bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-School Football and Midlife Brain Health Problems
Authors: Iverson Grant L. , Merz Zachary C. , Terry Douglas P. 
Published: April 2021

Objective:
To examine whether middle-aged men who played high-school football experience worse mental health or cognitive functioning than men who did not play high-school football.

Design:
Cross-sectional cohort study.

Setting:
Online survey completed remotely.

Participants:
A total of 435 men between the ages of 35 and 55 completed the study, of whom 407 were included in the analyses after excluding participants who answered embedded validity items incorrectly (n = 16), played semiprofessional football (n = 2), or experienced a recent concussion (n = 10).

Assessment of Risk Factors:
Self-reported high school football participation, compared with those who played contact sports, noncontact sports, and no sports.

Main Outcome Measures:
A lifetime history of depression or anxiety; mental health or cognitive problems in the past year; current depression symptoms, and post–concussion-like symptoms.

Results:
Middle-aged men who played high-school football did not have a higher prevalence of being prescribed medication for anxiety or depression or receiving treatment from a mental health professional. Similarly, there were no significant differences between groups on the rates in which they endorsed depression, anxiety, anger, concentration problems, memory problems, headaches, migraines, neck or back pain, or chronic pain over the past year. A greater proportion of those who played football reported sleep problems over the past year and reported being prescribed medication for chronic pain and for headaches.

Conclusions:
Men who played high-school football did not report worse brain health compared with those who played other contact sports, noncontact sports, or did not participate in sports during high school.
Usefulness of serial FIB-4 score measurement for predicting the risk of hepatocarcinogenesis after hepatitis C virus eradication
Authors: Kumada Takashi , Toyoda Hidenori , Yasuda Satoshi , Tada Toshifumi , Tanaka Junko 
Published: April 2021

Objectives
There is insufficient information to evaluate the correlation between fibrosis regression and hepatocellular carcinoma (HCC) risk after hepatitis C virus eradication. We analyzed serial changes in fibrosis (FIB)-4 scores after sustained virological response (SVR).

Methods
The subjects were 717 patients who achieved SVR by interferon (IFN)-based therapy (IFN Group) and 635 patients who achieved SVR by direct-acting antiviral (DAA) therapy (DAA Group). We performed propensity score matching because the baseline characteristics differed between the IFN and DAA groups, and then applied inverse probability weighting (IPW). We compared the changes in FIB-4 scores between the IFN and DAA groups. We also investigated the dynamics of FIB-4 scores, which are useful for predicting hepatocarcinogenesis.

Results
Using time-dependent receiver operating characteristic curve analysis and an IPW-adjusted Cox proportional hazards model, we identified an FIB-4 cutoff of 1.50 for predicting hepatocarcinogenesis. The percentages of patients in the IFN and DAA groups who demonstrated IPW-adjusted cumulative reduction and increase in FIB-4 scores indicated no significant differences. No HCC developed during the 5-year follow-up period in 547 of the 1352 patients whose FIB-4 score was <1.50 at SVR or improved from ≥1.50 to <1.50 during follow-up. Only one patient developed HCC, at 7.3 years; this individual had diabetes mellitus and excessive alcohol intake.

Conclusion
There was no difference in FIB-4 score reduction between the IFN and DAA groups. Patients whose FIB-4 scores improved to <1.50 or remained at <1.50 during follow-up after SVR had extremely low hepatocarcinogenesis rates.
Impact of pain on mental effort assessed as cardiovascular reactivity
Authors: Cancela Tamara , Silvestrini Nicolas 
Published: April 2021

Abstract

Introduction:
Pain typically impairs task performance, increases fatigue, and is associated with behavioral disengagement. Together, this suggests that pain impacts effort, defined as the mobilization of resources to carry out behavior. However, empirical evidence on this issue is lacking.

Objectives:
Drawing on motivational intensity theory, this study investigated the impact of pain on effort mobilization during cognitive task performance.

Methods:
We administered individually adjusted painful thermal stimulations during an easy memory task during which we measured effort as cardiovascular reactivity—a valid and objective measure. Control conditions included painful stimulations alone, the memory task alone, and the memory task with nonpainful heat stimulations. We expected pain to increase subjective difficulty due to additional demand on cognitive functioning, and in turn effort according to motivational intensity theory. Effort-related cardiovascular reactivity was predicted to increase along these conditions: pain-alone, task-alone, task with nonpainful stimulations, and the strongest effort when painful stimulations were administered during the task.

Results:
Overall, the findings offered support to our hypotheses. As predicted, results showed that pain increased subjective task difficulty (P = 0.020). Moreover, most of the effort-related cardiovascular measures showed the expected pattern with the strongest reactivity when painful stimulations were administered during the task compared with the other conditions (p < 0.02).

Conclusion:
These results are first evidence that pain impacts mental effort assessed as cardiovascular reactivity. We discuss how such extra effort might be related to the persistent feeling of fatigue and behavioral disengagement frequently observed in patients with chronic pain.
The impact of COVID-19 upon the delivery of exercise services within cystic fibrosis clinics in the United Kingdom
Authors: Tomlinson Owen W , Saynor Zoe L , Stevens Daniel , Urquhart Don , Williams Craig A 
Published: April 2021

ABSTRACTThe COVID-19 pandemic has resulted in unprecedent change to clinical practice. As the impact upon delivery of exercise services for people with cystic fibrosis (CF) in the UK was unknown, this was characterised via a national survey. In total, 31 CF centres participated. Principal findings included a significant reduction in exercise testing, and widespread adaptation to deliver exercise training using telehealth methods. Promisingly, 71% stated that they would continue to use virtual methods of engaging patients in future practice. This does, however, highlight a need to develop sustainable and more standardised telehealth services further to manage patients moving forwards.
A very simple model to account for the rapid rise of the British variant of SARS-CoV-2 in several countries and the world
Authors: Fort Hugo 
Published: April 2021

AbstractSince its first detection in the UK in September 2020, a highly contagious version of the coronavirus, called the British variant or B.1.1.7 SARS-CoV-2 virus lineage, is rapidly spreading across several countries and becoming the dominant strain in the outbreak.Here it is shown that a very simple evolutionary model, when including the latest available data from March 2021, can fit the observed change in frequency of B.1.1.7 for several countries, regions of countries and the whole world with a single parameter which is almost universal.
Protein-coding potential of RNAs measured by potentially translated island scores
Authors: Suenaga Yusuke , Kato Mamoru , Nagai Momoko , Nakatani Kazuma , Kogashi Hiroyuki , Kobatake Miho , Makino Takashi 
Published: April 2021

AbstractRecent studies have identified numerous RNAs that are functionally both coding and noncoding. However, the sequence characteristics that determine bifunctionality remain largely unknown. In this study, we developed and tested a potentially translated island (PTI) score, defined as the occupancy of the longest open reading frame (ORF) among all putative ORFs. We found that this score correlated with translation, including noncoding RNAs. In bacteria and archaea, coding and noncoding transcripts had narrow distributions of high and low PTI scores, respectively, whereas those of eukaryotes showed relatively broader distributions, with considerable overlap between coding and noncoding transcripts. The extent of overlap positively and negatively correlated with the mutation rates of genomes and effective population sizes of species, respectively. These overlaps were significantly increased in threatened species. In macroevolution, the appearance of the nucleus and multicellularity seem to have influenced the overlap of PTI score distributions, so that the probability of the existence of bifunctional RNAs is increased in eukaryotes. In mammalian testes, we observed an enrichment of noncoding RNAs with high PTI scores, which are candidates for bifunctional RNAs. These results suggest that the decrease in population size and the emergence of testes in eukaryotic multicellular organisms allow for the stable existence of bifunctional RNAs, consequently increasing the probability of the birth of novel coding and non-coding RNAs.
Germline testing data validate inferences of mutational status for variants detected from tumor-only sequencing
Authors: Jalloul Nahed , Gomy Israel , Stokes Samantha , Gusev Alexander , Johnson Bruce E. , Lindeman Neal I. , Macconaill Laura , Ganesan Shridar , Garber Judy E. , Khiabanian Hossein 
Published: April 2021

Structured AbstractBackgroundPathogenic germline variants (PGV) in cancer susceptibility genes are usually identified in cancer patients through germline testing of DNA from blood or saliva: their detection can impact patient treatment options and potential risk reduction strategies for relatives. PGV can also be identified, in tumor sequencing assays, often performed without matched normal specimens. It is then critical to determine whether detected variants are somatic or germline. Here, we evaluate the clinical utility of computational inference of mutational status in tumor-only sequencing compared to germline testing results.Patients and MethodsTumor-only sequencing data from 1,608 patients were retrospectively analyzed to infer germline-versus-somatic status of variants using an information-theoretic, gene-independent approach. Loss of heterozygosity (LOH) was also determined. The predicted mutational models were compared to clinical germline testing results. Statistical measures were computed to evaluate performance.ResultsTumor-only sequencing detected 3,988 variants across 70 cancer susceptibility genes for which germline testing data were available. Our analysis imputed germline-versus-somatic status for >75% of all detected variants, with a sensitivity of 65%, specificity of 88%, and overall accuracy of 86% for pathogenic variants. False omission rate was 3%, signifying minimal error in misclassifying true PGV. A higher portion of PGV in known hereditary tumor suppressors were found to be retained with LOH in the tumor specimens (72%) compared to variants of uncertain significance (58%).ConclusionsTumor-only sequencing provides sufficient power to distinguish germline and somatic variants and infer LOH. Although accurate detection of PGV from tumor-only data is possible, analyzing sequencing data in the context of specimens’ tumor cell content allows systematic exclusion of somatic variants, and suggests a balance between type 1 and 2 errors for identification of patients with candidate PGV for standard germline testing. Our approach, implemented in a user-friendly bioinformatics application, facilities objective analysis of tumor-only data in clinical settings.HighlightsMost pathogenic germline variants in cancer predisposition genes can be identified by analyzing tumor-only sequencing data.Information-theoretic gene-independent analysis of common sequencing data accurately infers germline vs. somatic status.A reasonable statistical balance can be established between sensitivity and specificity demonstrating clinical utility.Pathogenic germline variants are more often detected with loss of heterozygosity vs. germline variants of uncertain significance.
Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma
Authors: Bakouny Ziad , Sadagopan Ananthan , Ravi Praful , Metaferia Nebiyou Y. , Li Jiao , AbuHammad Shatha , Tang Stephen , Denize Thomas , Garner Emma R. , Gao Xin , Braun David A. , Hirsch Laure , Steinharter John A. , Bouchard Gabrielle , Walton Emily , West Destiny , Labaki Chris , Dudani Shaan , Gan Chun-Loo , Sethunath Vidyalakshmi , Carvalho Filipe LF. , Imamovic Alma , Ricker Cora , Vokes Natalie I. , Nyman Jackson , Park Jihye , Hirsch Michelle S. , Haq Rizwan , Lee Gwo-Shu Mary , McGregor Bradley A. , Chang Steven L. , Feldman Adam S. , Wu Catherine J. , McDermott David F. , Heng Daniel Y.C. , Signoretti Sabina , Van Allen Eliezer M. , Choueiri Toni K. , Viswanathan Srinivas R. 
Published: April 2021

ABSTRACTTranslocation renal cell carcinoma (tRCC) is an aggressive and poorly-characterized subtype of kidney cancer driven byMiT/TFEgene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 tRCC patients identified across multiple genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart fromMiT/TFEfusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to many targeted therapies. Consistently, we find that outcomes for tRCC patients treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKI) are worse than those treated with immune checkpoint inhibition (ICI). Multiparametric immunofluorescence confirmed the presence of CD8+tumor-infiltrating T cells compatible with a clinical benefit from ICI and revealed an exhaustion immunophenotype distinct from clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.
Exceptional ancient DNA preservation and fibre remains of a Sasanian saltmine sheep mummy in Chehrābād, Iran
Authors: Rossi Conor , Ruß-Popa Gabriela , Mattiangeli Valeria , McDaid Fionnuala , Hare Andrew J. , Davoudi Hossein , Laleh Haeedeh , Lorzadeh Zahra , Khazaeli Roya , Fathi Homa , Teasdale Matthew D. , A’ali Abolfazl , Stöllner Thomas , Mashkour Marjan , Daly Kevin G. 
Published: April 2021

AbstractMummified remains have long attracted interest as a potential source of ancient DNA. However, mummification is a rare process that requires an anhydrous environment to rapidly dehydrate and preserve tissue before complete decomposition occurs. We present the whole genome sequences of a ∼1600 year old naturally mummified sheep recovered from Chehrābād, a salt mine in northwestern Iran. Comparative analyses of published ancient sequences revealed remarkable DNA integrity of this mummy. Hallmarks of postmortem damage, fragmentation and hydrolytic deamination, are substantially reduced, likely due to the high-salinity of this taphonomic environment. Metagenomic analyses reflect the profound influence of high salt content on decomposition; its microbial profile is predominated by halophilic archaea and bacteria, possibly contributing to the preservation of this sample. Applying population genomic analyses we find consistent clustering of this sheep with Southwest Asian modern breeds, suggesting ancestry continuity. Genotyping of a locus influencing the woolly phenotype showed the existence of an ancestral “hairy” allele in this sheep, consistent with hair fibre imaging, further elucidating Sasanian-period animal husbandry.
CoolBox: A flexible toolkit for visual analysis of genomics data
Authors: Xu Weize , Zhong Quan , Lin Da , Li Guoliang , Cao Gang 
Published: April 2021

AbstractWe developed CoolBox, an open source toolkit for visual analysis of genomics data, which is highly compatible with the Python ecosystem, easy to use and highly customizable with a well-designed user interface. It can be used in various visualization situations like a Swiss army knife, for example, to produce high-quality genome track plots or fetch common used genomic data files with a Python script or command line, interactively explore genomic data within Jupyter environment or web browser. Moreover, owing to the highly extensible API design, users can customize their own tracks without difficulty, which can greatly facilitate analytical, comparative genomic data visualization tasks.
Does powder averaging remove dispersion bias in diffusion MRI diameter estimates within real 3D axonal architectures?
Authors: Andersson Mariam , Pizzolato Marco , Kjer Hans Martin , Skodborg Katrine Forum , Lundell Henrik , Dyrby Tim B. 
Published: April 2021

AbstractNoninvasive estimation of axon diameter with diffusion MRI holds potential to investigate the dynamic properties of the brain network and pathology of neurodegenerative diseases. Recent methods use powder averaging to account for complex white matter architectures, such as fibre crossing regions, but these have not been validated for real axonal geometries. Here, we present 120 – 313μm long segmented axons from X-ray nano-holotomography volumes of a splenium and crossing fibre region of a vervet monkey brain. We show that the axons in the complex crossing fibre region, which contains callosal, association, and corticospinal connections, are larger and exhibit a wider distribution than those of the splenium region. To accurately estimate the axon diameter in these regions, therefore, sensitivity to a wide range of diameters is required. We demonstrate how theq-value,b-value, signal-to-noise ratio and the assumed intra-axonal parallel diffusivity influence the range of measurable diameters with powder average approaches. Furthermore, we show how Gaussian distributed noise results in a wider range of measurable diameter at highb-values than Rician distributed noise, even at high signal-to-noise ratios of 100. The number of gradient directions is also shown to impose a lower bound on measurable diameter. Our results indicate that axon diameter estimation can be performed with only fewb-shells, and that additional shells do not improve the accuracy of the estimate. Through Monte Carlo simulations of diffusion, we show that powder averaging techniques succeed in providing accurate estimates of axon diameter across a range of sequence parameters and diffusion times, even in complex white matter architectures. At sufficiently lowb-values, the acquisition becomes sensitive to axonal microdispersion and the intra-axonal parallel diffusivity shows time dependency at both in vivo and ex vivo intrinsic diffusivities.
Incorporating family history of disease improves polygenic risk scores in diverse populations
Authors: Hujoel Margaux L.A. , Loh Po-Ru , Neale Benjamin M. , Price Alkes L. 
Published: April 2021

AbstractPolygenic risk scores derived from genotype data (PRS) and family history of disease (FH) both provide valuable information for predicting disease risk, enhancing prospects for clinical utility. PRS perform poorly when applied to diverse populations, but FH does not suffer this limitation. Here, we explore methods for combining both types of information (PRS-FH). We analyzed 10 complex diseases from the UK Biobank for which family history (parental and sibling history) was available for most target samples. PRS were trained using all British individuals (N=409K), and target samples consisted of unrelated non-British Europeans (N=42K), South Asians (N=7K), or Africans (N=7K). We evaluated PRS, FH, and PRS-FH using liability-scaleR2, focusing on three well-powered diseases (type 2 diabetes, hypertension, depression) withR2> 0.05 for PRS and/or FH in each target population. Averaging across these three diseases, PRS attained average predictionR2of 5.8%, 4.0%, and 0.53% in non-British Europeans, South Asians, and Africans, confirming poor cross-population transferability. In contrast, PRS-FH attained average predictionR2of 13%, 12%, and 10%, respectively, representing a large improvement in Europeans and an extremely large improvement in Africans; for each disease and each target population, the improvement was highly statistically significant. PRS-FH methods based on a logistic model and a liability threshold model performed similarly when covariates were not included in predictions (consistent with simulations), but the logistic model outperformed the liability threshold model when covariates were included. In conclusion, including family history greatly improves the accuracy of polygenic risk scores, particularly in diverse populations.
A complex CTCF binding code defines TAD boundary structure and function
Authors: Chang Li-Hsin , Ghosh Sourav , Papale Andrea , Miranda Mélanie , Piras Vincent , Degrouard Jéril , Poncelet Mallory , Lecouvreur Nathan , Bloyer Sébastien , Leforestier Amélie , Holcman David , Noordermeer Daan 
Published: April 2021

SummaryTopologically Associating Domains (TADs) compartmentalize vertebrate genomes into sub-Megabase functional neighbourhoods for gene regulation, DNA replication, recombination and repair1-10. TADs are formed by Cohesin-mediated loop extrusion, which compacts the DNA within the domain, followed by blocking of loop extrusion by the CTCF insulator protein at their boundaries11-20. CTCF blocks loop extrusion in an orientation dependent manner, with both experimental and in-silico studies assuming that a single site of static CTCF binding is sufficient to create a stable TAD boundary21-24. Here, we report that most TAD boundaries in mouse cells are modular entities where CTCF binding clusters within extended genomic intervals. Optimized ChIP-seq analysis reveals that this clustering of CTCF binding does not only occur among peaks but also frequently within those peaks. Using a newly developed multi-contact Nano-C assay, we confirm that individual CTCF binding sites additively contribute to TAD separation. This clustering of CTCF binding may counter against the dynamic DNA-binding kinetics of CTCF25-27, which urges a re-evaluation of current models for the blocking of loop extrusion21-23. Our work thus reveals an unanticipatedly complex code of CTCF binding at TAD boundaries that expands the regulatory potential for TAD structure and function and can help to explain how distant non-coding structural variation influences gene regulation, DNA replication, recombination and repair5,28-34.