tbuckley/cabot-search huggingface dataset:
Association of Sputum Neutrophil Extracellular Trap Subsets With IgA Anti–Citrullinated Protein Antibodies in Subjects at Risk for Rheumatoid Arthritis
Authors: Yuko Okamoto, Stephanie Devoe, Nickie Seto, Valerie Minarchick, Timothy Wilson, Heather M. Rothfuss, Michael P. Mohning, Jaron Arbet, Miranda Kroehl, Ashley Visser, Justin August, Stacey M. Thomas, Laura Lenis Charry, Chelsie Fleischer, Marie L. Feser, Ashley A. Frazer‐Abel, Jill M. Norris, Brian D. Cherrington, William J. Janssen, Mariana J. Kaplan, Kevin D. Deane, V. Michael Holers, M. Kristen Demoruelle
Journal: Arthritis & Rheumatology (2021)

Objective Mechanisms leading to anti–citrullinated protein antibody (ACPA) generation in rheumatoid arthritis (RA) are hypothesized to originate in the lung. We undertook this study to understand associations between neutrophil extracellular trap (NET) formation in the lung and local ACPA generation in subjects at risk of developing RA. Methods Induced sputum was collected from 49 subjects at risk of developing RA, 12 patients with RA, and 18 controls. Sputum neutrophils were tested for ex vivo NET formation, and sputum‐induced NET formation of control neutrophils was measured using immunofluorescence imaging. Sputum macrophages were tested for ex vivo endocytosis of apoptotic and opsonized cells. Levels of ACPA, NET remnants, and inflammatory proteins were quantified in sputum supernatant. Results Spontaneous citrullinated histone H3 (Cit‐H3)–expressing NET formation was higher in sputum neutrophils from at‐risk subjects and RA patients compared to controls (median 12%, 22%, and 0%, respectively; P &lt; 0.01). In at‐risk subjects, sputum IgA ACPA correlated with the percentage of neutrophils that underwent Cit‐H3+ NET formation (r = 0.49, P = 0.002) and levels of Cit‐H3+ NET remnants (r = 0.70, P &lt; 0.001). Reduced endocytic capacity of sputum macrophages was found in at‐risk subjects and RA patients compared to controls. Using a mediation model, we found that sputum inflammatory proteins were associated with sputum IgA ACPA through a pathway mediated by Cit‐H3+ NET remnants. Sputum‐induced Cit‐H3+ NET formation also correlated with sputum levels of interleukin‐1β (IL‐1β), IL‐6, and tumor necrosis factor in at‐risk subjects, suggesting a causal relationship. Conclusion These data support a potential mechanism for mucosal ACPA generation in subjects at risk of developing RA, whereby inflammation leads to increased citrullinated protein–expressing NETs that promote local ACPA generation.
t(3;16)(q27;p11)におけるBCL6のパートナーでありびまん性大細胞型B細胞リンパ腫において反復的に観察されるインターロイキン21受容体に対する遺伝子
Authors: Ueda C, Akasaka T, Ohno H, Uchiyama T
Journal: Blood (2001)
Covid-19: Delta infections threaten herd immunity vaccine strategy
Authors: Owen Dyer
Journal: BMJ (2021)

Covid-19: Delta infections threaten herd immunity vaccine strategy Owen DyerEpidemiologists are adjusting their expectations for the future course of the pandemic after data from a recent outbreak in Massachusetts in the US suggest that while vaccination remains highly protective against the worst consequences of infection, it may not be sufficient on its own to stop the spread of the delta variant.
1 Prospective associations of aerobic fitness and lipoprotein subclasses in a cohort of norwegian schoolchildren: the active smarter kids (ASK) study
Authors: PR Jones, T Rajalahti, GK Resaland, E Aadland, J Steene-Johannessen, SA Anderssen, TF Bathen, T Andreassen, OM Kvalheim, U Ekelund
Journal: British Journal of Sports Medicine (2021)

Aim Aerobic fitness is associated with cardiometabolic risk factors in children. Associations with traditional measures of lipid metabolism are uncertain. We investigated whether higher levels of fitness benefit lipid metabolism by exploring cross-sectional and prospective associations between aerobic fitness and a comprehensive lipoprotein profile. Methods We used targeted proton nuclear magnetic resonance ( 1 H NMR) spectroscopy to profile 29 measures of lipoprotein metabolism for 811 fifth-grade Norwegian schoolchildren (50.1% girls; mean age 10.2 years). Serum samples were taken on two occasions across the academic year. Aerobic fitness was measured at baseline using the Andersen aerobic fitness test. We used multiple linear regression adjusted for potential confounders to examine both cross-sectional and prospective — adjusted for baseline lipoprotein measure — associations between aerobic fitness and lipoprotein profiles. Results Higher levels of aerobic fitness were associated with all measures of lipoprotein metabolism in the cross-sectional analysis. There were inverse associations with the apolipoprotein B-containing (apo B) lipoprotein subclasses, including cholesterol and triglyceride concentration. The associations between aerobic fitness and the concentration of high-density lipoprotein (HDL) particles were divergent between larger and smaller subclasses. In the prospective analysis, the inverse associations between aerobic fitness and the measures of larger apo B-containing lipoprotein subclasses persisted as did all but one of the associations with triglyceride concentrations. Additional adjustment for adiposity attenuated most associations in both cross-sectional and prospective models, but an independent effect of fitness remained for certain measures. Conclusions Higher levels of aerobic fitness are associated with a favourable lipoprotein profile, partly independent of adiposity. Associations tended to be stronger and more consistent over time for the larger apo B-containing lipoprotein measures and those of triglyceride concentration. Our results suggest that improving children’s fitness levels should have beneficial effects on lipoprotein metabolism, though a concomitant reduction in adiposity would likely be more effective. References Anderssen SA, Cooper AR, Riddoch C, Sardinha LB, Harro M, Brage S, et al . Low cardiorespiratory fitness is a strong predictor for clustering of cardiovascular disease risk factors in children independent of country, age and sex. Eur J Cardiovasc Prev Rehabil 2007. Mintjens S, Menting MD, Daams JG, van Poppel MNM, Roseboom TJ, Gemke RJBJ. Cardiorespiratory fitness in childhood and adolescence affects future cardiovascular risk factors: a systematic review of longitudinal studies. Sports Med 2018 Nov 1; 48 (11):2577–605.
27313 The effect of the COVID-19 pandemic on patients’ perceptions of teledermatology
Authors: Sophia Ly, Caroline Porter, Steven R. Feldman
Journal: Journal of the American Academy of Dermatology (2021)

Background: As the COVID-19 pandemic has prompted dermatologists to greater use telemedicine, there are limited data on how COVID-19 has changed patient's perceptions of teledermatology. Objectives: To assess the COVID-19 pandemic's impact on people's willingness to use teledermatology and to investigate influencing factors. Methods: A total of 544 participants were surveyed via Amazon Mechanical Turk. A 5-point Likert scale was used to measure willingness to use teledermatology before, during, and after the COVID-19 pandemic. The survey evaluated participants' perceived importance of various features of teledermatology. Results: Of the 183 participants who were unwilling to use teledermatology prior to the COVID-19 pandemic, the majority increased their Likert score to neutral, slightly willing, or strongly willing for teledermatology usage during the pandemic (79.2%) and for future postpandemic use (66.5%). The two most important factors for participants were social distancing and avoiding in-person visits. The top reason for disinterest in teledermatology was concern for security and privacy (24.4%). Over half of participants (51.4%) were more likely to use teledermatology if stricter privacy regulations were enforced. A positive correlation exists between willingness to use teledermatology after the pandemic and importance rating of insurance coverage for telemedicine (P ˂ .00001). Limitations: Survey distribution was limited to Amazon Mechanical Turk users, who may be more technologically adept than average patient populations. The survey excluded non-English-speakers and individuals without internet access. Conclusions: The COVID-19 pandemic has increased the public's willingness to use teledermatology. Addressing concerns, such as insurance coverage and stricter privacy regulations, may boost patient utilization of teledermatology.
ハイブリッド損失のあるPatch-of-Interest-FuseNetを用いた3D超音波における効率的でロバストな機器セグメンテーション【JST・京大機械翻訳】
Authors: Yang Hongxu, Shan Caifeng, Bouwman Arthur, F Kolen Alexander
Journal: Medical Image Analysis (2021)
Recent trends of NFκB decoy oligodeoxynucleotide-based nanotherapeutics in lung diseases
Authors: Meenu Mehta, Keshav Raj Paudel, Shakti Dhar Shukla, Venkata Sita Rama Raju Allam, Vinod Kumar Kannaujiya, Nisha Panth, Amlan Das, Vipan Kumar Parihar, Amlan Chakraborty, Md Khadem Ali, Niraj Kumar Jha, Dikaia Xenaki, Qian Peter Su, Peter Richard Wich, Jon Adams, Philip Michael Hansbro, Dinesh Kumar Chellappan, Brian Gregory George Oliver, Kamal Dua
Journal: Journal of Controlled Release (2021)
<i>atg7</i> -Based Autophagy Activation Reverses Doxorubicin-Induced Cardiotoxicity
Authors: Yong Wang, Xiaoguang Lu, Xiaoping Wang, Qi Qiu, Ping Zhu, Lin Ma, Xiao Ma, Joerg Herrmann, Xueying Lin, Wei Wang, Xiaolei Xu
Journal: Circulation Research (2021)

[Figure: see text].
Polygenic Risk Scores Derived From Varying Definitions of Depression and Risk of Depression
Authors: Brittany L. Mitchell, Jackson G. Thorp, Yeda Wu, Adrian I. Campos, Dale R. Nyholt, Scott D. Gordon, David C. Whiteman, Catherine M. Olsen, Ian B. Hickie, Nicholas G. Martin, Sarah E. Medland, Naomi R. Wray, Enda M. Byrne
Journal: JAMA Psychiatry (2021)

Genetic studies with broad definitions of depression may not capture genetic risk specific to major depressive disorder (MDD), raising questions about how depression should be operationalized in future genetic studies.To use a large, well-phenotyped single study of MDD to investigate how different definitions of depression used in genetic studies are associated with estimation of MDD and phenotypes of MDD, using polygenic risk scores (PRSs).In this case-control polygenic risk score analysis, patients meeting diagnostic criteria for a diagnosis of MDD were drawn from the Australian Genetics of Depression Study, a cross-sectional, population-based study of depression, and controls and patients with self-reported depression were drawn from QSkin, a population-based cohort study. Data analyzed herein were collected before September 2018, and data analysis was conducted from September 10, 2020, to January 27, 2021.Polygenic risk scores generated from genome-wide association studies using different definitions of depression were evaluated for estimation of MDD in and within individuals with MDD for an association with age at onset, adverse childhood experiences, comorbid psychiatric and somatic disorders, and current physical and mental health.Participants included 12 106 (71% female; mean age, 42.3 years; range, 18-88 years) patients meeting criteria for MDD and 12 621 (55% female; mean age, 60.9 years; range, 43-87 years) control participants with no history of psychiatric disorders. The effect size of the PRS was proportional to the discovery sample size, with the largest study having the largest effect size with the odds ratio for MDD (1.75; 95% CI, 1.73-1.77) per SD of PRS and the PRS derived from ICD-10 codes documented in hospitalization records in a population health cohort having the lowest odds ratio (1.14; 95% CI, 1.12-1.16). When accounting for differences in sample size, the PRS from a genome-wide association study of patients meeting diagnostic criteria for MDD and control participants was the best estimator of MDD, but not in those with self-reported depression, and associations with higher odds ratios with childhood adverse experiences and measures of somatic distress.These findings suggest that increasing sample sizes, regardless of the depth of phenotyping, may be most informative for estimating risk of depression. The next generation of genome-wide association studies should, like the Australian Genetics of Depression Study, have both large sample sizes and extensive phenotyping to capture genetic risk factors for MDD not identified by other definitions of depression.
Heterogeneity of immune cells in human atherosclerosis revealed by scRNA-Seq
Authors: Jenifer Vallejo, Clément Cochain, Alma Zernecke, Klaus Ley
Journal: Cardiovascular Research (2021)

Immune cells in atherosclerosis include T, B, natural killer (NK) and NKT cells, macrophages, monocytes, dendritic cells (DCs), neutrophils, and mast cells. Advances in single-cell RNA sequencing (sRNA-Seq) have refined our understanding of immune cell subsets. Four recent studies have used scRNA-Seq of immune cells in human atherosclerotic lesions and peripheral blood mononuclear cells (PBMCs), some including cell surface phenotypes revealed by oligonucleotide-tagged antibodies, which confirmed known and identified new immune cell subsets and identified genes significantly up-regulated in PBMCs from HIV+ subjects with atherosclerosis compared to PBMCs from matched HIV+ subjects without atherosclerosis. The ability of scRNA-Seq to identify cell types is greatly augmented by adding cell surface phenotype using antibody sequencing. In this review, we summarize the latest data obtained by scRNA-Seq on plaques and human PBMCs in human subjects with atherosclerosis.
Comparison between non-pulmonary and pulmonary immune responses in a HIV decedent who succumbed to COVID-19
Authors: Denise Goh, Justina Nadia Lee, Tracy Tien, Jeffrey Chun Tatt Lim, Sherlly Lim, An Sen Tan, Jin Liu, Benedict Tan, Joe Yeong
Journal: Gut (2021)

<h3>Abstract</h3> Fast mapping of sequencing reads to taxonomic clades is a crucial step in metagenomics, which however raises computational challenges as the numbers of reads and of taxonomic clades increases. Besides alignment-based methods, which are accurate but computational costly, faster compositional approaches have recently been proposed to predict the taxonomic clade of a read based on the set of <i>k</i>-mers it contains. Machine learning-based compositional approaches, in particular, have recently reached accuracies similar to alignment-based models, while being considerably faster. It has been observed that the accuracy of these models increases with the length <i>k</i> of the <i>k</i>-mers they use, however existing methods are limited to handle <i>k</i>-mers of lengths up to <i>k</i> = 12 or 13 because of their large memory footprint needed to store the model coefficients for each possible <i>k</i>-mer. In order to explore the performance of machine learning-based compositional approaches for longer <i>k</i>-mers than currently possible, we propose to reduce the memory footprint of these methods by binning together <i>k</i>-mers that appear together in the sequencing reads used to train the models. We achieve this binning by learning a vector embedding for the vertices of a compacted de Bruijn graph, allowing us to embed any DNA sequence in a low-dimensional vector space where a machine learning system can be trained. The resulting method, which we call Brume, allows us to train compositional machine learning-based models with <i>k</i>-mers of length up to <i>k</i> = 31. We show on two metagenomics benchmark that Brume reaches better performance than previously achieved, thanks to the use of longer <i>k</i>-mers.
Dalpiciclib versus placebo plus fulvestrant in HR+/HER2- advanced breast cancer that relapsed or progressed on previous endocrine therapy (DAWNA-1): A multicenter, randomized, phase 3 study.
Authors: Binghe Xu, Qingyuan Zhang, Pin Zhang, Xichun Hu, Wei Li, Zhongsheng Tong, Tao Sun, Yuee Teng, Xinhong Wu, Quchang Ouyang, Xi Yan, Jing Cheng, Qiang Liu, Jifeng Feng, Xiaojia Wang, Xiaoyu Zhu, Fei Wu, Xiao Zhang, Jianjun Zou
Journal: Journal of Clinical Oncology (2021)

1002 Background: Dalpiciclib (SHR6390), a novel CDK4/6 inhibitor, as monotherapy has demonstrated tolerability and preliminary antitumor activity in pretreated HR+/HER2− advanced breast cancer (ABC). Here we evaluated dalpiciclib with fulvestrant in ABC. Methods: In this randomized, double-blind, phase 3 trial, patients (pts) with HR+/HER2− locally advanced or metastatic breast cancer who had relapsed or progressed on previous endocrine therapy were enrolled. Eligible pts were randomized 2:1 to receive dalpiciclib (dalp; 150 mg po qd, d1-21, q4w) or placebo (PBO) with fulvestrant (fulv; 500 mg im, cycle 1 d1, d15, then d1 q4w). The primary endpoint was investigator (INV)-assessed PFS. As of Nov. 15, 2020, 162 (71.4% of total projected) events of disease progression or death had occurred and a preplanned interim analysis was done. The corresponding superiority boundary was 1-sided P = 0.0080 (Lan-DeMets [O’Brien-Fleming] boundary). Results: Overall, 361 pts were randomized to receive dalp-fulv (n = 241) or PBO-fulv (n = 120). With a median follow-up of 10.5 mo, dalp-fulv significantly improved INV-assessed PFS versus PBO-fulv (median, 15.7 [95% CI 11.1-NR] vs 7.2 [95% CI 5.6-9.2] mo; HR, 0.42 [95% CI 0.31-0.58]; P &lt; 0.0001). PFS per IRC were consistent with INV assessment (Table). The benefit of dalpiciclib extended beyond initial study treatment based on time to first subsequent chemotherapy (TFSCT; HR, 0.47 [95% CI 0.32-0.69]; P &lt; 0.0001). OS data were not mature with a total of 25 deaths documented. Median duration of exposure was 9.4 (IQR, 4.3-11.4) mo with dalpiciclib and 9.9 (4.7-11.9) mo with fulvestrant in the dalp-fulv group and was 6.1 (3.7-11.0) mo with fulvestrant in the PBO-fulv group. The most common (incidence ≥3%) grade 3 or 4 AEs with dalp-fulv were neutropenia (84.2%; vs 0% with PBO-fulv) and leukopenia (62.1%; vs 0%). Treatment discontinuation due to AE was reported for 2.5% of pts with dalp-fulv vs 3.3% with PBO-fulv. The incidence of SAE was 5.8% with dalp-fulv vs 6.7% with PBO-fulv. Conclusions: The study met its primary endpoint, demonstrating that dalpiciclib plus fulvestrant significantly improved PFS versus placebo plus fulvestrant, with a manageable safety profile. Our findings support dalpiciclib plus fulvestrant as a new treatment option in pts with HR+/HER2- ABC who relapsed or progressed on endocrine therapy. Clinical trial information: NCT03927456 .[Table: see text]
26452 Impact of COVID-19 on patient willingness to seek in-person dermatologic care
Authors: Rima I. Ghamrawi, Esther A. Balogh, Matthew L. Hrin, Quan Pham, Jacob J. Subash, William W. Huang, Steven R. Feldman
Journal: Journal of the American Academy of Dermatology (2021)

The coronavirus-19 (COVID) pandemic has hindered health care provider operations, and its impact on patient willingness to seek in-person dermatologic care lacks extensive study. Understanding how a pandemic may influence patient motivation to consult a dermatologist may facilitate efficient allocation of health care provider resources both during and after COVID. Participants (n = 416) were recruited through Amazon Mechanical Turk, a web-based survey platform. Subjects were randomized to one of fourteen groups, each entailing a pre-COVID or during-COVID hypothetical scenario of a socially stigmatized skin condition: scalp psoriasis, herpes labialis, acne vulgaris, rosacea, tinea faciei, melanoma, or a benign nevus. Subjects rated their willingness to schedule an in-person dermatology appointment on a 5-point Likert scale (ie, willingness score). Sociodemographic data were collected. Herpes labialis, tinea faciei, and melanoma prompted higher willingness scores during COVID (3.94; 4.03; 3.54) compared with pre-COVID (3.81; 4.0; 3.32); scalp psoriasis, acne vulgaris, rosacea, and benign nevi prompted lower willingness scores during COVID (3.33; 2.88; 3.67; 3.07) compared with pre-COVID (3.93; 3.19; 4.21; 3.7). The benign nevus group displayed the largest decrease in willingness scores from pre-COVID (3.7) to during COVID (3.07). Patients reported higher willingness to seek in-person evaluation for conditions associated with stronger social stigmas, such as scalp psoriasis and herpes labialis, during COVID. We did not control for subject familiarity with each skin condition, and perceived degree of disfigurement was not measured. Patient willingness to seek treatment during COVID may be changing rapidly and, at this time, does not appear to be largely affected by the pandemic.
Genome-wide sequencing as a first-tier screening test for short tandem repeat expansions
Authors: Indhu-Shree Rajan-Babu, Junran J. Peng, Readman Chiu, Patricia Birch, Madeline Couse, Colleen Guimond, Anna Lehman, Jill Mwenifumbo, Clara van Karnebeek, Jan Friedman, Shelin Adam, Christele Du Souich, Alison Elliott, Anna Lehman, Jill Mwenifumbo, Tanya Nelson, Clara van Karnebeek, Jan Friedman, Chenkai Li, Arezoo Mohajeri, Egor Dolzhenko, Michael A. Eberle, Inanc Birol, Jan M. Friedman
Journal: Genome Medicine (2021)

Abstract Background Screening for short tandem repeat (STR) expansions in next-generation sequencing data can enable diagnosis, optimal clinical management/treatment, and accurate genetic counseling of patients with repeat expansion disorders. We aimed to develop an efficient computational workflow for reliable detection of STR expansions in next-generation sequencing data and demonstrate its clinical utility. Methods We characterized the performance of eight STR analysis methods (lobSTR, HipSTR, RepeatSeq, ExpansionHunter, TREDPARSE, GangSTR, STRetch, and exSTRa) on next-generation sequencing datasets of samples with known disease-causing full-mutation STR expansions and genomes simulated to harbor repeat expansions at selected loci and optimized their sensitivity. We then used a machine learning decision tree classifier to identify an optimal combination of methods for full-mutation detection. In Burrows-Wheeler Aligner (BWA)-aligned genomes, the ensemble approach of using ExpansionHunter, STRetch, and exSTRa performed the best (precision = 82%, recall = 100%, F1-score = 90%). We applied this pipeline to screen 301 families of children with suspected genetic disorders. Results We identified 10 individuals with full-mutations in the AR , ATXN1 , ATXN8 , DMPK , FXN , or HTT disease STR locus in the analyzed families. Additional candidates identified in our analysis include two probands with borderline ATXN2 expansions between the established repeat size range for reduced-penetrance and full-penetrance full-mutation and seven individuals with FMR1 CGG repeats in the intermediate/premutation repeat size range. In 67 probands with a prior negative clinical PCR test for the FMR1 , FXN , or DMPK disease STR locus, or the spinocerebellar ataxia disease STR panel, our pipeline did not falsely identify aberrant expansion. We performed clinical PCR tests on seven (out of 10) full-mutation samples identified by our pipeline and confirmed the expansion status in all, showing absolute concordance between our bioinformatics and molecular findings. Conclusions We have successfully demonstrated the application of a well-optimized bioinformatics pipeline that promotes the utility of genome-wide sequencing as a first-tier screening test to detect expansions of known disease STRs. Interrogating clinical next-generation sequencing data for pathogenic STR expansions using our ensemble pipeline can improve diagnostic yield and enhance clinical outcomes for patients with repeat expansion disorders.