bluuebunny/crossref_metadata_2025 huggingface dataset:
Mavorixafor; CXCR4 antagonist a novel treatment for whim syndrome, first FDA approval 2024 (Editorial)
Authors: Waheed Aiman , Gul Muhammad Hamza , Ilmaguook Badr , Wardak Abdul Baseer , Ahmad Sadeed , Hussaini Helai , Ahmad Sarah
Published: February 2025

WHIM syndrome is a rare autosomal dominant disorder characterized by gain-of-function mutations in the Chemokine receptor type-4 (CXCR4 receptor). The acronym WHIM stands for Warts, Hypogammaglobulinemia, recurrent bacterial Infections, and Myelokathexis. Traditionally, WHIM syndrome has been managed with intravenous immunoglobulin (IVIG) and filgrastim (Granulocyte Colony-Stimulating Factor, G-CSF). IVIG is used to provide passive immunity to counteract hypogammaglobulinemia, while filgrastim stimulates the production and release of neutrophils from the bone marrow to address neutropenia. However, these treatments have limited efficacy, require frequent administration, and involve significant costs and patient burden. The recent Food and Drug Administration (FDA) approval of Mavorixafor, a small molecule CXCR4 antagonist, marks a significant advancement in the management of WHIM syndrome. Mavorixafor enhances white blood cell mobilization from the bone marrow, directly targeting the underlying cause of the disease. In a pivotal Phase-3 trial conducted by Badalato R et al. (2024), involving 30 participants randomized to receive Mavorixafor 400 mg daily or placebo for 52 weeks, Mavorixafor demonstrated a statistically significant increase in absolute neutrophil count (ANC) (p<0.01) and a notable reduction in annual infection frequency compared to placebo. Additionally, a Phase-2 study reported a 75% reduction in cutaneous warts and an annual infection rate of 2.27 occurrences with adequate dosing. Mavorixafor maintained a favorable safety profile and required fewer administration complexities than IVIG and filgrastim, with 78% of patients achieving an overall response compared to 10% in the placebo group. These findings underscore the potential of Mavorixafor to significantly improve clinical outcomes for patients with WHIM syndrome, offering a more effective and targeted treatment option. The approval of Mavorixafor not only enhances current therapeutic strategies but also paves the way for future research into CXCR4 antagonists, potentially revolutionizing the management of WHIM syndrome and similar immunodeficiencies.
Moral competence and conflict management styles in emergency nurses: a cross-sectional study
Authors: Amirkhanlou Zeinab , Esmaeili Ravanbakhsh , Zeydi AmirEmami , Khademlu Mohammad , Ghorbani Vajargah Pooyan , Karkhah Samad , Jafari Hedayat
Published: February 2025

Background:

This study aimed to evaluate the moral competence and conflict management styles in emergency nurses

Materials and methods:

This cross-sectional study was conducted among emergency department nurses. Convenience sampling was employed. The data collection tools comprised a demographic-occupational questionnaire, a questionnaire assessing the moral competence of clinical nurses, and another questionnaire focused on exploring conflict management styles.

Results:

190 emergency department nurses were involved in this study. The study revealed that emergency department nurses’ average moral competence score was 159.81 (SD = 13.00), ranging from 121 to 184 points. Among emergency department nurses, the average score for conflict management styles stood at 105.61 (SD = 10.67), ranging from 41 to 132 points. The study findings revealed statistically significant associations between several factors and nurses’ overall moral competence score; age group (P = 0.004) and type of employment (P = 0.035) showed substantial relationships. Significant associations emerged between the overall conflict management score, job position (P = 0.021), and age group (P = 0.044).

Conclusion:

Emergency nurses demonstrated a commendable average score in moral competence and predominantly utilized conflict management styles over participation styles when handling conflicts. A robust and direct correlation between ethical competence and conflict management was also observed.
Neurocysticercosis presenting as postpartum psychosis: a case report on challenging clinical insight with review of the literature
Authors: Yogi Tek Nath , Rauniyar Krish , Bhusal Amrit , Bk Himal , Darai Anju , Yadav Ajay , Shahi Shishir , Shah Bipesh Kumar , Kafle Rijan , Bam Prabin Kumar , Duwadee Prabin , Pokhrel Sushan
Published: February 2025

Introduction:

Postpartum psychosis (PPP) is a psychiatric emergency with symptoms such as mania, depression, hallucinations, and delusions appearing shortly after childbirth. Neurocysticercosis (NCC), a CNS infection from Taenia solium, can also manifest psychiatric symptoms, complicating diagnosis. This report discusses a rare case of NCC presenting as PPP, emphasizing diagnostic complexities and the need for a multidisciplinary approach.

Case Presentation:

A 23-year-old female presented with psychotic symptoms 15 days postpartum, initially treated for PPP with lorazepam, olanzapine, and haloperidol. Following the development of generalized seizures, neuroimaging revealed NCC lesions. Treatment with albendazole and steroids led to symptom resolution.

Discussion:

This case highlights NCC’s rare presentation as PPP. A thorough evaluation is crucial, as PPP poses risks to both mother and infant. In regions where NCC is endemic, psychiatric presentations due to this infection create diagnostic challenges, especially in limited-resource settings. Neuroimaging is vital for precise diagnosis, and early intervention with a multidisciplinary team enhances outcomes.

Conclusion:

The case underscores the complexity of PPP diagnosis and management when coexisting with NCC. Clinicians in endemic regions should consider NCC in postpartum women with atypical psychiatric symptoms, ensuring appropriate investigations. A multidisciplinary approach involving psychiatry, neurology, and radiology is essential for effective management.
Initiation of Dolutegravir vs Efavirenz on Viral Suppression and Retention at 6-months: A Regression Discontinuity Design
Authors: Zheng Amy , Fox Matthew P. , Greener Ross , Kileel Emma M. , Bor Jacob , Venter Willem Df , Pisa Pedro T. , Brennan Alana T. , Maskew Mhairi
Published: February 2025

Background:

In 2019, South Africa’s Antiretroviral Therapy (ART) Treatment Guidelines replaced efavirenz with dolutegravir in first-line ART.

Setting:

We assessed the impact of this national guideline change on retention and viral suppression in the Themba Lethu Clinical Cohort, Johannesburg, South Africa. We applied a regression discontinuity design in a prospective cohort study of 1654 adults living with HIV initiating first-line ART within 12 months (±12 months) of the guideline change.

Methods:

We compared outcomes in individuals presenting just before and after the guideline change and estimated intention-to-treat effects on initiating a dolutegravir- vs efavirenz-based regimen. Primary outcomes were retention and viral suppression. Participants were defined as retained in care if a visit took place within +3-months of the 6-month endpoint. Viral suppression was defined as having a viral load < 1000 copies/mL 3-months prior to and up to 6-months after the 6-month endpoint.

Results:

The 2019 guideline change led to an increase in uptake of dolutegravir. We noted a 26.6 percentage point increase in the proportion initiating dolutegravir (95% Confidence Interval (CI): 14.1, 38.6). We saw a small increase in viral suppression (Risk Difference (RD): 7.4 percentage points; 95% CI: -1.6, 16.5) and no change in retention (RD: -1.7 percentage points; 95% CI: -13.9, 10.5) at 6 months, though our findings were imprecise.

Conclusion:

Our estimates suggest early uptake of the revised treatment guidelines after implementation. Despite this, there was no meaningful change in viral suppression and retention rates at 6-months.
Pre- and postinjury financial hardship among trauma survivors: A national survey study
Authors: Clark Nina M. , Hernandez Alex H. , Knowlton Lisa M. , Stewart Barclay T. , Bulger Eileen M. , Malloy Alexander , Anderson Geoffrey , Dieleman Joseph L. , Zatzick Douglas , Scott John W.
Published: February 2025

BACKGROUND

National estimates of financial hardship because of injury are lacking, which limits our ability to both define and mitigate the impacts of financial outcomes of trauma care. Furthermore, the absence of preinjury data limits our understanding of the association between injury and financial hardship.

METHODS

We analyzed data from the 2014–2021 Medical Expenditure Panel Survey. We compared injured adults (18–64 years old) to uninjured controls using coarsened-exact matching on age, sex, race/ethnicity, income, payer, survey panel, and comorbidities. Our main outcome of interest was financial hardship, a composite of difficulty paying medical bills, paying medical bills off over time, and delaying medical care because of cost. As a secondary analysis, we evaluated the link between difficulty paying medical bills, delaying care, and poor health.

RESULTS

We included a weighted sample of more than 79 million injured patients over the 8-year study period. Difference-in-differences analysis using uninjured, matched controls showed that injured patients experienced an 8.2 percentage point increase in financial hardship (23% relative increase, with 40.6% reporting financial hardship postinjury, p < 0.001) and 4.5 percentage point increase in poor health (20% relative increase, p < 0.001). Injured patients who reported difficulty with medical bills were more likely to report delaying care because of costs (adjusted odds ratio, 3.3; 95% confidence interval, 2.5–4.4), and those who delayed care were more likely to report poor health (adjusted odds ratio, 1.5; 95% confidence interval, 1.2–2.0).

CONCLUSION

In this national analysis of financial hardship before and after injury, 40% of injured patients reported difficulty with medical bills and delayed medical care because of cost. Programs aimed at disrupting the path from injury to financial hardship to poor long-term health have the potential to benefit millions of injury survivors.

LEVEL OF EVIDENCE

Retrospective Cohort Study; Level III.
Drug-disease networks and drug repurposing
Authors: Polanco Austin , Newman M. E. J.
Published: February 2025

Repurposing existing drugs to treat new diseases is a cost-effective alternative tode novodrug development, but there are millions of potential drug-disease combinations to be considered with only a small fraction being viable. In silico predictions of drug-disease associations can be invaluable for reducing the size of the search space. In this work we present a novel network of drugs and the diseases they treat, compiled using a combination of existing machine-readable and textual databases, natural-language processing tools, and hand curation, and analyze it using a selection of network-based link prediction methods to identify potential drug-disease combinations. We measure the efficacy of these methods using cross-validation tests and find that several methods, particularly those based on graph embedding and network model fitting, achieve impressive prediction performance, with area under the ROC curve above 0.95 and average precision almost a thousand times better than chance.
Enhancing ecosystem service provision through the silvicultural management of European black pine stands from afforestation and reforestation
Authors: Vangi Elia , Sacchelli Sandro , Nocentini Susanna , Plutino Manuela , Dalmonech Daniela , Collalti Alessio , Travaglini Davide , Corona Piermaria
Published: February 2025

Afforestation and reforestation are integral components of the wider field of land management. When these initiatives integrate the diverse eco-biological, landscape, cultural, and socioeconomic characteristics of the intervention area they can achieve substantial environmental improvements also by improving ecosystem functions, commonly referred to as ecosystem services (ES). European black pines (Austrian pine (Pinus nigra Arnold) and Corsican pine (Pinus laricio (Poir.) Maire) are some of Europe's most frequently used tree species for afforestation and reforestation, thanks to their ability to grow in poor soil conditions and their resistance to environmental stressors. In this study, we adopted a validated process-based modeling approach to explore the effects of thinning intensity and frequency on the provision of some ES from European black pine stands, which have been established through afforestation and reforestation. We found a net financial gain when basal area removal reaches 25% with a 25-year thinning interval, highlighting the higher financial efficiency of more intensive interventions. Non-provisioning ES (erosion protection, carbon sequestration, and aesthetic/recreational value) tend to decrease with increased basal area removal and benefit from longer intervals between thinning. Remarkably, the economic values of aesthetic appeal and carbon sequestration far exceed those of timber production and erosion protection, regardless of thinning regime. Based on our results, we claim that strategic, long-term planning of thinning operations is essential to ensure a balanced trade-off between wood production and other ES while maintaining the cost-effectiveness of operations. Ultimately, our approach can provide guidelines for forest managers to ensure the provision of multiple ES.
Mobile genetic elements exhibit associated patterns of host range variation and sequence diversity within the gut microbiome of the European Honey bee
Authors: Robinson Chris R. P. , Dolezal Adam G. , Liachko Ivan , Newton Irene L. G.
Published: February 2025

Mobile genetic elements (MGEs), such as plasmids and bacteriophages, are major contributors to the ecology and evolution of host-associated microbes due to a continuum of symbiotic interactions and by mediating gene flow via horizontal gene transmission. However, while myriad studies have investigated relationships between MGEs and variation in fitness among microbial and eukaryotic hosts, few studies have incorporated this variation into the context of MGE evolution and ecology. Combining HiC-resolved metagenomics with the model honey bee worker gut microbiome, we show that the worker gut contains a dense, nested MGE community that exhibits a wide degree of host range variation among microbial hosts. Using measures of gene similarity and syntenty, we show that plasmids likely mediate gene flow between individual honey bee colonies, though these plasmids exhibit broad host range variation within their individual microbiomes. We further show that phage-microbe networks exhibit high variation among individual metagenomes, and that phages show broad host range with respect to both the number and phylogenetic distance of their hosts. Finally, we provide evidence that measures of nucleotide variation positively correlate with host range in bee-associated phages, and that functional targets of diversifying selection are partitioning differently between broad or narrow host range phages. Our work underscores the variability of MGE x microbial interactions within host-associated microbial communities and highlights the genomic variation associated with MGE host range diversity.
The Sequential Multispecies Coalescent
Authors: Milkey Analisa , Chen Ming-Hui , Wang Yu-Bo , Li Aolan , Lewis Paul O.
Published: February 2025

The multispecies coalescent (MSC) model applies coalescent theory to gene evolution within and among reproductively isolated populations (“species”) to estimate a species tree in the face of gene tree conflict resulting from deep coalescence. Sequential Monte Carlo (SMC) uses particle filtering to sample a posterior distribution, providing a fully-Bayesian and easily parallelized alternative to traditional MSC tree inference approaches. The method we propose samples first from the joint posterior distribution of gene and species trees, then samples species trees conditional on gene trees sampled previously, employing SMC for both rounds. Analyses of simulated and empirical datasets yield results comparable to state-of-the-art Bayesian MCMC approaches. Sampling the multispecies coalescent using SMC retains the advantages of fully Bayesian methods and is parallelizable in ways that Bayesian MCMC methods are not but also adds unique challenges. We demonstrate the performance of SMC compared to other commonly-used species tree methods using two empirical datasets and 400 simulated datasets.
Thermodynamics shape thein vivoenzyme burden of glycolytic pathways
Authors: Khana Daven B. , Jen Annie , Shishkova Evgenia , Thusoo Eashant , Williams Jonathan , Henkel Alex , Stevenson David M. , Coon Joshua J. , Amador-Noguez Daniel
Published: February 2025

Thermodynamically constrained reactions and pathways are hypothesized to impose greater protein demands on cells, requiring higher enzyme amounts to sustain a given flux compared to those with stronger thermodynamics. To test this, we quantified the absolute concentrations of glycolytic enzymes in three bacterial species —Zymomonas mobilis,Escherichia coli, andClostridium thermocellum— which employ distinct glycolytic pathways with varying thermodynamic driving forces.

By integrating enzyme concentration data with correspondingin vivometabolic fluxes andΔGmeasurements, we found that the highly favorable Entner-Doudoroff (ED) pathway inZ. mobilisrequires only one-fourth the amount of enzymatic protein to sustain the same flux as the thermodynamically constrained pyrophosphate-dependent glycolytic pathway inC. thermocellum, with the Embden-Meyerhof-Parnas (EMP) pathway inE. coliexhibiting intermediate thermodynamic favorability and enzyme demand. Across all three pathways, early reactions with stronger thermodynamic driving forces generally required lower enzyme investment than later, less favorable steps. Additionally, reflecting differences in glycolytic strategies, the highly reversible ethanol fermentation pathway inC. thermocellumrequires 10-fold more protein to maintain the same flux as the irreversible, forward-driven ethanol fermentation pathway inZ. mobilis.

Thus, thermodynamic driving forces constitute a majorin vivodeterminant of the enzyme burden in metabolic pathways.
Tumor-associated stroma shapes the spatial tumor immune microenvironment of primary Ewing sarcomas
Authors: Kuo Christopher , Giannikou Krinio , Wang Nuoya , Warren Mikako , Goodspeed Andrew , Shillingford Nick , Hayashi Masanori , Raredon Micha Sam Brickman , Amatruda James F.
Published: February 2025

To date, few studies have detailed the tumor microenvironment (TME) of Ewing sarcoma (EwS). The TME has a vital role in cancer survival and progression with implications in drug resistance and immune escape. By performing spatially resolved transcriptomic analysis of primary treatment-naïve EwS samples, we discovered greater stromal enrichment in localized EwS tumors compared to metastatic EwS tumors. Through spatial ligand-receptor analysis, we show that the stromal enriched regions harbor unique extracellular matrix related cytokines, immune recruitment and proinflammatory microenvironmental signals, implying EwS stroma may play an anti-tumorigenic role by acting as an immune recruitment center. All EwS tumors expressed pro-tumorigenic MIF-CD74 immune signaling, suggesting a potential immune-evasive mechanism and immunotherapy target. Our findings provide insight into tumor cell/stromal cell interactions in EwS and serve as a valuable resource for further investigations in the tumor immune microenvironment of EwS.
Dynamical interactions among compositionally distinct protocell populations and its implications for evolution of early membranes
Authors: Das Souradeep , Pal Ruchira , Rajamani Sudha
Published: February 2025

The spontaneous self-assembly of single chain amphiphiles (SCAs) would have resulted in multiple protocell species in an early-Earth niche. Considering the heterogeneity inherent in a prebiotic milieu, interactions between physicochemically distinct protocell populations was evaluated to discern if emergent properties occurred at a systems level. This study demonstrates that depending on the physicochemical properties of the membrane, interacting populations are endowed with varied emergent properties owing to their coexistence. In a multispecies paradigm involving a two-candidate protocell system, the fitter population acted as a predator and grew at the expense of the less-fit prey population. The observed growth could be attributed to the predator attaining a more robust membrane via chemical evolution. Importantly, the prey population also accrued emergent properties like molecular crowding, and coexist in balance with the predator population, without being completely outcompeted. When extrapolating these results to a three-candidate population, the outcomes were multipronged. These findings suggest a possible route for protocell membrane evolution that could have occurred even in the absence of any sophisticated protein machinery, benefitting coexisting populations, while also illustrating evolutionary trajectories that potentially resulted in functionally complex protocells.
Risk stratification of childhood infection using host markers of immune and endothelial activation: a multi-country prospective cohort study in Asia (Spot Sepsis)
Authors: Chandna Arjun , Koshiaris Constantinos , Mahajan Raman , Ahmad Riris Adono , Anh Dinh Thi Van , Keang Suy , Nguyen Phung Nguyen The , Rattanavong Sayaphet , Shams Khalid , Vannachone Souphaphone ,   Spot Sepsis Investigator Group, Yosia Mikhael , Waithira Naomi , Abdad Mohammad Yazid , Thaipadungpanit Janjira , Turner Paul , Phuc Phan Huu , Mondal Dinesh , Mayxay Mayfong , Liem Bui Thanh , Ashley Elizabeth A , Arguni Eggi , Perera-Salazar Rafael , Richard-Greenblatt Melissa , Lubell Yoel , Burza Sakib
Published: February 2025

Background

Circulating markers of immune and endothelial activation risk stratify infection syndromes agnostic to disease aetiology. However, their utility in children presenting from the community remains unclear.

Methods

This study recruited children aged 1-59 months presenting with community-acquired acute febrile illnesses to seven hospitals in Bangladesh, Cambodia, Indonesia, Laos, and Viet Nam. Clinical parameters and biomarker concentrations were measured at presentation. The outcome measure was death or receipt of vital organ support within two days of enrolment. Prognostic performance of endothelial (Ang-1, Ang-2, sFlt-1) and immune (CHI3L1, CRP, IP-10, IL-1ra, IL-6, IL-8, IL-10, PCT, sTNFR-1, sTREM-1, suPAR) activation markers, WHO Danger Signs, and two validated severity scores (LqSOFA, SIRS) was compared.

Results

3,423 participants were recruited. 133 met the outcome (weighted prevalence: 0.34%; 95% CI 0.28-0.41). sTREM-1 exhibited highest prognostic accuracy (AUC 0.86; 95% CI 0.82-0.90), outperforming WHO Danger Signs (AUC 0.75; 95% CI 0.70-0.80; p < 0.001), LqSOFA (AUC 0.74; 95% CI 0.70-0.78; p < 0.001), and SIRS (AUC 0.63; 95% CI 0.58-0.68; p < 0.001). Discrimination of immune and endothelial activation markers was particularly strong for children who deteriorated later in the course of their illness. Compared to WHO Danger Signs, an sTREM-1-based triage strategy improved recognition of children at risk of progression to life-threatening infection (sensitivity: 0.80 vs. 0.72), while maintaining comparable specificity (0.81 vs. 0.79).

Conclusions

Measuring circulating markers of immune and endothelial activation may help earlier recognition of febrile children at risk of poor outcomes in resource-constrained community settings.
Impact of a machine learning-powered algorithm on pathologist HER2 IHC scoring in breast cancer
Authors: Shamshoian John , Shanis Zahil , Cabeen Ryan , Yu Limin , Chakraborty Shreya , Thibault Marc , Martin Blake , Pagidela Harshith , Juyal Dinkar , Javed Syed Ashar , Qian William , Kim Juhyun , Gerardin Ylaine , Rucker Beckett , Brosnan-Cashman Jacqueline , Pokkalla Harsha , Mehta Jimish , Taylor-Weiner Amaro , Walk Eric , Beck Andrew , Montalto Michael C. , Glass Ben , Balasubramanian Santhosh
Published: February 2025

Background

HER2 expression level is a key factor in determining the optimal treatment course for breast cancer patients. Roughly 15% of breast cancers are HER2(+), and determination of HER2 status is routinely assessed by immunohistochemistry (IHC). Accurate assessment of the HER2 IHC score by pathologists is therefore critical, especially in light of novel therapeutic approaches demonstrating efficacy in the HER2-low setting. However, there is an opportunity to improve inter-pathologist agreement at the lower levels of HER2 scoring (0, 1+, and 2+).

Methods

A machine learning model (AIM-HER2) was developed to generate accurate, slide-level HER2 scores aligned with ASCO-CAP guidelines in clinical breast cancer HER2 IHC specimens. AIM-HER2 was assessed as an AI-assist tool in a retrospective reader study, where 20 HER2-trained pathologists scored breast cancer cases (N=200) with and without AIM-HER2 assistance using a 2-cohort crossover design with a 3-week washout. A separate panel of 5 expert HER2 pathologists read all 200 cases manually to establish reference scores.

Results

In a significant fraction of cases examined, less than 70% inter-pathologist agreement was observed. When used as an AI assist tool, AIM-HER2 improved inter-rater agreement overall and specifically at the 0/1+ and 1+/2+ cutoffs. Similarly, AIM-HER2 AI-assist significantly increased PPA at the 0/1+ and 1+/2+ cutoffs. When interacting with the AI-assist tool, pathologists displayed a wide range of override rates, and the quality of a pathologist’s overrides was correlated with their manual accuracy. Lastly, the impact of the reference panel on AIM-HER2 accuracy metrics was assessed, revealing that measurements of model accuracy are highly dependent on reference panel composition.

Conclusions

The use of AIM-HER2 as an AI-assist tool for scoring HER2 IHC in breast cancer may improve pathologist reproducibility and accuracy, particularly at the 0/1+ and 1+/2+ cutoffs.
Post-Hurricane Fluid Conservation Measures Fail to Reduce IV Fluid Use in Critically Ill Children
Authors: Dixon Celeste G. , Odum James , Kothari Ulka , Martin Susan D. , Fitzgerald Julie C. , Shah Ami , Dapul Heda , Braun Chloe G. , Barbera Andrew , Terry Nina , Weiss Scott L. , Hasson Denise C. , Dziorny Adam C.
Published: February 2025

Introduction

Fluid overload (FO) due to excessive fluid administration in critically ill children is associated with worse pediatric intensive care unit (PICU) outcomes. Damage to intravenous fluid (IVF) production plants due to Hurricane Helene resulted in a national IVF shortage, leading many hospitals to implement IVF conservation guidelines. We hypothesized that these guidelines would lead to a reduction in IVF use and a decrease in % cumulative fluid balance (CFB).

Methods

Four-site cohort study of critically ill children utilizing a federated data collection framework to extract patient age, sex, weight, and daily fluid intake/output for all admissions one month prior to and one month after the implementation of IVF conservation guidelines. Guidelines were individualized per institution. Total fluid intake, total IVF intake, % intake from IVF, and % CFB, as total intake minus total output divided by PICU admission weight, were compared between pre and post IVF conservation groups.

Results

There were 633 pre and 619 post IVF conservation encounters, with similar age and size distributions. There was no significant difference in IVF use pre and post IVF conservation. All sites had similar conservation recommendations.

Conclusions

Simple recommendations without structured change was insufficient to change IVF administration practices, indicating additional practices will be needed to reduce IVF intake and % CFB in this vulnerable population.
Plasma proteomics of seizure-associated changes in epilepsy
Authors: Akel Sarah , Ashtiani Saman Hosseini , Sarangdhar Mayuresh Anant , Axelsson Markus , Zelano Johan
Published: February 2025

Fluid biomarkers are emerging as crucial markers for diagnosis and disease monitoring in neurology. Epilepsy remains an exception despite seizures being known to result in metabolic changes, inflammation, and altered brain protein levels. Insight into how seizures affect the blood proteome is greatly needed.

This cross-sectional study used plasma samples from adults aged 18-50 with epilepsy recruited at five different neurology outpatient clinics in region Västra Götaland, Sweden to the Prospective Regional Epilepsy Database and Biobank for Individualized Clinical Treatment (PREDICT). Patients were categorized based on the presence of seizures; those with seizures ≤1 year (n=88, median number of seizures for patients who have experienced seizures in the last two months = 1) and those seizure-free (n=88) for >1 year.

Plasma proteomics was performed using four Olink Explore384 panels to analyze a total of 1447 proteins. Normalized Protein eXpression (NPX) values were compared between seizure and seizure-free participants. Two machine learning models, one linear and one non-linear, identified protein expression differences associated with seizure status through feature selection, resulting in 51 unique discriminative proteins. Twenty-three proteins were considered top differentially expressed after FDR adjustment (p≤0.05), including neurofilament light and several cytokines.

Protein-protein interaction (PPI) analysis identified several clusters among the 51 discriminative proteins, with the largest clusters primarily associated with inflammatory processes. In addition, machine-learning independent gene set enrichment analysis identified 34 gene sets, mainly related to immune and inflammatory processes, that were also enriched in association with seizures.

In this study, persons with epilepsy and seizures had different plasma protein profiles compared to those seizure-free, primarily suggesting altered inflammatory/immune processes. The findings fit well with the growing evidence of inflammation as a key process in epilepsy. In addition to new therapeutic targets, immune processes need further exploration as candidate biomarkers for the monitoring of treatment responses in epilepsy.
Development of a digital twin for the diagnosis of cardiac perfusion defects
Authors: Criseo Elisabetta , Baggiano Andrea , Pelagi Giovanni Montino , Nannini Guido , Redaelli Alberto , Pontone Gianluca , Vergara Christian
Published: February 2025

Myocardial Blood Flow (MBF) is a key indicator of myocardial perfusion, typically assessed through additional clinical tests like dynamic CT perfusion under stress. This study introduces a digital twin designed to enhance coronary artery disease diagnosis by predicting MBF using data from routine CT images and clinical measurements. The digital twin employs AI methods to reconstruct coronary and myocardial geometries and integrates a computational model, featuring 3D coronary arteries and a three-compartment myocardial model, blindly calibrated with data from six representative patients. Validation on 28 additional patients showed MBF predictions consistent with experimental and clinical measurements. Confusion matrix analysis assessed the twin's ability to classify at-risk patients (averaged MBF < 230 ml/min/100g) versus non-at-risk patients, yielding a recall of 0.77, with precision and accuracy at 0.72. This work represents the first attempt to predict and validate MBF on such a large cohort, paving the way for future clinical applications.
Bile acid dysmetabolism in Bangladeshi infants is associated with poor linear growth, enteric inflammation, and small intestine bacterial overgrowth
Authors: Hasan Farah , Hylemon Phillip B , Haque Rashidul , Petri William A , Faruque Abu S.G. , Kirkpatrick Beth D. , Alam Masud , Ferdous Tahsin , Sharma Talat , Moreau Brett , Ramakrishnan Girija , Zhou Huiping , Chesney Alden , Garcia Felix Medrano , Smirnova Ekaterina , Prem Preethi , Huang Yingsi , Bojja Rashmi , Thapaliya Anubhav , Donowitz Jeffrey R
Published: February 2025

Introduction: Environmental enteric dysfunction (EED) is a subclinical condition caused by fecal-oral contamination leading to enteric inflammation and dysbiosis. This study investigates bile acid metabolism in Bangladeshi children with EED and its association with growth impairment. Methods: We conducted a cross sectional study of 100 Bangladeshi infants (aged 6-9 months) and quantified serum and fecal bile acids using LC-MS/MS. We compared profiles to a control group of 6 American children (6-12 months) and 80 older Bangladeshi children (aged 2 years). Results: Bangladeshi infants had higher levels of plasma unconjugated primary (65.23% vs. 44.25%, p = .003) and sulfated primary bile acids (12.98% vs. <0.001%, p = .01), with lower primary conjugated bile acids (0.69% vs 2.74%, p = <0.001) compared to American children. Stool unconjugated primary bile acids were inversely associated with weight-for-age (regression coefficient [B] = -0.01, p = 0.01) and height-for-age z scores (B; = -0.01, p = 0.03). Conjugated secondary bile acids were inversely associated with small intestine bacterial overgrowth (B; = -1096.68, p = 0.05). Fecal myeloperoxidase was associated with sulfated secondary bile acids (B; = -0.40, p = 0.04). Compared to 2-year-old children, the Bangladeshi infant's serum had higher levels of unconjugated primary bile acids (65.23% vs. 9.20%, p = <0.001) and lower levels of primary conjugated bile acids (0.69% vs 80.38%, p = <0.001). Discussion: Our data suggests an age-dependent defect in conjugation of primary bile acids in Bangladeshi children with compensatory hydrophilic shunting. Additionally, bile acid profiles are associated with intestinal overgrowth.
Predicting Levels of Anemia among Adolescents in Ethiopia Using homogeneous ensemble Machine Learning algorithm
Authors: Ayele Misganaw Ketema , Enyew Eyob Teshager
Published: February 2025

Anemia significantly impacts adolescent girls’ health and quality of life in Ethiopia. Effective interventions require identifying key risk factors and predicting anemia severity. While traditional studies primarily use statistical methods, this research aims to leverage machine learning models to predict anemia risk and analyze contributing socio-economic, environmental, and cultural factors.

We applied machine learning models, including Random Forest, Extra Trees, CatBoost, XGBoost, and AdaBoost, to predict anemia severity using features from the Ethiopian Demographic and Health Survey (EDHS). Performance was evaluated using accuracy, ROC AUC, precision, recall, and F1-score, with feature importance analysis to identify key anemia risk factors. Random Forest and Extra Trees outperformed others, achieving accuracy rates of 82.51% and 82.41% and ROC AUC scores of 94.87% and 94.48%, respectively. CatBoost showed competitive performance (80.99% accuracy, 93.08% ROC AUC). XGBoost and AdaBoost were less effective. Key risk factors included region, education, wealth index, household size, and altitude.

Random Forest and Extra Trees are effective for predicting anemia severity and identifying key socio-economic and environmental risk factors. Interventions focusing on education, healthcare access, and nutrition are vital to reducing anemia prevalence among adolescent girls in Ethiopia. Future work should refine models and expand datasets for improved public health outcomes.
Relationship between intragastric meal distribution, gastric emptying and gastric neuromuscular dysfunction in chronic gastroduodenal disorders
Authors: Varghese Chris , Gharibans Armen A , Foong Daphne , Schamberg Gabriel , Calder Stefan , Ho Vincent , Anand Reena , Andrews Christopher N , Maurer Alan H , Abell Thomas , Parkman Henry P , O’Grady Greg
Published: February 2025

Background

Chronic gastroduodenal symptoms arise from heterogenous gastric motor dysfunctions. This study applied multimodal physiological testing using gastric emptying scintigraphy (GES) with intragastric meal distribution (IMD) and Gastric Alimetry® body surface gastric mapping (BSGM) to define motility and symptom associations.

Methods

Patients with chronic gastroduodenal symptoms underwent simultaneous supine GES and BSGM with 30 m baseline, 99mTC-labelled egg meal, and 4 h postprandial recording. IMD (ratio of counts in the proximal half of the stomach to the total gastric counts) was calculated immediately after the meal (IMD0), with <0.568 defining impaired accommodation. BSGM phenotyping followed a consensus approach, based on normative spectral reference intervals.

Results

Among 67 patients (84% female, median age 40, median BMI 24), median IMD0 was 0.76 (IQR 0.69-0.86) with 5 (7.5%) meeting impaired accommodation criteria. Delayed gastric emptying (n=18) was associated with higher IMD0 (median 0.9 vs 0.7, p=0.004). On BSGM, 15 patients had abnormal spectrograms (5 [7.5%] high frequency and 10 (14.9%) low rhythm stability and/or amplitude); and in these patients, higher IMD0 (proximal retention) strongly correlated to delayed BSGM meal responses (R=-0.71, p=0.003). Lower IMD, indicating antral distribution, correlated with higher gastric frequencies (R=-0.27, p=0.03). BSGM abnormalities paired with impaired accommodation were associated with worse dyspeptic symptoms.

Conclusion

Proximal retention of food as assessed by intragastric meal distribution correlated with delayed emptying, and in the presence of neuromuscular spectral abnormalities (abnormal frequencies or rhythms), delayed motility responses on BSGM. Patients with multiple motor abnormalities experience worse dyspeptic symptoms.
Impact of Ebola and COVID-19 pandemic on patterns in uptake of short-acting and long-acting contraceptive methods in Sierra Leone: a country-wide observational study
Authors: Kamara Idrissa Mohamed , Molleh Bailah , Lakoh Sulaiman , Sevalie Stephen , Kenneh Sartie M. , Chan Adrienne K. , Mishra Sharmistha , Moses Francis , Bah Abdulai Jawo
Published: February 2025

Background

The Ebola epidemic and COVID-19 pandemic disrupted essential healthcare services globally, including family planning, but the extent of disruptions in Sierra Leone is largely unknown. This study aimed to evaluates the impact of these crises on the uptake of contraceptive methods—short-acting contraceptives (SAC) and long-acting reversible contraceptives (LARC)— among adolescent girls and women ages 10-45 years in Sierra Leone from 2013 to 2022.

Methods

We conducted a retrospective, cross-sectional study using aggregated DHIS2 data from adolescent girls and women aged 10-45 years. We describe and visualize the trends in the uptake of SAC and LARC before Ebola (March 2013 to April 2014), during Ebola (May 2014 to February 2016), after Ebola and before COVID-19 (March 2016 to February 2020), and during COVID-19 (March 2020 to February 2022). Proportional shifts and age-specific patterns were assessed to identify changes in contraceptive preferences.

Results

During the Ebola outbreak (2014–2016), SAC uptake declined temporarily while LARC uptake modestly increased. A recovery in SAC uptake followed during the inter-epidemic period (2016–2019). Conversely, the COVID-19 pandemic (2020–2022) saw an initial spike in SAC uptake, which subsequently returned to pre-pandemic levels. In contrast, LARC uptake consistently increased throughout both pandemics and the post-pandemic period. Notably, a proportional shift toward LARC methods was observed. Trends across age groups were variable, with adolescents demonstrating resilience in their use of contraceptives during the COVID-19 pandemic.

Conclusion

LARC services demonstrated remarkable stability during health emergencies, underscoring the resilience of long-term methods and the adaptability of women in making informed choices about their reproductive health amidst disruptions. These findings highlight the importance of strengthening healthcare systems to ensure continued access to reliable contraceptive options, particularly during crises.
Using a stable protein scaffold to display peptides that bind to alpha-synuclein fibrils
Authors: Bismut Samuel , Schneider Matthias M. , Miyasaki Masashi , Feng Yuqing , Wilde Ellis J. , Gunawardena M. Dylan , Knowles Tuomas P.J. , Kaminski Schierle Gabrielle S. , Itzhaki Laura S. , Kumita Janet R.
Published: February 2025

Amyloid fibrils are ordered aggregates that are a pathological hallmark of many neurodegenerative disorders including Alzheimer’s Disease and Parkinson’s Disease. The process of amyloid formation involves a complex cascade by which soluble monomeric protein converts to insoluble, ordered aggregates (amyloid fibrils). Although inhibiting the aggregation pathway is a key target for therapeutic development, the heterogeneous collection of aggregation-prone species formed in this process, including oligomers, protofibrils and fibrils, represent other targets for modifying disease pathology. Developing molecules that can bind to amyloid fibrils and potentially disrupt the harmful interactions between the fibrils and the cellular components would be advantageous. Designing peptide modulators for α-synuclein aggregation is of great interest, however effective inhibitory peptides are often hydrophobic and hence difficult to handle; therefore, developing strategies to display these peptides in a soluble scaffold would be very beneficial. Here we demonstrate that the ultra-stable consensus-designed tetratricopeptide repeat (CTPR) protein scaffold can be grafted with “KLVFF” derived peptides previously identified to inhibit protein aggregation and interact with amyloid fibrils, to produce proteins that bind along the surface of α-synuclein fibrils with micromolar affinity. Given the ability to insert hydrophobic peptides to produce soluble, CTPR-based binders, this method may prove beneficial in screening for peptide modulators of protein aggregation.

Short statement

Consensus-designed tetratricopeptide repeat (CTPR) proteins can be endowed with additional functionality including specific client recruitment. Here we created stable, soluble CTPR-based binders that recognise α-synuclein fibrils with micromolar affinity. The CTPR scaffold provides a facile way to test potential fibril-binding or aggregation-modulating peptides and to probe their mechanisms of action.
Post-transcriptional Modifications of the Large Ribosome Subunit Assembly Intermediates inE. coliExpressing Helicase-Inactive DbpA Variant
Authors: Gracia Mazuca Luis A. , Mohl Jonathon E. , Cho Samuel S. , Koculi Eda
Published: February 2025

RNA post-transcriptional modifications are ubiquitous across all organisms and serve as fundamental regulators of cellular homeostasis, growth, and stress adaptation. Techniques for the simultaneous detection of multiple RNA modifications in a high-throughput, single-nucleotide-resolution manner are largely absent in the field, and developing such techniques is of paramount importance. We used theEscherichia coliribosome as a model system to develop novel techniques for RNA post-transcriptional modification detection, leveraging its extensive and diverse array of modifications. For modification detection, we performed reverse transcriptase reactions in the presence of Mn2⁺ and quantified the reverse transcriptase deletions and misincorporations at modification positions using Illumina next-generation sequencing. We simultaneously detected the following modifications in ribosomal RNA (rRNA): 1-methylguanosine (m1G), 2-methylguanosine (m2G), 3-methylpseudouridine, N6,N6-dimethyladenosine, and 3-methyluridine, without chemical treatment. Furthermore, subjecting the rRNA samples to 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate followed by alkaline conditions allowed us to simultaneously detect pseudouridine, 7-methylguanosine (m7G), 5-hydroxycytidine (OH5C), 2-methyladenosine, and dihydrouridine (D). Finally, subjecting the rRNA samples to KMnO4followed by alkaline conditions allowed us to simultaneously detect m7G, OH5C, and D. Our results reveal that m1G, m2G, m7G, and D are incorporated prior to the accumulation of the 27S, 35S, and 45S large subunit intermediates in cells expressing the helicase-inactive R331A DbpA construct. These intermediates belong to three distinct stages and pathways of large subunit ribosome assembly. Therefore, our results identify the time points in three pathways at which m1G, m2G, m7G, and D are incorporated into the large ribosome subunit and provide a framework for broader studies on RNA modification dynamics.
Transcription can be sufficient, but is not necessary, to advance replication timing
Authors: Vouzas Athanasios E. , Sasaki Takayo , Rivera-Mulia Juan Carlos , Turner Jesse L. , Brown Amber N. , Alexander Karen E. , Brueckner Laura , van Steensel Bas , Gilbert David M.
Published: February 2025

DNA replication timing (RT) is correlated with transcription during cell fate changes but there are many exceptions and our understanding of this relationship suffers from a paucity of reductionist approaches. Here, we manipulated length and strength of transcription in hybrid-genome mouse embryonic stem cells (mESCs) at a single locus upstream of the silent, late replicating, Pleiotrophin (Ptn) gene, directly comparing RT to nascent transcription rates at engineered vs. wild-type alleles. First, we inserted four reporter genes that differ only in their promoter. Two promoters transcribed the reporter gene at high rates and advanced RT. The other two transcribed at lower rates and did not advance RT. Since these promoters may prove useful in applications where effects on RT are undesirable, we confirmed the inability of one of them to advance RT at numerous ectopic sites. We next juxtaposed these same four promoters upstream of the Ptn transcription start site where they all transcribed the 96kb Ptn gene and advanced RT to different extents correlated with transcription rates. Indeed, a doxycycline-responsive promoter, which could not advance RT when induced as a small reporter gene, elicited a rapid and reversible RT advance proportional to the rate of transcription, providing direct evidence that transcription itself can advance RT. However, deletion of the Ptn promoter and enhancer, followed by directed differentiation to neural precursors, eliminated induction of transcription throughout the entire Ptn replication domain, without preventing the switch to early replication. Our results provide a solid empirical base with which to re-evaluate many decades of literature, demonstrating that length and strength of transcription is sufficient but not necessary to advance RT. Our results also provide a robust system in which to rapidly effect an RT change, permitting mechanistic studies of the role of transcription in RT and the consequences of RT changes to epigenomic remodeling.