bluuebunny/crossref_metadata_2025 huggingface dataset:
“It’s a moving target”: Experiences of pacing to reduce symptom exacerbation among adults living with Long COVID – Results from an international community-engaged qualitative research study
Authors: McDuff Kiera , Brown Darren A. , St. Clair-Sullivan Natalie , Chan Carusone Soo , Erlandson Kristine M. , Avery Lisa , Bannan Ciaran , Bergin Colm , Cheung Angela M. , Harding Richard , Kelly Mary , Martin Jessica M. , McCorkell Lisa , O’Connell Sarah , O’Donovan Imelda , O’Hara Margaret , Roche Niamh , Stokes Ruth , Thomson Catherine , Townsend Liam , Vera Jaimie H. , Wei Hannah , Solomon Patricia , O’Brien Kelly K.
Published: December 2024

Introduction

Long COVID is a multisystem condition that negatively impacts daily function. Pacing is a self-management strategy to mitigate symptoms. Our aim was to describe experiences of pacing from the perspectives of adults living with Long COVID.

Methods

We conducted a community-engaged qualitative descriptive study involving one-on-one online interviews with adults living with Long COVID from Canada, Ireland, United Kingdom, and United States to explore experiences of disability. We asked participants about strategies they used to deal with health challenges living with Long COVID. Interviews were audio recorded and transcribed verbatim. We analyzed data using group-based content analytical techniques.

Results

Among the 40 participants living with Long COVID, the majority were women (n=25; 63%), white (n=29;73%) and heterosexual (n=30;75%). The median age of participants was 39 years (25th, 75th percentile: 32, 49). Most participants (n=37;93%) used pacing to mitigate or prevent symptoms. Participant described experiences of pacing across five main areas: 1) using pacing as a living strategy (pacing to mitigate multidimensional health challenges; applying pacing to many types of activities; process of pacing experienced as a moving target; pacing experienced as a helpful strategy, but not a cure for Long COVID); 2) learning how to pace (acquiring knowledge about pacing; developing strategies and skills to support pacing); 3) encountering challenges with pacing (learning how to pace; experiencing inequitable access to pacing; experiencing stigma and judgement; undergoing psychological and emotional adjustment from beliefs of ‘fighting’ or ‘pushing through’ to balancing rest with activity; making sacrifices; and encountering unexpected obstacles); 4) experiencing consequences of not pacing; and 5) conceptualising and describing pacing using analogies or metaphors.

Discussion

Pacing is a challenging and complex strategy used to mitigate symptoms of Long COVID. Healthcare providers should work collaboratively with patients to further refine and implement this strategy, when appropriate.
WebGWAS: A web server for instant GWAS on arbitrary phenotypes
Authors: Zietz Michael , Gisladottir Undina , Brown Kathleen LaRow , Tatonetti Nicholas P.
Published: December 2024

Abstract

Complex disease genetics is a key area of research for reducing disease and improving human health. Genome-wide association studies (GWAS) help in this research by identifying regions of the genome that contribute to complex disease risk. However, GWAS are computationally intensive and require access to individual-level genetic and health information, which presents concerns about privacy and imposes costs on researchers seeking to study complex diseases. Publicly released pan-biobank GWAS summary statistics provide immediate access to results for a subset of phenotypes, but they do not inform about all phenotypes or hand-crafted phenotype definitions, which are often more relevant to study. Here, we present WebGWAS, a new tool that allows researchers to obtain GWAS summary statistics for a phenotype of interest without needing access to individual-level genetic and phenotypic data. Our public web app can be used to study custom phenotype definitions, including inclusion and exclusion criteria, and to produce approximate GWAS summary statistics for that phenotype. WebGWAS computes approximate GWAS summary statistics very quickly (<10 seconds), and it does not store private health information. We also show how the statistical approximation underlying WebGWAS can be used to accelerate the computation of multi-phenotype GWAS among correlated phenotypes. Our tool provides a faster approach to GWAS for researchers interested in complex disease, providing approximate summary statistics in short order, without the need to collect, process, and produce GWAS results. Overall, this method advances complex disease research by facilitating more accessible and cost-effective genetic studies using large observational data.
Evaluation of kindergarten through grade 12 school absenteeism data as an indicator and predictor of respiratory disease
Authors: Oberholtzer Zachary W. , Jeon Seonghye , Fineman Lillian , Adkins Susan Hocevar , Kang Gloria J. , Imberi-Olivares Kristi , Barrios Lisa C. , Meltzer Martin I.
Published: December 2024

Objective

Increases in school children absenteeism may precede increases in incidence of community-level respiratory diseases. This study assessed the correlations and predictive values between absenteeism in Kindergarten through Grade 12 students and community-level increases in influenza and COVID-19.

Methods

Absenteeism data from 4 districts between Fall 2018 and Spring 2022 was used to calculate correlations between school absenteeism and community-level cases of influenza, percent influenza-like-illnesses, and COVID-19. We estimated the positive predictive value (PPV) of a ≥20% increase in school absences to predict a ≥20% increase in community respiratory disease one or two weeks later.

Results

We observed a median correlation of 0.4 between absenteeism and influenza cases across school years and districts, with a maximum of 0.8. COVID-19 cases had a median correlation of 0.1 with school absenteeism during the 2021-2022 school year. The median PPV for predicting increases in influenza 2 weeks ahead was 0.4 (maximum 0.6), and for COVID-19, the median PPV was 0.3.

Conclusions

Correlations and PPVs between school absenteeism and respiratory disease were variable, often below 0.5. School and public health officials may find absenteeism an inconsistent predictor of community-level respiratory diseases, limiting its utility for syndromic surveillance. Standardizing absence definitions and improving reporting timeliness may enhance its effectiveness.

SUMMARY BOX

1) What is the current understanding of this subject?

Previous research has shown that K-12 student absenteeism may potentially anticipate surges in community influenza.

2) What does this report add to the literature?

Correlations and predictive values between school absenteeism and community levels of respiratory diseases (influenza, influenza-like illnesses, COVID-19) were found to be variable and often below 0.5, suggesting limitations in using school absences as a form of syndromic surveillance.

3) What are the implications for public health practice?

For school absenteeism to be a reliable syndromic surveillance tool, standardizing definitions of absences and improving reporting timeliness should be explored.
Fe starvation induces a second LHCI tetramer to photosystem I in green algae
Authors: Liu Helen W. , Khera Radhika , Grob Patricia , Gallaher Sean D. , Purvine Samuel O. , Nicora Carrie D. , Lipton Mary S. , Niyogi Krishna K. , Nogales Eva , Iwai Masakazu , Merchant Sabeeha S.
Published: December 2024

Iron (Fe) availability limits photosynthesis at a global scale where Fe-rich photosystem (PS) I abundance is drastically reduced in Fe-poor environments. We used single-particle cryo-electron microscopy to reveal a unique Fe starvation-dependent arrangement of light-harvesting chlorophyll (LHC) proteins where Fe starvation-induced TIDI1 is found in an additional tetramer of LHC proteins associated with PSI inDunaliella tertiolectaandDunaliella salina. These cosmopolitan green algae are resilient to poor Fe nutrition. TIDI1 is a distinct LHC protein that co- occurs in diverse algae with flavodoxin (an Fe-independent replacement for the Fe-containing ferredoxin). The antenna expansion in eukaryotic algae we describe here is reminiscent of the iron-starvation induced (isiA-encoding) antenna ring in cyanobacteria, which typically co-occurs withisiB, encoding flavodoxin. Our work showcases the convergent strategies that evolved after the Great Oxidation Event to maintain PSI capacity.
Direct Intercellular Vesicle Exchange between Adjacent Cells
Authors: Minakawa Tomohiro , Katsuno Tatsuya , Okamoto-Furuta Keiko , Ando Ryoko , Ishidate Fumiyoshi , Fujiwara Takahiro K. , Cho Dooseon , Takehana Sho , Sato Yoshikatsu , Tabata Yasuhiko , Miyawaki Atsushi , Yamashita Jun K.
Published: December 2024

Intercellular communication plays a central role in the development and integrity of multicellular organisms. Vesicle transfer, especially through extracellular space, has recently been highlighted as a critical intercellular communication modality, carrying nucleic acids, proteins, and others to distant cells. Previously, we demonstrated that extracellular vesicles induce “phenotypic synchronization of cells (PSyC)” during stem cell differentiation. While examining the mechanism underlying PSyC, we discovered a novel form of cellular communication mediated by direct intercellular vesicle exchange (DIVE) between adjacent cells across the plasma membrane (PM). By achieving cell-wide and high-spatiotemporal resolution imaging of vesicles labeled with fusion proteins of CD63 or CD81 to StayGold, a photostable fluorescent marker, we observed small vesicles (50-500 nm in diameter) directly transferred between adjacent cells. These vesicles moved at approximately 1 µm/s and crossed PM in approximately 10-20 seconds. Furthermore, multiple vesicles traversed nearly identical sites of PM, suggesting the presence of specific routes or structures, potentially including a pore, mediating the vesicle transfer. Three-dimensional electron microscopy provided supportive observations for traversing vesicles with single membrane. These vesicles, named InterCellular Vesicles (InterCVs), were observed to colocalize with nucleic acids, including mRNA, microRNA, and DNA, suggesting the exchange of nucleic acid-mediated information, potentially inducing PSyC, between adjacent cells. Our discovery, DIVE, reveals a previously unknown modality of cell-cell communication, with the potential to reshape our understanding of cellular biology.
Constitutive differences in immune gene expression and energy storage phenotypes co-vary with winter environment in wood frogs
Authors: Vaziri Grace J. , Reid Noah M. , Rittenhouse Tracy A.G. , Bolnick Daniel I.
Published: December 2024

Many terrestrial ectotherms have gone to great evolutionary lengths to adapt to long cold winters; some have even evolved the ability to tolerate the freezing of most of the water in the body. Now, however, high-elevation, and high-latitude winters are experiencing an accelerated period of warming. Specialized winter adaptations that promoted fitness in a seasonally frozen environment may soon be superfluous or even maladaptive. We ask whether winter adaptations include changes in immune functions, and whether changing winter conditions could exert disparate effects on populations of a wide-ranging terrestrial ectotherm, the wood frog (Lithobates sylvaticus). By rearing wood frogs from ancestral winter environments that vary in length and temperature in a common garden, and reciprocally exposing post-metamorphic frogs to unfrozen and frozen artificial winter conditions in the lab, we were able to decompose transcriptomic differences in ventral skin gene expression into those that were environmentally induced (responsive to temperature), genetically determined, and those that varied as an interaction between genotype and environment. We found that frogs from harsh ancestral winter environments constitutively upregulated immune processes, including cellular immunity, inflammatory processes, and adaptive immune processes, as compared to frogs from mild ancestral winter environments. Further, we saw that expression of several genes varied in an interaction between genotype and artificial winter. We suggest that just as winter climates likely served as the selective force resulting in remarkable winter adaptations such as freeze tolerance, they also induced constitutive changes in immune gene expression.
PlateletBase: A Comprehensive Knowledgebase for Platelet Research and Disease Insights
Authors: Luo Huaichao , Wu Changchun , Yu Sisi , Ren Hanxiao , Yin Xing , Zu Ruiling , Rao Lubei , zhang Peiying , Zhang Xingmei , Wu Ruohao , Leng Ping , Zhang Kaijiong , Peng Qi , Cao Bangrong , Qin Rui , Wei Hulin , Qiao Jianlin , Xu Shanling , Yi Qun , Zhang Yang , Huang Jian , Wang Dongsheng
Published: December 2024

Platelets are vital in many pathophysiological processes, yet there is a lack of a comprehensive resource dedicated specifically to platelet research. To fill this gap, we have developed PlateletBase, a knowledge base aimed at enhancing the understanding and study of platelets and related diseases. Our team retrieved information from various public databases, specifically extracting and analyzing RNA-seq data from 3,711 samples across 41 different conditions available on NCBI. PlateletBase offers six analytical and visualization tools, enabling users to perform gene similarity analysis, pair correlation, multi-correlation, expression ranking, clinical information association, and gene annotation for platelets. The current version of PlateletBase includes 10,278 genomic entries, 31,758 transcriptomic entries, 4,869 proteomic entries, 2,614 omics knowledge entries, 1,833 drugs, 97 platelet resources, 438 diseases/traits, and six analysis modules. Each entry has been carefully curated and supported by experimental evidence. Additionally, PlateletBase features a user-friendly interface designed for efficient querying, manipulation, browsing, visualization, and analysis of detailed platelet protein and gene information. Case study results, such as those from gray platelet syndrome and angina pectoris, demonstrate that this tool can aid in identifying diagnostic biomarkers and exploring disease mechanisms, significantly advancing research in platelet functionality and its applications. PlateletBase is accessible athttp://plateletbase.clinlabomics.org.cn/.
DNMT/G9a Complex Inhibition Uncovers Epigenetic Vulnerabilities and Induces IFN-Response in Acute Myeloid Leukemia
Authors: Schönefeld Angelique , Zanetti Costanza , Schmitt Eric C. , Woods Kevin , Westerback Ashley , Mitsch Sidney M. , Rühle Frank , Kelekci Simge , Fol Lisa , Shah Viral , Sanchez-Saez Miriam , Thevissen Sophia , Schäffer Alexander , Schmits Ulrike Regina , Sasca Daniel , Kindler Thomas , Wölfel Catherine , Feuerstein-Akgoz Clarissa , Gerhäuser Clarissa , Lutsik Pavlo , Rivière Jennifer , Hecker Judith S , Götze Katharina S , Platzbecker Uwe , Echchannaoui Hakim , Theobald Matthias , Plass Christoph , Padeken Jan , Medyouf Hind , Guezguez Borhane
Published: December 2024

Epigenetic dysregulation is a hallmark of Acute Myeloid Leukemia (AML), with mutations in DNA Methyltransferases (e.g., DNMT3A) being frequent and promising therapeutic targets. DNMTs form complexes with Histone Methyltransferases (HMTs), driving gene silencing loop via chromatin methylation crosstalk. However, potential connections between this DNMTs/HMTs cooperative activity and oncogenic requirements across the AML mutational spectrum remain poorly understood. Here, we demonstrate that AMLs carrying DNMT3A and Nucleophosmin (NPM1) mutations exhibit a specific epigenetic vulnerability toward a complex formed by DNMTs and G9a, a specific histone H3 Lysine 9 Methyltransferase (H3K9-HMT). Dual inhibition of DNMT/G9a restores differentiation, reduces tumor growth, and spares healthy progenitors compared to standard hypomethylating agents. Mechanistically, DNMT/G9a regulates NPM1 stability, inhibits HOXA9/MEIS1 activity, and triggers interferons (IFN) response via viral mimicry pathways by modulating hypermethylated retrotransposons. Collectively, our data unravel specific epigenetic vulnerabilities within the complex AML mutational landscape and provide a compelling rationale for the design of personalized epigenetic therapies with enhanced efficacy and safer clinical outcomes.
Sex-Specific Regulation of Behavioral Responses to Single Prolonged Stress: Role of PACAP
Authors: Smail Marissa A. , Cotella Evelin M. , Martelle Susan E. , Chambers James B. , Parikh Ria K. , Moore Christine E. , Packard Ben A. , Nawreen Nawshaba , Moloney Rachel D. , Herman James P.
Published: December 2024

Post-Traumatic Stress Disorder (PTSD) is a debilitating condition in which a traumatic experience triggers symptoms related to re-experiencing, avoidance, arousal, and mood dysregulation. PTSD negatively impacts 6% of people during their lifetime, with women being disproportionally affected and exhibiting different, more severe symptoms than men. Despite this widespread impact, the molecular mechanisms underlying PTSD and its sex differences remain poorly understood. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is a neuropeptide which participates in fine-tuning circuitry throughout the brain and has been associated with PTSD in humans, especially in women. Here, we use Single Prolonged Stress (SPS), an animal model of PTSD, to explore the roles of PACAP and sex in PTSD-like behaviors. Specifically, a PACAP agonist or antagonist was infused into the infralimbic (IL) prefrontal cortex, a region key to regulating fear- and anxiety-related behaviors, prior to SPS in male and female rats. One week later, rats were tested in open field/novel object, elevated plus maze, and social interaction. Utilizing a behavioral indexing method, we were able to uncover SPS effects in PTSD-related behavioral domains that were differentially impacted by PACAP manipulations in males and females. While both sexes exhibited increased threat avoidance and decreased threat assessment following SPS, females increased sociability while males decreased sociability. Males also appeared to be protected by IL PACAP antagonism while female SPS phenotypes were exacerbated by IL PACAP agonism. Furthermore, RNAscope revealed that PACAP in the prefrontal cortex responds differently to SPS in males and females. Together, these findings suggest complex relationships between SPS, sex, and IL PACAP which may have important implications for treating PTSD in men and women.

HIGHLIGHTS

SPS induces different PTSD-like phenotypes in male and female rats

SPS increases threat avoidance and decreases threat appraisal in both sexes

Sociability is decreased in males but increased in females following SPS

IL PACAP manipulation exerts diverging SPS behavioral effects in males and females

Prefrontal PACAP signaling plays a sex-specific role in SPS molecular mechanisms
An improved isochronous pulse after lentiviral knock-down of STEP in Area X of juvenile zebra finches
Authors: Norton Philipp , Breslav Daniel , Mendoza Ezequiel
Published: December 2024

The zebra finch is one of the most commonly used animal models for studying the genetic mechanisms underlying vocal learning. To investigate the genetic basis of vocal learning, various genes have been knocked down in Area X—a brain region involved in birdsong acquisition—during the critical learning period. All genes that affect speech when mutated in humans similarly impair song learning in zebra finches. To date, no study has demonstrated that not all genes downregulated in Area X result in decreased song learning. Therefore, we sought a candidate gene to knock down in Area X that could either have no effect or potentially improve song learning. STEP is a protein that dephosphorylates many targets in the brain, and its knockout in mice has resulted in enhanced learning. In this study, a lentiviral knockdown of STEP in Area X during song learning resulted in birds producing normal song in almost all parameters and levels of song analysis. This stands in contrast to the knockdown of other genes like all FoxP subfamily members, which resulted in diminished song learning in previous studies. The only parameter positively affected by STEP knockdown was song rhythmicity, as evidenced by a lower deviation of song element onsets from an isochronous pulse than even their tutors. These results demonstrate for the first time that not all knockdowns in Area X lead to deterioration of song learning and validate the specificity of the method and previous findings.

Significance Statement

This is the first coding gene knockdown in Area X without negatively affecting song learning.
The adaptive state determines the impact of mutations on evolving populations
Authors: Weh Malgorzata Tyczynska , Kumar Pragya , Marusyk Viktoriya , Marusyk Andriy , Basanta David
Published: December 2024

Darwinian evolution results from an interplay between stochastic diversification of heritable phenotypes, impacting the chance of survival and reproduction, and fitness-based selection. The ability of populations to evolve and adapt to environmental changes depends on rates of mutational diversification and the distribution of fitness effects of random mutations. In turn, the distribution of fitness effects of stochastic mutations can be expected to depend on the adaptive state of a population. To systematically study the impact of the interplay between the adaptive state of a population on the ability of asexual populations to adapt, we used a spatial agent-based model of a neoplastic population adapting to a selection pressure of continuous exposure to targeted therapy. We found favorable mutations were overrepresented at the extinction bottleneck but depleted at the adaptive peak. The model-based predictions were tested using an experimental cancer model of an evolution of resistance to a targeted therapy. Consistent with the model’s prediction, we found that enhancement of the mutation rate was highly beneficial under therapy but moderately detrimental under the baseline conditions. Our results highlight the importance of considering population fitness in evaluating the fitness distribution of random mutations and support the potential therapeutic utility of restricting mutational variability.
A Time Machine for Taxonomy
Authors: Davis-Richardson Austin , Reynolds Timothy
Published: December 2024

The NCBI Taxonomy Database is the primary resource for linking genomic information to taxonomic relationships, widely used across scientific disciplines and critically important to bioinformatics. This database is continuously changing as researchers discover and refine taxonomic relationships. Yet, tracking and comparing past taxonomic states is challenging due to frequent changes and the need to sift through numerous historical snapshots. To address this, we developed the Taxonomy Time Machine: a database for storing many snapshots of a taxonomic tree in a space-efficient manner. We have also created a web-based and programmatic (API) interface to make this data more accessible. This tool is capable of accurately reconstructing taxonomic lineages at any point in the history of the NCBI Taxonomy Database. We demonstrate that this tool is both perfectly accurate and significantly more efficient than loading and querying individual taxonomy snapshots, enabling its use on desktop computers as well as commodity web servers. We have made this tool available on the web (https://taxonomy.onecodex.com) as well as open source under the MIT license (https://github.com/onecodex/taxonomy-time-machine).
Cytosolic fructose - an underestimated player in the regulation of the sucrose biosynthesis?
Authors: Giesbrecht Oliver , Bonn Christina , Fürtauer Lisa
Published: December 2024

Plants must continuously adapt to environmental fluctuations, which significantly influence their photosynthetic performance and overall metabolism. The sucrose cycling system within plant cells plays a critical regulatory role during stress conditions. This study employed a systems biology approach to analyze system stabilities mathematically under various regulatory conditions impacting sucrose cycling dynamics. We investigated the effects of mutations within this cycle, specifically HEXOKINASE1 (Arabidopsis thaliana gin2-1), alongside high-light exposure. Finally, we confirmed the modelling output in vitro by enzyme assays. The implementation of experimental subcellular metabolite data into a Structural Kinetic Model (SKM) enabled exploration of regulatory responses and system stabilities within a three-compartment model. Within system instabilities,gin2-1was more instable than its wild type. Thegin2-1mutation particularly was destabilized when fructokinase function was impaired by phosphorylated sugars. Additionally, we confirmed that phosphorylated sugars serve as stronger activators of sucrose-phosphate synthase (SPS) than glucose does. Interestingly, models with fructose SPS activation exhibited a similar stability pattern. Consequently, we proposed and confirmed in silico a triple activation of SPS by highly activating phosphorylated sugars and lower activating nonphosphorylated hexoses. Additionally, we biochemically confirmed the previously unknown, but now predicted, activation of SPS by fructose in vitro. In summary, our study highlights the essential role of sucrose cycling in plant cells under stress conditions. The in silico findings reveal that phosphorylated sugars are stronger activators of SPS than glucose and introduce a previously unknown activation mechanism by fructose. These potential activation capacities were confirmed in vitro through SPS enzyme activity assays, underscoring the efficiency of our systems biology approach. Overall, this research provides valuable insights into carbohydrate metabolism regulation and paves the way for future investigations to deepen our understanding of the complexities involved in sucrose cycling and biosynthesis in plants.
Conformational plasticity of human acid-sensing ion channel 1a
Authors: Cahill James , Hartfield Kimberly A. , Heusser Stephanie Andrea , Poulsen Mette Homann , Yoshioka Craig , Pless Stephan Alexander , Baconguis Isabelle
Published: December 2024

Acid-sensing ion channels (ASICs) are typically activated by acidic environments and contribute to nociception and synaptic plasticity. ASIC1a is the most abundant subunit in the central nervous system and forms homomeric channels permeable to Na+and Ca2+, making it a compelling therapeutic target for acidotic pathologies including stroke and traumatic brain injury. However, a complete conformational library of human ASIC1a in its various functional states has yet to be described. Using cryo-EM, we obtained hASIC1a structures across a pH range between 8.5 and 5.7, as well as in the presence of a toxin agonist and a gating-modulating mutation. We identify six major conformations that establish linear transmembrane helices to be associated with an open state, delineate mechanistic differences between proton and toxin activation, and demonstrate that desensitization leads to unexpected conformational diversity in the transmembrane domain. Together, they provide a three-dimensional rationalization of decades of structure-function studies on ASIC.
MetaBiome: A Multiscale Model Integrating Agent-Based Modeling and Metabolic Networks Reveals Spatial Regulation in Mucosal Microbial Communities
Authors: Aminian-Dehkordi Javad , Dickson Andrew , Valiei Amin , Mofrad Mohammad R.K.
Published: December 2024

Mucosal microbial communities (MMCs) are complex ecosystems near the mucosal layers of the gut, essential for maintaining health and modulating disease states. Despite advances in high-throughput omics technologies, current methodologies struggle to capture the dynamic metabolic interactions and spatiotemporal variations within MMCs. In this work, we presentMetaBiome, a multiscale model integrating agent-based modeling (ABM), finite volume methods, and constraint-based models to explore the metabolic interactions within these communities. Integrating ABM allows for the detailed representation of individual microbial agents, each governed by rules that dictate cell growth, division, and interactions with their surroundings. Through a layered approach—encompassing environmental conditions, agent information, and metabolic pathways—we simulated different communities to showcase the potential of the model. Using ourin-silicoplatform, we explored the dynamics and spatiotemporal patterns of MMCs in the proximal small intestine and the cecum, simulating the physiological conditions of the two gut regions. Our findings revealed how specific microbes adapt their metabolic processes based on substrate availability and local environmental conditions, shedding light on spatial metabolite regulation and informing targeted therapies for localized gut diseases.MetaBiome provides a detailed representation of microbial agents and their interactions, surpassing the limitations of traditional grid-based systems. This work marks a significant advancement in microbial ecology as it offers new insights into predicting and analyzing microbial communities.

Importance

Our study presents a novel multiscale model that combines agent-based modeling, finite volume methods, and genome-scale metabolic models to simulate the complex dynamics of mucosal microbial communities in the gut. This integrated approach allows us to capture spatial and temporal variations in microbial interactions and metabolism that are difficult to study experimentally.

Key findings from our model include:

Prediction of metabolic cross-feeding and spatial organization in multi-species communities

Insights into how oxygen gradients and nutrient availability shape community composition in different gut regions

Identification of spatially-regulated metabolic pathways and enzymes in E. coli

We believe this work represents a significant advance in computational modeling of microbial communities and provides new insights into the spatial regulation of gut microbiome metabolism. The multiscale modeling approach we have developed could be broadly applicable for studying other complex microbial ecosystems.
Host-microbiome determinants of ready-to-use supplemental food efficacy in acute childhood malnutrition
Authors: Jamil Zehra , Hanson Gabriel F. , Iqbal Junaid , Moreau G. Brett , Iqbal Najeeha Talat , Ahmed Sheraz , Hotwani Aneeta , Kabir Furqan , Umrani Fayaz , Sadiq Kamran , Ahmed Kumail , Mallawaarachchi Indika , Ma Jennie Z. , Aziz Fatima , Ali S Asad , Moore Sean
Published: December 2024

Ready-to-use supplemental foods (RUSF) are energy-dense meals formulated to prevent and treat moderate and severe childhood acute malnutrition (MAM and SAM) in high-risk settings. Although lifesaving, the degree and durability of weight recovery with RUSF is unpredictable. We examined whether environmental enteric dysfunction (EED) and gut microbiota perturbations are risk factors for RUSF failure in a birth cohort of 416 rural Pakistani children followed for growth, common childhood illnesses, and biomarkers from blood, urine, and stool. Infants who developed wasting (weight-for-length Z score <-2, n=187, 45%) during surveillance received Acha Mum (a chickpea-based RUSF) daily for eight weeks. Machine learning identified seven biomarkers that predicted RUSF response (n=75) vs. non-response (n=112) with 73% accuracy. Remarkably, gut microbiome composition predicted RUSF response with 93% (pre-supplementation) and 98% (post-supplementation) accuracy. Seven outliers whose microbiome falsely predicted positive response experienced extraordinary burdens of inflammation and illness during supplementation. These findings identify gut microbial signatures and biomarkers of gut and systemic inflammation as robust predictors of RUSF response in infants free from intercurrent illness during recovery, setting the stage for predictive models to guide precision use of RUSF and adjunct therapies in undernourished children.
Assessment of Awareness and Willingness to Use Pre-Exposure Prophylaxis for HIV Prevention among Female Sex Workers in Rwanda
Authors: Nzungize Albert , Munyaneza Athanase
Published: December 2024

Background

Female sex workers (FSWs) in sub Saharan Africa bear a disproportionate burden of HIV infection. While pre exposure prophylaxis (PrEP) is increasingly accessible in the region, limited data exist on FSWs awareness of and willingness to use PrEP. This study aimed to assess PrEP awareness and willingness to use it, along with associated factors, among FSWs in Kigali, Rwanda.

Methods

This cross sectional study, conducted from April to September 2024, evaluated PrEP awareness and willingness to use it among 333 FSWs recruited through community based FSW associations. Data were analyzed using SPSS, with logistic regression employed to explore associations between participant characteristics and PrEP awareness and willingness. Ethical approval was obtained from the Rwanda National Ethics Committee.

Results

The mean age of participants was 30 years (SD: 7.26), with 47% aged between 25 and 34. Most were single (67%) and unemployed (66%), with nearly half (49.5%) reporting only primary education. A significant proportion (81%) had undergone HIV testing in the past six months, and 50% had been involved in sex work for 2 to 5 years. The median number of sexual partners in the past week was 7.

Awareness of PrEP was high (81%), however, consistent condom users were less likely to be aware of PrEP (adjusted odds ratio (aOR): 0.40, 95% confidence interval (CI): 0.19, 0.83), as were those not screened for sexually transmitted infections (STIs) compared to those who were screened (aOR: 0.43, 95% CI: 0.22, 0.85). Willingness to use PrEP was reported by 80% of participants. Those with a primary education were more willing to use PrEP compared to those with no formal education (aOR: 4.09, 95% CI: 1.62, 10.33). Conversely, participants screened for STIs were less likely to report willingness compared to those not screened (aOR: 0.28, 95% CI: 0.12, 0.62).

Conclusion

This study demonstrates high awareness and willingness to use PrEP among FSWs in Kigali. However, consistent condom users and those unscreened for STIs were less aware of PrEP, and willingness to use it varied based on education and STI screening status. These findings underscore the need for targeted health education and STI screening initiatives to enhance PrEP uptake and strengthen HIV prevention efforts in this vulnerable population.
Mobility-driven synthetic contact matrices: a scalable solution for real-time pandemic response modeling
Authors: Di Domenico Laura , Bosetti Paolo , Sabbatini Chiara E. , Opatowski Lulla , Colizza Vittoria
Published: December 2024

Non-pharmaceutical interventions during the COVID-19 pandemic significantly disrupted social mixing patterns, creating a need for updated mathematical models to guide an effective response. Accurately capturing evolving, age-specific social contacts has proven challenging. This study evaluates the effectiveness of mobility-driven synthetic contact matrices against survey-based empirical matrices in capturing the dynamics of COVID-19 observed in France from March 2020 to May 2022. Both matrices showed a gradual increase in average contacts following the first lockdown, with the closest agreement during school closures. However, when schools were open, empirical matrices recorded 3.4 times more contacts for individuals under 19 than synthetic matrices. The model parameterized with mobility-driven contact matrices provided the best fit to hospital admission data and captured hospitalization patterns for adolescents, adults, and seniors, whereas deviations remained for children across both models. Neither matrix allowed models to accurately reproduce serological trends in children in 2021, highlighting the challenges both approaches face in capturing disease-relevant contacts in children. These findings demonstrate the value of synthetic matrices as flexible, cost-effective tools for epidemic modeling, operationally ready in real-time. Routine collection of age-stratified mobility data is essential to improve pandemic response.
Quantification of Brain Functional Connectivity Deviations in Individuals: A Scoping Review of Functional MRI Studies
Authors: Toloknieiev Artur , Voitsekhivskyi Dmytro , Kholodkov Hlib , Lvovich Roman , Matiushko Petro , Rekretiuk Daria , Dikhtiar Andrii , Viter Antonii , Pokras Volodymyr , Wunderlich Stephan , Stoecklein Sophia
Published: December 2024

Functional connectivity magnetic resonance imaging (fcMRI) is a well-established technique for studying brain networks in both healthy and diseased individuals. However, no fcMRI-based biomarker has yet achieved clinical relevance. To establish better understanding of the state of the art in quantifying abnormal connectivity in comparison to a reference distribution, for potential use in individual patients, we have conducted a scoping review over 5672 entries from the last 10 years. We have located five publications proposing methods of abnormal connectivity quantification, reported these methods and formalized them. We also illustrated the emerging trends and technical innovations in fcMRI research that may facilitate development of individualized fcMRI-based abnormal connectivity metrics.
Quantitative bias analysis for mismeasured variables in health research: a review of software tools
Authors: Wood Codie J.C. , Tilling Kate M. , Bartlett Jonathan W. , Hughes Rachael A.
Published: December 2024

Background

Mismeasurement (measurement error or misclassification) can cause bias or loss of power. However, sensitivity analyses (e.g. using quantitative bias analysis, QBA) are rarely used.

Methods

We reviewed software tools for QBA for mismeasurement in health research identified by searching Web of Science, the CRAN archive, and the IDEAS/RePEc software components database. Tools were included if they were purpose-built, had documentation and were applicable to epidemiological research.

Results

16 freely available software tools for QBA were identified, accessible via R and online web tools. The tools handle various types of mismeasurement, including classical measurement error and binary misclassification. Only one software tool handles misclassification of categorical variables, and few tackle non-classical measurement error.

Conclusions

Efforts should be made to create tools that can assess multiple mismeasurement scenarios simultaneously, to increase the clarity of documentation for existing tools, and provide tutorials for their usage.
UVESCREEN1: A randomised feasibility study of imaging-based uveitis screening for children with juvenile idiopathic arthritis- Study Protocol
Authors: Dave Sonali , Rahi Jugnoo , Petrushkin Harry , Testi Ilaria , Patel Dipesh E , Solebo Ameenat Lola
Published: December 2024

Children with Juvenile Idiopathic Arthritis (JIA) are at a currently unpredictable risk of a blinding, often asymptomatic, co-existent eye disorder, anterior uveitis which requires prompt treatment. The unpredictability of this insidious disorder commits children with JIA to three-monthly expert clinical examination in specialist eye centres often located far from their homes. Optical coherence tomography of the ocular anterior segment (AS-OCT) has been shown to be an acceptable, repeatable and sensitive modality for uveitis detection, but is not standard care. This feasibility randomised controlled trial (RCT) aims to inform a future full-scale RCT comparing current routine practice (expert slit lamp examination, SLE) to AS-OCT for the surveillance of uveitis in children at risk.

Eighty children aged between 2 and 12 years old and diagnosed with JIA within the preceding year will be included. Participants with an existing diagnosis of uveitis, other ocular co-morbidities or those unable to complete examinations or provide informed assent will be excluded. Participants will be randomised to SLE (control) or AS-OCT (intervention) examination at a frequency consistent with the current national programme for childhood uveitis surveillance. Children in the intervention arm will also have standard examination at 6 and 12 months after study entrance. Outcomes of interest will be feasibility (recruitment and attrition rates), clinical metrics (proportion diagnosed with uveitis or other ocular disorders at 12 months after study entrance), quality of life outcomes (PedsQL), and resource use. Additionally, comparative analysis of AS-OCT versus SLE (‘gold standard’ reference testing) findings at 6 and 12 months for those in the intervention arm will provide the proof-of-concept data necessary to develop and undertake a larger scale trial.

Trial registration: This trial has been registered withclinicaltrails.gov(NCT05984758).

Anterior uveitis is a rare form of eye disease that is commonly associated with Juvenile Idiopathic Arthritis (JIA). Childhood uveitis is potentially blinding, so children with JIA must travel to a specialist centre every two to three months for an eye examination to pick up signs of uveitis. This feasibility study will compare routine Slit Lamp Examination (SLE) with imaging-based surveillance using Optical Coherence Tomography of the Anterior Segment (AS-OCT) to support the design of a future study. Eighty children between the ages of two and twelve years old who have been diagnosed with JIA in the past year will be invited to take part. Children will be randomised into one of two arms (SLE or AS-OCT) and will have their routine uveitis screening appointments over one year using either of the screening modalities. This study will provide the proof-of-concept data necessary to develop and undertake a larger scale trial.
Sex-specific Risk Factors for Survival in B-cell Non-Hodgkin Lymphoma Patients after Anti-CD19 CAR T-Cell Therapy
Authors: Patel Manishkumar S. , Mian Agrima , Jalota Akansha , Bazeley Peter , Patil Sujata , Hill Brian T. , Gupta Neetu
Published: December 2024

Sex bias is well documented in autoimmune diseases, cancer and immune responses to infectious agents. Here, we investigated if pre-treatment risk factors that influence the survival of B-cell non-Hodgkin lymphoma (NHL) patients after anti-CD19 CAR T-cell therapy are sexually dimorphic. We measured pre-leukapheresis tumor burden (lactate dehydrogenase levels), C-reactive protein (CRP) and serum cytokine and chemokine concentration in 67 B-cell NHL patients treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Association of relative abundance of each factor with progression-free survival (PFS) and overall survival (OS) was analyzed in male and female patients together, or only within the male cohort or only within the female cohort. No differences in PFS or OS or in pre-treatment tumor burden, CRP and cytokine/chemokine levels were observed between male and female patients undergoing axi-cel or tisa-cel therapy. However, within the male group, patients with higher pre-treatment tumor burden and greater relative abundance of CRP and pro-inflammatory cytokines and chemokines conferred greater risk of poor progression-free survival (PFS) and/or overall survival (OS). In contrast, within the female group, patient survival was largely agnostic to variations in tumor burden, CRP and cytokine/chemokine abundance. Specifically, higher relative abundance of IL-6, IL-8, IL-27, TNF-α, Eotaxin-1, MIP-1β and MCP-1 was associated with poor PFS and/or OS after CAR T-cell therapy within the male group, whereas higher IL-27 and IFNα2 abundance was associated with better PFS and poorer OS, respectively, within the female group. Our data suggest that biological sex may modulate the impact of baseline risk factors on survival outcomes of CAR T-cell therapy in B-cell NHL.
PNEUMOCOCCAL SEROTYPE DISTRIBUTION AND COVERAGE OF EXISTING AND PIPELINE PNEUMOCOCCAL VACCINES
Authors: King Laura M , Andrejko Kristin L , Kobayashi Miwako , Xing Wei , Cohen Adam L , Self Wesley H , Resser J Jackson , Whitney Cynthia G , Baughman Adrienne , Kio Mai , Grijalva Carlos G , Traenkner Jessica , Rouphael Nadine , Lewnard Joseph A
Published: December 2024

Background

Streptococcus pneumoniae(pneumococcus) causes invasive pneumococcal disease (IPD) and non-invasive acute respiratory infections (ARIs). Three pneumococcal conjugate vaccines (PCVs) are recommended in the United States with additional products in clinical trials. We aimed to estimate 1) proportions of IPD cases and pneumococcal ARIs caused by serotypes targeted by existing and pipeline PCVs and 2) annual U.S. pneumococcal burdens potentially preventable by PCVs.

Methods

We estimated serotype distribution and proportions of non-invasive pneumococcal ARIs (AOM [children only], sinusitis, non-bacteremic pneumonia) and IPD attributable to serotypes targeted by each PCV using Markov chain Monte Carlo approaches incorporating data from studies of serotype distribution in ARIs and Active Bacterial Core Surveillance (ABCs) data. We then estimated annual numbers of outpatient-managed pneumococcal ARIs, non-bacteremic pneumococcal pneumonia hospitalizations, and IPD cases potentially preventable by PCVs in the United States by multiplying pneumococcal disease incidence rates by PCV-targeted proportions of disease and vaccine effectiveness estimates.

Results

In children, PCV15, PCV20, PCV24, PCV25, and PCV31 serotypes account for 16% (95% confidence interval: 15–17%), 31% (30–32%), 34% (32–35%), 43% (42–44%), and 68% (67–69%) of pneumococcal acute otitis media cases, respectively. In adults, PCV15, PCV20, PCV21, PCV24, PCV25, and PCV31 serotypes account for 43% (38–47%), 52% (47–57%), 69% (64–73%), 65% (61–70%), 62% (57–67%), and 87% (83–90%) of pneumococcal non-bacteremic pneumonia cases. For IPD, 42–85% of pediatric and 42–94% of adult cases were due to PCV-targeted serotypes. PCV-preventable burdens encompassed 270 thousand–3.3 million outpatient-managed ARIs, 2–17 thousand non-bacteremic pneumonia hospitalizations, and 3–14 thousand IPD cases in the United States annually.

Conclusions

Across pneumococcal conditions, coverage and preventable burdens were lowest for PCV15 and highest for PCV31, with PCV21 also targeting sizeable burdens of adult disease. Serotype distribution across syndromes may inform vaccine formulations and policy.
HIV Risk and Intention to use PrEP among Sexually Active Female University Students in Zambia: A Cross-Sectional Survey to Understand Influential Factors
Authors: Hampanda K , Bolt M , Nayame L , Hamoonga T , Sehrt M , Thorne J , Harrison M , Pintye J , Amstutz A , Abuogi L , Mweemba O
Published: December 2024

Background

Limited research exists on pre-exposure prophylaxis (PrEP) interest or use among female university students in high HIV-prevalence African settings. This study sought to establish the relationship between epidemiologic and perceived HIV risk and PrEP intention among Zambian female university students.

Methods

We recruited female students at an urban university to complete a survey on intention to use PrEP in the next year (primary outcome); other PrEP knowledge, attitudes, and behaviors; demographics; epidemiologic HIV risk and risk perception. Descriptive statistics, regression and mediation analyses were used.

Results

Of the 454 sexually active participants, 118 (26%) reported PrEP intention. Actual PrEP use was rare (< 5%). The odds of PrEP intention increased for those with perceived high HIV risk (aOR 3.08; 95% CI 1.71-5.55) and with each year at university (aOR 1.47; 95% CI 1.21-1.80) but decreased with higher PrEP stigma (aOR 0.91; 95% CI 0.86-0.96) and more negative PrEP perceptions (aOR 0.91; 95% CI 0.85-0.97). More epidemiologic risk factors were originally associated with PrEP intention (OR 1.24; 95% CI 1.01-1.53 for each risk factor), though this relationship weakened after adjustment for perceived HIV risk, which mediated 69% of the relationship between epidemiologic HIV risk and PrEP intention. Only 29% of high-risk participants recognized their high epidemiological HIV risk (3+ risk factors).

Conclusions

Along with PrEP education and stigma reduction, there is a need for approaches that help female university students in Zambia accurately identify their HIV risk to make informed PrEP decisions.