tbuckley/cabot-search huggingface dataset:
Safety of ixekizumab in patients with psoriatic arthritis: data from four clinical trials with over 2000 patient-years of exposure
Authors: Atul A Deodhar, Bernard Combe, Ana P Accioly, Rebecca Bolce, Danting Zhu, Amanda M Gellett, Aubrey Trevelin Sprabery, Gerd-Rüdiger R Burmester
Journal: Annals of the Rheumatic Diseases (2022)

Objectives Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin 17A (IL-17A), has shown significant efficacy in the treatment of psoriatic arthritis (PsA) and sustained long-term clinical response without unexpected new safety outcome for an IL-17A inhibitor. Here, we report the updated safety profile of ixekizumab up to 3 years in patients with PsA. Methods This is an integrated safety analysis from four clinical trials in patients with PsA who received at least one dose of ixekizumab. Treatment-emergent adverse events (TEAEs) and selected adverse events (AEs) exposure-adjusted incidence rates (EAIRs) per 100 patient-years up to 3 years of exposure are reported. Results A total of 1401 patients with a cumulative ixekizumab exposure of 2247.7 patient-years were included in this analysis. The EAIR of patients with ≥1 TEAE was 50.3 per 100 patient-years and most TEAEs were mild to moderate in severity. Serious AEs were reported by 134 patients (EAIR=6.0). The most reported TEAEs were nasopharyngitis (EAIR=9.0) and upper respiratory tract infection (EAIR=8.3). Infections in general and injection site reactions were the most common TEAEs; the incidence rates of serious cases were low (EAIR ≤1.2). The EAIRs of malignancies (EAIR=0.7), inflammatory bowel disease (EAIR=0.1) including ulcerative colitis and Crohn’s disease, depression (EAIR=1.6), and major adverse cerebro-cardiovascular events (EAIR=0.5) were low. As assessed, based on year of exposure, incidence rates were decreasing or constant over time. Conclusions In this analysis, the overall safety profile and tolerability of ixekizumab are consistent with the known safety profile in patients with PsA. No new or unexpected safety events were detected. Trial registration number NCT01695239 , NCT02349295 , NCT02584855 , NCT03151551 .
JAX-CNV: A Whole-Genome Sequencing-Based Algorithm for Copy Number Detection at Clinical Grade Level
Authors: Wan-Ping Lee, Qihui Zhu, Xiaofei Yang, Silvia Liu, Eliza Cerveira, Mallory Ryan, Adam Mil-Homens, Lauren Bellfy, Kai Ye, Charles Lee, Chengsheng Zhang
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract We aimed to develop a whole-genome sequencing (WGS)-based copy number variant (CNV) calling algorithm with the potential of replacing chromosomal microarray assay (CMA) for clinical diagnosis. JAX-CNV is thus developed for CNV detection from WGS data. The performance of this CNV calling algorithm was evaluated in a blinded manner on 31 samples and compared to the 112 CNVs reported by clinically validated CMAs for these 31 samples. The result showed that JAX-CNV recalled 100% of these CNVs. Besides, JAX-CNV identified an average of 30 CNVs per individual, respresenting an approximately seven-fold increase compared to calls of clinically validated CMAs. Experimental validation of 24 randomly selected CNVs showed one false positive, i.e., a false discovery rate (FDR) of 4.17%. A robustness test on lower-coverage data revealed a 100% sensitivity for CNVs larger than 300 kb (the current threshold for College of American Pathologists) down to 10× coverage. For CNVs larger than 50 kb, sensitivities were 100% for coverages deeper than 20×, 97% for 15×, and 95% for 10×. We developed a WGS-based CNV pipeline, including this newly developed CNV caller JAX-CNV, and found it capable of detecting CMA-reported CNVs at a sensitivity of 100% with about a FDR of 4%. We propose that JAX-CNV could be further examined in a multi-institutional study to justify the transition of first-tier genetic testing from CMAs to WGS. JAX-CNV is available at https://github.com/TheJacksonLaboratory/JAX-CNV.
E-Cigarettes and Cardiopulmonary Health: Review for Clinicians
Authors: Evan W. Neczypor, Matthew J. Mears, Arunava Ghosh, M. Flori Sassano, Richard J. Gumina, Loren E. Wold, Robert Tarran
Journal: Circulation (2022)

Electronic cigarettes (e-cigarettes) are battery powered electronic nicotine delivery systems that use a propylene glycol/vegetable glycerin base to deliver vaporized nicotine and flavorings to the body. E-cigarettes became commercially available without evidence regarding their risks, long-term safety, or utility in smoking cessation. Recent clinical trials suggest that e-cigarette use with counseling may be effective in reducing cigarette use but not nicotine dependence. However, meta-analyses of observational studies demonstrate that e-cigarette use is not associated with smoking cessation. Cardiovascular studies reported sympathetic activation, vascular stiffening, and endothelial dysfunction, which are associated with adverse cardiovascular events. The majority of pulmonary clinical trials in e-cigarette users included standard spirometry as the primary outcome measure, reporting no change in lung function. However, studies reported increased biomarkers of pulmonary disease in e-cigarette users. These studies were conducted in adults, but >30% of high school-age adolescents reported e-cigarette use. The effects of e-cigarette use on cardiopulmonary endpoints in adolescents and young adults remain unstudied. Because of adverse clinical findings and associations between e-cigarette use and increased incidence of respiratory diseases in people who have never smoked, large longitudinal studies are needed to understand the risk profile of e-cigarettes. Consistent with the Centers for Disease Control and Prevention recommendations, clinicians should monitor the health risks of e-cigarette use, discourage nonsmokers and adolescents from using e-cigarettes, and discourage smokers from engaging in dual use without cigarette reduction or cessation.
Abstract 068: Investigation Of Familial Hypercholesterolemia Subtypes In The UK Biobank
Authors: Alexander S Berry, Laney Jones, Amy C Sturm, Samuel Gidding, Matthew T Oetjens
Journal: Circulation (2022)

Familial hypercholesterolemia (FH) is an inherited disorder characterized by lifelong elevated low density lipoprotein cholesterol (LDL-C) and dramatically increased risk for premature atherosclerotic cardiovascular disease (ASCVD). FH diagnosis currently requires either the presence of a pathogenic variant in an FH gene, or phenotypic characteristics. However, genetic studies now suggest that FH encompasses four discrete subtypes: 1) presence of a monogenic FH variant, 2) a high LDL-C polygenic score, “polygenic FH,” 3) elevated lipoprotein(a), and 4) LDL-C &gt; 190 mg/dl and a positive family history without an identifiable genetic cause, or true “phenotypic FH.” Here, we screened 134,444 unrelated white British individuals with exome sequences available in the UK Biobank for individuals with FH subtypes. We classified 358 individuals (1 in 376; 0.27%) with a pathogenic variant in their exome sequence as monogenic FH, 2,800 had polygenic FH (1 in 48; 2.1%), 2,246 had elevated lipoprotein (a) (1 in 60; 1.7%), and 3,146 had phenotypic FH (1 in 43; 2.3%). The remaining 125,894 samples without an FH subtype were classified as controls. We stratified the cohort into statin treated and untreated individuals. Those with an FH subtype were 2.8 times more likely to be prescribed a lipid lowering medication at the baseline interview compared to controls. In the statin treated group (n=21,875), those with monogenic FH were at the highest risk for 10-year incident ASCVD. We observed a 2.7 (95% confidence interval (95% CI): 1.6-4.3) fold higher ASCVD risk in monogenic FH compared to controls as measured by the hazard ratio (HR). Those with elevated lipoprotein (a) and phenotypic FH were also at increased risk for ASCVD (HR = 1.5 (95% CI: 1.1-2.1) and HR = 1.6 (95% CI: 1.3-2.1), respectively). In contrast, we do not observe elevated rates of incident ASCVD in those with polygenic FH relative to controls among treated individuals. In the untreated group (n=112,569), the risk of ASCVD in FH subtypes was more pronounced relative to controls. Individuals with elevated lipoprotein (a) were at the highest risk of incident ASCVD (HR = 2.9, 95% CI: 2.4-3.7) among the four subgroups. In conclusion, we observed differences in ASCVD risk among subtypes of FH. These findings demonstrate the importance of considering subtypes in ASCVD risk assessment for patients who present with the FH phenotype.
Abstract 12113: Deletion of Extracellular Signal-Regulated Kinases 2 Using SM22α-Cre Driver Causes Cardiac Failure and Vascular Dysfunction
Authors: Kazuki Kagami, Yusuke Yumita, Midori Iwashita, Ishinoda Yuki, Takayuki Namba, Takumi Toya, Yukinori Ikegami, Risako Yasuda, Nobuyuki Masaki, Yasuo Ido, Yuji Nagatomo, Takeshi Adachi
Journal: Circulation (2021)

Background: Extracellular signal-regulated kinases 1/2 (ERK1/2) play significant roles in proliferation, migration, and cell death. Tyrosine kinase inhibitors (TKIs) have a serious concern for cardiotoxicity and these agents target to EGFR/Ras/Raf/MEK/ERK pathway. In previous reports, SM22α-Cre drived EGFR receptor knockout mice revealed cardiac dysfunction. Hypothesis: We hypothesized if SM22α-Cre drived ERK2 contributed to the cardiac dysfunction mimicking toxicity of TKIs. Methods &amp; Results: We generated SM22α-drived ERK2 knockout mice (SM22α-EKO) by crossing SM22α-Cre mice and ERK2-flox mice. The protein expressions of ERK2 in aorta and heart were markedly lowered in SM22α-EKO, whereas similar in brain, kidney, liver, spleen, and bone marrow. SM22α-EKO displayed lower exercise tolerance and peak oxygen consumptions. Echocardiography revealed left ventricular thickness and dilatation with decreased % fraction shortening (21±4 vs. 38±2%, p=0.0002). Pathological study showed that heart weight was twice accompanied by increases in cardiomyocyte volume, stronger cardiac fibrosis, and inflammations (Figure 1). Western blot analysis showed that the phosphorylation of Akt, p-38 MAP kinase, and STAT3 were also up-regulated in SM22α-EKO with control. Phenylephrine - induced vascular contraction was increased and acetylcholine - induced relaxation was impaired in SM22α-EKO. Finally, SM22α-EKO significantly reduced life span in the Kaplan-Meier plot (Figure 2). Conclusion: SM22α-EKO mice revealed spontaneous cardiac dysfunction with the activation of multiple signaling cascades for hypertrophy and inflammation resulting in sudden death. Deletion of ERK2 in heart and smooth muscle cells also led to hypercontraction of phenylephrine / endothelial dysfunction and perivascular cardiac fibrosis and inflammation. SM22α-EKO might be a valuable model for TKI - induced cardiotoxicity.
Atypical imported loiasis characterised by recurrent anaemia in a patient from China
Authors: Xiaocheng Luo, Sha Li, Qian Li, Peiyi Zhang, Zhiyong Tao, Yunliang Shi, Xiaodong Huang, Fenghua Fang, Honghua Shao, Xiaolu Luo
Journal: The Lancet Infectious Diseases (2022)
FDG-Avid Tracheal Mass and Cartilage Involvements in ANCA-Negative Granulomatosis With Polyangiitis
Authors: Hiroki Tanaka, Makoto Hosono, Kazuna Kawabata, Goichi Kageyama, Mai Yamashita
Journal: Clinical Nuclear Medicine (2021)

Abstract A 57-year-old woman was referred for progressive dyspnea. CT showed a tracheal mass, suspicious of tracheal neoplasm. The lesion was partially resected, and nonspecific granulation tissue was observed on histology. Her symptoms and CT findings worsened. FDG PET/CT showed increased FDG accumulation in the nasal septum and left eustachian tube in addition to the tracheobronchial lesions. Although the patient was ANCA (antineutrophil cytoplasmic antibodies) negative, a differential diagnosis of granulomatosis with polyangiitis was established and confirmed pathologically. FDG PET/CT was useful for diagnosis of ANCA-negative granulomatosis with polyangiitis, in which tracheobronchial and cartilage lesions were prominent.
Ovarian cancer immunogenicity is governed by a narrow subset of progenitor tissue-resident memory T cells
Authors: Carmen M. Anadon, Xiaoqing Yu, Kay Hänggi, Subir Biswas, Ricardo A. Chaurio, Alexandra Martin, Kyle K. Payne, Gunjan Mandal, Patrick Innamarato, Carly M. Harro, Jessica A. Mine, Kimberly B. Sprenger, Carla Cortina, John J. Powers, Tara Lee Costich, Bradford A. Perez, Chandler D. Gatenbee, Sandhya Prabhakaran, Douglas Marchion, Mirjam H.M. Heemskerk, Tyler J. Curiel, Alexander R. Anderson, Robert M. Wenham, Paulo C. Rodriguez, Jose R. Conejo-Garcia
Journal: Cancer Cell (2022)

Despite repeated associations between T cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that the hallmarks of tumor recognition in ovarian cancer-infiltrating T cells are primarily restricted to tissue-resident memory (TRM) cells. Single-cell RNA/TCR/ATAC sequencing of 83,454 CD3
Accessory Thyroid Tissue Detected Using 131I SPECT/CT Imaging
Authors: Wilson Chun Tao, Owen Kang, Robert Russo, Robert Mansberg
Journal: Clinical Nuclear Medicine (2022)

Abstract Thyroid ectopia has been described as a rare congenital anomaly, characterized by the presence of a thyroid gland in locations other than the orthotopic pretracheal location. The prevalence of accessory thyroid tissue in patients undergoing postablative radioiodine therapy in a 12-month period at a tertiary hospital nuclear medicine department was assessed. Fifty-seven patients were treated between September 2020 and September 2021. Retrospective analysis identified the presence and location of all accessory thyroid tissue separate from the orthotopic pretracheal thyroid gland. Accessory thyroid tissue was present in 21.1% (12/57) of the patients. Accessory thyroid tissue was most commonly located in the lingual region.
Measurement practices exacerbate the generalizability crisis: Novel digital measures can help
Authors: Brittany I. Davidson, David A. Ellis, Clemens Stachl, Paul J. Taylor, Adam N. Joinson
Journal: Behavioral and Brain Sciences (2022)

Abstract Psychology's tendency to focus on confirmatory analyses before ensuring constructs are clearly defined and accurately measured is exacerbating the generalizability crisis. Our growing use of digital behaviors as predictors has revealed the fragility of subjective measures and the latent constructs they scaffold. However, new technologies can provide opportunities to improve conceptualizations, theories, and measurement practices.
Perspectives on the use of modelling and economic analysis to guide HIV programmes in sub-Saharan Africa
Authors: Paul Revill, Ajay Rangaraj, Albert Makochekanwa, Amon Mpofu, Andrea L. Ciaranello, Andreas Jahn, Andrew Gonani, Andrew N. Phillips, Anna Bershteyn, Benson Zwizwai, Brooke E. Nichols, Carel Pretorius, Cliff C. Kerr, Cindy Carlson, Debra Ten Brink, Edinah Mudimu, Edward Kataika, Erik Lamontagne, Fern Terris-Prestholt, Frances M. Cowan, Gerald Manthalu, Gemma Oberth, Gesine Mayer-Rath, Iris Semini, Isaac Taramusi, Jeffrey W. Eaton, Jinjou Zhao, John Stover, Jose A Izazola-Licea, Katherine Kripke, Leigh Johnson, Loveleen Bansi-Matharu, Marelize Gorgons, Michelle Morrison, Newton Chagoma, Owen Mugurungi, Robyn M. Stuart, Rowan Martin-Hughes, Rose Nyirenda, Ruanne V. Barnabas, Sakshi Mohan, Sherrie L. Kelly, Sibusiso Sibandze, Simon Walker, Stephen Banda, R. Scott Braithwaite, Thato Chidarikire, Timothy B. Hallett, Thoko Kalua, Tsitsi Apollo, Valentina Cambiano
Journal: The Lancet HIV (2022)
Colorectal cancer incidence, mortality, tumour characteristics, and treatment before and after introduction of the faecal immunochemical testing-based screening programme in the Netherlands: a population-based study
Authors: Emilie C H Breekveldt, Iris Lansdorp-Vogelaar, Esther Toes-Zoutendijk, Manon C W Spaander, Anneke J van Vuuren, Folkert J van Kemenade, Christian R B Ramakers, Evelien Dekker, Iris D Nagtegaal, Myrtle F Krul, Niels F M Kok, Koert F D Kuhlmann, Geraldine R Vink, Monique E van Leerdam, Marloes A G Elferink, Jeroen van Bergeijk, Tjerk Wiersma, Wilhelmina van Grevenstein, Marieke Frasa, Linda van Gestel, Gerrit Meijer
Journal: The Lancet. Gastroenterology & hepatology (2021)
Abstract P013: Associations Between Diastolic Blood Pressure With Cognitive Functioning: Differences By Systolic Blood Pressure Among US Adults.
Authors: Alvin Matthew, Lauren Nahodyl, Robert A Mesa, Julien Tremblay, Tatjana Rundek, Adina Zeki Al Hazzouri, Tali Elfassy
Journal: Circulation (2022)

Introduction: While elevated systolic blood pressure (BP) is a known contributor to cognitive decline, the role of elevated diastolic BP (DBP) as an independent risk factor for cognitive decline is less clear, especially in relationship to systolic BP (SBP) levels. Objectives: To characterize the association between DBP and cognitive functioning at differing levels of SBP. Methods: The National Health and Nutrition Examination Survey is a nationally representative survey of U.S. adults conducted annually. Our sample included data from participants of the 1999-2002 and 2011-2014 cycles, age 60+, with measured BP and cognition (N=5,480). BP was measured three times manually with a standardized sphygmomanometer and averaged. Cognitive functioning was measured using the digit symbol substitution test (DSST), a measure of executive functioning (with higher scores indicating better performance: range 0-100). We tested for a statistical interaction between SBP and DBP. To determine whether DBP was associated with DSST score, we used linear regression analyses and stratified by categories of SBP. Models were adjusted for: age, sex, race, education, income, insurance, marital status, BMI, diabetes, BP medication, and cholesterol. All analyses accounted for the complex survey design. Results: Almost half (48.9%, SE=1.1) of the sample was aged 60-69 with 55.3% (SE=0.7) female. The association between DBP and cognitive functioning differed by SBP (p&lt;0.01), leading to stratified analyses. Every 5 mmHg increment of DBP was associated with significantly higher DSST scores among individuals with SBP 110-119 mmHg only (beta: 0.76, 95% CI: 0.24, 1.27). Results were not significant among participants with SBP &lt; 110mmHg (beta: 0.84, 95% CI: -0.09, 1.77), SBP 120-129 mmHg (beta: 0.09, 95% CI:-0.49, 0.69), SBP 130-140 mmHg (beta: 0.29, 95% CI: -0.10, 0.69), SBP 140-159 mmHg (beta: 0.23, 95% CI: -0.15, 0.61), or SBP ≥160mmHg (beta: -0.08, 95% CI: -0.56, 0.39). Conclusion: In a population-based sample of older US adults, higher DBP was associated with greater executive functioning only among individuals with normal SBP. The results suggest that at non-hypertensive levels of SBP, higher DBP may not be detrimental for cognitive performance.
The relevance of organelle interactions in cellular senescence
Authors: Jiewu Huang, Ping Meng, Cheng Wang, Yunfang Zhang, Lili Zhou
Journal: Theranostics (2022)

Organelles are tiny structures with specific functions in eukaryotic cells. Since they are covered with membranes, different organelles can perform biological processes that are incompatible. Organelles can also actively communicate with each other to maintain cellular homeostasis via the vesicular trafficking pathways and membrane contact sites (MCSs), which allow the exchange of metabolites and other information required for normal cellular physiology. An imbalance in organelle interactions may result in multiple pathological processes. Growing evidence shows that abnormal organelle communication contributes to cellular senescence and is associated with organ aging. However, the key role of organelle interactions in aging has not yet been broadly reviewed and fully investigated. In this review, we summarize the role of organelle interactions in cellular senescence, and highlight their relevance for cellular calcium homeostasis, protein and lipid homeostasis, and mitochondrial quality control. Our review reveals important mechanisms of organelle interactions in cellular senescence and provides important clues for intervention strategies from a new perspective.
Relevant Outcomes in Superficial Venous Ablation Treatments
Authors: Peter Henke
Journal: JAMA Surgery (2022)

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<i>deCS</i>: A Tool for Systematic Cell Type Annotations of Single-Cell RNA Sequencing Data Among Human Tissues
Authors: Guangsheng Pei, Fangfang Yan, Lukas M. Simon, Yulin Dai, Peilin Jia, Zhongming Zhao
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract Single-cell RNA sequencing (scRNA-seq) is revolutionizing the study of complex and dynamic cellular mechanisms. However, cell type annotation remains a main challenge as it largely relies on a priori knowledge and manual curation, which is cumbersome and subjective. The increasing number of scRNA-seq datasets, as well as numerous published genetic studies, has motivated us to build a comprehensive human cell type reference atlas. Here, we present decoding Cell type Specificity (deCS), an automatic cell type annotation method augmented by a comprehensive collection of human cell type expression profiles and marker genes. We used deCS to annotate scRNA-seq data from various tissue types and systematically evaluated the annotation accuracy under different conditions, including reference panels, sequencing depth, and feature selection strategies. Our results demonstrate that expanding the references is critical for improving annotation accuracy. Compared to many existing state-of-the-art annotation tools, deCS significantly reduced computation time and increased accuracy. deCS can be integrated into the standard scRNA-seq analytical pipeline to enhance cell type annotation. Finally, we demonstrated the broad utility of deCS to identify trait–cell type associations in 51 human complex traits, providing deep insights into the cellular mechanisms underlying disease pathogenesis. All documents for deCS, including source code, user manual, demo data, and tutorials, are freely available at https://github.com/bsml320/deCS.