bluuebunny/crossref_metadata_2025_split huggingface dataset:
“…but I know something’s not right here”: Exploring the diagnosis and disclosure experiences of persons living with ALS
Authors: Foldvari Kathleen M. , Stolee Paul , Neiterman Elena , Boscart Veronique , Tong Catherine 
Published: March 2024

AbstractBackgroundAmyotrophic Lateral Sclerosis (ALS), an incurable motor neuron disease, primarily affects those between the ages of 60-79, and has an approximate post-diagnosis life--expectancy of only two to five years. The condition has an unpredictable but ultimately terminal trajectory that poses a number of challenges for patients, caregivers and healthcare providers. While the diagnosis and disclosure are critical periods for intervention and support, knowledge regarding the relational, communicational and psychodynamic forces that occur within the process of diagnostic disclosure is relatively limited.ObjectivesThe purpose of this study was to explore the experiences of persons living with ALS in the diagnosis and disclosure of the condition, and the experiences of their caregivers.MethodsWe conducted a focus group and in-depth individual interviews with Canadians living with ALS (n = 9), family caregivers (n = 7), a professional caregiver (n = 1), and one past caregiver (1). The interviews were transcribed, cleaned, and anonymized, and then entered into NVivo 11 for thematic analysis.ResultsParticipants discussed the diagnosis process, including the inklings and subtle changes prior to diagnosis, attempts at self-diagnosis, and the lengthy assessment process. Time was also a consideration in the disclosure process, in which participants shared how the diagnosis disclosure was the product of longstanding conversations with their care providers. It was described as rarely a shock to finally have confirmation. Additionally, participants shared their information seeking strategies and needs for a diagnosis that, for them, typically came with insufficient information on the disease, prognosis, and next steps.SignificanceThis project serves as an initial step in bridging the relevant gaps in our knowledge and understanding towards improved patient-centered care practices in the diagnosis and disclosure of ALS.
Multiple paralogues and recombination mechanisms drive the high incidence of 22q11.2 Deletion Syndrome
Authors: Vervoort Lisanne , Dierckxsens Nicolas , Santos Marta Sousa , Meynants Senne , Souche Erika , Cools Ruben , Heung Tracy , Devriendt Koen , Peeters Hilde , McDonald-McGinn Donna M. , Swillen Ann , Breckpot Jeroen , Emanuel Beverly S. , Van Esch Hilde , Bassett Anne S. , Vermeesch Joris R. 
Published: March 2024

AbstractThe 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder. Why the incidence of 22q11.2DS is much greater than that of other genomic disorders remains unknown. Short read sequencing cannot resolve the complex segmental duplicon structure to provide direct confirmation of the hypothesis that the rearrangements are caused by non-allelic homologous recombination between the low copy repeats on chromosome 22 (LCR22s). To enable haplotype-specific assembly and rearrangement mapping in LCR22 regions, we combined fiber-FISH optical mapping with whole genome (ultra-)long read sequencing or rearrangement-specific long-range PCR on 24 duos (22q11.2DS patient and parent-of-origin) comprising several different LCR22-mediated rearrangements. Unexpectedly, we demonstrate that not only different paralogous segmental duplicon but also palindromic AT-rich repeats (PATRR) are driving 22q11.2 rearrangements. In addition, we show the existence of two different inversion polymorphisms preceding rearrangement, and somatic mosaicism. The existence of different recombination sites and mechanisms in paralogues and PATRRs which are copy number expanding in the human population are a likely explanation for the high 22q11.2DS incidence.
Endogenous Precision of the Number Sense
Authors: Prat-Carrabin Arthur , Woodford Michael 
Published: March 2024

AbstractThe behavioral variability in psychophysical experiments and the stochasticity of sensory neurons have revealed the inherent imprecision in the brain’s representations of environmental variables1–6. Numerosity studies yield similar results, pointing to an imprecise ‘number sense’ in the brain7–13. If the imprecision in representations reflects an optimal allocation of limited cognitive resources, as suggested by efficient-coding models14–26, then it should depend on the context in which representations are elicited25,27. Through an estimation task and a discrimination task, both involving numerosities, we show that the scale of subjects’ imprecision increases, but sublinearly, with the width of the prior distribution from which numbers are sampled. This sublinear relation is notably different in the two tasks. The double dependence of the imprecision — both on the prior and on the task — is consistent with the optimization of a tradeoff between the expected reward, different for each task, and a resource cost of the encoding neurons’ activity. Comparing the two tasks allows us to clarify the form of the resource constraint. Our results suggest that perceptual noise is endogenously determined, and that the precision of percepts varies both with the context in which they are elicited, and with the observer’s objective.
Generating clinical-grade pathology reports from gigapixel whole slide images with HistoGPT
Authors: Tran Manuel , Schmidle Paul , Wagner Sophia J. , Koch Valentin , Novotny Brenna , Lupperger Valerio , Feuchtinger Annette , Böhner Alexander , Kaczmarczyk Robert , Biedermann Tilo , Comfere Nneka I. , Guo Ruifeng (Ray) , Wang Chen , Eyerich Kilian , Braun Stephan A. , Peng Tingying , Marr Carsten 
Published: March 2024

AbstractHistopathology is considered the reference standard for diagnosing the presence and nature of many malignancies, including cancer. However, analyzing tissue samples and writing pathology reports is time-consuming, labor-intensive, and non-standardized. To address this problem, we present HistoGPT, the first vision language model that simultaneously generates reports from multiple pathology images. It was trained on more than 15,000 whole slide images from over 6,000 dermatology patients with corresponding pathology reports. The generated reports match the quality of human-written reports, as confirmed by a variety of natural language processing metrics and domain expert evaluations. We show that HistoGPT generalizes to six geographically diverse cohorts and can predict tumor subtypes and tumor thickness in a zero-shot fashion. Our model demonstrates the potential of an AI assistant that supports pathologists in evaluating, reporting, and understanding routine dermatopathology cases.
Mapping structural variants to rare disease genes using long-read whole genome sequencing and trait-relevant polygenic scores
Authors: LeMaster Cas , Schwendinger-Schreck Carl , Ge Bing , Cheung Warren A. , McLennan Rebecca , Johnston Jeffrey J. , Pastinen Tomi , Smail Craig 
Published: March 2024

ABSTRACTRecent studies have revealed the pervasive landscape of rare structural variants (rSVs) present in human genomes. rSVs can have extreme effects on the expression of proximal genes and, in a rare disease context, have been implicated in patient cases where no diagnostic single nucleotide variant (SNV) was found. Approaches for integrating rSVs to date have focused on targeted approaches in known Mendelian rare disease genes. This approach is intractable for rare diseases with many causal loci or patients with complex, multi-phenotype syndromes. We hypothesized that integrating trait-relevant polygenic scores (PGS) would provide a substantial reduction in the number of candidate disease genes in which to assess rSV effects. We further implemented a method for ranking PGS genes to define a set of core/key genes where a rSV has the potential to exert relatively larger effects on disease risk. Among a subset of patients enrolled in the Genomic Answers for Kids (GA4K) rare disease program (N=497), we used PacBio HiFi long-read whole genome sequencing (lrWGS) to identify rSVs intersecting genes in trait-relevant PGSs. Illustrating our approach in Autism (N=54 cases), we identified 22,019 deletions, 2,041 duplications, 87,826 insertions, and 214 inversions overlapping putative core/key PGS genes. Additionally, by integrating genomic constraint annotations from gnomAD, we observed that rare duplications overlapping putative core/key PGS genes were frequently in higher constraint regions compared to controls (P = 1×10−03). This difference was not observed in the lowest-ranked gene set (P = 0.15). Overall, our study provides a framework for the annotation of long-read rSVs from lrWGS data and prioritization of disease-linked genomic regions for downstream functional validation of rSV impacts. To enable reuse by other researchers, we have made SV allele frequencies and gene associations freely available.
The benefit of a complete reference genome for cancer structural variant analysis
Authors: Paulin Luis F , Fan Jeremy , O’Neill Kieran , Pleasance Erin , Porter Vanessa L. , Jones Steven J.M , Sedlazeck Fritz J. 
Published: March 2024

AbstractThe complexities of cancer genomes are becoming more easily interpreted due to advancements in sequencing technologies and improved bioinformatic analysis. Structural variants (SVs) represent an important subset of somatic events in tumors. While detection of SVs has been markedly improved by the development of long-read sequencing, somatic variant identification and annotation remains challenging.We hypothesized that use of a completed human reference genome (CHM13-T2T) would improve somatic SV calling. Our findings in a tumour/normal matched benchmark sample and two patient samples show that the CHM13-T2T improves SV detection and prioritization accuracy compared to GRCh38, with a notable reduction in false positive calls. We also overcame the lack of annotation resources for CHM13-T2T by lifting over CHM13-T2T-aligned reads to the GRCh38 genome, therefore combining both improved alignment and advanced annotations.In this process, we assessed the current SV benchmark set for COLO829/COLO829BL across four replicates sequenced at different centers with different long-read technologies. We discovered instability of this cell line across these replicates; 346 SVs (1.13%) were only discoverable in a single replicate. We identify 49 somatic SVs, which appear to be stable as they are consistently present across the four replicates. As such, we propose this consensus set as an updated benchmark for somatic SV calling and include both GRCh38 and CHM13-T2T coordinates in our benchmark. The benchmark is available at: 10.5281/zenodo.10819636 Our work demonstrates new approaches to optimize somatic SV prioritization in cancer with potential improvements in other genetic diseases.
ACUTE SEIZURES AFTER SPONTANEOUS INTRACEREBRAL HEMORRHAGE IN YOUNG INDIVIDUALS: 11-YEAR TRENDS AND ASSOCIATION WITH MORTALITY
Authors: Lekoubou Alain , Cohrs Austin , Dejuk Mariana , Hong Jinpyo , Sen Souvik , Bonilha Leonardo , Chinchilli Vernon M. 
Published: March 2024

AbstractOBJECTIVETo describe trends in acute seizures (AS) among young individuals with spontaneous intracerebral hemorrhage (sICH) and association with mortality.BACKGROUNDAcute seizures are frequent complications of sICH. The rate of sICH is rising among young Americans (18 to 60 years). Trends in AS incidence in this age group is largely unknown. Further, the association of AS with mortality has not been reported among young Americans.DESIGN/METHODSThe Merative MarketScan® Commercial Claims and Encounters database, for the years 2005 through 2015, served as the data source for this study. This period was chosen as spontaneous ICH incidence increased among young individuals between 2005 and 2015. Our study population included patients aged 18 to 64 years with ICH identified using the International Classification of Diseases, Ninth and Tenth Revision (ICD-9/10) codes 430, 431, 432.0, 432.1, 432.9, I61, I61.0, I61.1, I61.2, I61.3, I61.4, I61.5, I61.6, I61.8, and I61.9, excluding those with a prior diagnosis of seizures (ICD-9/10 codes 345.x,780.3x, G40, G41, and R56.8). We computed yearly AS incidence, mortality (in patients with and without seizures), and analyzed trends. We applied a logistic regression model to determine the independent association of AS with mortality accounting for demographic and clinical variables.RESULTSOf 81,878 sICH patients, 7,611 (9.3%) developed AS. AS incidence increased linearly between 2005 (incidence rate: 8.1%) and 2015 (incidence rate: 11.0%), which represents a 26% relative increase (P for trends <0.0001. In-hospital mortality rate was 14.3% among those who developed AS and 11.5% among those who did not. Between 2005 and 2015, overall, in-hospital mortality decreased from 13.0% to 9.7% among patients without AS but remained unchanged among those with AS. Patients who developed AS were 10% more likely to die than those who did not (OR: 1.10, 95% confidence interval: 1.02-1.18).CONCLUSIONSBetween 2005 and 2015, AS incidence increased by nearly 26% among young Americans with sICH. In-patient mortality remained unchanged among those who developed seizures but declined among those who did not. The occurrence of AS was independently associated with a 10% higher risk of in-hospital death. Future studies will test the benefit of treating AS to reduce mortality after sICH.
The evolutionary and molecular history of a chikungunya virus outbreak lineage
Authors: Krambrich Janina , Mihalič Filip , Gaunt Michael W. , Bohlin Jon , Hesson Jenny , Lundkvist Åke , de Lamballerie Xavier , Li Cixiu , Shi Weifeng , Pettersson John H.-O. 
Published: March 2024

AbstractIn 2018–2019, Thailand experienced a nationwide spread of chikungunya virus (CHIKV), with approximately 15,000 confirmed cases of disease reported. Here, we investigated the evolutionary and molecular history of the East/Central/South African (ECSA) genotype to determine the origins of the 2018–2019 CHIKV outbreak in Thailand. This was done using newly sequenced clinical samples from travellers returning to Sweden from Thailand in late 2018 and early 2019 and previously published genome sequences. Our phylogeographic analysis showed that before the outbreak in Thailand, the Indian Ocean lineage (IOL) found within the ESCA, had evolved and circulated in East Africa, South Asia, and Southeast Asia for about 15 years. In the first half of 2017, an introduction occurred into Thailand from another South Asian country, most likely Bangladesh, which subsequently developed into a large outbreak in Thailand with export to neighbouring countries. Based on comparative phylogenetic analyses of the complete CHIKV genome and protein modelling, we also identified amino acid substitutions that may be associated with immune evasion, increased spread, and virulence. We identified several mutations in the E1/E2 spike complex, such as E1 K211E and E2 V264A, which are highly relevant as they may lead to changes in vector competence, transmission efficiency and pathogenicity of the virus. A number of mutations (E2 G205S, Nsp3 D372E, Nsp2 V793A), that emerged shortly before the outbreak of the virus in Thailand in 2018 may have altered antibody binding and recognition due to their position. This study not only improves our understanding of the factors contributing to the epidemic in Southeast Asia, but also has implications for the development of effective response strategies and the potential development of new vaccines.Author SummaryWe investigated the evolutionary and molecular history of the East/Central/South African (ECSA) genotype to determine the origins of the 2018–2019 chikungunya virus (CHIKV) outbreak in Thailand. We used newly sequenced clinical samples from travellers returning to Sweden from Thailand in late 2018 and early 2019 together with previously published genome sequences. Our phylogeographic analysis shows that the Indian Ocean lineage (IOL), found within ECSA, evolved in Eastern Africa, Southern Asia, and Southeast Asia for about 15 years before the outbreak in Thailand in 2018. We have also identified amino acid substitutions that may be associated with immune evasion, increased spread, and higher virulence that occurred prior to the outbreak and may have played a critical role in the rapid spread of the virus. Our study concludes that monitoring and understanding CHIKV dynamics remains critical for an effective response to the previously unpredictable outbreaks of the virus.
Alpha7 nicotinic acetylcholine receptor agonist PHA 568487 dampens inflammation in PBMCs from patients with newly discovered coronary artery disease
Authors: Mjörnstedt Filip , Wilhelmsson Rebecka , Ulleryd Marcus , Hammarlund Maria , Bergström Göran , Gummesson Anders , Johansson Maria E 
Published: March 2024

AbstractBackgroundThe alpha7 nicotinic acetylcholine receptor (α7nAChR) controls inflammation in experimental models. The α7nAChR is expressed in human peripheral blood mononuclear cells (PBMCs) as well as in human atherosclerotic plaques, yet, its role in regulating inflammation in patients with cardiovascular disease remains unknown. In this study we aim to investigate whether stimulation of the α7nAChR can dampen the immune response in patients with newly discovered coronary artery disease (CAD).MethodsHuman peripheral blood mononuclear cells (PBMCs) extracted from patients with verified CAD (n=38) and control participants with healthy vessels (n=38) were challenged in vitro with lipopolysaccharide (LPS) in combination with α7nAChR agonist PHA 568487. Supernatants were analyzed for cytokines using multiplex immunoassay. The CAD group was re-examined after 6 months.Resultsα7nAChR stimulation decreased TNF-α in all groups, in control participants and in CAD patients, both at the first visit as well as the follow-up visit after 6 months. The most pronounced effect of α7nAChR stimulation was seen in CAD patients at their first visit, where 12 of 17 cytokines were decreased (TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-7, IL-10, IL-17A, GM-CSF, MCP-1, MIP-1β and IL12(p70)).ConclusionsStimulation of α7nAChR dampens the inflammatory response in human PBMCs. This suggests that the anti-inflammatory properties of the α7nAChR may have a role in treating CAD.
Sustainable and Ecofriendly Nanoparticle Synthesis Using Microbial Strains Isolated From Heavy Metal Rich Industrial Effluent
Authors: Nathan Soshina , Mathunny Soumya , Anjana J 
Published: March 2024

ABSTRACTGiven the enormous potential of metal nanomaterials, their sustainable production is of paramount importance and is a key area of focus worldwide. In this regard, bacteria are highly valued because of their potential for rapid, cost-effective and eco-friendly metal nanomaterial synthesis. In this study, culture supernatants ofBacillus cereusandCurvulariasp isolated from heavy metal rich Titanium industry effluent effectively synthesised cobalt and copper nanoparticles of narrow size range at room temperature, neutral pH and static conditions within 2-7 days. This was verified by visible colour changes, UV-Vis spectroscopy and FT-IR. The UV-Visible spectra of the biosynthesized cobalt and copper nanoparticles exhibited sharp narrow peaks at 341 and 342 nm. This suggested that the cobalt and copper nanoparticles were not only small but also had a narrow size distribution, a feature rarely reported in biosynthesis studies. Furthermore, our approach was conducted at room temperature using cell-free supernatant, eliminating the need for additional heating or cooling, and minimising processing thus making the process energy-efficient, cost effective and sustainable. This is a first report on the production of monodisperse cobalt and copper nanoparticles by microbes isolated from this novel extreme environment.Graphical abstract
Single-cell RNA sequencing unraveled the expression heterogeneity of hematopoietic stem and progenitor cells and lymphoid cell development dysregulation in childhood asthma
Authors: Zhu Danying , Li Guang , Yuan Lang , Zeng Zeyu , Dong Na , Wang Chao , Chen Ming , Xie Lijian , Ding Guohui , Shen Libing , Dong Xiaoyan 
Published: March 2024

AbstractAsthma is a long-term inflammatory disease affecting airways and lungs with usual onset in childhood. Its cause is not fully understood up to now. Here, using single-cell RNA sequencing, we profile peripheral blood mononuclear cells (PBMCs) from three pediatric patients with onset asthma and four age-matched healthy controls to investigate the cellular etiology of childhood asthma. The overall expression features among three asthma patients’ PBMCs demonstrate that innate immunity is commonly upregulated while adaptive immunity is commonly downregulated in childhood asthma, but each patient has different molecular phenotypes. The analyses of the expression profiles of hematopoietic stem and progenitor cells (HSPCs) further show that the HSPCs of asthma patients have heterogeneous expression backgrounds with more specific differentially expressed genes (DEGs) in each patient than common DEGs and a common feature of low S100 protein binding gene expression. S100A8, S100A9, S100A12, and RETN are universally upregulated in various cell types of asthma patients. The cell developmental trajectories in three asthma cases exhibit an abnormal immune cell development pattern compared to that in health control. The dysregulated lymphoid lineage development is observed in all 3 patients, but there is no identical abnormal pattern for each patient. The pseudo-time analyses of gene expression show that the expression dynamics of two proto-oncogenes, JUN and SPI1, and six inflammatory response related genes (S100A8, S100A9, S100A12, IL7R, IL32, CCL5) are relevant to abnormal immune cell development in asthma patients. The cell-cell communication analyses reveal the contribution of incoming annexin signal towards dendritic cells and the outgoing resistin signal from dendritic cells to asthma heterogeneity. Interestingly, the plasma blast cells of asthma patient 3 with severe symptoms exhibit dual cell identities of both plasma blast cells and T cells. Our scRNA-Seq analyses for three asthma patients reveal a complex cellular etiology for childhood asthma and provide a new research direction for the comprehensive and systematic understanding of key molecular mechanisms of childhood asthma.