bluuebunny/crossref_metadata_2025 huggingface dataset:
Sociodemographic predictors of acute corneal hydrops in patients with unstable keratoconus
Authors: Kanu Levi N , Boychev Nikolay , Fry Meredith , Margolis Leah , Le Cherry , Paneru Rimsha , Ng Veronica , Hutchison Jules , Ciolino Joseph B.
Published: February 2025

Objective

To determine whether sociodemographic factors affect the outcomes of patients with unstable keratoconus.

Design

Retrospective case control study

Subjects

All patients diagnosed with unstable keratoconus at Mass Eye and Ear between January 2016 and October 2022. Those who experienced acute corneal hydrops during the study period were considered cases, and those who did not were considered controls.

Methods

Potential subjects were identified by billing code and verified with review of clinical documentation. Charts were reviewed for pertinent sociodemographic, medical, and ocular risk factors.

Main Outcome Measures

Clinical diagnosis of acute corneal hydrops was the primary outcome. Receipt of corneal crosslinking (CXL) was a secondary outcome.

Results

Of 762 patients diagnosed with unstable keratoconus, we identified 128 episodes of hydrops in 113 patients (14.9%). Compared to controls, cases were a significantly higher proportion Black (27.6% vs 14.6%,P<0.0001), unemployed (22.4% vs 12.5%,P<0.01), and/or covered by public health insurance plans (50.4% vs 27.7%,P<0.0001). Body mass index (BMI) was significantly higher in cases (34.1±10.0) than controls (29.2±8.1, mean±SD,P<0.0001). Developmental delay (17.7% vs 3.4%,P<0.0001), atopy (48.9% vs 30.4%,P=0.0001), sleep apnea (9.7% vs 1.2%,P<0.0001), and eye rubbing (85.5% vs 67.7%,P<0.01) were all more common in the hydrops group. In a stepwise multivariable logistic regression analysis, Black race [2.10 (1.02-4.27),P=0.041], public health insurance coverage [2.06 (1.12-3.80),P=0.020], BMI [1.05 (1.02-1.08),P=0.003], and developmental delay [16.42 (5.62-56.30),P<0.001] were each associated with a higher odds of incident hydrops [OR (95%CI)]. Similar trends were found to influence the receipt of CXL, with male sex [0.34 (0.13-0.77),P=0.015], Black race [0.39 (0.16-0.97),P=0.038], and public health insurance [0.37 (0.16-0.82),P=0.014] negatively influencing the odds of receiving CXL.

Conclusions

This study establishes several sociodemographic (Black race, unemployment, and publicly insured) and medical (high BMI and developmental delay) factors as independent risk factors influencing the incidence of hydrops and/or the receipt of CXL in a large group of patients with unstable keratoconus. Special attention is warranted when caring for patients within these subpopulations with unstable keratoconus, and further study into the mechanisms of these associations is warranted.
Estimating extreme displacements under a Lomax generalized linear model framework: the role of sample size and threshold choice
Authors: Rudolph Francisca Javiera , Ponciano José Miguel
Published: February 2025

Understanding ecological variation is fundamental to predicting the dynamics of natural systems, and it becomes increasingly more complex when rare or extreme events are involved. Extreme value statistics are a useful but underutilized tool in ecological analysis, and in this paper we showcase a simulation based study that uses extreme value distributions to estimate rare events. Focused on long-distance dispersal events, we simulate individual variation in seed dispersal events within heterogeneous populations by using finite mixture models. We employ three different approaches to model fitting extreme value distributions, and we particularly incorporate the special case of a Lomax distribution. Using a modified generalized extreme value distribution and comparing to a peak over threshold model fitting approach, we assess which models are able to capture the true underlying parameters. Additionally, we used a well-known linear bootstrap bias-corrrection and evaluate its utility to correct the bias in the estimation. Our results show that threshold models are the best at capturing the true underlying probability of long-distance dispersal models, and that the bias correction is somewhat useful, depending on the sample size. Estimating rare events in ecology is an important and statistically challenging process and in this study we provide a simple probabilistic approach to doing so.
Dose Escalation in Pentylenetetrazol Kindling Detects Differences in Chronic Seizure Susceptibility
Authors: Moyer Mitchell B. , Langbein Jenna , Tsymbalyuk Orest , McAfee Darrian , Chen Chixiang , Bachani Muznabanu , Gerzanich Volodymyr , Simard J. Marc , Ksendzovsky Alexander
Published: February 2025

Objective

Pentylenetetrazol (PTZ) kindling is a widely used model for inducing epileptogenesis and evaluating long-term seizure susceptibility differences among animals. This model is typically performed by chronic, repetitive exposures to a constant subconvulsive PTZ dose. However, the effectiveness of the commonly used subconvulsive dose (35mg/kg) varies among different animal groups and experimental conditions due to factors such as species, age, sex, and genetic background. The objective of this study was to characterize a novel model of kindling, the PTZ Dose Escalation (PTZ-DE) model, which assesses chronic seizure threshold with enhanced sensitivity by empirically determining the minimally effective dose to induce PTZ kindling for specific experimental conditions.

Methods

This study investigated the efficacy and validity of the PTZ-DE model by comparing its performance to the standard PTZ kindling approach across a series of conditions. First, the ability of the PTZ-DE model to produce the gradual increase in chronic seizure severity response characteristic of PTZ kindling was compared to the standard model across animal background characteristics (strain, sex). Next, the validity of this model was investigated by determining if the PTZ-DE model could replicate similar changes in chronic seizure susceptibility previously published using the standard approach after traumatic brain injury (TBI). Lastly, the PTZ-DE model’s efficacy to detect seizure differences was measured in a condition (glyburide treatment) in which alterations to chronic seizure susceptibility were not detected with standard kindling.

Results

This study found that the PTZ-DE model corrects for background differences in PTZ susceptibility, replicates known differences in chronic seizure thresholds after TBI, and identifies new alterations in seizure threshold not detected with traditional kindling methods.

Significance

The PTZ-DE model may prove to be a superior tool to standard PTZ kindling for discovering new pathological mechanisms of epileptogenesis and for developing targeted therapies for chronic seizure management, as evidenced by its ability to detect subtle differences in seizure susceptibility across various experimental conditions.
Moving northwards: Invasive Green Crab (Carcinusspp.) Expands into the Southwestern Atlantic
Authors: Baigorria Micaela Müller , Narvarte Maite , Bonel Nicolás , Hünicken Leandro
Published: February 2025

The invasive European green crab (Carcinusspp.) has become a significant ecological concern due to its rapid global spread and impact on coastal ecosystems. In the Southwestern Atlantic, the northernmost population was recently recorded in the San Matías Gulf, providing an opportunity to study its demographic and life-history traits at the leading edge of its range. We conducted a comprehensive analysis of this population, assessing sex ratio, population density, size distribution, and the size at which 50% of females were ovigerous (SM50). Our findings revealed a pronounced male-biased sex ratio (1.50 males per female) and a relatively low population density (0.52 crabs.m-2), suggesting early-stage population establishment. The size range of individuals aligned more closely withCarcinus aestuariithanC. maenas, raising the possibility of hybridization or misidentification. Ovigerous females were present throughout most of the year, highlighting an extended reproductive period and adaptability to local environmental conditions. These traits, combined with rapid range expansion, underscore the invasive potential ofCarcinusspp. and its ecological implications for the San Matías Gulf. Long-term monitoring and genetic analyses are essential to clarify species composition and inform management strategies to mitigate further spread and impacts of this invasive population.

Simple Summary

Green crabs are invasive species that threaten coastal ecosystems around the world by competing with native animals and damaging habitats. Recently, a population of green crabs was discovered in the San Matías Gulf in Argentina, marking the furthest north this species has been found in the Southwestern Atlantic. We studied this population to understand its characteristics and how it might grow and spread in the future. We found that male crabs were more abundant and larger than females, and the overall population density was relatively low, which suggests that the population is still becoming established. Interestingly, the size of the crabs in this area is more similar to a related, less common species of green crab, which has also been reported in the Southwestern Atlantic, than to the more widely studied species. Since these two species are nearly identical in appearance, they are often misidentified, making it important to study their genetic makeup. Female crabs carrying eggs were found throughout most of the year, showing that this population can adapt well to local conditions and reproduce for extended periods. These findings suggest that the population could expand further and have serious impacts on native species and ecosystems. Monitoring this population over time will help scientists and policymakers better manage the spread of this invasive crab.
Belowground competition increases root allocation in agreement with game-theoretical predictions, but only when plants simultaneously compete aboveground
Authors: Kopp Emanuel B. , Anten Niels P.R. , Niklaus Pascal A. , Wuest Samuel E.
Published: February 2025

Evolutionary game theory posits that plants competing with neighbours preferentially allocate resources towards resource-foraging structures, which reduces the marginal gain per investment unit and the ability of plants to produce seeds. This phenomenon is known as the tragedy of the commons (TOC), and undesirable in grain crops. Specifically, changes in light quality due to neighbour plants often induce costly responses like petiole or stem elongation, increasing individual competitiveness at the expense of stand-level yield. Similarly, it has been postulated that belowground competition can induce increased root production in the vicinity of neighbours, which can also reduce seed yield.

There has been a long-standing debate about the interpretation of resource allocation patterns observed in plant-plant competition experiments in crops. Experimental setups using pot systems and artificial dividers to manipulate competitive interactions have been questioned because of the difficulty of simultaneously controlling pot volume, nutrient amount, and nutrient concentration. Moreover, observations of root growth under competition have been inconsistent, ranging from increased root production to spatial root system segregation. Here, using soybean as a model system, we conducted a competition experiment to disentangle above- and belowground drivers of biomass allocation patterns. Specifically, we used above- and belowground physical dividers and varied inter-plant distances (between 3 and 24 cm) to avoid a confounding of divider treatments with plant-available soil volume. Plants closer together had higher root-to-shoot ratios, indicating that an increased fraction of assimilated was diverted to root growth, but this only happened when they competed both above- and belowground (no dividers). Aboveground competition triggered shade avoidance responses, resulting in slender plant habit and reduced total root and shoot biomass. Overall, our results provide evidence for a preferential allocation to root biomass in soybean plants when exposed simultaneously to above and belowground competitions. As effects of belowground competition became only evident when plants were allowed to also compete aboveground, we interpret the competition cues to be processed hierarchically, with aboveground signals having precedence over belowground signals. More generally, our findings show that varying the distance between competing plants allows to avoid the confounding of divider treatments with plant-available soil volume. A reduced total biomass production of plants competing above- and belowground may be interpreted as a consequence of lowered marginal gains arising from allocation patterns that optimize individual but not group performance.
Hyper-mutational processes provide a head-start for non-optimal cancer driver mutations explaining atypicalKRASvariants
Authors: Nicholson Michael D. , Tomlinson Ian
Published: February 2025

In hypermutant cancers, both the mutation rate per cell division and the genomic locations of new mutations are vastly altered. Such cancers often display atypical driver gene variants, which may provide sub-optimal oncogenic advantages. Why such weaker cancer drivers prevail in these tumours is unclear. Here, we examine the null hypothesis that aberrant mutational processes alone can account for the detection of weaker, rather than canonical, driver mutations. Using a mathematical modelling analysis, we find that simply increasing the mutation rate per-division can lead to the detection of weaker drivers, an effect which is further compounded by the biassing of mutations towards weaker driver sequence contexts. Focusing onPOLE-mutant (DNA polymerase epsilon proofreading-deficient) colorectal cancers andKRASdriver mutations, we quantify the mutational bias towards non-canonicalKRASdrivers in bothPOLE-mutant and non-hypermutant colorectal cancers. The observed bias, coupled with the increased mutation rate ofPOLE-mutant cancers, is sufficient to explain the enrichment of atypicalKRASdrivers inPOLE-mutant cancers with plausible selection parameters. Thus, within our model, differential selection between these cancer types need not be invoked to understand the observed variation in driver mutations.
DARG: a Database of Alzheimer Related Genes in Model Organisms
Authors: Song Julia Y. , Zhou Eric , Hu Yanhui
Published: February 2025

Alzheimer disease is affecting a significant portion of the aging population worldwide. Despite extensive research over the years, a comprehensive understanding of its underlying mechanisms and effective treatments remains elusive. Meanwhile, animal models, such as mouse, zebrafish, Drosophila, and C. elegans, have proven invaluable in studying human diseases. In response, we have developed DARG, a Database of Alzheimer disease-related genes in model organisms, designed to bridge the gap between human geneticists investigating the molecular mechanisms of the disease and the model organisms that can be used to explore the functions of disease-associated genes. DARG allows users to search and browse Alzheimer-related human genes from various resources and datasets, identify orthologs in model organisms, and access data on their gene expression and related phenotypes inDrosophila.
Benchmarking Long-read Sequencing Tools for Chromosome End-specific Telomere Analysis
Authors: Reed Jake , Oelkuct Mark , Coombes Kevin
Published: February 2025

Measuring chromosome end-specific telomeres is of great importance and could help elucidate better treatment algorithms and aid in a better understanding of cancer, aging, cardiovascular disease, and neurodegenerative diseases. In this study, we present a comparison of two cutting edge long-read sequencing telomere length analysis tools, TECAT and Telogator. We perform a comprehensive bench-marking of these two tools using Telseq as the standard. Our analysis included evaluating these tools on sensitivity, accuracy, and computational efficiency using a diverse data set of 9 samples from the 1000 Genomes Project which have matched long-read and short-read sequencing data. We found that while Teloga-tor demonstrated superior sensitivity, identifying on average 31% more telomeric reads across all samples, TECAT showed better accuracy with measurements more closely aligned with established literature values and Telseq benchmarks (R² = 0.74 vs 0.37), and TECAT displayed better computational efficiency, com-pleting tasks approximately 41% faster. Both tools successfully mapped telomere lengths to individual chromosome arms, demonstrating unprecedented resolution for telomere length analysis. Our results provide crucial insights for researchers selecting tools for telomere length analysis and highlight the current capabilities and limitations of computational approaches in telomere biology.
Neuromark dFNC Patterns: A fully automated pipeline to estimate subject-specific states from rs-fMRI data via constrained ICA of dFNC in +100k Subjects
Authors: Esfahani M. Moein , Esaulov Vladislav , Venkateswara Hemanth , Calhoun Vince
Published: February 2025

Resting-state functional MRI (rs-fMRI) provides valuable insights into brain function during rest, but faces challenges in clinical applications due to individual differences in functional connectivity. While Independent Component Analysis (ICA) is commonly used, it struggles to balance individual variations with inter-subject information. To address this, constrained ICA (cICA) approaches have been developed using templates from multiple datasets to improve accuracy and comparability. In this study, we collected rs-fMRI data from 100,517 individuals across diverse datasets. Data were preprocessed through a standard fMRI pipeline. Our method first used replicable fMRI component templates as priors in constrained ICA (the NeuroMark pipeline), then estimated dynamic functional network connectivity (dFNC). Through clustering analysis, we generated replicable dFNC states, which were then used as priors in constrained ICA to automatically estimate subject-specific states from new subjects.This approach provides a robust framework for analyzing individual rs-fMRI data while maintaining consistency across large datasets, potentially advancing clinical applications of rs-fMRI.
Chronic Antigen Stimulation in Solid Tumors Induces T Cell Exhaustion and Limits Efficacy of T Cell Bispecific Therapies
Authors: Hutter-Karakoc Idil , Varypataki Eleni Maria , Neelakandhan Aparna , Lang Simone , Kramar Vesna , Varol Ahmet , Simons Sasha , Richard Marine , Pincha Mudita , Venetz Dario , Joller Nicole , Münz Christian , Umana Pablo , Klein Christian , Amann Maria
Published: February 2025

T cell bispecific antibodies (TCBs) have demonstrated promising results in patients with solid tumors. However, the underlying immunological and molecular mechanisms influencing these clinical outcomes require in depth evaluation. T cell exhaustion, a state induced by prolonged antigen exposure, is known to undermine T cell-based immunotherapies, though its specific impact on TCB efficacy remains unclear. In this study, we assessed the effectiveness of TCBs on tumor-specific T cells, focusing on their functional status. Utilizing a fully immunocompetent mouse model with a solid tumor expressing an immunogenic antigen, we showed that tumor-specific T cells acquire an exhausted phenotype and fail to expand under TCB treatment. By employing both mouse and human tumor-specific T cellsin vitro, our study established that chronically stimulated tumor-specific T cells show impaired response to TCB treatment. The comparison of TCB efficacy in T cell-inflamed tumors with immunogenic antigens versus non-inflamed tumors with low antigen presence in mice revealed TCB success in solid tumors is more reliant on T cell functional fitness than on their abundance before treatment. The data also indicate that solid tumors with elevated levels of both, intratumoral regulatory T cells, and T cells expressing co-inhibitory receptors, show diminished responses to TCB therapy, aligning with similar observations described in hematological cancers. These findings highlight the critical role of T cell exhaustion due to chronic antigen exposure and illustrate that exhausted tumor-specific T cells are likely not the driver population redirected by TCBs for tumor elimination. Our research highlights the importance of maintaining T cell fitness and preventing T cell exhaustion to improve TCB therapy outcomes. This may help better identify patient populations with solid tumors that could benefit from TCB treatments most in clinical settings.
Dietary Menaquinone-9 Supplementation Does Not Influence Bone Tissue Quality or Bone Mineral Density in Mice
Authors: Liu Minying , Liu Chongshan , Cevallos Nicolas , Orbach Benjamin N , Hernandez Christopher J , Fu Xueyan , Lee Jennifer , Booth Sarah L , Shea M Kyla
Published: February 2025

Vitamin K has been implicated in skeletal health because vitamin K-dependent proteins are present in bone. While there are multiple forms of vitamin K, most research has focused on phylloquinone, which is found mainly in plant-based foods, and its metabolite menaquinone-4 (MK4). However, there are additional forms of vitamin K that are bacterially produced that appear to influence bone health but have not yet been studied extensively. Herein, we evaluated the effects of menaquinone-9 (MK9), a bacterially produced form of vitamin K on bone tissue quality and density in young mice. Four-week-old male (n=32) and female (n=32) C57BL/6 mice were supplemented with 0.06 mg/kg diet or 2.1 mg/kg diet of MK9 for 12 weeks. During week 11, a sub-group of mice (n=7/sex/group) received daily deuterium-labeled MK9 to trace its metabolic fate in bone. Liver MK4 and MK9 were significantly higher in mice fed 2.1 mg MK9/kg compared to those receiving 0.06 mg MK9/kg, regardless of sex (all p ≤ 0.017). MK4 was the only vitamin K form detected in bone, with 63-67% of skeletal MK4 in mice fed 2.1 mg MK9/kg derived from deuterium-labeled MK9. Femoral tissue strength, maximum bending moment, section modulus, and bone mineral density did not differ significantly across diet groups in either sex (all p≥0.083). Cross-sectional area (p=0.003) and moment of inertia (p=0.001) were lower in female mice receiving 2.1 mg MK9/kg compared to those receiving 0.06 mg MK9/kg, but no differences were found in male mice. Higher bone MK4 concentrations did not correlate with higher bone tissue quality or density. Despite dietary MK9 being a dietary precursor to MK4 in bone, dietary MK9 supplementation did not affect bone tissue quality or bone mineral density.

Lay summary

Most research about vitamin K and bone health has focused on phylloquinone, the plant-based vitamin K form, and its metabolite menaquinone-4. Because interest in bacterially produced forms of vitamin K, which are abundant in the intestinal microbiome, is growing, we evaluated the effect of menaquinone-9 (a bacterially-produced form of vitamin K) on skeletal health. We supplemented mice with low and high doses of menaquinone-9 and also used stable-isotope labeled menaquinone-9 to trace its conversion to menaquinone-4 in bone. We found menaquinone-9 served as a precursor to menaquinone-4 in bone, but menaquinone-9 supplementation did not improve bone health.
Regulation of Ordinal DNA Translocation Cycle in Bacteriophage Φ29 through Trans-Subunit Interactions
Authors: Dargis Rokas , Pajak Joshua , Ariyawansa Pavan , Morais Marc C. , Jardine Paul J. , Arya Gaurav
Published: February 2025

Certain viruses such as tailed bacteriophages and herpes simplex virus package double-stranded DNA into empty procapsids via powerful, ring-shaped molecular motors. High resolution structures and force measurements on the DNA packaging motor of bacteriophage Φ29 revealed that its five ATPase subunits coordinate ATP hydrolysis with each other to maintain the proper cyclic sequence of DNA translocation steps about the ring. Here, we explore how the Φ29 motor regulates translocation by timing key events, namely ATP binding/hydrolysis and DNA gripping, through trans-subunit interactions. We used subunit dimers bound to DNA as our model system, a minimal system that still captures the conformation and trans-subunit interactions of the full pentametric motor complex. Molecular dynamics simulations of all-ATP and mixed ATP-ADP dimers revealed that the nucleotide occupancy of one subunit strongly affects the ability to hydrolyze ATP in the adjacent subunit by altering the free energy landscape of its catalytic glutamate approaching the gamma phosphate of ATP. Specifically, one ATP-bound subunit donates residues in trans that sterically block the neighboring subunit’s catalytic glutamate. This steric hindrance is resolved when the first subunit hydrolyzes ATP and is ADP-bound. This obstructive mechanism is supported by functional mutagenesis and appears to be conserved across several Φ29 relatives. Mutual information analysis of our simulations revealed intersubunit signaling pathways, via the trans-acting obstructive residues, that allow for sensing and communication between the binding pockets of adjacent subunits. This work shows that the sequential order of DNA translocation events amongst subunits is preserved through novel trans-subunit interactions and pathways.
A Clinical Trial to Determine the Impact of Tumor Size, Histological Subtype, and Vitamin D Status on the Therapeutic Response of Basal Cell Carcinoma to Photodynamic Therapy
Authors: Maytin Edward V. , Zeitouni Nathalie C. , Updyke Abigail , Negrey Jeffrey , Shen Alan S. , Heusinkveld Lauren E. , Mack Judith A. , Hu Bo , Anand Sanjay , Maytin Terence A. , Giostra Laura , Warren Christine B. , Hasan Tayyaba
Published: February 2025

Photodynamic therapy (PDT) with topical aminolevulinic acid (ALA) can be effective for select basal cell carcinoma (BCC) lesions. However, the histological depth and subtype of tumors that respond to PDT remain uncertain. Here, we report a clinical trial of high-dose oral Vitamin D (VD), used as a PDT neoadjuvant for BCC. In this multi-institutional, intra-patient, randomized trial, 35 patients (9 with Gorlin Syndrome) received three PDT sessions (20% ALA; 417 nm blue light) preceded by oral VD, placebo, or no pretreatment. Tumors (122 BC) were monitored using 3D photography and computer-assisted volumetric analysis. Values for absolute volume (3DAbsVol) and average height (3DAvHt) were calculated and used to quantify tumor response kinetics. From histological sections, 3DAvHt was found to correlate with actual tumor depth, although 3DAvHt is only ∼10-20% of the latter. Importantly, 3DAvHt measurements revealed a distinct depth threshold that predicts PDT responsiveness. Of 122 tumors analyzed, 70% cleared after PDT; remaining tumors were micronodular or other aggressive histologic subtypes. To evaluate VD’s effects upon treatment response kinetics after PDT, only 40% of original lesions were available for analysis. By stratifying remaining tumors by 3DAvHt, we found 65% of thin tumors to be VD-responsive, whereas only 28% of thick tumors responded to VD. Overall, PDT was effective for the majority of BCC lesions in our study. Tumors most likely to respond can be predicted histologically and by noninvasive 3D morphometry. For PDT-appropriate BCC lesions, neoadjuvant oral Vitamin D represents a safe and beneficial way to accelerate tumor resolution.

CLINICAL TRANSLATION STATEMENT

For photodynamic therapy (PDT) of basal cell carcinoma (BCC), a clinical challenge is deciding which tumors to treat since the penetration depth of visible light into the skin is limited. In this clinical trial, noninvasive 3D photography and computer analysis were used to determine the height and volume of BCC tumors and to correlate these calculated parameters with tumor clearance after PDT, with or without the use of oral vitamin D3 (VD) as a neoadjuvant. Two very practical findings emerged. First, tumor height (3DAvHt) was found to correlate with BCC tumor depth and to predict therapeutic response; tumors below a height threshold of 0.13 mm (∼1.5 - 2 mm histological depth) were highly likely to respond. Second, adding VD as a neoadjuvant prior to PDT of appropriate BCC tumors (superficial and thin nodular subtypes) is a safe and effective way to boost PDT efficacy.
Segmentation-Free Pretherapeutic Assessment of BRAF-Status in Pediatric Low-Grade Gliomas
Authors: Kudus Kareem , Wagner Matthias , Sheng Min , Bennett Julie , Liu Anthony , Tabori Uri , Hawkins Cynthia , Ertl-Wagner Birgit Betina , Khalvati Farzad
Published: February 2025

Background

BRAF status is crucial for treating pediatric low-grade gliomas (pLGG) and can be assessed non-invasively from segmented tumor regions on MRI using machine learning (ML). However, there are inherent limitations to manual and automated tumor segmentations.

Purpose

To assess the performance of automated segmentation algorithms and to develop and assess a segmentation-free ML classification pipeline that identifies BRAF status from whole-brain FLAIR MRI sequences.

Materials and Methods

In this REB-approved retrospective study, molecularly-characterized tumors and whole-brain FLAIR MR images were collected from 455 patients with pLGG treated between 1999 and 2023 at a single tertiary care children’s hospital. We trained and evaluated three medical segmentation models, TransBTS, MedNeXt, and MedicalNet. Next, we developed a model to identify BRAF status from whole-brain FLAIR MRI, without any reliance on manual or automated segmentations. We then implemented a novel pretraining regimen that embedded segmentation knowledge into the whole-brain FLAIR MRI classification model. Finally, we trained and evaluated a baseline model that used manual segmentations as inputs. All ML models were trained and evaluated under a nested-cross validation scheme, and mean performance across all test folds was compared using the corresponding t-test.

Results

The MedNeXt segmentation model (mean Dice score: 0.555) outperformed both the convolutional neural network (CNN) based MedicalNet (0.516) and the CNN-transformer hybrid TransBTS (0.449) (p <0.05 for all comparisons). The MedNeXt style classification model achieved a one-vs-rest area under the ROC curve of 0.741 using the whole brain FLAIR sequence as an input, without any segmentation knowledge. This was improved to 0.772 through pretraining on the segmentation task, which was not significantly different from the baseline manual segmentation-based model (0.756, p-value: 0.141).

Conclusion

BRAF status can be assessed non-invasively using ML models based on whole-brain FLAIR sequences. Dependence on inconsistent manual or automated segmentations can be reduced by integrating tumor region information into the model through pretraining.
Gender Differences in Work Expectations and Psychological Distress: Insights from the United States and South Korea
Authors: Dang Linh , Antonucci Toni , Mendes de Leon Carlos , Mezuk Briana
Published: February 2025

Objectives

Over the past 50 years, women’s roles have changed significantly, from primarily domestic roles to active labor force participation. Women from the “Baby Boom” cohort (born 1948-1965) have experienced unprecedented access to educational and employment opportunities, which has implications for work and mental health later in life. This study examined gender differences in the association between work expectations and psychological distress among Baby Boomers in the United States and South Korea.

Methods

Data came from the 2006-2018 waves of the Health and Retirement Study (n=14,005) and Korean Longitudinal Study of Aging (n=2,362). Perceived expectations of working in the next five years were reported on a probability scale (0-100%). Psychological distress was assessed by the Center for Epidemiologic Studies Depression Scale. Multivariate mixed-effects logistic regression models were used to examine the longitudinal association between work expectations and psychological distress for men and women.

Results

In both countries, women had higher CES-D scores and lower expectations of working in the next 5 years than men. Higher work expectations were robustly associated with lower odds of psychological distress among both men and women in Korea; however, this inverse association was more modest in the US. Moreover, the association between work expectations and distress was stronger among Korean men (ORmen=0.82 [0.78, 0.87]) compared to women (ORwomen=0.88 [0.83, 0.93]), but there were no gender differences among US respondents (ORmen=0.99 [0.96, 1.01]; ORwomen=0.96 [0.95, 0.98]).

Discussion

Findings highlight the complex interplay between biology sex and social contexts in shaping expectations regarding work in later life.
Genetic control of the leaf ionome in pearl millet and correlation with root and agromorphological traits
Authors: Nakombo-Gbassault Princia , Arenas Sebastian , Affortit Pablo , Faye Awa , Flis Paulina , Sine Bassirou , Moukouanga Daniel , Gantet Pascal , Kosh Komba Ephrem , Kane Ndjido , Bennett Malcolm , Wells Darren , Cubry Philippe , Bailey Elizabeth , Grondin Alexandre , Vigouroux Yves , Laplaze Laurent
Published: February 2025

Pearl millet (Pennisetum glaucum) thrives in arid and nutrient-poor environments, establishing its role as a crucial cereal crop for food security in sub-Saharan Africa. Despite its remarkable adaptability, its yields remain below genetic potential, primarily due to limited water and nutrient availability. In this study, we conducted ionomic profiling and genome-wide association studies (GWAS) in field conditions across two growing seasons to unravel the genetic basis of nutrient acquisition in pearl millet. Soil ion content analyses revealed significant differences in nutrient distribution between field sites, while certain ions, such as phosphorus (P) and zinc (Zn), consistently displayed stratified accumulation patterns across years, suggesting stable depth-dependent trends. Evaluation of a genetically diverse panel of inbred lines revealed substantial variation in leaf ion concentrations, with high heritability estimates. Correlations between leaf ion content and root anatomical or agromorphological traits highlighted the intricate interplay between genetic and environmental factors shaping leaf ion accumulation. These analyses also uncovered potential trade-offs in nutrient acquisition strategies. GWAS identified genomic regions associated with leaf ion concentrations, and the integration of genetic and gene expression data facilitated the identification of candidate genes implicated in ion transport and homeostasis. Our findings provide valuable insights into the genetic regulation of nutrient acquisition in pearl millet, offering potential targets for breeding nutrient-efficient and climate-resilient varieties. This study underscores the importance of integrating genetic, physiological, and root architectural traits to enhance agricultural productivity and sustainability in resource-constrained environments.
Activation of alternative oxidase ensures carbon supply for ethylene and carotenoid biosynthesis during tomato fruit ripening
Authors: Iglesias-Sanchez Ariadna , Del-Saz Nestor Fernandez , Ezquerro Miguel , Feixes-Prats Elisenda , Ribas-Carbo Miquel , Fernie Alisdair R. , Rodriguez-Concepción Manuel , Florez-Sarasa Igor
Published: February 2025

Tomato (Solanum lycopersicum) is a climacteric fruit displaying a peak of respiration at the onset of ripening accompanied by increased synthesis of ethylene and carotenoid pigments. Chromoplast and mitochondrial respiration participate at different stages of fruit ripening, but theirin vivoregulation and function remains unclear. We determined thein vivoactivities of the mitochondrial alternative oxidase (AOX) and cytochrome oxidase pathways and quantified the levels of respiratory- and ripening-related gene transcripts, primary metabolites and carotenoids in ripening tomato fruits with or without a functional chromorespiration. Furthermore, we carried out physiological, molecular and metabolic analyses of CRISPR-Cas9 mutants defective in AOX1a, the main AOX isoform up-regulated during tomato fruit ripening. We confirmed that PTOX-dependent chromorespiration is only relevant at late stages of ripening and found thatin vivoAOX activity significantly increased at the breaker stage, becoming the main contributor to climacteric respiration when ripening is unleashed. This activation did not correlate with gene expression but was likely due to increased levels of AOX activators such as pyruvate (a metabolic precursor of carotenoids), 2-oxoglutarate and succinate. A strong alteration of ripening-related metabolites was observed inaox1amutant fruits, highlighting a key role of the AOX pathway at the onset of ripening. Our data suggest that increased supply of TCA cycle intermediates at climacteric stage allosterically enhance AOX activity, thus allowing the reoxidation of NAD(P)H to ensure carbon supply for triggering ethylene and carotenoid biosynthesis.
B cell stimulation changes the structure and higher-order organization of the inactive X chromosome
Authors: Sierra Isabel , Toothacre Natalie E. , van der Weide Robin H. , Lovell Claudia D. , Nguyen Son C. , Jordan Barnett R. , Cook Ashley L. , Ryu Han-Seul , Pyfrom Sarah , Wang Harrison , Beiting Daniel , Philips-Cremins Jennifer E. , Joyce Eric F. , Anguera Montserrat C.
Published: February 2025

X Chromosome Inactivation (XCI) equalizes X-linked gene expression between sexes. B cells exhibit dynamic XCI, with Xist RNA/heterochromatic marks absent on the inactive X (Xi) in naive B cells but returning following mitogenic stimulation. The impact of dynamic XCI on Xi structure and maintenance was previously unknown. Here, we find dosage compensation of the Xi with state-specific XCI escape genes in naive andin vitroactivated B cells. Allele-specific OligoPaints indicate similar Xi and Xa territories in B cells that are less compact than in fibroblasts. Allele-specific Hi-C reveals a lack of TAD-like structures on the Xi of naive B cells, and stimulation-induced alterations in TAD-like boundary strength independent of gene expression. Notably,Xistdeletion in B cells changes TAD boundaries and large-scale Xi compaction. Altogether, our results uncover B cell-specific Xi plasticity which could underlie sex-biased biological mechanisms.
Association Between Telehealth Use and Downstream 30-Day Medicare Spending
Authors: Ellimoottil Chad , Kulkarni Ashwin J. , Zhu Ziwei , Dunn Rodney L. , Chang Chiang-Hua , Chun Elena , Hou Hechuan , Lee James D. , McCullough Jeffrey S. , Thompson Michael P.
Published: February 2025

Objectives

The objective of this study was to investigate whether healthcare visits initiated by telehealth had higher or lower 30-day spending compared to in-person-initiated visits. The study compared the overall spending, rates of return visits, laboratory tests, and imaging procedures within 30 days for Medicare fee-for-service patients who underwent in-person and telehealth evaluations between July 1, 2020 and December 31, 2022.

Study Design

A large-scale retrospective cohort study using propensity score matching.

Methods

This study included 100% of Medicare fee-for-service beneficiaries who are aged >65 years while excluding those with Medicare Advantage coverage and those without continuous Medicare Parts A and B. We identified patients with no prior visits and 30-day episodes of care initiated by outpatient telehealth or in-person visits from July 1, 2020 through December 31, 2022. We then compared adjusted 30-day total Medicare spending, rates of return visits, laboratory tests, and imaging utilization between propensity-matched index visits initiated by telehealth versus in-person.

Results

Telehealth-initiated visits were associated with lower 30-day spending ($260 vs. $342; net: −$82), though return visit rates were higher for telehealth (16.1% vs. 14.1%). Both lab test rates (7.8% vs. 24.2%) and imaging rates (3.5% vs 7.8%) were lower for telehealth-initiated episodes compared to in-person-initiated episodes.

Conclusions

Telehealth-initiated episodes of care were associated with lower 30-day Medicare spending and reduced utilization of labs and imaging. These findings suggest that telehealth, when used as a substitute for office visits, may reduce overall Medicare spending.
Factors Influencing Early Childhood Caries in a University-Based Infant Oral Health Clinic
Authors: Ijaz Anum , Mugayar Leda Regina F , Noorullah Khatija , Molena Kelly Fernanda , AlSaleh Majd , Bilal Sobia
Published: February 2025

Introduction

Early Childhood Caries (ECC) is a major public health issue that poses significant challenges in pediatric dentistry, affecting infants and preschool children globally. Socioeconomic factors, dietary habits, and parental health literacy play crucial roles in ECC’s development and progression.

Objective

The study aims to identify and evaluate factors contributing to ECC in pediatric patients at a university-based infant oral health clinic, with a secondary objective of assessing the effectiveness of newly developed oral health promotional materials through a pilot study.

Methods

A retrospective and cross-sectional design was employed to analyze data from 514 pediatric patients. The study examined demographic information, parental and environmental factors, dietary habits, and feeding practices. Statistical analysis was conducted to identify significant predictors of ECC. The pilot study involved 10 participants who provided feedback on the content and face validity of promotional materials.

Results

Key factors associated with ECC included race, socioeconomic status, parental health literacy, dietary habits, and bottle use at night. Early detection and preventive strategies, such as regular dental checkups, were found to be critical in reducing caries risk. The pilot study showed positive feedback on promotional materials, indicating relevance, clarity, and visual appeal, with ongoing feedback used to refine the materials.

Conclusion

The study highlights the importance of comprehensive preventive strategies that encompass both individual and community-level interventions. It underscores the role of early detection, preventive measures, and tailored oral health education in reducing ECC risk. Limitations include the retrospective design and potential generalization issues due to the study’s focus on a single clinic. Future research should aim to address these limitations through longitudinal studies and larger, more diverse samples to validate the findings and enhance the effectiveness of oral health promotional materials.
Pregnancy outcomes and HIV amongst women in Northwest Tanzania, from 2015-2016
Authors: Hariharan Samika , Mosha Neema , Materu Jacqueline , Baker Margaret , Kishawame Coleman , Urassa Mark
Published: February 2025

Background

Adverse pregnancy outcomes are rampant across Sub Saharan Africa and significantly increase the risk of neonatal deaths. HIV infection is a key contributor to adverse pregnancy outcomes and has a disproportionately high burden amongst women in both Sub Saharan Africa and Tanzania. Socio-demographic factors and care-seeking behaviors can either exacerbate or prevent HIV infection and adverse pregnancy outcomes.

Objectives

This study aims to determine HIV prevalence by age, residence, marital status, and education and to determine how pregnancy outcomes are impacted by HIV infection, the use of health services, and socio-demographic factors.

Methods

This study utilized secondary data from an epidemiological Sero Survey Round 8 (2015-2016) within the Kisesa HIV cohort in Magu District, Mwanza, Tanzania. All data was analyzed using the statistical software “Stata Version 17.0.” The variables were re-coded for operational use and cross-tabulations with chi-squared tests and logistic regression models were conducted.

Results

Data analysis showed an HIV prevalence of 9.5% amongst women who had been pregnant before. HIV positive women were more likely to lose a child (AOR=1.4; 95% CI: 1.1,1.7). Women with higher education had significantly lower odds of adverse pregnancy outcomes as compared to women with no formal education (AOR=0.5; 95% CI: 0.4, 0.7). Women with more children, especially 10+ children, also had higher odds of adverse outcomes as compared to mothers with 1-3 children (AOR=25.1; 95% CI: 17.0, 37.0). Elderly mothers had seven times the odds of losing a child as compared to young mothers (AOR=7.0; 95% CI: 2.5, 19.6).

Conclusions

This study provides needed insight into factors that contribute to HIV infection and adverse pregnancy outcomes. The results support the implementation of new policies that target HIV prevention and treatment amongst women and emphasize maternal education to reduce adverse pregnancy outcomes.
Prevalence, Geographical Distribution and Determinants of Zero Dose Vaccination Status in Uttar Pradesh, India: An Analysis of The National Family Health Survey – 5 Data
Authors: Singh Prem , Sharma Varun , Srivastava Ashish , John Alan Noble , Tripathi Bhupendra , Kumar Somesh
Published: February 2025

Background

Recent decades have witnessed considerable progress in immunization, leading to significant improvements in vaccination coverage worldwide. Despite these global achievements, regional disparities in vaccine uptake remain a challenge. In Uttar Pradesh (UP), India, there’s been a rise in the number of Zero-dose (ZD) children – those who have not received any routine vaccinations – over the past few years. This study delves into household-level data from the National Family Health Survey (NFHS-5, 2019-2021), aiming to uncover the prevalence and key factors contributing to the ZD status in UP.

Methods

Utilizing unit-level data from NFHS-5, we conducted a nested case-control analysis focusing on children aged 12-23 months. The primary outcome variable was ZD children, operationally defined as children who had not received the first dose of the pentavalent vaccine. The study focused on socio-demographic factors, maternal health, post-natal care, and systems’ engagement as potential predictors for ZD prevalence. These variables included type of residence, caste, religion, economic status, maternal education, place of delivery, antenatal care visits, and post-natal check-ups. Interactions with health workers and benefits received from community health programs were also considered.

Results

The prevalence of ZD children stands at 6.4% in UP. A significant urban-rural divide was observed, with 11.9% of urban children classified as ZD compared to 8.4% in rural areas. Bi-variate analysis revealed a significant association between ZD prevalence and residence type (χ2 =28.6421; p<0.01), with urban children being 37.1% more likely to be ZD than their rural counterparts at 24.5%. Economic status also showed a notable impact, with the poorest wealth quintile having 32.7% ZD children, significantly higher than the richer (23.4%) and richest (27.7%) quintiles. Maternal religion also showed significant association with ZD status, with 34.4% of children from Muslim households being ZD as compared to 24.9% in Hindu households. Maternal health indicators such as children of mothers with no antenatal care visits had 3.7 times higher odds (CI: 2.351 - 5.69; p<0.001) of being ZD compared to those whose mothers had 4+ visits. Engagement with health systems also influenced ZD rates; children from households that had not met community health workers were 1.6 times more likely to be ZD (OR: 1.566; CI: 1.135-2.16; p=0.006).

Conclusions

The higher prevalence of ZD children among specific groups underscores the need for targeted interventions. Strategies to address this issue must encompass an integration of maternal and child health services with existing immunization program.