-based long terminal repeat retrotransposon (LTR-RT) detection algorithm, outperforming existing tools in both sensitivity and precision. It also introduces a novel de-redundancy algorithm, which eliminates highly divergent redundant TE instances, significantly reducing the size of the TE library. Additionally, panHiTE can detect low-copy TEs, which are overlooked in individual genome analyses and absent from existing databases due to their rarity. Furthermore, panHiTE allows for TE-gene association analysis, enabling comprehensive insights into TE-driven phenotypic variation. panHiTE, powered by a Nextflow pipeline, enables efficient and scalable TE detection in large plant genomes and has successfully been applied to hundreds of plant population genomes, demonstrating its effectiveness and scalability.
Time for a standardized neurological assessment in acute setting: the modified Neurological Impairment scale
Authors: Padovani Alessandro , Mattioli Irene , Comunale Tiziana , Zoppi Nicola , Zatti Cinzia , Guso Enis , Catania Marcello , Morotti Andrea , Agosti Chiara , Gipponi Stefano , Turner-Stokes Lynne , Pilotto Andrea
Published: February 2025

Background

Given the increasing diversity among neurological patients, standardized protocols are essential for evaluating the severity and complexity of the variety of conditions. Aim of the present work was to standardize the assessment of the severity and complexity of neurological impairment in an acute setting by using a modified version of the Neurological Impairment Scale (mNIS).

Methods

consecutively hospitalized neurological inpatients underwent a multidimensional standardized assessment of multimorbidity, frailty, functional dependency, and neurological impairment using mNIS and other validated scales. Inter-rater reliability of the mNIS total and sub-scores was evaluated. Construct validity was assessed separately in patients with Cerebrovascular disease performing correlations between corresponding sub-scores of mNIS, original NIS, and National Institutes of Health Stroke Scale (NIHSS). mNIS Complexity Index (mNIS-CI) for neurological severity was used to classify patients into subtle, mild, moderate, and severe impairment.

Results

one thousand eighty-one neurological patients admitted to a neurological ward from the emergency setting were enrolled. The inter-rater reliability was remarkable for mNIS total and sub-scores (ICC 0.90, 95% CI 0.82–0.95). The mNIS showed strong construct validity for total and sub-scores compared to other clinical scales (r 0.47-0.97, p<0.001) and 52.7% of patients scored at least one in one of the four newly listed items. The stratification of patients according to mNIS-CI exhibited high construct validity distinguishing the extent of impairment and involved domains.

Conclusions

The mNIS is valuable for measuring neurologic severity and complexity in acute inpatients and holds significant potential for application in different settings.

What is already known on this topic

Standardization of neurological assessment and development of functional rating scales of global impairment are pivotal to characterize and follow up patients both in the clinical practice and in the research setting.

What this study adds

mNIS is a valuable tool to measure neurologic severity and complexity in acute inpatients: the four added items are useful for capturing a broader spectrum of signs and symptoms; the severity and complexity scores provide different information about neurological status and domain imapired at individual level.

How this study might affect research, practice, or policy

mNIS can be instrumental in grading the severity of neurological conditions, tracking clinical progress, and gauging response to treatments in the acute setting.
f4-statistics-based ancestry profiling and convolutional neural network phenotyping shed new light on the structure of genetic and spike shape diversity inAegilops tauschiiCoss
Authors: Koyama Yoshihiro , Nasu Mizuki , Matsuoka Yoshihiro
Published: February 2025

Aegilops tauschiiCoss., a progenitor of bread wheat, is an important wild genetic resource for breeding. The species comprises three genetically defined lineages (TauL1, TauL2, and TauL3), each displaying distinctive phenotypes in various agronomic traits, including spike shape. In the present work, we studied the relationship between population structure and spike shape variation patterns using a collection of 249 accessions.f4-statistics-based ancestry profiling confirmed the previously identified lineages and revealed a genetic component derived from TauL3 in the genomes of some southern Caspian and Transcaucasus TauL1 and TauL2 accessions. Spike shape variation patterns were analyzed using a convolutional neural network-based approach, trained on green and dry spike image datasets. This analysis showed that spike shape diversity is structured according to lineages and demonstrated that the lineages can be distinguished based on spike shape. The implications of these findings for the origins of common wheat and the intraspecific taxonomy ofAe. tauschiiare discussed.

Plain Language Summary

Wild wheat,Aegilops tauschii, represents a vast reservoir of alleles that have not yet been utilized in breeding. These alleles may confer beneficial phenotypes, such as drought tolerance and disease resistance, when introduced into bread wheat. To fully leverage this reservoir, it is essential to quickly identify strains with potentially useful alleles. InAe. tauschii, which consists of strain groups (lineages) with unique genetic makeups, this can be done by determining a strain’s lineage based on spike shape. In this work, we trained machine learning models for this purpose and found that spike shape diversity reflects lineage structure. These models demonstrated potential for practical use in assigning strains to their respective lineages based on spike shape. Our work opens new avenues for the application of machine learning in wheat improvement, as well as in the genetic and evolutionary studies of wheat morphology.
Combining machine learning and publicly available aerial data (NAIP and NEON) to achieve high-resolution remote sensing of grass-shrub-tree mosaics in the Central Great Plains (U.S.A.)
Authors: Noble Brynn , Ratajczak Zak
Published: February 2025

Woody plant encroachment (WPE)—a phenomenon similar to species invasion—is shifting many grasslands and savannas into shrub and evergreen-dominated ecosystems. Tracking WPE is difficult because shrubs and small trees are much smaller than the coarse resolution of common remote sensing platforms (> 10 m2) and the impassibility of encroaching woody thickets slows ground-based approaches. Many agencies have been investing in fine resolution (< 2 m2) remote sensing through programs such as the United States Department of Agriculture (USDA) National Agriculture Imagery Program (NAIP) and the National Ecological Observatory Network (NEON). Both use low-flying planes and provide data to end users in an easy-to-use format at large spatial extents. By removing entry barriers, these publicly available open-source programs could increase the accessibility and extent of remote sensing. We compared two common methods of machine learning classification of land cover (random forests and support vector machines) factorially crossed with these two freely available remote sensing platforms to determine if we could quickly and accurately develop remote sensing of major vegetation types in a tallgrass prairie landscape undergoing encroachment by shrubs and trees. Our work took place at Konza Prairie Biological Station—a landscape scale experiment that results in a wide range of land cover types. All models had very high overall classification accuracy (>90%), with the NEON-based models a few percent more accurate than NAIP. A model using both inputs had the highest accuracy. However, the accuracies of NAIP and NEON models differed for woody vegetation: compared to NEON, NAIP accuracy was, 82-93% compared to 94-98% for shrubs, 72-92% compared to 93-98% for deciduous trees, and 52-78% compared to 83-86% for evergreen trees (specificallyJuniperus virginiana). NEON-based models relied on canopy height (LiDAR) to make classifications, whereas the several bands of light make similar contributions to accuracy in the NAIP models. Finally, we found that both machine learning approaches had similar accuracy, but random forests ran substantially faster. We conclude that with large training datasets, publicly available aerial imagery and similar products (e.g., UAVs, micro-satellites) can produce fine-scale, high-accuracy remote sensing of WPE in this region with low up-front costs.
Heat Shock-Induced PI(4)P Increase Drives HSPA1A Translocation to the Plasma Membrane in Cancer and Stressed Cells through PI4KIII Alpha Activation
Authors: Arce Alberto , Altman Rachel , Badolian Allen , Low Jensen , Cuaresma Azalea Blythe , Keshet Uri , Fiehn Oliver , Stahelin Robert V. , Nikolaidis Nikolas
Published: February 2025

HSPA1A, a major heat shock protein, is known to translocate to the plasma membrane (PM) in response to cellular stress and cancer, where it plays protective roles in membrane integrity and stress resistance. Although phosphatidylinositol 4-phosphate [PI(4)P] is essential in this translocation, the signals that trigger and facilitate HSPA1A’s movement remain undefined.Given that membrane lipid composition dynamically shifts during stress, we hypothesized that heat shock-induced PI(4)P changes are crucial for HSPA1A’s PM localization. To test this hypothesis, we investigated the mechanisms driving PI(4)P changes and HSPA1A PM localization under heat shock. Lipidomic analysis, enzyme-linked immunosorbent assay (ELISA), and confocal imaging revealed a rapid PI(4)P increase at the PM post-heat shock, with levels peaking at 0 hours and declining by 8 hours. RNA sequencing and protein quantification indicated no transcriptional increase in PI4KIII alpha, the kinase responsible for PI(4)P synthesis, suggesting an alternative regulatory mechanism. Hypothesizing that heat shock enhances PI4KIII alpha activity, we performed ELISA coupled with immunoprecipitation, confirming a significant rise in PI4KIII alpha activity following heat shock. Functional analyses further demonstrated that RNAi-mediated PI4KIII alpha depletion or pharmacological PI(4)P reduction, using GSK-A1, impairs HSPA1A’s localization to the PM, confirming that HSPA1A translocation is PI(4)P-dependent. Our findings identify PI4KIII alpha activity as a key regulator of PI(4)P accumulation and subsequent HSPA1A recruitment to the PM in stressed and cancer cells. This lipid-mediated response offers new insights into stress adaptation and potentially modifiable pathways for therapeutic interventions to control HSPA1A function in cancer.
Self-Supervised Learning Can Distinguish Myelodysplastic Neoplasms from Clinical Mimics Using Bone Marrow Biopsies
Authors: Mehrtash Vahid , Le Hortense , Jafarzadeh Bita , Loghavi Sanam , Garcia-Manero Guillermo , Tsirigos Aristotelis , Park Christopher Y.
Published: February 2025

The diagnosis of myelodysplastic neoplasms (MDS) requires examination of the bone marrow for morphologic evidence of dysplasia. We sought to determine if a self-supervised learning (SSL) AI image analysis approach may be utilized to reliably distinguish MDS from its clinically relevant mimics using bone marrow biopsies (BMBx). Whole slide images (WSIs) of H&E- and reticulin-stained BMBx sections from 243 unique patients (89 MDS, 55 non-MDS cytopenic controls [NMCC], and 99 negative control [NC] cases) were segmented into tiles and analyzed. These tiles were then processed using the Barlow Twins SSL model to generate histomorphologic phenotype clusters (HPCs). Review of the HPCs revealed the clusters enriched in MDS captured known histopathologic features of MDS including hypercellularity, dysplastic and clustered megakaryocytes, increased immature hematopoietic cells, increased vascularity, fibrosis, and cell streaming patterns. Assessment of 95 MDS BMBx images from a second institution showed consistent HPC enrichment patterns, validating the robustness of the model. The trained ensemble model using H&E- and reticulin-stained slides distinguished MDS from NCs with an AUC of 0.89, and from age-matched, NMCCs with an AUC of 0.84. These findings demonstrate the potential of SSL approaches to capture diagnostically relevant morphologic patterns and to improve the reproducibility of MDS diagnosis.
Long term consequences of Total Ankle Replacement versus Ankle Fusion; a 25 year national population study of 41,000 patients
Authors: Hennessy Conor , Abram Simon , Brown Rick , Loizou Constantinos , Sharp Robert , Kendal Adrian
Published: February 2025

Aims

Definitive and successful treatment of end stage ankle arthritis is either Total Ankle Replacement (TAR) or Ankle Fusion (AF). Both options place patients on an irreversible pathway that risks harm from further surgery. AF may predispose patients to subsequent hindfoot joint fusion and TAR is associated with high rates of complex revision surgery. The aim is to improve decision making by investigating the risks of further surgery, adjacent joint surgery and rare but serious complications of AF versus TAR.

Methods

An England population cohort study was performed using the Hospital Episode Statistics database, linked to ONS mortality data (19982023). The primary outcome was Kaplan Meier curve analysis of revision surgery free survival of TAR versus AF. Secondary outcome measures were the rates of adjacent joint/hindfoot fusion, any further reintervention to the ankle, perioperative mortality, 90 day complications, and serious adverse events.

Results

10,335 TAR and 30,704 AF were analysed. The AF revision rate was significantly lower than TAR at all time points including; 5 years (2% vs 6.1%, RR 0.12; 95% CI 0.10 to 0.16), 10 years (2.5% vs 10.2%, RR 0.12; 95% CI 0.08 to 0.18) and 20 years (3.1% vs 13.55%, RR 0.12; 95% CI 0.01 to 0.23).

There was no significant difference in 25 year risk of adjacent joint fusion following AF (8.64%, 95% CI 7.79% to 9.58%) versus TAR (6.82%; 95% CI 5.36% to 8.66%). TAR was associated with higher risks of intra operative fracture (0.42% vs 0.10%, RR = 4.35) and reintervention for wound infection (0.26% vs 0.15%, RR 1.74) but fewer pulmonary emboli (0.23% vs 0.58%, RR = 0.40).

Conclusion

Both TAR and AF are safe definitive treatments of ankle arthritis with low perioperative risk. TAR is associated with a significantly higher rate of further revision surgery than AF. AF does not predispose patients to hindfoot fusion surgery.
Human milk-derived extracellular vesicle treatment promotes the heat shock response in neonates with perinatal high fat diet exposure
Authors: Storm Jasmyne A. , Lu Jueqin , Obtial Mon Francis , Wijenayake Sanoji
Published: February 2025

Maternal consumption of a high-fat diet (mHFD) during perinatal life (the collective prenatal and postnatal periods) influences neonatal development, initiates hypothalamic-pituitary-adrenal (HPA) axis activation, and impacts the long-term physiological and metabolic health of offspring. Milk-derived extracellular vesicles (MEVs) are lipid-coated nanovesicles found in mammalian milk that survive intestinal degradation and cross complex biological barriers, including the blood-brain barrier. MEVs have known cytoprotective activity in peripheral organs; however, their pro-survival functions in response to chronic pro-inflammation stemming from early life nutrient stress remain unknown in the neonatal brain. Further, sex differences resulting from MEV treatment require investigation, as male and female neonates illicit variable responses to early life nutrient stress. We investigated whether MEVs promote the heat shock response (HSR), a principal pro-survival mechanism responsible for refolding or degrading misfolded protein aggregates through the action of heat shock protein (HSP) chaperones. We investigated the interaction between MEVs and the HSR in the liver, hypothalamus, and prefrontal cortex in male and female neonatal rats exposed to perinatal mHFD within the stress hyporesponsive period at postnatal day 11. MEV treatment robustly modulated the HSR in female neonates with the largest response recorded in the prefrontal cortex. Specifically, in the prefrontal cortex, MEV treatment led to an upregulation of the main transcription factor (HSF1), while downregulating the negative regulators of HSF1 (Hsp70 and Hsp90). These results suggest that MEVs may influence pro-survival outcomes in the prefrontal cortex by activating HSF1-mediated pro-survival in a sex specific manner in response to mHFD.
Exploring the Impact of Volumetric Additive Manufacturing of Photo-crosslinkable Gelatin on Mesenchymal Stromal Cell Behavior and Differentiation
Authors: Pien Nele , Bogaert Bryan , Meeremans Marguerite , Popovici Cezar-Stefan , Dubruel Peter , De Schauwer Catharina , Van Vlierberghe Sandra
Published: February 2025

This study explores the application of photo-crosslinkable gelatin hydrogels (constituting GelSH and GelNB) for biofabrication using volumetric additive manufacturing (VAM). Three GelSH variants were prepared, yielding degree of substitutions (DS) of 39%, 54%, and 63%, and GelNB with a DS of 60%, alongside GelNB-GelSH formulations at concentrations of 5, 7.5, and 10% (w/v). Physico-chemical analyses confirmed that these variations led to differences in mass swelling ratio and mechanical properties. VAM enabled the fabrication of complex, high-fidelity 3D structures from the optimized GelNB-GelSH formulations, demonstrating its capacity to encapsulate mesenchymal stromal cells (MSCs) within a biomimetic matrix. Compared to the film casted constructs, the VAM-printed scaffolds exhibited significantly higher ALP activity and calcium deposition, confirming effective osteogenesis. Conversely, chondrogenic and adipogenic differentiation were more pronounced in the film casted groups due to their lower crosslinking density and lower compressive elastic modulus, emphasizing the role of the mechanical environment role in guiding cell differentiation. This study highlights the potential of VAM to produce complex and functional hydrogel scaffolds for tissue engineering, and lays the groundwork for future work on finetuning bioresin formulations to enhance differentiation across multiple lineages for various tissue engineering applications, including softer tissues.

Abstract Figure

This study investigates photo-crosslinkable gelatin hydrogels (GelSH and GelNB) for volumetric additive manufacturing (VAM) in biofabrication. Different formulations influenced swelling and mechanical properties. VAM produced complex 3D scaffolds encapsulating mesenchymal stromal cells, enhancing osteogenesis compared to film-cast constructs. The findings highlight VAM’s potential for tissue engineering and optimizing bioresins for multi-lineage differentiation, including softer tissues.
Impact of nephrotoxins and oxidants on survival and transport function of hiPSC-derived renal proximal tubular cells
Authors: Mboni-Johnston Isaac Musong , Hartmann Sören , Kroll Christian , Berndt Carsten , Adjaye James , Schupp Nicole
Published: February 2025

Due to their role in excretion, renal proximal tubule cells are susceptible to damage by toxic metabolites and xenobiotics. The regenerative capacity of the kidney allows for the replacement of damaged cells, a process involving differentiation programs. However, kidney function tends to decline, suggesting that the replacement cells may not achieve full functionality. To understand possible causes of this decline, we investigated effects of nephrotoxins and oxidants on the differentiation of induced pluripotent stem cells (iPSC) into proximal tubular epithelial-like cells (PTELC). Proliferation, apoptosis, senescence and expression of oxidative defense genes were analyzed in iPSCs, differentiating and differentiated cells treated with cisplatin (CisPt, up to 45 µM), cyclosporin A (CycA, up to 12 µM) and the oxidants menadione (Mena, up to 50 µM) and tert-butylhydroquinone (tBHQ, up to 50 µM). We found that differentiating cells were most sensitive to oxidants and showed increased sensitivity to CisPt, whereas all differentiation stages showed similar sensitivity to CycA. Both oxidative stress and CisPt triggered apoptosis in all differentiation stages, whereas CycA mainly induced senescence. Treatment during differentiation resulted in long-term effects on gene expression in differentiated cells. While oxidants had no effect on transport function of differentiated cells, CisPt and CycA impaired albumin uptake. Our data suggest a substantial sensitivity of differentiating cells to nephrotoxins and oxidants, an aspect that could potentially interfere with regenerative processes.
Dynamic regulation of NeuroD1 expression level by a novel viral construct during astrocyte-to-neuron reprogramming
Authors: Mseis-Jackson Natalie , Jiang Mei , Sharma Mehek , Ranchod Arya , Williams Christine , Chen Xuanyu , Li Hedong
Published: February 2025

Astrocyte-to-neuron reprogramming presents a viable approach for regenerative medicine. The reprogramming factor NeuroD1 has demonstrated capability of neuronal reprogramming with high efficiency both in culture and in the injured central nervous system. High level of NeuroD1 expression is required to break down the cellular identity barrier for a successful reprogramming, and yet persistence of this high level drives the reprogrammed neurons primarily to glutamatergic subtype. This is consistent with the critical role of NeuroD1 in determination of glutamatergic neuronal lineage during development. However, diversified neuronal subtypes are needed to establish appropriate neuronal connectivity in disease/injury conditions. We reason that continuously high level of NeuroD1 expression forces the reprogrammed neurons into glutamatergic subtype, and that reducing NeuroD1 level after reprogramming may allow generation of neurons with diversified subtypes. For this purpose, we engineered a novel viral expression vector by which NeuroD1 expression can be dynamically regulated during the reprogramming process. Specifically, the target site of a neuron-specific microRNA (miR-124) is incorporated in the expression system. Therefore, this novel construct would still achieve a high NeuroD1 expression level in astrocytes for reprogramming to occur and yet reduce its level in the reprogrammed neurons by suppression of endogenous miR-124. In this study, we demonstrated that this construct elicits a dynamic gene expression pattern with much reduced level of NeuroD1 at later stages of neuronal reprogramming. We also showed that this construct still retains relatively high reprogramming efficiency and can generate mature neurons with an enhanced GABAergic neuronal phenotype.
Bridging the Nutrition Education Gap: From Theory to Practice- A Scalable Model for Nutrition Practicums in Medical Training
Authors: John Anjum , Reshma V.R , El-Hazimy Khadija
Published: February 2025

Background

With Kerala’s rising burden of non-communicable diseases (NCDs), it is crucial to strengthen nutrition education for medical students to equip future physicians’ with the ability to provide evidence-based dietary guidance. This study examined the effectiveness of incorporating practical demonstrations into the nutrition curriculum of a private medical college in Kerala, Southern India. This aims to enhance student engagement, deepen understanding of dietetic principles through practical application, and improve confidence in providing dietary counseling.

Methods

The study incorporated practical demonstrations such as meal planning, dietary assessments, and food label interpretation into the nutrition curriculum for third year medical students. Student feedback was collected through open-ended discussions and reflective exercises to assess their engagement and perceptions of the perceived learning outcomes.

Results

Qualitative feedback indicated that students found practical demonstrations highly engaging, improving their confidence in applying nutritional knowledge. Thematic analysis identified key benefits such as enhanced experiential learning, increased ability to interpret nutrition labels, and improved patient counseling skills. However, challenges included limited time for hands-on activities, variability in prior nutrition knowledge, and limited faculty expertise in nutrition education.

Conclusions

Practical demonstrations are an effective strategy for integrating nutrition education into medical curricula in Kerala as underscored by this study. By aligning with the National Medical Commission’s emphasis on integrated, application-based learning, and Kerala’s goals of addressing its rising burden of non-communicable diseases linked to malnutrition, this study offers a scalable model to strengthen clinical nutrition education, ultimately contributing to better public health outcomes nationwide.
Influence of Sex and Race/ Ethnicity on Major Adverse Cardiovascular Outcomes Following Coronary Artery Bypass Surgery in a Large Integrated Healthcare System
Authors: Yang Janine Y. , Stram Douglas , Doan John , Fairman Alix P. , Merchant Maqdooda , Triplett Cynthia , Sheikh Ahmad Y. , Ha Richard V. , Pursnani Seema K.
Published: February 2025

Background

We aimed to evaluate the influence of sex and race/ ethnicity on major adverse cardiovascular events (MACE) following coronary artery bypass grafting (CABG) in our integrated healthcare system.

Methods

This was a retrospective study of Kaiser Permanente Northern California members who underwent CABG from 2008-2019, evaluating odds of MACE (MI, stroke, serial percutaneous intervention (PCI), repeat CABG, death) at 30 days, 1 year, and up to 12 years follow-up using multivariable logistic and Cox proportional regression analyses. We adjusted for demographic, clinical, socioeconomic risk factors, and surgical characteristics.

Results

Cohort included n=7405, mean age 65.2 yrs, 47% diabetic, 62% hypertensive, 20% with prior revascularization (PCI or CABG). There were n=6082 males and n=1323 females with 2179 (35.8%) and 639 (48.3%) MACE, respectively. MACE occurred in 40.4% of White, 38.1% of Hispanic, 32.9% of Filipino, 27.9% of South Asian, 29.1% of Other Asian/ Pacific Islander, 47.0% of Black, and 42.3% of Other Race/ Ethnicity patients (p<0.001). Older age, higher HbA1c, diabetes, end-stage renal disease, lower hemoglobin, higher creatinine, smoking, lack of cardiopulmonary bypass, and use of non-arterial graft were significant predictors of long-term MACE. Female sex was associated with an increased odds of MACE at 30 days (OR 1.62, 95% CI, 1.19-2.21) and 1-year (HR 1.24, 95% CI, 1.02-1.51). Asian race/ ethnicity was associated with lower 12-year hazard of MACE (HR Filipino 0.72; 95% CI, 0.60-0.87; South Asian 0.72, 95% CI, 0.50-1.03; Other Asian 0.71, 95% CI, 0.58-0.87).

Conclusion

Female, Black, and Other Race/ Ethnicity groups had the greatest incidence of MACE at up to 12 years follow-up post CABG. These differences are largely driven by increased risk factor burden in these groups, and Black and Other race/ ethnicity were not independently associated with long-term CABG risk in multivariable modeling. Further understanding of the mechanisms for these sex and race/ethnic differences is required to improve upstream preventive efforts.
Environmental and geographic drivers of global bat phylogenetic diversity
Authors: Green Abigail E. , Calderón-Acevedo Camilo A. , Soto-Centeno J. Angel , Pelletier Tara A.
Published: February 2025

Aim

Understanding patterns of biodiversity is vital to conserving species. We aimed to combine open-source genetic, environmental, and geographic information to analyze patterns of bat phylogenetic diversity (PD) in continuous ecoregions across the globe. This information is important for developing bat conservation strategies, and our methodology can work with any taxa that has sufficient georeferenced genetic data available.

Location

Global.

Time period

Last Interglacial to Present Day.

Major taxa studied

Chiroptera.

Methods

After curating a global dataset containing 14,037 COI DNA sequences from 343 described species of bats, we calculated PD for two sets of continuous ecoregions at different spatial scales. To avoid the possible difficulties of using current species names, we used genetic OTUs identified by a single-locus species delimitation method to calculate PD. We then estimated a lineage through time plot and used random forest predictive modeling to identify the environmental and geographic predictors of PD.

Results

We found that temperature variables were most closely associated with PD. In addition to temperature during the present, temperature during the last glacial maxima and temperature changes since the last interglacial were deemed important. However, when looking at different spatial scales, top variables differed slightly. Southeast Asia and South America had the highest levels of PD, along with some parts of Africa and the Himalayas. We demonstrate that, regardless of spatial scale and uneven sampling across the globe, single-locus genetic data is enough to reflect species diversity gradients.

Main conclusions

We show that publicly available, single-locus data can be used to analyze large-scale evolutionary patterns and inform effective and efficient conservation efforts. Additionally, choice of biodiversity measure and spatial scale matter when assessing species patterns. When looking at bats, temperature variables with a historical component are most important for predicting PD.
Functional interaction of electrical coupling and H-current and its putative impact on inhibitory transmission
Authors: Trigo Federico F. , Alcamí Pepe , Curti Sebastian
Published: February 2025

The flow of information within neural circuits depends on the communication between neurons, primarily taking place at chemical and electrical synapses. The coexistence of these two modalities of synaptic transmission and their dynamical interaction with voltage-gated membrane conductances enables a rich repertoire of complex functional operations. One such operation, coincidence detection, allows electrically coupled neurons to respond more strongly to simultaneous synaptic inputs than to temporally dispersed ones. Using the mesencephalic trigeminal (MesV) nucleus—a structure composed of large, somatically coupled neurons—as an experimental model, we first demonstrate that electrical coupling strength in the hyperpolarized voltage range is highly time-dependent due to the involvement of the IH current. We then show how this property influences the coincidence detection of hyperpolarizing signals. Specifically, simultaneous hyperpolarizing inputs induce larger membrane potential changes, resulting in stronger IH current activation. This, in turn, shortens the temporal window for coincidence detection. We propose that this phenomenon may be crucial for networks dynamics in circuits of electrically coupled neurons that receive inhibitory synaptic inputs and express the IH current. In particular, molecular layer interneurons (MLIs) of the cerebellar cortex provide an ideal model for studying coincidence detection of inhibitory synaptic inputs, and how this operation is shaped by the voltage-dependent conductances like the IH current, potentially impacting on motor coordination and learning.
Common tandem repeat variants associated with glaucoma risk in individuals of African ancestry
Authors: Pham Kenneth , Lee Roy , Di Rosa Isabel , Salowe Rebecca , Jin Fangming , Bradford Yuki , Ying Gui-Shuang , Phillips-Cremins Jennifer E. , Setia-Verma Shefali , O’Brien Joan
Published: February 2025

The contribution of common tandem repeats (TR) variants to common, complex disease remains unknown, especially in populations historically underrepresented in genetic research. We identified common TR variants associated with risk of primary open-angle glaucoma (POAG) in individuals of African ancestry. The POAG-associated TR variants were predominantly found at Alu poly(A) tail elements, regions, retinal development enhancers, and harbor binding sites of a POAG-associated transcription factor, LMX1B, suggesting a convergent mechanism of how common TR variation arises and contributes to POAG pathophysiology.
Development and external validation of prediction models for major osteoporotic fracture and hip fracture in people with intellectual disability
Authors: Smith Margaret , Roast Jan , Collins Gary S. , Holt Tim A. , Frighi Valeria
Published: February 2025

Purpose

Compared with the general population, people with intellectual disabilities (ID) have higher incidences of major osteoporotic fracture (MOF) and hip fracture (HF), and osteoporosis develops at a younger age. The rate of HF in those aged 50 years and over is two and four times higher than that in women and men, respectively, without ID. It is essential to identify people with ID at risk of such fractures so that a targeted fracture prevention strategy can be designed. However, current fracture prediction models are derived from the general population and may underestimate risk in the ID population.

Methods

Prediction models (IDFracture) for the 10-year risk of HF and MOF were developed and validated in populations of people with ID aged 30-79 years. Models were developed in the CPRD GOLD database and temporally validated in the Aurum database. The predictors included those in current fracture prediction models and ID-specific predictors such as Down syndrome. All the predictors were included in the Cox regression models. Bootstrapping was used to adjust for overfitting.

Results

The development cohort included 38,665 people with IDs, 1045 with MOFs and 360 with HFs within 10 years. The external validation cohort included 76,385 people, 2420 MOFs and 1001 HFs. Discrimination, as judged by the C statistic, was good: MOF 0.775, HF 0.839. The calibration was also good but tended to overpredict at the highest predicted risks.

Conclusion

IDFracture has potential as a screening tool in clinical practice to identify people with ID who are at increased risk of MOF and HF.

Mini Abstract

Brief rationale

People with intellectual disability (ID) have a relatively high incidence of fracture, so current risk prediction models are not appropriate.

Main result

A new prediction model for people with ID showed good calibration and discrimination in external validation.

Significance of paper

This is the first such prediction model developed for people with ID.
Dissecting the genetic etiology of intestinal obstruction: mendelian randomization identifies potential therapeutic targets
Authors: Haodong Zhao , Baoping Cai , Jiongjiong Chen , Jia Chen , hui Liu , Yu Wang , bocheng Ding
Published: February 2025

Intestinal obstruction, a prevalent and serious condition, necessitates deeper understanding of its genetic architecture. This study rigorously employed two-sample Mendelian randomization to dissect the causal influence of gene expression on intestinal obstruction risk, leveraging comprehensive summary-level data from eQTLGen and FinnGen GWAS. To enhance causal inference, Summary-data-based Mendelian Randomization was integrated, utilizing GTEx eQTL data to specifically assess tissue-relevant gene expression. Our multi-pronged analyses provide compelling genetic evidence supporting causal roles for genetically predicted expression ofCHRNB2andMIATin intestinal obstruction. Specifically, increased genetically proxiedCHRNB2expression was associated with a protective effect, while higher genetically proxiedMIATexpression suggested an elevated susceptibility to intestinal obstruction. Colocalization analysis, alongside HEIDI heterogeneity testing within the SMR framework, further bolstered the robustness of these findings by distinguishing causality from linkage disequilibrium. These convergent results offer novel mechanistic insights into intestinal obstruction pathogenesis, positioningCHRNB2andMIATas promising therapeutic targets for both prevention and treatment strategies. Future research is crucial to validate these findings across diverse ancestries and to fully elucidate the intricate biological mechanisms underpinning these gene-disease associations.
Risk Stratification for Endometrial Cancer Reveals Independent Contributions of Polygenic Risk and Body Mass Index
Authors: Wang Xuemin , Dossus Laure , Gunter Marc J. , Crosbie Emma J. , Ong Jue-Sheng , Glubb Dylan M. , O’Mara Tracy A.
Published: February 2025

Background

Obesity is a major risk factor for endometrial cancer, but it is unknown whether it impacts the association between genetic risk and endometrial cancer. We incorporated polygenic risk score and epidemiological risk factors in the prediction of and investigated associations of BMI and polygenic risk score with endometrial cancer risk

Methods

We generated polygenic risk score for endometrial cancer in 129,829 unrelated female participants of European ancestry (including 956 incident cases with endometrial cancer) in the UK Biobank and predicted endometrial cancer using endometrial cancer polygenic risk score and established epidemiological risk factors, including BMI. We evaluated the performance of endometrial cancer prediction models by odds ratios and area under the receiver operating characteristic curves (AUCs) to using logistic regression. Individual and joint associations of BMI and polygenic risk score with endometrial cancer were assessed using Cox proportional hazards models.

Results

An integrated model incorporating both polygenic risk score and epidemiological risk factors achieved a modest, but statistically significant, improvement in predicting endometrial cancer status compared with the model that included epidemiologic risk factors alone (AUC = 0.74 versus 0.73;P= 3.98 × 10−5). Obese participants (BMI ≥ 30 kg/m2) in the top polygenic risk tertile had the highest endometrial cancer risk. We observed independent effects of genetic risk and BMI on endometrial cancer risk.

Conclusion

Integrating polygenic risk score with epidemiological risk factors may offer insights into population stratification for endometrial cancer susceptibility. Higher endometrial cancer polygenic risk is associated with endometrial cancer, irrespective of BMI.