tbuckley/cabot-search huggingface dataset:
Cross‐reactive carbohydrate determinant‐specific IgE obscures true atopy and exhibits ⍺‐1,3‐fucose epitope‐specific inverse associations with asthma
Authors: Gyaviira Nkurunungi, Harriet Mpairwe, Serge A. Versteeg, Angela van Diepen, Jacent Nassuuna, Joyce Kabagenyi, Irene Nambuya, Richard E. Sanya, Margaret Nampijja, Sonia Serna, Niels‐Christian Reichardt, Cornelis H. Hokke, Emily L. Webb, Ronald van Ree, Maria Yazdanbakhsh, Alison M. Elliott
Journal: Allergy (2020)

In high-income, temperate countries, IgE to allergen extracts is a risk factor for, and mediator of, allergy-related diseases (ARDs). In the tropics, positive IgE tests are also prevalent, but rarely associated with ARD. Instead, IgE responses to ubiquitous cross-reactive carbohydrate determinants (CCDs) on plant, insect and parasite glycoproteins, rather than to established major allergens, are dominant. Because anti-CCD IgE has limited clinical relevance, it may impact ARD phenotyping and assessment of contribution of atopy to ARD.Using an allergen extract-based test, a glycan and an allergen (glyco)protein microarray, we mapped IgE fine specificity among Ugandan rural Schistosoma mansoni (Sm)-endemic communities, proximate urban communities, and importantly in asthmatic and nonasthmatic schoolchildren.Overall, IgE sensitization to extracts was highly prevalent (43%-73%) but allergen arrays indicated that this was not attributable to established major allergenic components of the extracts (0%-36%); instead, over 40% of all participants recognized CCD-bearing components. Using glycan arrays, we dissected IgE responses to specific glycan moieties and found that reactivity to classical CCD epitopes (core β-1,2-xylose, α-1,3-fucose) was positively associated with sensitization to extracts, rural environment and Sm infection, but not with skin reactivity to extracts or sensitization to their major allergenic components. Interestingly, we discovered that reactivity to only a subset of core α-1,3-fucose-carrying N-glycans was inversely associated with asthma.CCD reactivity is not just an epiphenomenon of parasite exposure hampering specificity of allergy diagnostics; mechanistic studies should investigate whether specific CCD moieties identified here are implicated in the protective effect of certain environmental exposures against asthma.
Long-term efficacy and safety of canakinumab in patients with colchicine-resistant familial Mediterranean fever: results from the randomised phase III CLUSTER trial
Authors: Seza Ozen, Eldad Ben-Cherit, Ivan Foeldvari, Gil Amarilyo, Huri Ozdogan, Steven Vanderschueren, Katherine Marzan, J Michelle Kahlenberg, Elise Dekker, Fabrizio De Benedetti, Isabelle Koné-Paut
Journal: Annals of the Rheumatic Diseases (2020)

<h3>Objectives</h3> To evaluate the long-term efficacy and safety of canakinumab to treat patients with colchicine-resistant familial Mediterranean fever (crFMF) during Epoch 4 (weeks 41 to 113) of the CLUSTER study. <h3>Methods</h3> Patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks during a 72-week period. We evaluated disease activity every 8 weeks using the physician global assessment (PGA) of disease activity, counting the number of flares, and measuring concentrations of C reactive protein (CRP) and serum amyloid A (SAA). Safety was studied by determination and classification of observed adverse events (AEs). We analysed safety and efficacy separately in two subgroups of patients receiving a cumulative dose of less than 2700 mg, or equal or more than 2700 mg. <h3>Results</h3> Of the 61 patients that started the CLUSTER study, 60 entered Epoch 4 and 57 completed it. During the 72-week period, 35/60 (58.3%) patients experienced no flares, and 23/60 (38.3%) had one flare, as compared with a median of 17.5 flares per year reported at baseline. PGA scores indicated no disease activity for the majority of patients throughout the study. Median CRP concentrations were always lower than 10 mg/L, while median SAA concentrations remained over the limit of normal (10 mg/L) but under the 30 mg/L threshold. No new or unexpected AEs were reported. <h3>Conclusion</h3> crFMF patients treated with canakinumab during 72 weeks experienced a minimal incidence of flares and good control of clinical disease activity, with no new safety concerns reported.
Luminal microbiota related to Crohn’s disease recurrence after surgery
Authors: Amy L. Hamilton, Michael A. Kamm, Peter De Cruz, Emily K. Wright, Hai Feng, Josef Wagner, Joseph J. Y. Sung, Carl D. Kirkwood, Michael Inouye, Shu-Mei Teo
Journal: Gut Microbes (2020)

Microbial factors are likely to be involved in the recurrence of Crohn's disease (CD) after bowel resection. We investigated the luminal microbiota before and longitudinally after surgery, in relation to disease recurrence, using 16S metagenomic techniques.In the prospective Post-Operative Crohn's Endoscopic Recurrence (POCER) study, fecal samples were obtained before surgery and 6, 12, and 18 months after surgery from 130 CD patients. Endoscopy was undertaken to detect disease recurrence, defined as Rutgeerts score ≥i2, at 6 months in two-thirds of patients and all patients at 18 months after surgery. The V2 region of the 16S rRNA gene was sequenced using Illumina MiSeq. Cluster analysis was performed at family level, assessing microbiome community differences between patients with and without recurrence.Six microbial cluster groups were identified. The cluster associated with maintenance of remission was enriched for the Lachnospiraceae family [adjusted OR 0.47 (0.27-0.82), P = .007]. The OTU diversity of Lachnospiraceae within this cluster was significantly greater than in all other clusters. The cluster enriched for Enterobacteriaceae was associated with an increased risk of disease recurrence [adjusted OR 6.35 (1.24-32.44), P = .026]. OTU diversity of Enterobacteriaceae within this cluster was significantly greater than in other clusters.Luminal bacterial communities are associated with protection from, and the occurrence of, Crohn's disease recurrence after surgery. Recurrence may relate to a higher abundance of facultatively anaerobic pathobionts from the Enterobacteriaceae family. The ecologic change of depleted Lachnospiraceae, a genus of butyrate-producing bacteria, may permit expansion of Enterobacteriaceae through luminal environmental perturbation.
Abstract A17: Pan-solid tumor comparison of variant detection in paired liquid and tissue biopsies
Authors: Zoe June F. Assaf, Smruthy Sivakumar, Dexter X. Jin, Sophia L. Maund, Svetlana Lyalina, Guneet Walia, Ethan S. Sokol, Sally E. Trabucco
Journal: Clinical Cancer Research (2020)

Abstract Comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) provides an opportunity to noninvasively monitor a patient’s tumor burden via liquid biopsy. Liquid biopsies can assess a patient’s mutational landscape through time and provide information on treatment response and relapse. It has become increasingly common to have paired genomic data analysis between liquid and tissue biopsies from the same patient. However, the impact of clinical, temporal, and biologic factors on percentage of positive agreement (PPA) of variant detection between these biopsies is unclear. For our study, we leveraged two databases containing CGP data from paired liquid and tissue biopsy specimens tested by Foundation Medicine (FMI): the FMI database (&amp;gt;1700 paired samples) and the Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB). The CGDB is a subset of the FMI database linked with the Flatiron Health nationwide de-identified EHR-derived database, which includes demographic, treatment, and clinical outcomes information (&amp;gt;500 paired samples). We report pan-solid tumor and per-indication prevalence and PPA for variants commonly assayed in both liquid and tissue tests. We found that PPA depended on the tumor DNA concentration in plasma and tissue biopsies, as well as the amount of time between tests. We also investigated the effect of treatments administered in the time between liquid and tissue tests on the detected variants and observed some well-described resistance alterations at a higher frequency in liquid samples, including a higher prevalence of ESR1 point mutations in breast cancer, more EGFR T790M alterations in lung cancer, and frequent KRAS Q61H alterations in colorectal cancer. Liquid biopsies can also contain DNA shed from multiple metastatic sites. We observed evidence of this in the form of polyclonal resistance alterations, which may also account for differences in PPA over time. Our findings indicate that while PPA is generally high between samples, it may be influenced by factors such as intervening therapies, resistance, therapy efficacy, and polyclonality of liquid samples. Citation Format: Zoe June F. Assaf, Smruthy Sivakumar, Dexter X. Jin, Sophia L. Maund, Svetlana Lyalina, Guneet Walia, Ethan S. Sokol, Sally E. Trabucco. Pan-solid tumor comparison of variant detection in paired liquid and tissue biopsies [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A17.
Case 21-2020: A 66-Year-Old Homeless Man with Covid-19
Authors: Jessie M. Gaeta, Denise De Las Nueces, David G. Munson, Joshua A. Barocas, Kathleen E. Walsh
Journal: New England Journal of Medicine (2020)

A Homeless Man with Covid-19 A 66-year-old homeless man was evaluated for cough and rhinorrhea during the Covid-19 pandemic. He had tested positive for SARS-CoV-2 through a universal testing progra...
Effect of Intraoperative Dexamethasone on Major Complications and Mortality Among Infants Undergoing Cardiac Surgery
Authors: Vladimir Lomivorotov, Igor Kornilov, Vladimir Boboshko, Vladimir Shmyrev, Ilya Bondarenko, Ilya Soynov, Alexey Voytov, Stanislav Polyanskih, Oleg Strunin, Alexander Bogachev-Prokophiev, Giovanni Landoni, Caetano Nigro Neto, Gretel Oliveira Nicolau, Leonardo Saurith Izquierdo, Vinícius Nogueira Nascimento, Zhang Wen, Hu Renjie, Zhang Haibo, Vladlen Bazylev, Mikhail Evdokimov, Shahrijar Sulejmanov, Aleksei Chernogrivov, Dmitry Ponomarev
Journal: JAMA (2020)

Corticosteroids are widely used in pediatric cardiac surgery to blunt systemic inflammatory response and to reduce complications; nevertheless, their clinical efficacy is uncertain.To determine whether intraoperative administration of dexamethasone is more effective than placebo for reducing major complications and mortality during pediatric cardiac surgery.The Intraoperative Dexamethasone in Pediatric Cardiac Surgery was an investigator-initiated, double-blind, multicenter randomized trial that involved 4 centers in China, Brazil, and Russia. A total of 394 infants younger than 12 months, undergoing cardiac surgery with cardiopulmonary bypass were enrolled from December 2015 to October 2018, with follow-up completed in November 2018.The dexamethasone group (n = 194) received 1 mg/kg of dexamethasone; the control group (n = 200) received an equivolume of 0.9% sodium chloride intravenously after anesthesia induction.The primary end point was a composite of death, nonfatal myocardial infarction, need for extracorporeal membrane oxygenation, need for cardiopulmonary resuscitation, acute kidney injury, prolonged mechanical ventilation, or neurological complications within 30 days after surgery. There were 17 secondary end points, including the individual components of the primary end point, and duration of mechanical ventilation, inotropic index, intensive care unit stay, readmission to intensive care unit, and length of hospitalization.All of the 394 patients randomized (median age, 6 months; 47.2% boys) completed the trial. The primary end point occurred in 74 patients (38.1%) in the dexamethasone group vs 91 patients (45.5%) in the control group (absolute risk reduction, 7.4%; 95% CI, -0.8% to 15.3%; hazard ratio, 0.82; 95% CI, 0.60 to 1.10; P = .20). Of the 17 prespecified secondary end points, none showed a statistically significant difference between groups. Infections occurred in 4 patients (2.0%) in the dexamethasone group vs 3 patients (1.5%) in the control group.Among infants younger than 12 months undergoing cardiac surgery with cardiopulmonary bypass, intraoperative administration of dexamethasone, compared with placebo, did not significantly reduce major complications and mortality at 30 days. However, the study may have been underpowered to detect a clinically important difference.ClinicalTrials.gov Identifier: NCT02615262.
Response to: ‘Confunding by indication and ethnicity difference? Comment on ‘Hypersensitivity reactions with allopurinol and febuxostat: a study using the Medicare claims data’’ by Hsu<i>et al</i>
Authors: Jasvinder A Singh
Journal: Annals of the Rheumatic Diseases (2020)

Hypersensitivity reactions with allopurinol versus febuxostat in the US elderly.Response to: 'Confunding by indication and ethnicity difference?Comment on 'Hypersensitivity reactions with allopurinol and febuxostat: a study using the Medicare claims data'' by Hsu et alWe appreciate the comments by Drs Wei and Hsu 1 on our recently published study on hypersensitivity reactions (HSRs) with allopurinol versus febuxostat. 2 Drs Wei and Hsu bring up an important point of confounding by indication in all observational studies including those focused on pharmacovigilance.We agree that this potential bias applies to all observational studies of HSRs with allopurinol performed to date and to those that will be done in the future.By using a propensity-matched analysis, we tried to minimise the bias due to confounding by indication.Despite having similar populations and key characteristics for allopurinol-exposed versus febuxostat-exposed populations in propensity-matched analysis (the main study analysis), some residual confounding is still possible.We acknowledged this in the study limitations section.Differences in country settings and study populations, which might also reflect differences in HLA-B*5801 allele frequencies, also underlie differences in our study findings in those from the previous studies, another limitation discussed previously.Finally, we regret the first decimal error in the abstract for crude HSR incidence rates; the correct values are presented in the tables, results and appendices.All of these values including those in the abstract when rounded off to the nearest digit per 1000 provide the same number of people experiencing HSR.
Abstract A18: Plasma circulating tumor DNA is scarce and confounded by clonal hematopoiesis in metastatic renal cell carcinoma
Authors: Jack V. W. Bacon, Matti Annala, Maryam Soleimani, Jean-Michel Lavoie, Alan I. So, Martin E. Gleave, Ladan Fazli, Kim N. Chi, Christian K. Kollmannsberger, Alexander W. Wyatt, Lucia Nappi
Journal: Clinical Cancer Research (2020)

Despite the recent implementation of novel targeted therapies, the 5-year survival rate for metastatic renal cell carcinoma (mRCC) remains dismal. Prognostic and predictive biomarkers are urgently required to avoid unnecessary patient morbidity and financial toxicity. Exploratory studies leveraging archival primary tumor tissue are considered suboptimal in this setting due to the considerable heterogeneity of metastatic lesions. Circulating tumor DNA (ctDNA) permits the noninvasive characterization of metastatic cancers using a simple blood draw. In this study, we sought to establish the utility of a ctDNA-based assay as a tool to profile the somatic genome of patients with mRCC. We collected whole blood from 55 progressing mRCC patients. All patients were systemic therapy naïve at the time of sample collection. Plasma cell-free DNA (cfDNA) and matched leukocyte DNA were subjected to targeted sequencing across 981 cancer-associated genes. Matched tumor tissue from 14 patients was also analyzed. The median cfDNA sequencing depth for this cohort was 938x. 33% of patients had evidence for RCC-derived ctDNA above 1% of total cfDNA; this was significantly lower than prostate or bladder cancer patients analyzed using the same approach. Among ctDNA-positive patients, ctDNA fraction averaged only 3.9% and showed no association with clinical variables or cfDNA yield. In these patients, the most commonly mutated genes were VHL, BAP1, and PBRM1, and matched tissue concordance was 77%. Evidence of somatic expansions unrelated to RCC, such as clonal hematopoiesis of indeterminate potential (CHIP), was detected in 43% of patients. Pathogenic germline mutations in DNA repair genes were detected in 11% of patients. Patients with ctDNA above 1% had shorter overall survival and progression-free survival on first-line therapy. Patients with evidence of CHIP but not ctDNA had an intermediate prognosis compared to ctDNA-positive and ctDNA-negative patients. CfDNA sequencing enables characterization of the somatic RCC genome in only a minority of metastatic RCC patients. Due to low ctDNA abundance and presence of non-RCC derived somatic clones in circulation, cfDNA sequencing may not be a simple pan-patient alternative to tissue biopsy in metastatic RCC.Citation Format: Jack V. W. Bacon, Matti Annala, Maryam Soleimani, Jean-Michel Lavoie, Alan I. So, Martin E. Gleave, Ladan Fazli, Kim N. Chi, Christian K. Kollmannsberger, Alexander W. Wyatt, Lucia Nappi. Plasma circulating tumor DNA is scarce and confounded by clonal hematopoiesis in metastatic renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A18.
Change in Traffic Fatality Rates in the First 4 States to Legalize Recreational Marijuana
Authors: Russell S. Kamer, Stephen Warshafsky, Gordon C. Kamer
Journal: JAMA Internal Medicine (2020)

Julian Santaella-Tenorio, DrPH; Katherine Wheeler-Martin, MPH; Charles J. DiMaggio, PhD; Alvaro Castillo-Carniglia, PhD; Katherine M. Keyes, PhD; Deborah Hasin, PhD, PhD; Magdalena Cerdá, DrPH
Reduction in Osteoarthritis Risk After Treatment With Ticagrelor Compared to Clopidogrel: A Propensity Score–Matching Analysis
Authors: Matthew C. Baker, Yingjie Weng, William H. Robinson, Neera Ahuja, Nidhi Rohatgi
Journal: Arthritis & Rheumatology (2020)

Osteoarthritis (OA) is a common cause of joint pain and disability, and effective treatments are lacking. Extracellular adenosine has antiinflammatory effects and can prevent and treat OA in animal models. Ticagrelor and clopidogrel are both used in patients with coronary artery disease, but only ticagrelor increases extracellular adenosine levels. This study was undertaken to determine whether treatment with ticagrelor was associated with a lower risk of OA.We conducted a 1:2 propensity score-matching analysis using data from 2011-2017 in the Optum Clinformatics Data Mart. Patients who had received either ticagrelor or clopidogrel for ≥90 days were included in our study, and patients with a prior diagnosis of OA or inflammatory arthritis were excluded. OA was identified using International Classification of Diseases codes. The primary outcome was the time to diagnosis of OA after treatment with ticagrelor versus clopidogrel.Our propensity score-matched cohort consisted of 7,007 ticagrelor-treated patients and 14,014 clopidogrel-treated patients, with a median number of days receiving treatment of 287 and 284, respectively. For both groups, the mean age was 64 years, and 73% of the patients were male. Multivariate Cox regression analysis estimated a hazard ratio for developing OA of 0.71 (95% confidence interval 0.64-0.79) (P < 0.001) after treatment with ticagrelor compared to clopidogrel.Treatment with ticagrelor was associated with a 29% lower risk of developing OA compared to treatment with clopidogrel over 5 years of follow-up. We hypothesize that the reduction in OA seen in patients who received ticagrelor may in part be due to increased extracellular adenosine levels.
Genomewide Association Study of Severe Covid-19 with Respiratory Failure
Authors: David Ellinghaus, Frauke Degenhardt, Luis Bujanda, Maria Buti, Agustín Albillos, Pietro Invernizzi, Javier Fernández, Daniele Prati, Guido Baselli, Rosanna Asselta, Marit M Grimsrud, Chiara Milani, Fátima Aziz, Jan Kässens, Sandra May, Mareike Wendorff, Lars Wienbrandt, Florian Uellendahl-Werth, Tenghao Zheng, Xiaoli Yi, Raúl de Pablo, Adolfo G Chercoles, Adriana Palom, Alba-Estela Garcia-Fernandez, Francisco Rodriguez-Frias, Alberto Zanella, Alessandra Bandera, Alessandro Protti, Alessio Aghemo, Ana Lleo, Andrea Biondi, Andrea Caballero-Garralda, Andrea Gori, Anja Tanck, Anna Carreras Nolla, Anna Latiano, Anna Ludovica Fracanzani, Anna Peschuck, Antonio Julià, Antonio Pesenti, Antonio Voza, David Jiménez, Beatriz Mateos, Beatriz Nafria Jimenez, Carmen Quereda, Cinzia Paccapelo, Christoph Gassner, Claudio Angelini, Cristina Cea, Aurora Solier, David Pestaña, Eduardo Muñiz-Diaz, Elena Sandoval, Elvezia M Paraboschi, Enrique Navas, Félix García Sánchez, Ferruccio Ceriotti, Filippo Martinelli-Boneschi, Flora Peyvandi, Francesco Blasi, Luis Téllez, Albert Blanco-Grau, Georg Hemmrich-Stanisak, Giacomo Grasselli, Giorgio Costantino, Giulia Cardamone, Giuseppe Foti, Serena Aneli, Hayato Kurihara, Hesham ElAbd, Ilaria My, Iván Galván-Femenia, Javier Martín, Jeanette Erdmann, Jose Ferrusquía-Acosta, Koldo Garcia-Etxebarria, Laura Izquierdo-Sanchez, Laura R Bettini, Lauro Sumoy, Leonardo Terranova, Leticia Moreira, Luigi Santoro, Luigia Scudeller, Francisco Mesonero, Luisa Roade, Malte C Rühlemann, Marco Schaefer, Maria Carrabba, Mar Riveiro-Barciela, Maria E Figuera Basso, Maria G Valsecchi, María Hernandez-Tejero, Marialbert Acosta-Herrera, Mariella D'Angiò, Marina Baldini, Marina Cazzaniga, Martin Schulzky, Maurizio Cecconi, Michael Wittig, Michele Ciccarelli, Miguel Rodríguez-Gandía, Monica Bocciolone, Monica Miozzo, Nicola Montano, Nicole Braun, Nicoletta Sacchi, Nilda Martínez, Onur Özer, Orazio Palmieri, Paola Faverio, Paoletta Preatoni, Paolo Bonfanti, Paolo Omodei, Paolo Tentorio, Pedro Castro, Pedro M Rodrigues, Aaron Blandino Ortiz, Rafael de Cid, Ricard Ferrer, Roberta Gualtierotti, Rosa Nieto, Siegfried Goerg, Salvatore Badalamenti, Sara Marsal, Giuseppe Matullo, Serena Pelusi, Simonas Juzenas, Stefano Aliberti, Valter Monzani, Victor Moreno, Tanja Wesse, Tobias L Lenz, Tomas Pumarola, Valeria Rimoldi, Silvano Bosari, Wolfgang Albrecht, Wolfgang Peter, Manuel Romero-Gómez, Mauro D'Amato, Stefano Duga, Jesus M Banales, Johannes R Hov, Trine Folseraas, Luca Valenti, Andre Franke, Tom H Karlsen
Journal: New England Journal of Medicine (2020)

There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19.
The minimal clinically important difference of the Severe Respiratory Insufficiency questionnaire in severe COPD
Authors: Tim Raveling, Janine Kort, Gerrie Bladder, Wolfram Windisch, Peter J. Wijkstra, Marieke L. Duiverman
Journal: European Respiratory Journal (2020)

<b>The SRI is frequently used to measure quality of life in severe COPD patients treated with NIV, but its MCID is unknown. This paper shows MCID estimates between 4.5–6.2, so that we suggest an increase of approximately 5 points is clinically relevant.</b>https://bit.ly/3e0M7MT