bluuebunny/crossref_metadata_2025 huggingface dataset:
The inability to predict futility in hemorrhaging trauma patients using 4-hour transfusion volumes and rates
Authors: Van Gent Jan-Michael , Clements Thomas W. , Rosario-Rivera Bedda L. , Wisniewski Stephen R. , Cannon Jeremy W. , Schreiber Martin A. , Moore Ernest E. , Namias Nicholas , Sperry Jason L. , Cotton Bryan A.
Published: January 2025

BACKGROUND

Blood shortages and utilization stewardship have motivated the trauma community to evaluate futility cutoffs during massive transfusions (MTs). Recent single-center studies have confirmed meaningful survival in ultra-MT (≥20 U) and super-MT (≥50 U), while others advocate for earlier futility cut points. We sought to evaluate whether transfusion volume and intensity cut points could predict 100% mortality in a multicenter analysis.

METHODS

A prospective, multicenter, observational cohort study was performed at seven trauma centers. Injured patients at risk for MT who required both blood transfusion and hemorrhage control procedures were enrolled. Four-hour volumes and intensities (average units per hour) were evaluated. Primary outcome of interest was 28-day mortality.

RESULTS

A total of 1,047 patients met the study inclusion with an overall mortality rate of 17% (n = 176). The median age was 35 years, 80% were male, and 62% had a penetrating mechanism, with an Injury Severity Score of 22. At 4 hours, transfusion volumes below 110 U and transfusion intensity averaging up to 21 U/h did not demonstrate futility. Total transfusion volume above 110 U was associated with 100% mortality (n = 9). Multivariable analysis noted only nonmodifiable risk factors as predictors of increased mortality (blunt mechanism, shock index).

CONCLUSION

In this study from seven Level 1 trauma centers, survival was observed at transfusion volumes up to 110 U and at transfusion velocities up to 21 U/h during the first 4 hours of resuscitation. Data are limited on transfusion volumes above 110 U in the first 4 hours. Survival can be observed in both the ultra and super-MT settings.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level II.
The abdomen does not lie, but the labs might: Predictors of intra-abdominal injury on computed tomography imaging in pediatric blunt trauma patients
Authors: Otaibi Banan W. , Khurshid Muhammad Haris , Hejazi Omar , Hage Kati , Stewart Collin , Colosimo Christina , Spencer Audrey L. , Ditillo Michael , Magnotti Louis J. , Joseph Bellal
Published: January 2025

INTRODUCTION

Multiple studies have indicated that isolated abnormal laboratory results necessitate obtaining abdominal computed tomography (CT) for pediatric patients with blunt abdominal trauma (BAT), regardless of the normal abdominal examination. This study aims to identify the predictors of intra-abdominal injury (IAI) and the role of laboratory tests in CT imaging among pediatric BAT patients.

METHODS

This is a retrospective review at a Level II pediatric trauma center (2018–2022). Children (younger than 18 years) who presented with BAT and received abdominal CT imaging were included. Outcomes were rates of IAI and interventions. Multivariable regression analysis was performed.

RESULTS

Over 5 years, 483 patients met the inclusion criteria. The mean age was 13 years, 58.2% were male, and the median Glasgow Coma Scale was 15. Overall, 19.3% had abdominal pain; 6.2%, postinjury emesis; 26.1%, abdominal tenderness; and 10.6%, pelvic tenderness. On initial imaging, 7.0% had a positive focused assessment with sonography in trauma examination, and 7.2% had an abnormal plain x-ray. On initial laboratory testing, 7.9% had abnormal serum aspartate aminotransferase (AST), 3.1% had abnormal hematocrit, 1.2% had abnormal urine analysis, and 0.8% had abnormal lipase. Seventeen percent had at least one IAI, of which 17% underwent intervention. Multivariable regression analysis identified abdominal tenderness, abnormal plain x-ray, positive focused assessment with sonography in trauma, blood transfusion requirements, and abnormal AST as independent predictors of IAI on abdominal CT imaging. Moreover, among patients with IAI, only 37.3% had abnormal laboratory results, and all had at least one of the predictors of IAI (in addition to or other than abnormal AST). Among patients with abnormal laboratory results (n = 57), nine patients had none of the predictors of IAI, out of which none were found to have IAI on abdominal CT.

CONCLUSION

More than 80% of all abdominal CT imaging had negative results. Our findings highlight the significance of clinical findings in the trauma bay, regardless of laboratory findings, when deciding to order abdominal CT imaging for pediatric BAT patients.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level III.
Antibacterial activity of Cinnamomum verum and Thymus vulgaris essential oils on multidrug-resistant zoonotic bacteria isolated from dogs in southern Benin

Authors: Yaovi Ayaovi Bruno , Das Arpita , Behera Rama N. , Azokpota Paulin , Farougou Souaïbou , Baba-Moussa Lamine , Michels Franck , Fauconnier Marie-Laure , Ambatipudi Kiran , Sessou Philippe
Published: January 2025

Objective

Antibiotic resistance is a major public health problem. The search for new therapeutic alternatives is becoming urgent. Essential oils are a promising alternative. This study aimed to evaluate the antibacterial activities of essential oils from selected plants on multidrug-resistant zoonotic strains isolated from dogs.

Methods

Essential oils from dried Thymus vulgaris leaves, Cinnamomum verum bark, and Cuminum cyminum seeds were extracted and tested on five multidrug-resistant Escherichia coli and four S. aureus isolated from dogs in southern Benin.

Results

The study showed that Thymus vulgaris essential oil was bacteriostatic, with a Minimum Inhibitory Concentration (MIC) equal to 2.5 μl/ml and a Minimum Bactericidal Concentration (MBC) of 17 μl/ml for E. coli strains and 11.25 μl/ml for S. aureus strains. Regarding Cinnamomum verum essential oil, its bacteriostatic power was characterized by an MIC of 1.25 μl/ml for the isolates tested and an average MBC of 11.50 μl/ml for E. coli and 12.19 μl/ml for S. aureus. On the other hand, Cuminum cyminum essential oil was ineffective on the strains investigated. Additionally, T. vulgaris essential oil contained predominantly thymol (36.57%), p-cymene (30.51%), and carvacrol (7.62%), while C. verum essential oil contained cinnamaldehyde (88.76%).

Conclusion

This study reveals the antibacterial activity of T. vulgaris dry leaf and C. verum bark essential oils on multi-resistant E. coli and S. aureus isolated from dogs. These two essential oils may be alternative candidates for combating antibiotic-resistant E. coli and S. aureus infections.
Import of global high-risk clones is the primary driver of carbapenemase-producing Pseudomonas aeruginosa in Norway
Authors: Haldorsen Bjørg Christina , Samuelsen Ørjan , Janice Jessin , Sare Miriam , Molvik Mari , Sundsfjord Arnfinn ,   The Norwegian Study Group on CP-Pa, Pedersen Torunn
Published: January 2025

Introduction. Infections by carbapenemase-producing Pseudomonas aeruginosa (CP-Pa) are concerning due to limited treatment options. The emergence of multidrug-resistant (MDR) high-risk clones is an essential driver in the global rise of CP-Pa.

Hypothesis/Gap Statement. Insights into the molecular epidemiology of CP-Pa are crucial to understanding its clinical and public health impact. Despite the low incidence of infections in Norway, global spread requires an understanding of regional dissemination patterns.

Aim. This study aimed to investigate the phenotypic and genotypic characteristics of CP-Pa isolates in Norway and molecular epidemiology by utilizing available metadata.

Methodology. The study collection comprised all verified CP-Pa isolated in Norway from 2006 to 2022 (n=67) obtained from clinical (75%; n=50) or screening samples (22%; n=15) or had no available information (3%; n=2). Phenotypic analyses included antimicrobial susceptibility testing against clinically relevant antipseudomonal antibiotics and comparative testing for carbapenemase production using three different methods (β-CARBA, IMI/IMD gradient test and Coris O.K.N.V.I RESIST-5). Whole-genome sequencing was performed to identify virulence factors, resistance determinants and genomic relatedness.

Results. The isolates were categorized as MDR (n=39) encoding Verona integron-encoded metallo-β-lactamase (VIM) (n=28), New Delhi metallo-β-lactamase (NDM) (n=6), imipenemase metallo-β-lactamase (IMP) (n=4) or Guiana extended spectrum metallo-β-lactamase (n=1) carbapenemases or extensively drug-resistant (XDR; n=28) encoding VIM (n=11), NDM (n=9) or IMP (n=8) carbapenemases. CP-Pa numbers ranged from 1 to 7 annually, peaking at 17 in 2022. Most isolates (n=64) were associated with international travel or hospitalization abroad. Phylogenetic analyses identified nine clusters of closely related genomes, with one suspected case of domestic patient-to-patient transmission. Among 21 detected sequence types, several were global high-risk clones, including ST235 (n=12), ST111 (n=9), ST773 (n=9), ST253 (n=3), ST357 (n=3), ST395 (n=3), ST823 (n=3), ST233 (n=2), ST654 (n=2), ST260 (n=1) and ST308 (n=1), covering 72% of the Norwegian isolates. ST1047 (IMP-1) and ST773 (NDM-1) were associated with Ukrainian war victims. Carbapenemase detection rates for phenotypic tests were 88% (β-CARBA), 91% (IMI/IMD) and 94% (Coris) in our collection.

Conclusion. The study highlights the low incidence yet high genomic diversity of CP-Pa in Norway and the dominance of high-risk clones linked to imports, contributing to the high proportion of XDR.
ChronicStaphylococcus aureusinfection of osteocytes promotes an intracellular viable-but-non-culturable phenotype
Authors: Gunn Nicholas J. , Zelmer Anja R. , Kidd Stephen P. , Solomon L. Bogdan , Carda-Diéguez Miguel , Mira Alex , Yang Dongqing , Atkins Gerald J.
Published: January 2025

Introductory paragraph

Infectious osteomyelitis is a potentially severe disease with an increased incidence of 10% over the last 10 years (1, 2) and a 20% recurrence rate creating chronic infections (3). Diagnosis and pathogen identification remain challenging, with culture-negative results in 7-39% of cases (4–6), of which 14-27% are PCR-positive from drained fluids (7). Of recent intensive research focus, osteomyelitis associated with Prosthetic Joint Infection (PJI) is a serious and growing complication of orthopaedic joint replacement surgery, with a failure to cure rate within 2-years internationally of between 15-46% (8, 9). Osteocytes act as potential long-term reservoirs for intracellularStaphylococcus aureus, protecting it against the immune responses and antimicrobial treatment (10–15). However, the intra-osteocytic adaptation mechanisms byS. aureusremain understudied, and it is unknown why so many infections are culture-negative but PCR-positive. Here, we found that in chronic intra-osteocytic infections,S. aureusconsistently adopts a viable but non-culturable (VBNC) state. Whole genome sequencing of parental and a revertant strain indicated that initially,S. aureuscells possessing TarP and a complete T7SS dominate the bacterial community but these cell numbers declined with genetic rearrangements seemingly linked with the shift to a VBNC state. The subsequent acquisition of a single nucleotide polymorphism (SNP) insrrBwas associated with resuscitation to a culturable state, suggesting at least one mechanism underlying entrance and exit from the intracellular VBNC state.
Does combination treatment with progesterone and vaginal cervical cerclage improve pregnancy outcomes in women at high risk of preterm birth? A retrospective, secondary analysis of the C-STICH suture thread for cerclage trial data
Authors: Hodgetts Morton V , Morris RK , Toozs-Hobson P , Middleton L , Pilarski N , Bell L , Hogg M , Man R , Israfil-Bayli F , Shennan A , Simpson N , Lees C , Moakes CA
Published: January 2025

Background

Vaginal cervical cerclage and progesterone are established treatments for prevention of pregnancy loss and prematurity. There is limited data to assess the effect of these treatments in combination.

Objective

To investigate the association between progesterone and no progesterone treatment on pregnancy outcomes in women at high risk of preterm birth who have received a vaginal cervical cerclage.

Study Design

This is a secondary analysis of women recruited to the CSTICH trial, which recruited in 75 obstetric units in the UK. The primary outcome was pregnancy loss, defined as miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life. Secondary maternal outcomes included miscarriage and previable neonatal death; stillbirth; gestational age at delivery; preterm pre labour rupture of membranes and sepsis. Secondary neonatal outcomes included early/late neonatal death and sepsis. For each outcome, regression models were fitted adjusting for pre-specified prognostic variables.

Results

1943 women had a vaginal cerclage placed, with available progesterone data. From the 2048 women recruited to CSTICH; 843 (43%) women received progesterone and 1109 (57%) did not receive progesterone. Pregnancy loss occurred in 49 (5.9%) of 832 women who received progesterone and 91 (8.3%) of 1103 women who did not receive progesterone (adjusted risk ratio 0.70, 95% confidence interval (CI): 0.50 to 0.99; adjusted risk difference - 0.02, 95% CI: −0.04 to −0.001).

Conclusion

There appears to be an association with progesterone use in women who receive a vaginal cervical cerclage and a reduction in pregnancy loss. This combination therapy may be an important opportunity to further reduce the risk of pregnancy loss in this high risk cohort.
A kinetic model for USP14 regulated substrate degradation in 26S proteasome
Authors: Wu Di , Ouyang Qi , Wang Hongli , Mao Youdong
Published: January 2025

Despite high-resolution structural studies on the USP14-proteasome-substrate complexes, time-resolved cryo-electron microscopy (cryo-EM) results on USP14-regulated allostery of the 26S proteasome are still very limited and a quantitative understanding of substrate degradation dynamics remains elusive. In this study, we propose a mean field model of ordinary differential equations (ODEs) for USP14 regulated substrate degradation in 26S proteasome. The kinetic model incorporates recent cryo-EM findings on the allostery of 26S proteasome and generates results in good agreement with time-resolved experimental observations. The model elucidates that USP14 typically reduces the substrate degradation rate and reveals the functional dependence of this rate on the concentrations of substrate and adenosine triphosphate (ATP). The half-maximal effective concentration (EC50) of the substrate for different ATP concentrations is predicted. When multiple substrates are present, the model suggests that substrates that are easier to insert into the OB-ring and disengage from the proteasome, or less likely to undergo deubiquitination would be more favored to be degraded by the USP14-bound proteasome.

Author Summary

The proteasome is a crucial protein complex involved in the degradation of damaged or unnecessary proteins within cells, requiring ATP and ubiquitin for its functioning. It is regulated by cellular factors that transiently associate with it, often referred to as proteasome-associated proteins. USP14 is such a protein that activates its deubiquitination activity through reversible binding to the proteasome, thereby decreasing the substrate degradation activity of the proteasome. In this study, we developed a kinetic model to describe how USP14 regulates substrate degradation in proteasome based on recent experimental findings. The model yields result consistent with experimental observations, demonstrating that the mean-field description of mass action law for chemical reactions also applies to complex biomolecular machineries.
A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis
Authors: Bowman Christopher John , Stibor Dorothea , Sun Xiaofei , Shimizu Hiromichi , Yamashita Emily , Lenci Nika , Advincula Rommel , Kim Min Cheol , Turnbaugh Jessie A. , Sun Yang , Razani Bahram , Turnbaugh Peter J. , Ye Chun Jimmie , Malynn Barbara A. , Ma Averil
Published: January 2025

A20, encoded by theTNFAIP3gene, is a protein linked to Crohn’s disease and celiac disease in humans. We now find that mice expressing point mutations in A20’s M1 ubiquitin binding motif (ZF7) spontaneously develop proximate enteritis that requires both luminal microbes and T cells. Cellular and transcriptomic profiling reveal expansion of TH17/22 cells and aberrant expression of IL-17A and IL-22 in intestinal lamina propria of A20ZF7mice. While deletion of IL-17A from A20ZF7/ZF7mice exacerbates enteritis, deletion of IL-22 abrogates intestinal epithelial cell hyperproliferation, barrier dysfunction, and alarmin expression. A20ZF7/ZF7TH17/22 cells autonomously express more RORψt and IL-22 after differentiationin vitro. ATAC sequencing identified an enhancer region upstream of theIl22gene in A20ZF7/ZF7T cells, and this enhancer demonstrated increased activating histone acetylation coupled with exaggeratedIl22transcription. Finally, CRISPR/Cas9-mediated ablation of A20ZF7in human T cells increases RORψt expression andIL22transcription. These studies link A20’s M1 ubiquitin binding function with RORψt expression, epigenetic activation of TH17/22 cells, and IL-22 driven enteritis.
Autophagy-Mediated Downregulation of AXL and TIM-1 Promotes Sustained Zika Virus Infection
Authors: Yu Jingyou , Zheng Yi-Min , Sheridan Megan A. , Ezashi Toshihiko , Roberts R Michael , Liu Shan-Lu
Published: January 2025

Zika virus (ZIKV) infection can lead to a variety of clinical outcomes, including severe congenital abnormalities. The phosphatidylserine (PS) receptors AXL and TIM-1 are recognized as critical entry factors for ZIKVin vitro. However, it remains unclear if and how ZIKV regulates these receptors during infection. In this study, we investigated AXL and TIM-1 expression in human alveolar basal epithelial A549 cells, glioblastoma U87 cells, and embryonic stem cells-derived trophoblast following ZIKV infection. We found that both the Asian strain FSS13025 and the African strain MR766 of ZIKV downregulate AXL, with a milder effect on TIM-1. We identified several ZIKV proteins, notably envelope (E), NS2A, NS3, and NS4B, that contribute to this downregulation. Notably, treatment with lysosomal inhibitor NH4Cl or the autophagy inhibitor 3-Methyladenine (3-MA) mitigated the AXL/TIM-1 downregulation, indicating autophagy’s involvement in the process. Importantly, this downregulation facilitates sustained viral replication and promotes viral spread by preventing superinfection and limiting cell death, which is also associated with impaired innate immune signaling. Our findings uncover a mechanism by which ZIKV downregulates entry factors to enhance prolonged viral replication and spread.

AUTHOR SUMMARY

Zika virus (ZIKV) infection has been associated with severe birth defects, yet the mechanisms underlying its pathogenesis remain poorly understood. In this study, we investigated phosphatidylserine (PS) receptors AXL and TIM-1 and discovered that they promote ZIKV entry but are downregulated by the virus infection. We identified several ZIKV proteins involved in AXL and TIM-1 down-regulation through an autophagy-mediated process. Mechanistically, this loss of surface receptors protects host cells from superinfection and cell death, while dampening the innate immune response, ultimately promoting viral spread. Our results contribute to a better understanding of ZIKV’s interactions with host cells and offer insight into viral entry, innate signaling, and pathogenesis.
Neural circuits between nodose ganglion and pulmonary neuroendocrine cells regulate lung inflammatory responses
Authors: Chen Jie , Xie Shitao , Lin Zhekai , Zhao Caiqi , Tao Rujia , Ma Yingying , Chen Xiaoyan , Wu Renlan , Sui Pengfei , Wang Sheng , Ji Hongbin , Song Hai , Zhang Xiaoming , Sun Yangang , Song Yuanlin , Su Xiao
Published: January 2025

The lungs are organs exposed to the external environment, and the air we inhale contains various pathogens, such as endotoxins. The vagus nerve, which innervates the lungs, may play a role in detecting pathogens that invade the lungs. Through transcriptome analysis, tissue clearance imaging, electrical excitability recording, and gene- and cell-specific knockout experiments, we found that vagus nerve endings innervate pulmonary neuroendocrine cells (PNECs). These nerve endings sense bacterial endotoxins via pain receptors (TRPA1) rather than toll-like receptors (TLR4), eliciting electrical excitation and enhancing the production of neuropeptides (αCGRP) in the nodose ganglia. In turn, αCGRP released by sensory neurons from the nodose ganglia promotes both neuropeptide production and the proliferation of PNECs, thereby amplifying endotoxin-induced lung inflammatory responses. This reveals that the neural circuits between the nodose ganglion and PNECs play a critical role in regulating lung inflammatory responses.
Developmental synaptic pruning in the olivo-cerebellar circuit sculpts predictive processing
Authors: Verma Shivangi , Narayanan Sriram , Thirumalai Vatsala
Published: January 2025

Synaptic pruning is a dominant process of circuit assembly, known to eliminate a large proportion of synapses formed during development. Yet, very little is understood about how the drastic elimination of a large number of synapses affects circuit computation and behavior. Here, using the olivocerebellar system of larval zebrafish, we first establish the timelines of olivary climbing fiber to Purkinje neuron synaptic pruning. We then show that during this window, encoding of sensory-motor mismatches is improved, sensory representations are fine-tuned, and predictive signals are more robust. All of these lead to faster and better behavioral responses which are adaptable to current sensory input. Thus, developmental synaptic pruning makes circuits fit for complex computations such as predictive processing.
Orally Delivered Milk-Derived Nanovesicles Loaded with Connexin 43 Peptides for Targeted Cardiac Ischemia-Reperfusion Therapy
Authors: Marsh Spencer R. , Amin Md Ruhul , Toldo Stefano , Beard Claire , Dogan Alan B. , Mezzaroma Eleonora , Andres Ethan , Stout Randy F. , Bannon Mark S. , Payne Laura Beth , Abbate Antonio , Sassi Yassine , Letteri Rachel A. , Gourdie Robert G.
Published: January 2025

Extracellular vesicles have emerged as promising nanocarriers for targeted drug delivery, but their therapeutic potential is limited by challenges related to administration route, loading, targeted delivery and production at scale. Here, we report an innovative approach for targeted delivery of therapeutic peptides to injured tissues using milk-derived small extracellular vesicles (mEVs) as an abundant, safe, orally administrable nanoplatform. We demonstrate that a sub-population of mEVs naturally contain Connexin 43 (Cx43) and its Carboxyl-Terminal (CT) polypeptides, which have been shown to play crucial roles in wound healing and tissue repair. Leveraging this intrinsic property, we developed an esterification method to efficiently and uniformly load mEVs with enhanced levels of an exogenous Cx43 CT peptide (αCT11 - RPRPDDLEI), as assessed by flow cytometry-based vesicle quantification and mass spectrometry. These engineered mEVs exhibited remarkable injury targeting capabilities, with > 30-fold increases in uptake by injured cells compared to non-wounded cells in vitro and preferential accumulation in wounded tissues in vivo. Notably, αCT11-loaded mEVs orally administered after myocardial infarction reduced infarct size by >60% and preserved heart function in a mouse model of ischemia-reperfusion injury. This study represents a significant advance in nanomedicine, demonstrating the utilization of naturally occurring milk-derived extracellular vesicles as an oral delivery system for therapeutic peptides, achieving unprecedented targeting efficiency and efficacy in the treatment of myocardial ischemia-reperfusion injury.
Integrating GWAS and Transcriptome Data through PrediXcan and Multimodal Deep Learning to Reveal Genetic Basis and Novel Drug Repositioning Opportunities for Alzheimer’s Disease
Authors: Tian Xuecong , Su Ying , Zhang Sizhe , Sun Haiqing , Chen Chen , Chen Cheng , Zhou Luyu , Lv Xiaoyi , Roussos Panos , Zhang Wen
Published: January 2025

Alzheimer’s Disease (AD) is the leading cause of dementia, imposing significant economic and social burdens. Although genome-wide association studies (GWAS) have identified approximately 70 risk loci, the functional mechanisms underlying AD remain unclear. In this study, we integrated the GWAS summary statistics from Jiang et al. with gene expression data from the GTEx project using S-PrediXcan method, encompassing 61 brain-related traits across 49 tissues. Comprehensive analysis identified five significant traits, including family history of AD, and highlighted key genes such as APOE, APOC1, and TOMM40, which play crucial roles in cholesterol metabolism, immune response, and neuroinflammation. Validation using the ROSMAP dataset confirmed the association of these genes with AD phenotypes. Furthermore, we developed AD-MIF, a novel deep multi-layer information fusion model that integrates multi-omics data, achieving a 10-20% improvement in AUC performance for predicting AD-related traits compared to traditional models. Gene enrichment analysis emphasized the importance of pathways such as cholesterol metabolism and immune response in the pathogenesis of AD. Additionally, drug repositioning analysis identified candidate drugs, including Dasatinib and Sirolimus, which may alleviate AD progression by reducing neuroinflammation and clearing senescent cells. Our findings advance the understanding of the genetic architecture of AD, improve predictive models, and propose potential therapeutic drugs.
Social Determinants of Healthy Aging: An Investigation using the All of Us Cohort
Authors: Chen Wei-Han , Lee Yao-An , Tang Huilin , Li Chenyu , Lu Ying , Huang Yu , Yin Rui , Armstrong Melissa J. , Yang Yang , Štiglic Gregor , Bian Jiang , Guo Jingchuan
Published: January 2025

Introduction

The increasing aging population raises significant concerns about the ability of individuals to age healthily, avoiding chronic diseases and maintaining cognitive and physical functions. However, the pathways through which SDOH factors are associated with healthy aging remain unclear.

Methods

This retrospective cohort study used the registered tier data from theAll of UsResearch Program (AoURP) registered tier dataset v7. Eligible study participants are those aged 50 and older who have responded to any of the SDOH survey questions with available EHR data. Three different algorithms were trained (logistic regression [LR], multi-layer perceptron [MLP], and extreme gradient boosting [XGBoost]). The outcome is healthy aging, which is measured by a composite score of the status for 1) comorbidities, 2) cognitive conditions, and 3) mobility function. We evaluate the model performance by area under the receiver operating characteristic curve (AUROC) and assess the fairness of best-performed model through predictive parity. Feature importance is analyzed using SHapley Additive exPlanations (SHAP) values.

Results

Our study included 99,935 participants aged 50 and above, and the mean (SD) age was 74 (9.3), with 55,294 (55.3%) females, 67,457 (67.5%) Whites, 11,109 (11.1%) Hispanic ethnicity, and 44,109 (44.1%) are classified as healthy aging. Most of the individuals lived in their own house (64%), were married (51%), obtained college or advanced degrees (74%), and had Medicare (56.2%). The best predictive model was XGBoost with random oversampler, with a performance of AUROC [95% CI]: 0.793 [0.788-0.796], F1 score: 0.697 [0.692-0.701], recall: 0.739 [0.732-0.748], precision: 0.659 [0.655-0.663], and accuracy: 0.716 [0.712-0.720], and the XGBoost model achieved predictive parity by similar positive and negative predictive values across race and sex groups (0.86-1.06). In feature importance analysis, health insurance type is ranked as the most predictive feature, followed by employment status, substance use, and health insurance coverage (yes/no).

Conclusion

In this cohort study, XGBoost model accurately predicted individuals achieving healthy aging, outperforming LR and MLP. Our findings underscore the significant role of health insurance in contributing to healthy aging.
Dopaminergic network connectivity alterations are associated with postoperative cognitive dysfunction
Authors: Lammers-Lietz Florian , Borchers Friedrich , Feinkohl Insa , Kanar Cicek , Krampe Henning , Lichtner Gregor , Sreekanth Jayanth , Wiebach Janine , Weygandt Martin , Spies Claudia , Winterer Georg , Paul Friedemann ,   the BioCog consortium
Published: January 2025

Postoperative cognitive dysfunction (POCD) is a detrimental complication after surgery with a lasting impact on the patients’ daily life. It is most common after postoperative delirium. Dopaminergic dysfunction has been suggested to play a role in delirium, but little knowledge exists regarding its relevance for POCD. We hypothesized that POCD is associated with altered resting-state functional connectivity of the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) in functional magnetic resonance imaging (fMRI) before surgery and at postoperative follow-up after three months.

Patients ≥65 years old underwent resting-state fMRI and neuropsychological assessment before major elective surgery and at follow-up three months later. POCD was determined as the reliable change index. Connectivity between VTA or SNc and 132 regions were calculated. Principal component analysis (PCA) was used for dimensionality reduction in preoperative connectivity, and components explaining >5% of variance were retained for analysis. To study postoperative changes in patients with POCD, we applied the same transformation to postoperative connectivity, and multi-factor analysis. Regression analyses were used to describe connectivity alterations while adjusting for age, sex, MMSE, surgery and anaesthesia.

Of 214 patients, 26 (12%) developed POCD. Among 132 principal components, four components for VTA- and SNc-FC were selected for further analysis. For both VTA and SNc connectivity, one component was significantly associated with POCD. No postoperative alterations of dopaminergic networks were associated with POCD.

Altered preoperative functional connectivity of the dopaminergic system predisposes to POCD. Particularly relevant regions are associated with sensory, especially spatial perception and higher cognitive functions.

HIGHLIGHTS

Dopaminergic dysfunction is a hallmark ofdelirium

No evidence for postoperative cognitive dysfunction (POCD)

Methods: resting-state functional connectivity of the VTA and SNc

Connectivity alterations of the VTA and SNc predispose for POCD

Affected areas involed in perception, spatial processing and cognition
Halting predicted vertebrate declines requires tackling multiple drivers of biodiversity loss
Authors: Capdevila Pol , O’Brien Duncan , Marconi Valentina , Johnson Thomas F. , Freeman Robin , McRae Louise , Clements Christopher F.
Published: January 2025

Anthropogenic threats are reshaping Earth’s biodiversity at an unprecedented rate and scale1–3. Conservation policies often prioritise threats like habitat loss and exploitation based on their global prevalence. However, these assessments rarely quantify the impacts of individual or interacting threats, potential masking the true effects of the Anthropocene4–6. Here, we quantitatively analyse the trends of 3,129 vertebrate populations worldwide with documented exposure to specific and multiple threats. Populations impacted solely by habitat loss or exploitation, the most prevalent threats, do not show the fastest declines. Rather, populations exposed to disease, invasive species, pollution, and climate change decline more rapidly. However, habitat loss and exploitation – along with climate change – do act as additive interactive threats, amplifying population declines. Notably, these interactive threats contribute to population declines, more than temporal or spatial sources of variation. Finally, counterfactual scenarios show that to achieve global non-negative vertebrate population trends, we need to mitigate the effects of multiple threats. These findings underscore the urgency of addressing the compounding effects of multiple threats to halt biodiversity loss and suggest that the local-scale impacts of climate change may be more severe than previously recognized.
Safety Monitoring of Health Outcomes following Influenza Vaccination during the 2023-2024 Season among U.S. Medicare Beneficiaries Aged 65 Years and Older
Authors: Lloyd Patricia C. , Acharya Gyanada , Zhao Henu , Shah Nimesh , Anguzu Godwin , Ambarsoomzadeh Derick , Clarke Tainya C. , Ng Xinyi , Hu Mao , Chillarige Yoganand , Forshee Richard A. , Anderson Steven A.
Published: January 2025

Background

Influenza vaccination is widely recommended for individuals aged 6 months and older in the United States (U.S.). While the safety of annual influenza vaccines is well established, FDA conducts routine monitoring and evaluation of safety. This study assessed the safety of 2023-2024 influenza vaccines among elderly U.S. Medicare beneficiaries.

Methods

A self-controlled case series (SCCS) analysis compared incidence rate ratios (IRR) of anaphylaxis, encephalitis/encephalomyelitis/acute disseminated encephalomyelitis, Guillain-Barré syndrome (GBS), transverse myelitis, hemorrhagic stroke (HS), non-hemorrhagic stroke (NHS), transient ischemic attack (TIA), and NHS or TIA, following 2023-2024 seasonal influenza vaccinations in risk and control intervals among Medicare beneficiaries aged 65 years and older. We used conditional Poisson regression to estimate IRRs and 95% confidence intervals (CIs) adjusted for event-dependent observation time for certain outcomes, seasonality, and uncertainty from outcome misclassification where feasible. For health outcomes with statistically significant associations, we stratified results by concomitant vaccination status.

Results

We observed a total of 20,258,006 influenza vaccinees among the Medicare population, and no statistically significant elevations of risk for anaphylaxis, encephalitis/encephalomyelitis (with ADEM), GBS, HS, or TM. For the combined NHS/TIA outcome (22-42-day risk window), we observed a small elevation in risk that was statistically significant in both the Fee-For-Service (FFS) and Medicare Advantage (MA) populations that received a high-dose vaccine. This risk was also statistically significant among MA beneficiaries that received any influenza vaccine. Additionally, we observed a small statistically significant risk for the individual TIA outcome (22-42-day risk window) among the MA population that received any influenza vaccine.

Conclusion

Results from this study indicate that the benefits of seasonal influenza vaccines continue to outweigh the risks. The small statistically significant increased risk of stroke outcomes observed in the study must be carefully considered in light of the known benefits of influenza vaccination.
GPS-Health: A Novel Analytic Infrastructure for Capturing, Visualizing, and Analyzing Multi-Level, Multi-Domain Geographically Distributed Social Determinants of Health
Authors: Huang Shuo Jim , Davis Esa M. , Nguyen Thu T. , Brooks Justin R. , Abaku Olohitare , Chun Se Woon , Akintoye Oluwadamilola , Aktay Sinan , Chin Matthew , Bandos Matthew , Pateel Sunil , Gohimukkula Vineeth , Felix Victor , Mahurkar Anup A. , McCoy Rozalina G.
Published: January 2025

Background

Health disparities across a range of conditions and outcomes exist across the life course and are driven by the uneven geographic distribution of multidimensional social determinants of health (SDOH). Previous multidimensional measures of SDOH (e.g. Area Deprivation Index, Social Vulnerability Index, Social Deprivation Index) collapse multiple measures into a single summary value applied to everyone living within a predefined map unit, engendering construct and internal validity issues.

Methods

We present a new SDOH data approach: the Geographic Patterns of Social Determinants of Health (GPS-Health). We use a theoretical framework weaving together kyriarchy, intersectionality, and structural violence to select SDOH domains that can elucidate how individuals experience multidimensional spatial distributions of SDOH. We apply the approach to Maryland.

Results

Our dataset includes 2,369,365 property parcels, from which we calculate distances to 8 types of SDOH exact locations.

Discussion

GPS-Health will aid in the understanding of how the SDOH influence individual health outcomes.
Safety Monitoring of Multiple Health Outcomes Following 2023–2024 COVID-19 Vaccination among Medicare Beneficiaries Aged 65 Years and Older in the United States
Authors: Gruber Joann F. , Ondari Michelle , Zelaya Carla E. , Xia Chunyi , Zhang Fengdi , Hervol Jessica R. , Ye Jin , Chen Meng , Qin Yutong , Hu Mao , Chillarige Yoganand , Forshee Richard A. , Anderson Steven A.
Published: January 2025

Background

COVID-19 vaccines are well-established as safe. However, continued surveillance of COVID-19 vaccines is important to ensure the safety of newly formulated vaccines. This study evaluated the association between vaccination with 2023-2024 formula COVID-19 vaccines and multiple health outcomes among Medicare beneficiaries aged 65 years and older in the United States.

Methods

The study used health plan data from the Medicare Fee-for-Service (FFS) claims database and extended from September 2023 to April 2024. We monitored the uptake of 2023–2024 COVID-19 vaccines (Pfizer-BioNTech, Moderna, Novavax), and where case counts were available, we used a self-controlled case series design to assess the association between vaccination and prespecified health outcomes. We used conditional Poisson regression to estimate incidence rate ratios (IRRs), attributable risks (ARs) and corresponding 99% confidence intervals (CIs). Analyses were adjusted for outcome seasonality, event-dependent observation time for outcomes with high case fatality rates, and outcome misclassification where feasible.

Results

Approximately 7.6 million Medicare FFS beneficiaries received a 2023–2024 COVID-19 vaccination. There was an even distribution of people who received Pfizer-BioNTech (3,689,356; 48.80%) or Moderna (3,841,245; 50.80%) vaccinations and very few who received Novavax (30,171; 0.40%). There was a statistically significant elevation in anaphylaxis risk associated with 2023–2024 Pfizer-BioNTech vaccines in the seasonality-adjusted analysis (IRR: [99% CI: 1.07, 15.30]) that was no longer statistically significant after accounting for potential outcome misclassification (IRR: 3.90 [99% CI: 0.49, 30.90]). Anaphylaxis cases attributable to 2023–2024 Pfizer-BioNTech vaccination were rare (AR per 100,000 doses: 0.09 [99% CI: −0.08, 0.25]). No other statistically significant elevations in risk were observed.

Conclusion

There were no new safety signals identified following 2023–2024 COVID-19 vaccinations among U.S. Medicare beneficiaries aged 65 years and older. A potential, but rare, elevation in anaphylaxis incidence rates following 2023–2024 Pfizer-BioNTech COVID-19 vaccination was observed.

HIGHLIGHTS

We studied 7,560,772 Medicare enrollees ≥65 years old who received 2023–2024 COVID-19 vaccines

No new safety signals were identified in the Medicare population ≥65 years old

A potential–but rare–elevation in anaphylaxis risk was associated with vaccination

No increased risk of any other prespecified health outcomes was found
Lateralized Circuitry for Verbal Fluency Changes After Subthalamic Nucleus Deep Brain Stimulation
Authors: Kim Min Jae , Zuccaroli Isabella , Del Bene Victor A. , Brinkerhoff Sarah A. , Martin Roy C. , Olson Joseph W. , Nelson Matthew J. , Gonzalez Christopher L. , Kamath Vidyulata , Bentley J. Nicole , Knight Robert T. , Walker Harrison C. , Mills Kelly A.
Published: January 2025

Background

Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor symptoms but can be associated with subtle cognitive changes, including declines in verbal fluency (VF). Network-based mechanisms underlying stimulation-induced fluency declines are not fully understood.

Objective

This study investigates how STN-DBS stimulation locations interact with brain connectivity patterns, and whether this differentially drives VF changes.

Methods

20 patients with Parkinson’s disease and unilateral STN-DBS were analyzed. Electrodes were localized with estimates for volume of tissue activation (VTA). VTAs were seeded in normative functional and structural connectomes to identify connectivity profiles correlating with VF changes (R-maps). Additionally, amongst the fibers passing through VTAs, a two-samplet-test assigned fibers associated with VF improvement or decline.

Results

VF declines occurred following unilateral left but not right STN-DBS. R-maps revealed that improvements correlated with greater connectivity to prefrontal structures in right hemisphere such as inferior and superior frontal gyrus, whereas declines localized to structures on the left. Fibers filtered from right VTAs were associated with VF improvements. Fibers from left VTAs were associated with declines, but the gradient of fiber t-scores were distributed across an anterior-posterior axis ranging from supplementary motor area to paracentral lobule.

Conclusion

Unilateral STN-DBS interacts with distributed cognitive networks that display strong hemispheric lateralization. Beyond the effects of implant hemisphere, our findings suggest that connectivity between local STN subregions to larger whole-brain networks impact VF performance, in a manner that could yield more tailored approaches to electrode targeting and clinical programming.
Brain-heart-eye axis revealed by multi-organ imaging genetics and proteomics
Authors: Boquet-Pujadas Aleix , Anagnostakis Filippos , Duggan Michael R. , Joynes Cassandra M. , Toga Arthur W. , Yang Zhijian , Walker Keenan A. ,   the MULTI consortium, Davatzikos Christos , Wen Junhao
Published: January 2025

Multi-organ research investigates interconnections among multiple human organ systems, enhancing our understanding of human aging and disease mechanisms. Here, we used multi- organ imaging (N=105,433), individual- and summary-level genetics, and proteomics (N=53,940) from the UK Biobank, Baltimore Longitudinal Study of Aging, FinnGen, and Psychiatric Genomics Consortium to delineate a brain-heart-eye axis via 2003 brain patterns of structural covariance1(PSC), 82 heart imaging-derived phenotypes2(IDP) and 84 eye IDPs3–5. Cross-organ phenotypic associations highlight the central autonomic network between the brain and heart and the central visual pathway between the brain and eye. Proteome-wide associations of the PSCs and IDPs show both within-organ specificity and cross-organ interconnections, verified by the RNA and protein expression profiles of the 2923 plasma proteins. Pleiotropic effects of common genetic variants are observed across multiple organs, and key genetic parameters, such as SNP-based heritability, polygenicity, and selection signatures, are comparatively evaluated among the three organs. A gene-drug-disease network shows the potential of drug repurposing for cross-organ diseases. Colocalization and causal analyses reveal cross-organ causal relationships between PSC/IDP and chronic diseases, such as Alzheimer’s disease, heart failure, and glaucoma. Finally, integrating multi-organ/omics features improves prediction for systemic disease categories and cognition compared to single-organ/omics features. This study depicts a detailed brain-heart-eye axis and highlights future avenues for modeling human aging and disease across multiple scales. All results are publicly available athttps://labs-laboratory.com/medicine/.
From dimer to tetramer: the evolutionary trajectory of C4 photosynthetic-NADP-ME oligomeric state in Poaceae
Authors: Böhm Jonas M. , Willms Simone , Ferrao Oja , Buitrago-Arango Martin , Hüdig Meike , Poschmann Gereon , Fazelnia Nazanin , Nagel-Steger Luitgard , Klinke Sebastián , Drakonaki Athina , Gatsogiannis Christos , Tronconi Marcos A. , Alvarez Clarisa E. , Maurino Veronica G.
Published: January 2025

The C4 carbon concentrating mechanism relies on specialized enzymes that have evolved unique expression patterns and biochemical properties distinct to their ancestral housekeeping forms. In maize and sorghum, the evolution of C4-NADP-malic enzyme (C4-NADP-ME) involved gene duplication and neofunctionalization, leading to the emergence of two plastidic isoforms: C4-NADP-ME and nonC4-NADP-ME, each with distinct kinetic and structural features. While C4-NADP-ME functions primarily as a tetramer, nonC4-NADP-ME exists in an equilibrium between dimeric and tetrameric forms, favoring the dimer in solution. This study shows which evolutionary changes in amino acid sequences influence the structure and function of these isoforms. By integrating X-ray crystallography, cryo-electron microscopy, computational molecular modeling and targeted biochemical analysis of mutant and truncated protein variants, we identify crucial roles for the N- and C-terminal regions and specific amino acid residues in governing isoform oligomerization. Our results reveal that the N-terminal region is essential for stabilizing the dimeric form of nonC4-NADP-ME, whereas specific adaptive substitutions and interactions with the C-terminal region enhance the stability of the tetrameric state characteristic of the C4-adapted isoform. We propose that differences in the N-terminal domain between the C4 and nonC4 isoforms reflect distinct selective pressures, which have driven their evolutionary divergence to fulfill specialized cellular functions.
The single amino acid change of R516K enables efficient generation of vesicular stomatitis virus-based Crimean-Congo hemorrhagic fever reporter virus
Authors: Ma Xue , Ma Yanlong , Wang Ziqiao , Feng Fei , Han Yutong , Sun Xinran , Li Liushuai , Gao Zhichao , Wang Manli , Zhang Rong
Published: January 2025

Crimean-Congo hemorrhagic fever virus (CCHFV) is a medically important tick-borne virus, causing severe hemorrhagic diseases in humans. There is no approved vaccines and therapeutics for CCHFV infection. The study of CCHFV authentic virus requires biosafety level 3 facilities, hindering the research and development of antivirals. Here we report the generation of a recombinant vesicular stomatitis virus (VSV) bearing both CCHFV glycoprotein precursor (GPC) and EGFP reporter (rVSV-CCHFV-GFP). We also find that the acquisition of an unexpected single R516K mutation in the GPC protein enables the packaging of high-titer pseudotyped particles. The replication-competent rVSV-CCHFV-GFP reporter virus resembles the entry properties of authentic virus and allows for rapid assessment of susceptible cell lines, neutralizing antibodies, and host entry factors such as heparan sulfate in fluorescence-based assays. This study provides valuable strategy for packaging of high-titer CCHFV pseudovirus, and the tool generated here can be served for the identification and evaluation of countermeasures against the cell entry of CCHFV.