bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time Kills: Impact of Socioeconomic Deprivation on Timely Access to Guideline-Concordant Treatment in Foregut Cancer
Authors: Fonseca Annabelle L , Ahmad Rida , Amin Krisha , Tripathi Manish , Vobbilisetty Vijay , Richman Joshua S , Hearld Larry , Bhatia Smita , Heslin Martin J 
Published: January 2024

BACKGROUND:
Receipt of guideline-concordant treatment (GCT) is associated with improved prognosis in foregut cancers. Studies show that patients living in areas of high neighborhood deprivation have worse healthcare outcomes; however, its effect on GCT in foregut cancers has not been evaluated. We studied the impact of the area deprivation index (ADI) as a barrier to GCT.

STUDY DESIGN:
A single-institution retrospective review of 498 foregut cancer patients (gastric, pancreatic, and hepatobiliary adenocarcinoma) from 2018 to 2022 was performed. GCT was defined based on National Comprehensive Cancer Network guidelines. ADI, a validated measure of neighborhood disadvantage was divided into terciles (low, medium, and high) with high ADI indicating the most disadvantage.

RESULTS:
Of 498 patients, 328 (66%) received GCT: 66%, 72%, and 59% in pancreatic, gastric, and hepatobiliary cancers, respectively. Median (interquartile range) time from symptoms to workup was 6 (3 to 13) weeks, from diagnosis to oncology appointment was 4 (1 to 10) weeks, and from oncology appointment to treatment was 4 (2 to 10) weeks. Forty-six percent were diagnosed in the emergency department. On multivariable analyses, age 75 years or older (odds ratio [OR] 0.39 [95% CI 0.18 to 0.87]), Black race (OR 0.52 [95% CI 0.31 to 0.86]), high ADI (OR 0.25 (95% CI 0.14 to 0.48]), 6 weeks or more from symptoms to workup (OR 0.44 [95% CI 0.27 to 0.73]), 4 weeks or more from diagnosis to oncology appointment (OR 0.76 [95% CI 0.46 to 0.93]), and 4 weeks or more from oncology appointment to treatment (OR 0.63 [95% CI 0.36 to 0.98]) were independently associated with nonreceipt of GCT.

CONCLUSIONS:
Residence in an area of high deprivation predicts nonreceipt of GCT. This is due to multiple individual- and system-level barriers. Identifying these barriers and developing effective interventions, including community outreach and collaboration, leveraging telehealth, and increasing oncologic expertise in underserved areas, may improve access to GCT.
Phenotypic characterization of cryptic species in the fungal pathogenHistoplasma
Authors: Sepúlveda Victoria E. , Rader Jonathan A. , Li Jingbaoyi (Janet) , Goldman William E. , Matute Daniel R. 
Published: January 2024

ABSTRACTHistoplasmosis is an endemic mycosis that often presents as a respiratory infection in immunocompromised patients. Hundreds of thousands of new infections are reported annually around the world. The etiological agent of the disease,Histoplasma,is a dimorphic fungus commonly found in the soil where it grows as mycelia. Humans can become infected byHistoplasmathrough inhalation of its spores (conidia) or mycelial particles. The fungi transitions into the yeast phase in the lungs at 37°C. Once in the lungs, yeast cells reside and proliferate inside alveolar macrophages. We have previously described thatHistoplasmais composed of at least five cryptic species that differ genetically, and assigned new names to the lineages. Here we evaluated multiple phenotypic characteristics of 12 strains from five phylogenetic species ofHistoplasmato identify phenotypic traits that differentiate between these species:H. capsulatum sensu stricto,H. ohiense,H. mississippiense,H. suramericanum, and an African lineage. We report diagnostic traits for two species. The other three species can be identified by a combination of traits. Our results suggest that 1) there are significant phenotypic differences among the cryptic species ofHistoplasma, and 2) that those differences can be used to positively distinguish those species in a clinical setting and for further study of the evolution of this fungal pathogen.IMPORTANCEIdentifying species boundaries is a critical component of evolutionary biology. Genome sequencing and the use of molecular markers have advanced our understanding of the evolutionary history of fungal pathogens, includingHistoplasma, and have allowed for the identification of new species. This is especially important in organisms where morphological characteristics cannot be used for this purpose. In this study, we revise the taxonomic status of the four named species of the genusHistoplasma:H. capsulatum sensu stricto,H. ohiense,H. mississippiense, andH. suramericanumand propose the use of species-specific phenotypic traits to aid their identification when genome sequencing is not available. These results have implications not only for evolutionary study ofHistoplasma, but also for clinicians, as theHistoplasmaspecies could determine the outcome of disease and treatment needed.
Substrate Specificities of DDX1: A Human DEAD-box protein
Authors: Moore Anthony F. T. , Berhie Yepeth , Weislow Isaac S. , Koculi Eda 
Published: January 2024

ABSTRACTDDX1 is a human protein which belongs to the DEAD-box protein family of enzymes and is involved in various stages of RNA metabolism from transcription to decay. Many members of the DEAD-box family of enzymes use the energy of ATP binding and hydrolysis to perform their cellular functions. On the other hand, a few members of the DEAD-box family of enzymes bind and/or hydrolyze other nucleotides in addition to ATP. Furthermore, the ATPase activity of DEAD-box family members is stimulated differently by nucleic acids of various structures. The identity of the nucleotides that the DDX1 hydrolyzes and the structure of the nucleic acids upon which it acts in the cell remain largely unknown. Identifying the DDX1 protein’sin vitrosubstrates is important for deciphering the molecular roles of DDX1 in cells. Here we identify the nucleic acid sequences and structures supporting the nucleotide hydrolysis activity of DDX1 and its nucleotide specificity. Our data demonstrate that the DDX1 protein hydrolyzes only ATP and deoxy-ATP in the presence of RNA. The ATP hydrolysis activity of DDX1 is stimulated by multiple molecules: single-stranded RNA molecules as short as ten nucleotides, a blunt-ended double-stranded RNA molecule, a hybrid of a double-stranded DNA-RNA molecule, and a single-stranded DNA molecule. Under our experimental conditions, the single-stranded DNA molecule stimulates the ATPase activity of DDX1 at a significantly reduced extent when compared to the other investigated RNA constructs or the hybrid double-stranded DNA/RNA molecule.
A CPC-shelterin-BTR axis regulates mitotic telomere deprotection
Authors: Romero-Zamora Diana , Rogers Samuel , Low Ronnie Ren Jie , Robinson Andrew B. , Page Scott G. , Lane Blake J. E. , Lamm Noa , Ishikawa Fuyuki , Hayashi Makoto T. , Cesare Anthony J. 
Published: January 2024

SUMMARYTelomeres prevent ATM activation by sequestering chromosome termini within telomere loops (t-loops). Mitotic arrest promotes telomere linearity and a localized ATM-dependent telomere DNA damage response (DDR) through an unknown mechanism. Using unbiased interactomics, biochemical screening, molecular biology, and super-resolution imaging, we found that mitotic arrest-dependent (MAD) telomere deprotection requires the combined activities of the Chromosome passenger complex (CPC) on shelterin, and the BLM-TOP3A-RMI1/2 (BTR) complex on t-loops. During mitotic arrest, the CPC component Aurora Kinase B (AURKB) phosphorylated both the TRF1 hinge and TRF2 basic domains. The former enhanced CPC and TRF1 interaction through the CPC Survivin subunit, while the latter promoted telomere linearity, telomere DDR activation dependent upon BTR double Holliday junction dissolution activity, and mitotic death. We identify that the TRF2 basic domain functions in mitosis-specific telomere protection and reveal TRF1 regulation over a physiological ATM-dependent telomere DDR. The data demonstrate that MAD telomere deprotection is a sophisticated active mechanism that exposes telomere ends to signal mitotic stress.
The glucocorticoid response element near the sphingosine-1-phopshate receptor 3 gene mitigates inflammatory processes and maladaptive behavior in females and stressed males
Authors: Corbett Brian F. , Arner Jay , Luz Sandra , Estela-Pro Valerie , Yan Jason , Osborne Brittany , Joannas Leonel , Henao-Mejia Jorge , Castro-Vildosola Jose , Hala Tamara , Bassing Craig , Harman Adele , Taylor Deanne , Bhatnagar Seema 
Published: January 2024

AbstractIt is well established that glucocorticoid receptors (GRs) bind DNA, regulate gene expression, reduce inflammatory processes, and modulate behavior. However, the precise loci bound by GRs that are necessary for these effects are not fully understood. Here, we deleted the GR binding site near the sphingosine-1-phospate receptor 3 gene using a CRISPR/Cas9 approach (S1PR3GR-/GR-rats). Defeated S1PR3GR-/GR-males displayed increased inflammatory markers and social anxiety-like behavior. Similar effects were observed in non-stressed females, indicating a greater dependence for GR-induced S1PR3 in females. Coherent neural activity between the locus coeruleus (LC) and medial prefrontal cortex (mPFC) was increased in S1PR3GR-/GR-males following 7 defeats. Chemogenetically inhibiting mPFC-projecting LC neurons during defeat increased subsequent social interaction in wild-type and S1PR3GR-/GR-males. Together, these findings demonstrate that GR-induced S1PR3 promotes resilience by mitigating stress-induced inflammatory processes and LC-mPFC coherence.One Sentence SummaryGlucocorticoid receptor-induced expression of sphingosine-1- phosphate receptor 3 reduces social anxiety-like behavior by mitigating stress-induced inflammatory processes and coherent neural activity between the locus coeruleus and medial prefrontal cortex.
Taking identity-by-descent analysis into the wild: Estimating realized relatedness in free-ranging macaques
Authors: Freudiger Annika , Jovanovic Vladimir M. , Huang Yilei , Snyder-Mackler Noah , Conrad Donald F. , Miller Brian , Montague Michael J. , Westphal Hendrikje , Stadler Peter F. , Bley Stefanie , Horvath Julie E. , Brent Lauren J. N. , Platt Michael L. , Ruiz-Lambides Angelina , Tung Jenny , Nowick Katja , Ringbauer Harald , Widdig Anja 
Published: January 2024

AbstractBiological relatedness is a key consideration in studies of behavior, population structure, and trait evolution. Except for parent-offspring dyads, pedigrees capture relatedness imperfectly. The number and length of DNA segments that are identical-by-descent (IBD) yield the most precise estimates of relatedness. Here, we leverage novel methods for estimating locus-specific IBD from low coverage whole genome resequencing data to demonstrate the feasibility and value of resolving fine-scaled gradients of relatedness in free-living animals. Using primarily 4-6× coverage data from a rhesus macaque (Macaca mulatta) population with available long-term pedigree data, we show that we can call the number and length of IBD segments across the genome with high accuracy even at 0.5× coverage. The resulting estimates demonstrate substantial variation in genetic relatedness within kin classes, leading to overlapping distributions between kin classes. They identify cryptic genetic relatives that are not represented in the pedigree and reveal elevated recombination rates in females relative to males, which allows us to discriminate maternal and paternal kin using genotype data alone. Our findings represent a breakthrough in the ability to understand the predictors and consequences of genetic relatedness in natural populations, contributing to our understanding of a fundamental component of population structure in the wild.
ER-detect: a pipeline for robust detection of early evoked responses in BIDS-iEEG electrical stimulation data
Authors: van den Boom Max A. , Gregg Nicholas M. , Valencia Gabriela Ojeda , Lundstrom Brian N. , Miller Kai J. , van Blooijs Dorien , Huiskamp Geertjan J.M. , Leijten Frans S.S. , Worrell Gregory A. , Hermes Dora 
Published: January 2024

AbstractHuman brain connectivity can be measured in different ways. Intracranial EEG (iEEG) measurements during single pulse electrical stimulation provide a unique way to assess the spread of electrical information with millisecond precision. To provide a robust workflow to process these cortico-cortical evoked potential (CCEP) data and detect early evoked responses in a fully automated and reproducible fashion, we developed Early Response (ER)-detect. ER-detect is an open-source Python package and Docker application to preprocess BIDS structured iEEG data and detect early evoked CCEP responses. ER-detect can use three response detection methods, which were validated against 14 manually annotated CCEP datasets from two different sites by four independent raters. Results showed that ER-detect’s automated detection performed on par with the inter-rater reliability (Cohen’s Kappa of ∼0.6). Moreover, ER-detect was optimized for processing large CCEP datasets, to be used in conjunction with other connectomic investigations. ER-detect provides a highly efficient standardized workflow such that iEEG-BIDS data can be processed in a consistent manner and enhance the reproducibility of CCEP based connectivity results.
Genome-wide Polygenic Risk Scores Predict Risk of Glioma and Molecular Subtypes
Authors: Nakase Taishi , Guerra Geno , Ostrom Quinn T. , Ge Tian , Melin Beatrice , Wrensch Margaret , Wiencke John K. , Jenkins Robert B. , Eckel-Passow Jeanette E. ,   Glioma International Case-Control Study (GICC), Bondy Melissa L. , Francis Stephen S. , Kachuri Linda 
Published: January 2024

ABSTRACTBackgroundPolygenic risk scores (PRS) aggregate the contribution of many risk variants to provide a personalized genetic susceptibility profile. Since sample sizes of glioma genome-wide association studies (GWAS) remain modest, there is a need to find efficient ways of capturing genetic risk factors using available germline data.MethodsWe developed a novel PRS (PRS-CS) that uses continuous shrinkage priors to model the joint effects of over 1 million polymorphisms on disease risk and compared it to an approach (PRS-CT) that selects a limited set of independent variants that reach genome-wide significance (P<5×10-8). PRS models were trained using GWAS results stratified by histological (10,346 cases, 14,687 controls) and molecular subtype (2,632 cases, 2,445 controls), and validated in two independent cohorts.ResultsPRS-CS was consistently more predictive than PRS-CT across glioma subtypes with an average increase in explained variance (R2) of 21%. Improvements were particularly pronounced for glioblastoma tumors, with PRS-CS yielding larger effect sizes (odds ratio (OR)=1.93, P=2.0×10-54vs. OR=1.83, P=9.4×10-50) and higher explained variance (R2=2.82% vs. R2=2.56%). Individuals in the 95thpercentile of the PRS-CS distribution had a 3-fold higher lifetime absolute risk ofIDHmutant (0.63%) andIDHwildtype (0.76%) glioma relative to individuals with average PRS. PRS-CS also showed high classification accuracy forIDHmutation status among cases (AUC=0.895).ConclusionsOur novel genome-wide PRS may improve the identification of high-risk individuals and help distinguish between prognostic glioma subtypes, increasing the potential clinical utility of germline genetics in glioma patient management.IMPORTANCE OF THE STUDYInherited genetic variation is one of only a few risk factors known to contribute to gliomagenesis. We leverage the largest available collection of genome-wide association studies for glioma to show that a genome-wide PRS approach that models the joint effect of correlated variants across the genome yields improved prediction of glioma risk. Our novel PRS also improves the classification of cases according toIDHmutation status. Additionally, we provide refined estimates of individual genetic susceptibility and show that risk scores in the highest percentiles of the PRS distribution confer significant increases in relative and lifetime absolute risk. Taken together, our findings provide further evidence of the potential for germline genotyping to be used as a clinical biomarker in the assessment of personalized glioma risk and the non-invasive management of patients with newly diagnosed brain tumors.
Obesity shapes selection for driver mutations in cancer
Authors: Tang Cerise , Castillon Venise Jan , Waters Michele , Fong Chris , Park Tricia , Boscenco Sonia , Kim Susie , Schultz Nikolaus , Ostrovnaya Irina , Gusev Alexander , Jee Justin , Reznik Ed 
Published: January 2024

AbstractObesity is a leading risk factor for cancer, but whether obesity is linked to specific genomic subtypes of cancer is unknown. Here, we examined the relationship between obesity and tumor genotype in two large clinicogenomic corpora. Obesity was associated with specific driver mutations in lung adenocarcinoma, endometrial carcinoma, and cancers of unknown primary, independent of clinical covariates and genetic ancestry. Obesity is therefore a putative driver of etiologic heterogeneity across cancers.
Generalizability in real-world trials
Authors: Näher Anatol-Fiete , Kopka Marvin , Balzer Felix , Schulte-Althoff Matthias 
Published: January 2024

AbstractReal-world evidence (RWE) trials have a key advantage over conventional randomized controlled trials (RCTs) due to their possibly higher external validity. This allows for better generalizability of results to larger populations, which is essential for evidence-based decision making in clinical medicine, pharmacoepidemiology, and health policy. Random sampling of RWE trial participants is regarded the gold standard for generalizability. Additionally, the use of sample correction procedures can increase the generalizability of trial results, even when using non-randomly sampled real-world data (RWD). This study presents descriptive evidence on the extent to which the design of currently planned or already conducted RWD/E trials takes sampling into account. It also examines whether random sampling or procedures for correcting non-random samples are considered. Based on text-mining of publicly available metadata provided during registrations of RWD/E trials onclinicaltrials.gov, EU-PAS, and the OSF-RWE registry, it is shown that the share of RWD/E trial registrations with information on sampling increased from 65.27% in 2002 to 97.43% in 2022, with a corresponding increase from 14.79% to 28.30% for trials with random samples. For RWD/E trials with non-random samples, there is an increase from 0.00% to 0.22% of trials in which sample correction procedures are used. We conclude that the potential benefits of RWD in terms of generalizing trial results are not yet being fully realized.
Multimorbidity in Older Adults with Depression Study (MODS) (Behavioural Activation to improve physical and mental functioning among older people with multiple long-term conditions): Protocol for a fully powered randomised controlled trial
Authors: Ryde Eloise , Hollingsworth Kelly , Littlewood Elizabeth , Atha Lucy , Bailey Della , Baker Heather , Bosanquet Katharine , Shearsmith Leanne , Chew-Graham Carolyn A. , McMillan Dean , Baird Kalpita , Coventry Peter , Crosland Suzanne , Fairhurst Caroline , Wang Han-I , Burke Lauren , Heeley Janine , Hewitt Catherine , Clegg Andrew , Gentry Tom , Hill Andrew , Lovell Karina , Dexter-Smith Sarah , Traviss-Turner Gemma , Webster Judith , Agnew Elizabeth , Stevens Heidi , Webb Katie , Gilbody Simon , Ekers David 
Published: January 2024

AbstractIntroductionOlder adults (65 years or over) and those with long-term health conditions (LTCs), represent a ‘high risk’ group for depression, with a risk two-to-three times the general population. This can lead to poorer quality of life and be costly to health and social care services. In the Multimorbidity in Older Adults with Depression Study (MODS) we will test whether a brief psychological intervention (Behavioural Activation), helps to improve physical/mental functioning in this group compared to treatment as usual.MethodsWe will conduct a two-arm, parallel-group randomised controlled trial, to evaluate the clinical and cost-effectiveness of the MODS intervention. Participants will be recruited via general practices across England. To be included, participants must be aged 65 years or over, with two or more LTCs and either sub-threshold depression or major depression. Randomisation will be simple 1:1. Intervention participants will receive up to eight sessions delivered by MODS support workers, supported by a self-help booklet. Control participants will receive usual care.A process evaluation will be undertaken to evaluate the processes and mechanisms underpinning intervention delivery, and to inform the development of an implementation framework. Semi-structured interviews will be conducted with intervention participants, participant’s caregivers/supportive others, and health and social care professionals. Focus groups and semi-structured interviews will be conducted with MODS support workers. Outcome data will be collected at four, eight, and twelve-months post-randomisation. The primary outcome is self-reported quality of life and functioning at the four-month follow up. Secondary outcomes include depression, anxiety, physical functioning, loneliness, social isolation, chronic pain, health related quality of life, and health services use.DiscussionThis study builds on our previous work and will evaluate a brief psychological intervention to improve physical and mental health functioning for older adults with multiple long-term conditions.Trial RegistrationClinicalTrials.Gov IdentifierISRCTN44184899, registered on 11thAugust 2022.
Gallein and isoniazid act synergistically to attenuateMycobacterium tuberculosisgrowth in human macrophages
Authors: Rijal Ramesh , Gomer Richard H. 
Published: January 2024

AbstractMycobacterium tuberculosis(Mtb), the bacterium that causes tuberculosis (TB), can be difficult to treat because of drug resistance. Increased intracellular polyphosphate (polyP) inMtbenhances resistance to antibiotics, and capsular polyP inNeisseria gonorrhoeaepotentiates resistance to antimicrobials. The mechanism by which bacteria utilize polyP to adapt to antimicrobial pressure is not known. In this study, we found thatMtbadapts to the TB frontline antibiotic isoniazid (INH) by enhancing the accumulation of cellular, extracellular, and cell surface polyP. Gallein, a broad-spectrum inhibitor of the polyphosphate kinase that synthesizes polyP, prevents this INH-induced increase in extracellular and cell surface polyP levels. Gallein and INH work synergistically to attenuateMtb’s ability to grow inin vitroculture and within human macrophages.Mtbwhen exposed to INH, and in the presence of INH, gallein inhibits cell envelope formation in most but not allMtbcells. Metabolomics indicated that INH or gallein have a modest impact on levels ofMtbmetabolites, but when used in combination, they significantly reduce levels of metabolites involved in cell envelope synthesis and amino acid, carbohydrate, and nucleoside metabolism, revealing a synergistic effect. These data suggest that gallein represents a promising avenue to potentiate the treatment of TB.Author summaryMycobacterium tuberculosis(Mtb) is the causative agent of tuberculosis (TB), which is responsible for more deaths than any other infectious disease. The alarming prevalence of drug-resistantMtbstrains has further exacerbated this global health crisis. Some pathogenic bacteria such asMtbappear to increase levels of polyphosphate as a defense against antibiotics. We found that gallein, a small molecule inhibitor of bacterial polyphosphate kinases, strongly potentiates the ability of the frontline anti-tuberculosis drug isoniazid to inhibit the growth ofMtbboth alone and in human macrophages. This has unveiled vulnerabilities inMtbthat could be strategically leveraged to reverse INH resistance.