bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of multi-month dispensing on viral suppression and continuity in treatment among children living with HIV aged 2 to 9 years: a cohort study in Western Kenya
Authors: Oyuga Roseline , Amadi Emmanuel , Blanco Natalia , Ndaga Angela , Abuya Kepha , Oneya Daniel , Ng'eno Caroline , Koech Emily , Lavoie Marie-Claude C. 
Published: April 2024

Background:
In Kenya, of the 82,000 children living with HIV; only 59% of these children are receiving ART, and 67% of these are virally suppressed. Early in the COVID-19 pandemic, the Ministry of Health recommended three multi-month dispensing (3MMD) of ART to all people living with HIV, including children. This study assess the association between 3MMD and clinical outcomes among children in Western Kenya.

Settings
and Methods: We conducted a retrospective cohort study using routinely collected de-identified patient-level data from 43 facilities in Kisii and Migori counties. The study included children 2-9 years old who had been previously initiated on ART and sought HIV services between March 01, 2020, and March 30, 2021. We used generalized linear models with Poisson regression models to assess the association of MMD on retention at 6 months and viral suppression (<1,000 copies/ml).

Results:
Among the 963 children, 65.2% were aged 5-9 years old, and 50.7% were females. Seventy-eight percent received 3MMD at least once during the study period. Children who received 3MMD were 12% [adjusted risk ratio (aRR) (95% CI) =1.12 (1.01-1.24)] more likely to be retained and 22% [aRR =1.22 (1.12-1.34)] more likely to be virally suppressed than those on < 3MMD. When stratified by viral suppression at entry, the association between 3MMD and retention ([aRR= (95% CI) =1.22 (1.02-1.46)]) and viral suppression [aRR= (95% CI) =1.76 (1.30-2.37)] was significant among individuals who were unsuppressed at baseline.

Conclusions:
3MMD was associated with comparable or improved HIV health outcomes among children.
Dose-Response after Low-dose Ionizing Radiation: Evidence from Life Span Study with Data-driven Deep Neural Network Model
Authors: Liu Zhenqiu , Shuryak Igor 
Published: April 2024

AbstractAccurately evaluating the disease risks after low-dose ionizing radiation (IR) exposure are crucial for protecting public health, setting safety standards, and advancing research in radiation safety. However, while much is known about the disease risks of high-dose irradiation, risk estimates at low dose remains controversial. To date, five different parametric models (supra-linear, linear no threshold, threshold, quadratic, and hormesis) for low doses have been studied in the literature. Different dose-response models may lead to inconsistent or even conflicting results.In this manuscript, we introduce a data-driven deep neural network (DNN) model designed to evaluate dose-response models at low doses using Life Span Study (LSS) data. DNNs possess the capability to approximate any continuous function with an adequate number of nodes in the hidden layers. Being data-driven, they circumvent the challenges associated with misspecification inherent in parametric models. Our simulation study highlights the effectiveness of DNNs as a valuable tool for precisely identifying dose-response models from available data. New findings from the LSS study provide robust support for a linear quadratic (LQ) dose-response model at low doses.While the linear no threshold (LNT) model tends to overestimate disease risk at very low doses and underestimate health risk at relatively high doses, it remains a reasonable approximation for the LQ model, given the minor impact of the quadratic term at low doses. Our demonstration underscores the power of DNNs in facilitating comprehensive investigations into dose-response associations.
Precise Timing Matters: Modulating Human Memory by Synchronizing Hippocampal Stimulation to Saccadic Event Related Potentials
Authors: Katz C.N , Patel K. , Schjetnan A.G. , Barkley V. , Groppe David , Zariffa J , Duncan K.D. , Valiante T.A 
Published: April 2024

AbstractEpisodic memory, the ability to record and relive experiences, is intricately connected to visual exploration in most humans. This study explores the possibility that eye movements create physiological states relevant for memory, analogous to those associated with hippocampal theta. Previous work has demonstrated that saccadic eye movements, which occur roughly at theta frequency, elicit hippocampal event-related potentials (ERPs). Building on the Separate Phases of Encoding and Retrieval (SPEAR) model, we asked if the peaks and troughs of this saccadic ERP are differentially important for memory formation. Specifically, we applied saccade-contingent hippocampal electrical stimulation at estimated ERP peaks and troughs while individuals with epilepsy visually explored natural scenes across 59 sessions. We subsequently assessed their recognition memory for scenes and their recall of associated targets. Results indicate that memory is robust when stimulation precisely targets the peak or trough, contrasting with impairments observed with random stimulation. Moreover, memory impairment is prominent when stimulation is applied within 100 ms of saccade initiation, a time that reflects high medial temporal lobe inhibition. Our findings suggest that the hippocampus rapidly evolves through memory-relevant states following each eye movement, while also challenging the assumption that human saccadic ERP peaks and troughs mirror the encoding and retrieval phases of theta rhythms studied in rodents. The study sheds light on the dynamic interplay between eye movements, hippocampal activity, and memory formation, offering theoretical insights with potential applications for memory modulation in neurological disorders.Significance StatementWhy do eye-movements enhance memory formation? Here, we causally tested if eye-movements initiate short-lived states critical for memory formation within the hippocampus, a brain region known to support memory. We built a system that could precisely apply hippocampal electrical stimulation at key moments after eye-movements to test how the timing of this stimulation influenced people’s ability to form memories. We found that stimulation was particularly disruptive to memory formation when applied within 100 ms of initiating an eye movement. By contrast, memory was robust to stimulation precisely timed to the peak and trough of hippocampal eye-movement responses. We interpret this temporal evolution of memory-relevant states within a prominent model of how theta phases relate to rodent memory.
An ascending vagal sensory-central noradrenergic pathway modulates retrieval of passive avoidance memory
Authors: Edwards Caitlyn M. , Guerrero Inge Estefania , Thompson Danielle , Dolezel Tyla , Rinaman Linda 
Published: April 2024

AbstractBackgroundVisceral feedback from the body is often subconscious, but plays an important role in guiding motivated behaviors. Vagal sensory neurons relay “gut feelings” to noradrenergic (NA) neurons in the caudal nucleus of the solitary tract (cNTS), which in turn project to the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST) and other hypothalamic-limbic forebrain regions. Prior work supports a role for these circuits in modulating memory consolidation and extinction, but a potential role in retrieval of conditioned avoidance remains untested.ResultsTo examine this, adult male rats underwent passive avoidance conditioning. We then lesioned gut-sensing vagal afferents by injecting cholecystokinin-conjugated saporin toxin (CSAP) into the vagal nodose ganglia (Experiment 1), or lesioned NA inputs to the vlBNST by injecting saporin toxin conjugated to an antibody against dopamine-beta hydroxylase (DSAP) into the vlBNST (Experiment 2). When avoidance behavior was later assessed, rats with vagal CSAP lesions or NA DSAP lesions displayed significantly increased conditioned passive avoidance.ConclusionsThese new findings support the view that a gut vagal afferent-to-cNTSNA-to-vlBNST circuit plays a role in modulating the expression/retrieval of learned passive avoidance. Overall, our data suggest a dynamic modulatory role of vagal sensory feedback to the limbic forebrain in integrating interoceptive signals with contextual cues that elicit conditioned avoidance behavior.
Deep learning models to predict mammographic density jointly on standard dose and low dose images
Authors: Squires Steven , Mackenzie Alistair , Evans D. Gareth , Howell Sacha J , Astley Susan M 
Published: April 2024

AbstractObjectivesMammographic density is associated with increased risk of developing breast cancer. Automated estimation of density in women below normal screening age would enable earlier risk stratification. We are piloting the use of low dose mammograms combined with models that can make accurate mammographic density estimates.MethodsThree models were trained on a joint set (107,619) of standard dose mammograms with associated density scores and their simulated low dose counterparts such that the models made predictions on standard and low dose mammograms. A second set of models was trained separately on the standard and simulated low dose mammograms. All models were tested on a held-out set from the training data and an independent dataset with 294 pairs of standard and real low dose mammograms.ResultsThe root mean squared errors (RMSE) between the model predictions and density scores on standard and simulated low dose images were 8.26 (8.16-8.36) and 8.27 (8.17-8.38) respectively. The RMSE between predictions on standard and simulated low dose images for the jointly trained models was 1.91 (1.88-1.96). The RMSE of the predictions on the real low dose images compared to the standard dose images is 3.79 (2.75-4.99).ConclusionsDeep learning models make density predictions on low dose images with similar quality as on standard dose images. Such automated analysis of low dose mammograms could contribute to accurate breast cancer risk estimation in younger women enabling stratification for further monitoring and preventative therapy.Advances in knowledgeMammographic density can be estimated in low dose mammograms with similar quality to standard dose mammograms.
Interrater agreement of annotations of epileptiform discharges and its impact on deep learning – A pilot study
Authors: Svantesson Mats , Eklund Anders , Thordstein Magnus 
Published: April 2024

1.AbstractBackgroundExpert interrater agreement for epileptiform discharges can be moderate. This reasonably will affect the performance when developing classifiers based on annotations performed by experts. In addition, evaluation of classifier performance will be difficult since the ground truth will have a variability. In this pilot study, these aspects were investigated to evaluate the feasibility of conducting a larger study on the subject.MethodsA multi-channel EEG of 78 minutes duration with abundant periodic discharges was independently annotated for epileptiform discharges by two experts. Based on this, several deep learning classifiers were developed which in turn produced new annotations. The agreements of all annotations were evaluated by pairwise comparisons using Cohen’s kappa and Gwet’s AC1. A cluster analysis was performed on all periodic discharges using a newly developed version of parametric t-SNE to assess the similarity between annotations.ResultsThe Cohen’s kappa values were 0.53 for the experts, 0.52–0.65 when comparing the experts to the classifiers, and 0.67–0.82 for the classifiers. The Gwet’s AC1 values were 0.92 for the experts, 0.92–0.94 when comparing the experts to the classifiers, and 0.94–0.96 for the classifiers. Although there were differences between all annotations regarding which discharges that had been selected as epileptiform, the selected discharges were mostly similar according to the cluster analysis. Almost all identified epileptiform discharges by the classifiers were also periodic discharges.ConclusionsThere was a discrepancy between agreement scores produced by Cohen’s kappa and Gwet’s AC1. This was probably due to the skewed prevalence of epileptiform discharges, which only constitutes a small part of the whole EEG. Gwet’s AC1 is often considered the better option and the results would then indicate an almost perfect agreement. However, this conclusion is questioned when considering the number of differently classified discharges. The difference in annotation between experts affected the learning of the classifiers, but the cluster analysis indicates that all annotations were relatively similar. The difference between experts and classifiers is speculated to be partly due to intrarater variability of the experts, and partly due to underperformance of the classifiers. For a larger study, in addition to using more experts, intrarater agreement should be assessed, the classifiers can be further optimized, and the cluster method hopefully be further improved.
Implicit Adaptation is Fast, Robust and Independent from Explicit Adaptation
Authors: D’Amario Sebastian , Ruttle Jennifer E. , ’t Hart Bernard Marius , Henriques Denise Y. P. 
Published: April 2024

AbstractDuring classical visuomotor adaptation, the implicit process is believed to emerge rather slowly; however, recent evidence has found this may not be true. Here, we further quantify the time-course of implicit learning in response to diverse feedback types, rotation magnitudes, feedback timing delays, and the role of continuous aiming on implicit learning. Contrary to conventional beliefs, we affirmed that implicit learning unfolds at a high rate in all feedback conditions. Increasing rotation size not only raises asymptotes, but also generally heightens explicit awareness, with no discernible difference in implicit rates. Cursor-jump and terminal feedback, with or without delays, predominantly enhance explicit adaptation while slightly diminishing the extent or the speed of implicit adaptation. In a continuous aiming reports condition, there is no discernible impact on implicit adaptation, and implicit and explicit adaptation progress at indistinguishable speeds. Finally, investigating the assumed negative correlation as an indicator of additivity of implicit and explicit processes, we consistently observe a weak association across conditions. Our observation of implicit learning early in training in all tested conditions signifies how fast and robust our innate adaptation system is.
Cross-reactivity of rPvs48/45, a recombinantPlasmodium vivaxprotein, with sera fromPlasmodium falciparumendemic areas of Africa
Authors: Balam Saidou , Miura Kazutoyo , Ayadi Imen , Konaté Drissa , Incandela Nathan C. , Agnolon Valentina , Guindo Merepen A , Diakité Seidina A.S. , Olugbile Sope , Nebie Issa , Herrera Sonia M , Long Carole , Kajava Andrey V. , Diakité Mahamadou , Corradin Giampietro , Herrera Socrates , Arevalo Herrera Myriam 
Published: April 2024

AbstractBackgroundPs48/45, aPlasmodiumgametocyte surface protein, is a promising candidate for malaria transmission-blocking (TB) vaccine. Due to its relevance for a multispecies vaccine, we explored the cross-reactivity and TB activity of a recombinantP. vivax Ps48/45 protein (rPvs48/45) with sera fromP. falciparum-exposed African donors.MethodsrPvs48/45 was produced in Chinese hamster ovary cell lines and tested by ELISA for its cross-reactivity with sera from Burkina Faso, Tanzania, Mali, and Nigeria – In addition, BALB/c mice were immunized with the rPvs48/45 protein formulated in Montanide ISA-51 and inoculated with a crude extract ofP. falciparumNF-54 gametocytes to evaluate the parasite-boosting effect on rPvs48/45 antibody titers. Specific anti-rPvs48/45 IgG purified from African sera was used to evaluate theex vivoTB activity onP. falciparum,using standard mosquito membrane feeding assays (SMFA).ResultsrPvs48/45 protein showed cross-reactivity with sera of individuals from all four African countries, in proportions ranging from 94% (Tanzania) to 40% (Nigeria). Also, the level of cross-reactive antibodies varied significantly between countries (p<0.0001), with a higher antibody level in Mali and the lowest in Nigeria. In addition, antibody levels were higher in adults (≥ 17 years) than young children (≤ 5 years) in both Mali and Tanzania, with a higher proportion of responders in adults (90%) than in children (61%) (p<0.0001) in Mali, where male (75%) and female (80%) displayed similar antibody responses. Furthermore, immunization of mice withP. falciparumgametocytes boosted anti-Pvs48/45 antibody responses, recognizingP. falciparumgametocytes in indirect immunofluorescence antibody test. Notably, rPvs48/45 affinity-purified African IgG exhibited a TB activity of 61% againstP. falciparumin SMFA.ConclusionAfrican sera (exposed only toP. falciparum)cross-recognized the rPvs48/45 protein. This, together with the functional activity of IgG, warrants further studies for the potential development of aP. vivaxandP. falciparumcross-protective TB vaccine.
Mondrian Abstraction and Language Model Embeddings for Differential Pathway Analysis
Authors: Al Abir Fuad , Chen Jake Y. 
Published: April 2024

AbstractIn this study, we introduce the Mondrian Map, an innovative visualization tool inspired by Piet Mondrian’s abstract art, to address the complexities inherent in visualizing biological networks. By converting intricate biological data into a structured and intuitive format, the Mondrian Map enables clear and meaningful representations of biological pathways, facilitating a deeper understanding of molecular dynamics. Each pathway is represented by a square whose size corresponds to fold change, with color indicating the direction of regulation (up or down) and statistical significance. The spatial arrangement of pathways is derived from language model embeddings, preserving neighborhood relationships and enabling the identification of clusters of related pathways. Additionally, colored lines highlight potential crosstalk between pathways, with distinctions between short- and long-range functional interactions. In a case study of glioblastoma multiforme (GBM), the Mondrian Map effectively revealed distinct pathway patterns across patient profiles at different stages of disease progression. These insights demonstrate the tool’s potential to enhance downstream bioinformatics analysis by providing a more comprehensive and visually accessible overview of pathway interactions, offering new avenues for therapeutic exploration and personalized medicine.
Chronic alcohol consumption alters sex-dependent BNST neuron function in rhesus macaques
Authors: Pleil Kristen E. , Grant Kathleen A. , Cuzon Carlson Verginia C. , Kash Thomas L. 
Published: April 2024

AbstractRepeated alcohol drinking contributes to a number of neuropsychiatric diseases, including alcohol use disorder and co-expressed anxiety and mood disorders. Women are more susceptible to the development and expression of these diseases with the same history of alcohol exposure as men, suggesting they may be more sensitive to alcohol-induced plasticity in limbic brain regions controlling alcohol drinking, stress responsivity, and reward processing, among other behaviors. Using a translational model of alcohol drinking in rhesus monkeys, we examined sex differences in the basal function and plasticity of neurons in the bed nucleus of the stria terminalis (BNST), a brain region in the extended amygdala shown to be a hub circuit node dysregulated in individuals with anxiety and alcohol use disorder. We performed slice electrophysiology recordings from BNST neurons in male and female monkeys following daily “open access” (22 hr/day) to 4% ethanol and water for more than one year or control conditions. We found that BNST neurons from control females had reduced overall current density, hyperpolarization-activated depolarizing current (Ih), and inward rectification, as well as higher membrane resistance and greater synaptic glutamatergic release and excitatory drive, than those from control males, suggesting that female BNST neurons are more basally excited than those from males. Chronic alcohol drinking produced a shift in these measures in both sexes, decreasing current density, Ih, and inward rectification and increasing synaptic excitation. In addition, network activity-dependent synaptic inhibition was basally higher in BNST neurons of males than females, and alcohol exposure increased this in both sexes, a putative homeostatic mechanism to counter hyperexcitability. Altogether, these results suggest that the rhesus BNST is more basally excited in females than males and chronic alcohol drinking produces an overall increase in excitability and synaptic excitation. These results shed light on the mechanisms contributing to the female-biased susceptibility to neuropsychiatric diseases including co-expressed anxiety and alcohol use disorder.
Plasmin Cleavage of Beta-2-Glycoprotein I Alters its Structure and Ability to Bind to Pathogenic Antibodies
Authors: Bradford Hannah F. , Lalaurie Christophe J. , Gor Jayesh , Gao Xin , Pericleous Charis , Perkins Stephen J. , Britt Hannah , Thalassinos Konstantinos , Giles Ian , Rahman Anisur , Delcea Mihaela , Dalby Paul A. , McDonnell Thomas C.R. 
Published: April 2024

AbstractBeta-2-Glycoprotein I (β2GPI) is the main autoantigenic target of antiphospholipid syndrome (APS) with antibodies leading to clinical manifestations. There are two known structural isomers of β2GPI, a J shape and a circular shaped one. The transition between these structures is incompletely understood, with the functional implications unknown. β2GPI is a substrate of the protease plasmin, which cleaves within the fifth domain of β2GPI leading to altered cellular binding. Very little is currently known regarding the structure and function of this protein variant. We present the first comprehensive structural characterisation plasmin-clipped β2GPI and the associated implications for pathogenic antibody binding to this protein.Methodsβ2GPI was purified using a novel acid-free process from healthy control plasma and cleaved with plasmin. Cleavage was confirmed by SDS-PAGE. Structural characterisation was undertaken using dynamic light scattering (DLS), small angle X-ray scattering (SAXS), ion mobility mass spectrometry (IMMS) and molecular dynamics simulation (MD). Activity was tested using inhibition of β2GPI ELISAs with patient samples and cleaved β2GPI in the fluid phase and cellular binding by flow cytometry using HUVEC cells.ResultsDLS revealed a significantly smaller hydrodynamic radius for plasmin-clipped β2GPI (p=0.0043). SAXS and MD analysis indicated a novel S-like structure of β2GPI only present in the plasmin-clipped sample whilst IMMS showed a different structure distributions in plasmin clipped compared to non-clipped B2GPI. The increased binding of autoantibodies was shown for plasmin-clipped β2GPI (p=0.056), implying a greater exposure of pathogenic epitopes following cleavage.ConclusionsCleavage of β2GPI by plasmin results in the production of a unique S-shaped structural conformation and higher patient antibody binding. This novel structure may explain the loss of binding to phospholipids and increase in anti-angiogenic potential described previously for plasmin-clipped β2GPI.