tbuckley/cabot-search huggingface dataset:
John Rupert Allen Chawner
Authors: Neville Hodges, Sally Watson
Journal: BMJ (2020)

Having trained in London, Nottingham and Liverpool, John Rupert Allen Chawner was appointed consultant obstetrician and gynaecologist to St David’s Hospital, Bangor, in 1972, drawn to north Wales by his love of climbing and sailing. He had taken up medicine only after completing his national service as Trooper Chawner in the Royal Tank Regiment.

He was a very skilled obstetrician and surgeon with a deserved reputation for competence among all his colleagues and referring general practitioners. He had a calm, even temperament and combined clinical abilities with considerable personal charm and empathy for his patients. To this day, many patients recall his care with gratitude for kindness and attention as well as the successful obstetric outcome. He had a clear logical brain for problem solution and was a good teacher of his craft, inspiring generations of admiring juniors and midwives

John believed strongly in the NHS and the centrality of the leadership role of the consultant in delivering its aims. The changes proposed in the early years of …
The Promises and Challenges of Tumor Mutation Burden as an Immunotherapy Biomarker: A Perspective from the International Association for the Study of Lung Cancer Pathology Committee
Authors: Lynette M. Sholl, Fred R. Hirsch, David Hwang, Johan Botling, Fernando Lopez-Rios, Lukas Bubendorf, Mari Mino-Kenudson, Anja C. Roden, Mary Beth Beasley, Alain Borczuk, Elisabeth Brambilla, Gang Chen, Teh-Ying Chou, Jin-Haeng Chung, Wendy A. Cooper, Sanja Dacic, Sylvie Lantuejoul, Deepali Jain, Dongmei Lin, Yuko Minami, Andre Moreira, Andrew G. Nicholson, Masayuki Noguchi, Mauro Papotti, Giuseppe Pelosi, Claudia Poleri, Natasha Rekhtman, Ming-Sound Tsao, Erik Thunnissen, William Travis, Yasushi Yatabe, Akihiko Yoshida, Jillian B. Daigneault, Ahmet Zehir, Solange Peters, Ignacio I. Wistuba, Keith M. Kerr, John W. Longshore
Journal: Journal of Thoracic Oncology (2020)
European genetic ancestry associated with risk of childhood ependymoma
Authors: Chenan Zhang, Quinn T Ostrom, Helen M Hansen, Julio Gonzalez-Maya, Donglei Hu, Elad Ziv, Libby Morimoto, Adam J de Smith, Ivo S Muskens, Cassie N Kline, Zalman Vaksman, Hakon Hakonarson, Sharon J Diskin, Carol Kruchko, Jill S Barnholtz-Sloan, Vijay Ramaswamy, Francis Ali-Osman, Melissa L Bondy, Michael D Taylor, Catherine Metayer, Joseph L Wiemels, Kyle M Walsh
Journal: Neuro-Oncology (2020)

Abstract Background Ependymoma is a histologically defined central nervous system tumor most commonly occurring in childhood. Population-level incidence differences by race/ethnicity are observed, with individuals of European ancestry at highest risk. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk in US populations. Methods In a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among recently admixed Hispanic and African American subjects and estimated European admixture among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local ancestry. We also evaluated race/ethnicity-stratified ependymoma incidence data from the Central Brain Tumor Registry of the United States (CBTRUS). Results CBTRUS data revealed that African American and Native American children have 33% and 36%, respectively, reduced incidence of ependymoma compared with non-Hispanic whites. In genetic analyses, a 20% increase in European ancestry was associated with a 1.31-fold higher odds of ependymoma among self-reported Hispanics and African Americans (95% CI: 1.08–1.59, Pmeta = 6.7 × 10−3). Additionally, eastern European ancestral substructure was associated with increased ependymoma risk in non-Hispanic whites (P = 0.030) and in Hispanics (P = 0.043). Admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and targeted fine-mapping identified a lead variant at rs6039499 near RSPO4 (odds ratio = 1.99; 95% CI: 1.45–2.73; P = 2.2 × 10−5) but which was not validated in an independent set of posterior fossa type A patients. Conclusions Interethnic differences in ependymoma risk are recapitulated in the genomic ancestry of ependymoma patients, implicating regions to target in future association studies.
Abstract 81: A retrospective analysis of 274 cases of Kawasaki disease
Authors: Kenjiro Goto
Journal: Circulation (2015)

Purpose: Haematological, biochemical and clinical parameters were retrospectively analysed in a group of patients with Kawasaki disease, to determine predictive variables on the effect of intravenous immunoglobulin (IVIG) therapy. Methods: We studied 274 cases of Kawasaki disease between October 2006 and September 2013 at a single centre (Kawasaki Municipal Tama Hospital, Japan). These cases were analysed on the basis of: (1) Requirement of additional therapy post IVIG (41 cases vs 200 cases not requiring additional therapy) (2) Presence of coronary artery lesions (CAL: Z score≧2.5) within a month (15 cases with CAL, 220 cases without CAL) Haematological, biochemical and clinical parameters including white blood cell, percentage of neutrophils, platelet, total-bilirubin, AST, ALT, Albumin, Sodium, C-reaction protein, Fibrinogen and D-dimmer as well as time to first post-IVIG treatment were compared in the categories shown above. Statistical analysis was performed with Mann-Whitney U test. Differences were considered to be significant when the two-tailed p-value was &lt; 0.05. Results: The percentage of neutrophils, total-bilirubin, AST, ALT, Albumin, Sodium, C-reaction protein, D-dimmer and time to first treatment show significant difference between the groups stratified on the requirement of post-IVIG therapy. In the stratification based on acute CAL- AST, ALT, Albumin and Sodium show significant difference between the groups. Conclusion: We suggest that ratio of neutrophil, total-bilirubin, AST, ALT, Albumin, Sodium, C-reaction protein, D-dimmer and time to first treatment are predictive factors of resistance to single IVIG therapy. Similarly, levels of AST, ALT, Albumin and Sodium are predictive factors of acute coronary artery lesions in Kawasaki disease.
An ELISA for PDGFR phosphorylation: Comparison of effects of STI571 on cellular Bcr-Abl, c-Kit and PDGFR-β protein kinases
Authors: Paul W. Manley, Juergen Mestan, Thomas Meyer, Doriano Fabbro
Journal: Cancer Research (2004)

1500  The platelet derived growth factor (PDGF) family comprises of isoforms A-D, which form disulfide-linked homo- and hetero-dimers: PDGF-AA, -BB, -AB, -CC and -DD. These proteins signal through the trans-membrane receptor tyrosine kinases PDGFR-α and PDGFR-β. Binding of two surface receptors to a PDGF-dimer, results in receptor dimerization and autophosphorylation of the intracellular tyrosine kinase domains. These phosphorylated domains provide binding sites for substrates, which are in turn phosphorylated to initiate an intracellular signaling cascade, leading to cell proliferation. PDGFR-α recognizes PDGF A, B and C while PDGFR-β only recognizes B and D. Therefore, homodimers of PDGFR-α bind PDGF-AA, -AB, -BB or -CC, while PDGFR-β homodimers bind PDGF-BB and -DD. PDGFR heterodimers (α/β) can be activated by PDGF-AB, -BB and -CC. As well as being involved in angiogenesis, PDGF signaling regulates the growth of fibroblasts, smooth muscle cells and glial cells. Aberrant PDGF signaling is implicated in fibrotic conditions, atherosclerosis and human malignancies, including melanomas, gliomas and prostate cancer. Mouse fibroblast A31 cells express PDGFR-α and PDGFR-β. A capture ELISA has been developed to measure PDGF-BB stimulated PDGFR auto-phosphorylation in A31 cell lysates, enabling the evaluation of drug effects on the kinase activity of the receptor. The assay format was optimized to allow for growth, treatment and lysis of cells in a 96-well tissue culture plate, followed by the transfer of the lysates to ELISA plates precoated with a rabbit polyclonal antibody (Upstate 06-495) specific for both PDGFR-α and PDGFR-β. The phosphorylation of the captured PDGFR protein was quantified using a phosphotyrosine specific Ab (PY20), directly labeled with alkaline phosphatase (AP) and a chemiluminescent AP-substrate. From a library of kinase inhibitors, the inhibition of PDGFR autophosphorylation was highly correlated with their anti-proliferative activity. The selectivity of protein kinase inhibitors is usually assessed through their effects on the phosphorylation of artificial substrates catalyzed by the recombinant kinase domains of these enzymes. Such inhibitory profiles can significantly differ to profiles obtained with full-length enzymes in cells. STI571 (Imatinib; Gleevec™) is an established inhibitor of the Bcr-Abl, c-Kit and PDGFR kinases. In cellular assays STI571 inhibits PDGFR, c-Kit and Bcr-Abl with IC50 values of 73 ± 12 nM (n = 10; A31 cells), 90 ± 10 nM (n = 7; GIST882 cells; Mestan et al. Blood 2003) and 191 ± 10 nM (n = 7; 32-D Bcr-Abl cells), whereas it inhibits the catalytic activity of recombinant PDGFR, Kit and Abl with IC50 values of 869 ± 117 nM (n = 12; [ATP] 1.0 μM), 579 ± 92 nM (n = 11; [ATP] 1.0 μM) and 170 ± 23 nM (n = 21; [ATP] 5.0 μM). Thus the kinase selectivity profile of STI571 markedly differs in cellular assays compared to that obtained using recombinant kinases.
The potential impact of COVID-19-related disruption on tuberculosis burden
Authors: C. Finn McQuaid, Nicky McCreesh, Jonathan M. Read, Tom Sumner, Rein M.G.J. Houben, Richard G. White, Rebecca C. Harris
Journal: European Respiratory Journal (2020)

<b>Any benefit of social distancing on TB deaths is likely to be outweighed by health service disruption. As such, it is crucially important to maintain and strengthen TB-related health services during, and after, the COVID-19 pandemic.</b>https://bit.ly/30aWZnp
THU0223 THE NEUROPSYCHIATRIC PHENOTYPE OF NZB/W LUPUS-PRONE MOUSE MODEL AT PRE-NEPHRITIC AND NEPHRITIC STAGES OF THE DISEASE: MURINE MODEL RECAPITULATES HUMAN DISEASE
Authors: D. Nikolopoulos, A. Polissidis, K. Karali, D. Boumpas
Journal: Annals of the Rheumatic Diseases (2020)

Background: The pathogenesis of neuropsychiatric lupus (NPSLE) remains ill-defined due to limited access to tissue and the diversity and complexity of clinical manifestations with most evidence deriving from animal studies in MLR/lpr lupus-prone mouse. Objectives: To phenotype and characterize the neuropsychiatric disease in New Zealand Black/White (NZΒ/W) F1 strain; a spontaneous lupus prone mouse which is characterized by systemic autoimmunity. Methods: Mice were tested in a comprehensive behavioral test battery to assess possible effects on general depressive-like disorders, anxiety, cognitive function and motor performance/coordination. The following tests were conducted in the same order for all subjects (All females, NZB/W strain n=13 and C57BL/6 n=14) at 3 and 6 months of age: Open field, Novel object recognition (NOR), Novel object location (NOL), Elevated plus maze (EPM), Rotarod, Tail suspension test (TST), Prepulse inhibition (PPI), and Sucrose preference test (SPT). For comparisons, statistical significance was indicated as a two-sided P&lt;0.05. Results: NZB/W mice at 3 months and 6 months of age exhibit depressive-like disorder as assessed by SPT and TST (P &lt;0.05 and &lt;0.0001, respectively). Anxiety-like phenotype was evident in lupus-prone mice at both time points based on EPM test (Graph 1). Open-field test revealed decreased locomotor activity and rotarod (Graph 2) showed impaired motor coordination in 3 month-old and 6 month-old NZB/W mice (P&lt;0.001 and &lt;0.01, respectively). NZB/W mice exhibit cognitive dysfunction at 3 and 6 months of age based on NOR test (P&lt;0.05). No differences in cognitive function was observed between the two groups (P=0.11). Prepulse inhibition test revealed decreased sensorimotor gating in 3 month-old NZB/W mice, a difference not reaching statistical significance (P=.078). It was not possible to interpret correctly the PPI at second time point (6 months of age) due to age-related hearing loss in B6 at 6 month-old. NZB/W become more anxious over the course of the disease as assessed by EPM (3 mo. versus 6 mo. P&lt;0.001, paired t-test, Graph 1). Conclusion: The NZB/W lupus-prone strain exhibit depressive-like behavior, anxiety, cognitive impairment and motor disturbances both at early and late stages of the disease. This polygenic murine model may be more suitable for investigating the autoimmunity-mediated neuroinflammation in human SLE. Disclosure of Interests: : None declared
Abstract A31: Tracking the evolution of soft tissue sarcoma and GIST using liquid biopsies
Authors: Heidi M. Namløs, Kjetil Boye, Seyed H Moosavi, Daniel Vodak, Nitin Sharma, Susanne Lorenz, Bodil Bjerkehagen, Stine Næss, Eivind Hovig, Nina Jebsen, Anders Ståhlberg, Ola Myklebost, Leonardo A. Meza-Zepeda
Journal: Clinical Cancer Research (2020)

Abstract Molecular analysis of circulating tumor DNA (ctDNA) has a large potential for clinical application by capturing mutations and heterogeneity through noninvasive sampling. The CircSarc studies aims to provide new insights into the clinical utility of liquid biopsies in soft tissue sarcomas (CircSarc STS) and gastrointestinal stromal tumors (CircSarc GIST). In CircSarc STS, we have enrolled 35 high-grade soft-tissue sarcoma patients with localized disease. Plasma from each patient has been collected longitudinally throughout the course of their disease, with a follow-up of up to 5 years. To identify patient-specific somatic mutations, the patients’ tumor and germline DNA have been exome sequenced. Somatic mutations in cfDNA are being identified using ultra-low-pass WGS or targeted NGS. At time of surgery and/or progression, we detect ctDNA in 30% of the first soft-tissue sarcoma samples with higher levels in larger or metastatic tumors. In a proof-of-concept study, we have shown that that levels of tumor-specific mutations in plasma correlated to clinical manifestation of metastatic disease. In CircSarc GIST, plasma has been collected for a cohort of 30 metastatic GISTs and at time of diagnosis for 50 GISTs. Somatic mutations in the tumor have been determined by targeted sequencing or whole-exome sequencing. Somatic mutations in ctDNA are identified using targeted NGS. The levels of somatic mutations in ctDNA are being correlated with clinicopathologic features. ctDNA was detected in 36% of treatment-naïve GIST patients, including all patients with metastatic disease, and the tumor burden was the most important detection determinant. Analysis of metastatic GISTs is ongoing, but repeated plasma samples in a progressing patient have demonstrated that clonal evolution can be monitored over time. ctDNA analysis of the patient revealed multiple resistance mutations, and these were spatially distributed in the primary tumor. Our work shows that detection of mutations in plasma is particularly feasible for patients with high tumor burden. Mutational analysis by use of liquid biopsies can capture the molecular heterogeneity of the tumor and guide treatment decisions during progression. Citation Format: Heidi M. Namløs, Kjetil Boye, Seyed H Moosavi, Daniel Vodak, Nitin Sharma, Susanne Lorenz, Bodil Bjerkehagen, Stine Næss, Eivind Hovig, Nina Jebsen, Anders Ståhlberg, Ola Myklebost, Leonardo A. Meza-Zepeda. Tracking the evolution of soft tissue sarcoma and GIST using liquid 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 A31.
US Food and Drug Administration Perspective on “Mortality and Paclitaxel-Coated Devices: An Individual Patient Data Meta-Analysis”
Authors: Sara Royce, Adrijo Chakraborty, Yu Zhao
Journal: Circulation (2020)

atsanos et al 1 identified a late mortality signal associated with paclitaxelcontaining devices that was similarly observed in a subsequent US Food and Drug Administration (FDA) review of US-approved devices 2,3 and discussed by multiple stakeholders at an advisory meeting in 2019. 4Despite these analyses, uncertainty remains regarding the magnitude of the risk and the mechanism for mortality.The FDA communicated that clinicians should consider the increased rate of long-term mortality when making treatment recommendations 4,5 and implemented updated labeling for this device class to communicate the risk.The uncertainty regarding the benefit-risk profile of these devices continues to affect patients with peripheral arterial disease and their physicians.The article by Rocha-Singh et al 6 on behalf of the Vascular Interventional Advances (VIVA) Physicians in this issue of Circulation provides an independent mortality assessment of manufacturer-supplied, deidentified patient-level data from randomized, controlled trials (RCTs) in an effort to provide additional clarity regarding the magnitude and mechanism for the identified mortality risk.The analysis includes data from 2185 patients in 8 RCTs that evaluated FDAapproved paclitaxel-coated balloons and stents when used to treat peripheral arterial disease.The primary analysis reported a 38% relative increase in mortality hazard (hazard ratio, 1.38 [95% CI, 1.06-1.80])through 5 years for paclitaxelcoated devices compared with uncoated control devices.The rate decreased to 27% (hazard ratio, 1.27 [95% CI, 1.03-1.58])after the recovery of additional vital status information.These data suggest increased mortality similar to the reports by Katsanos et al 1 and the FDA (relative risk of 1.93 and 1.57, respectively).No mechanism of action for the late-term mortality was identified.The VIVA analysis also included an assessment for dose response related to mortality (in tertile dose groupings), examined using a proportional hazards model with an adjustment for covariates using propensity scores.A clear dose-response association could not be determined.The results of the VIVA analysis provide important clarifying information on the late-term mortality signal that are consistent with the conclusions of Katsanos et al 1 and the FDA regarding the increased risk of mortality for patients treated with paclitaxel-containing devices.Their collaborative effort included the incorporation of patient-level, timeto-event data and baseline covariates across studies (8 RCTs) and the use of statistical models to account for both study-level and patient-level variation by considering study-level random effects and patient-level covariates.Although the primary analysis set was the intent-to-treat population, the article also summarizes an as-treated population analysis to account for bias attributable to
AB0350 EFFICACY OF ADDING IGURATIMOD THERAPY IN RHEUMATOID ARTHRITIS PATIENTS WHO HAD INADEQUATE RESPONSE TO BIOLOGIC DMARDS
Authors: T. Miyamoto, K. Yamazaki
Journal: Annals of the Rheumatic Diseases (2020)

Background: Iguratimod (IGU) was newly approved in Japan in June 2012 and recommended by JCR guideline 2014 in the treatment of rheumatoid arthritis (RA). Although there have been efficacy of monotherapy and concomitant MTX in clinical trials, however, there have been no reports of concomitant biologic DMARDs (Bio). Objectives: we investigated efficacy of concomitant IGU therapy in RA patients who had inadequate response to Bio at the author’s institution. Methods: Subjects were 107 patients adding IGU who had inadequate response to Bio from Janually 2014 to October 2018. Previous treatment Bio. was ADA. And baseline mean concomitant MTX was 12.3 mg/week). And baseline characteristics were Mean age 53.8 years, mean duration of illness 5.5 years, corticosteroid use 9.3%(mean 3.1mg/day). The course of DAS28, SDAI, CDAI and remission rates were analyzed. Results: Mean DAS28-ESR, SDAI, CDAI were significantly decreased from the initiation of IGU treatment at 24 weeks (3.1→2.3, 7.1→2.7, 6.5→2.4), at 52 weeks (2.1, 2.4, 2.0). Remission rates of DAS28-ESR, SDAI, CDAI were 69.2%, 68.2%, 70.1% at 24 weeks, 74.8%, 78.5%, 79.4% at 52 weeks. There were no side-effect that must be stopped after adding IGU. Conclusion: IGU might be a new RA treatment option for aiming remission in patients who had inadequate response to Bio. References: [1]Hara M et al: Safety and efficacy of combination therapy of iguratimod with methotrexate for patients with active rheumatoid arthritis with an inadequate response to methotrexate: an open-label extension of a randomized, double-blind, placebo-controlled trial. Mod Rheumatol. 2014; 24: 410—418. Disclosure of Interests: None declared
Impact of the COVID-19 Pandemic on Emergency Department Visits — United States, January 1, 2019–May 30, 2020
Authors: Kathleen P. Hartnett, Aaron Kite-Powell, Jourdan DeVies, Michael A. Coletta, Tegan K. Boehmer, Jennifer Adjemian, Adi V. Gundlapalli
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

On March 13, 2020, the United States declared a national emergency to combat coronavirus disease 2019 (COVID-19). As the number of persons hospitalized with COVID-19 increased, early reports from Austria (1), Hong Kong (2), Italy (3), and California (4) suggested sharp drops in the numbers of persons seeking emergency medical care for other reasons. To quantify the effect of COVID-19 on U.S. emergency department (ED) visits, CDC compared the volume of ED visits during four weeks early in the pandemic March 29-April 25, 2020 (weeks 14 to 17; the early pandemic period) to that during March 31-April 27, 2019 (the comparison period). During the early pandemic period, the total number of U.S. ED visits was 42% lower than during the same period a year earlier, with the largest declines in visits in persons aged ≤14 years, females, and the Northeast region. Health messages that reinforce the importance of immediately seeking care for symptoms of serious conditions, such as myocardial infarction, are needed. To minimize SARS-CoV-2, the virus that causes COVID-19, transmission risk and address public concerns about visiting the ED during the pandemic, CDC recommends continued use of virtual visits and triage help lines and adherence to CDC infection control guidance.
Jarisch-Herxheimer reaction.
Journal: BMJ (1967)

Jarisch Herxheimer reaction (JHR) was first described in the literature by Adolf Jarisch (Austrian dermatologist) in the late 1800s when he noticed an exacerbation of skin lesions in a syphilis patient after starting treatment with a mercurial compound. In the early 1900s, a similar phenomenon was reported by Karl Herxheimer (German dermatologist).JHR is a transient clinical phenomenon that occurs in patients infected by spirochetes who undergo antibiotic treatment. More specifically, the reaction occurs within 24 hours of antibiotic therapy for spirochetal infections, including syphilis, leptospirosis, Lyme disease, and relapsing fever. It usually manifests as fever, chills, rigors, nausea and vomiting, headache, tachycardia, hypotension, hyperventilation, flushing, myalgia, and exacerbation of skin lesions. JHR is an acute, self-limiting condition and it is important to identify JHR and to distinguish it from allergic reactions and sepsis, which can be life-threatening.
Abstract 13879: Heart Failure and Albuminuria During Hospitalization With ACS and Long Term Mortality Risk. The ABC Study on Acute Coronary Syndrome
Authors: Heba T Mahmoud, Giuseppe Berton, Rosa Palmieri, Francesco Bagato, Rocco Cordiano, Elisabetta Lorenzon, Fiorella Cavuto, Moemen M Mahmoud
Journal: Circulation (2019)

Purpose: To assess the combined effect of heart failure and albuminuria on the long-term mortality risk after acute coronary syndrome (ACS) through 20 years of follow-up. Methods: This study includ...