tbuckley/cabot-search huggingface dataset:
Trends in Use of Advanced Imaging in Pediatric Emergency Departments, 2009-2018
Authors: Jennifer R. Marin, Jonathan Rodean, Matt Hall, Elizabeth R. Alpern, Paul L. Aronson, Pradip P. Chaudhari, Eyal Cohen, Stephen B. Freedman, Rustin B. Morse, Alon Peltz, Margaret Samuels-Kalow, Samir S. Shah, Harold K. Simon, Mark I. Neuman
Journal: JAMA Pediatrics (2020)

There is increased awareness of radiation risks from computed tomography (CT) in pediatric patients. In emergency departments (EDs), evidence-based guidelines, improvements in imaging technology, and availability of nonradiating modalities have potentially reduced CT use.To evaluate changes over time and hospital variation in advanced imaging use.This cross-sectional study assessed 26 082 062 ED visits by children younger than 18 years from the Pediatric Health Information System administrative database from January 1, 2009, through December 31, 2018.Imaging.The primary outcome was the change in CT, ultrasonography, and magnetic resonance imaging (MRI) rates from January 1, 2009, to December 31, 2018. Imaging for specific diagnoses was examined using all patient-refined diagnosis related groups. Secondary outcomes were hospital admission and 3-day ED revisit rates and ED length of stay.There were a total of 26 082 062 visits by 9 868 406 children (mean [SD] age, 5.59 [5.15] years; 13 842 567 [53.1%] male; 9 273 181 [35.6%] non-Hispanic white) to 32 US pediatric EDs during the 10-year study period, with 1 or more advanced imaging studies used in 1 919 283 encounters (7.4%). The proportion of ED encounters with any advanced imaging increased from 6.4% (95% CI, 6.2%-6.2%) in 2009 to 8.7% (95% CI, 8.7%-8.8%) in 2018. The proportion of ED encounters with CT decreased from 3.9% (95% CI, 3.9%-3.9%) to 2.9% (95% CI, 2.9%-3.0%) (P < .001 for trend), with ultrasonography increased from 2.5% (95% CI, 2.5%-2.6%) to 5.8% (95% CI, 5.8%-5.9%) (P < .001 for trend), and with MRI increased from 0.3% (95% CI, 0.3%-0.4%) to 0.6% (95% CI, 0.6%-0.6%) (P < .001 for trend). The largest decreases in CT rates were for concussion (-23.0%), appendectomy (-14.9%), ventricular shunt procedures (-13.3%), and headaches (-12.4%). Factors associated with increased use of nonradiating imaging modalities included ultrasonography for abdominal pain (20.3%) and appendectomy (42.5%) and MRI for ventricular shunt procedures (17.9%) (P < .001 for trend). Across the study period, EDs varied widely in the use of ultrasonography for appendectomy (median, 57.5%; interquartile range [IQR], 40.4%-69.8%) and MRI (median, 15.8%; IQR, 8.3%-35.1%) and CT (median, 69.5%; IQR, 54.5%-76.4%) for ventricular shunt procedures. Overall, ED length of stay did not change, and hospitalization and 3-day ED revisit rates decreased during the study period.This study found that use of advanced imaging increased from 2009 to 2018. Although CT use decreased, this decrease was accompanied by a greater increase in the use of ultrasonography and MRI. There appears to be substantial variation in practice and a need to standardize imaging practices.
Breaking the menopause taboo: more must be done to support doctors, says BMA
Authors: Abi Rimmer
Journal: BMJ (2020)

Employers should take a proactive approach to normalising the topic of menopause and should spread awareness of the impact that symptoms can have on doctors’ work, the BMA has said.

On 6 August the association published a report on the issue,1 including the findings of a survey that received 2000 responses from BMA members.

Of the respondents, 93% (1860) said that they had experienced symptoms such as insomnia, fatigue, loss of confidence, and debilitating hot flushes as a result of menopause, and 65% (1300) had experienced physical and mental symptoms. Of the 1860 respondents, 90% (1800) said that the symptoms had affected …
Abstract B67: EGFR as a target in pediatric solid tumors
Authors: Catherine M. Albert, Navin R. Pinto, Erin R. Rudzinski, Julie R. Park
Journal: Cancer Research (2020)

Abstract The epidermal growth factor receptor (EGFR or HER1) is a cell surface tyrosine kinase receptor that is expressed in a diverse group of epithelial and nonepithelial tissues and broadly associated with cell proliferation and differentiation. Expression of wild-type EGFR and activating mutations are described in many malignancies, including a variety of pediatric solid tumors. In the setting of malignancy, EGFR has been associated with aggressive disease, chemotherapy resistance, and increased metastatic potential. Employment of anti-EGFR agents has yielded some promising results, but they are not always effective against all cancer-associated aberrant EGFR expression and are frequently associated with notable off-tumor toxicities due to the expression of EGFR in normal tissue. The unique EGFR monoclonal antibody (mAb) 806 selectively binds to an epitope on the extracellular portion of human EGFR expressed on the surface of tumor cells. This antibody recognizes the deletion mutant EGFRvIII commonly present in glioblastomas and some other solid tumors as well as wild-type EGFR. We designed a phase I trial for pediatric and young adult patients with recurrent or refractory solid tumors expressing epidermal growth factor (EGFR) to examine the safety and feasibility of administering autologous, peripheral blood-derived T cells that have been genetically modified to express a second-generation (2G) EGFR806-specific chimeric antigen receptor (CAR). Literature review and evaluation of EGFR immunohistochemistry (IHC) performed on several tissue microarrays were used to estimate the percentage of EGFR positivity among common subtypes of pediatric cancer. Using these tools, we hypothesized that 15-40% of otherwise eligible patients would meet the eligibility criteria of EGFR positivity. The trial opened in August of 2018. To date, a total of 33 patient tumors have undergone EGFR IHC to determine eligibility for the trial. 9/33 (27.3%) have been EGFR+. EGFR+ histologies include BCOR fusion sarcoma (3), germ cell tumor (2), osteosarcoma, Ewing sarcoma, desmoplastic small round cell tumor, and synovial sarcoma. Our eligibility testing thus far demonstrates EGFR expression by IHC in a variety of histologies. Two rare diseases, recurrent BCOR fusion sarcoma and refractory germ cell tumors, have demonstrated a significantly higher rate of EGFR IHC positivity, (3/3)100% and (2/3) 66.7%, respectively. These early results indicate that this trial and other anti-EGFR therapies may be most effectively targeted to certain subgroups of pediatric cancer patients. Citation Format: Catherine M. Albert, Navin R. Pinto, Erin R. Rudzinski, Julie R. Park. EGFR as a target in pediatric solid tumors [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B67.
Abstract 14722: Beneficial Bacteria Enhance Cardiovascular Health by Modulating Inflammation and Nrf2 Pathway Signaling
Authors: Crystal Naudin, Joshua Owens, Liping Luo, Rheinallt Jones
Journal: Circulation (2019)

Introduction: Studies have demonstrated a positive influence of beneficial bacteria administered as probiotics on myocardial infarction (MI), mostly with a focus on short-term outcomes after MI. Ho...
Interpretations and comments for expert consensus on the diagnosis and treatment of heat stroke in China
Authors: Shu-Yuan Liu, Qian Wang, Yun-Peng Lou, Yan Gao, Bo Ning, Qing Song, Hai-Ling Li
Journal: Military Medical Research (2020)

Abstract Heat stroke is the most severe type of heat illness, it is often accompanied by severe multiorgan damage and has a high fatality rate. In January 2020, based on new research evidence and the experiences of Chinese experts in heat stroke, the Expert Group of Heat Stroke Prevention and Treatment of the Chinese People’s Liberation Army (PLA) and the Professional Committee of Critical Care Medicine of the Chinese PLA jointly issued a new Expert Consensus on the Diagnosis and Treatment of Heat Stroke in China . This article aims to interpret and supplement the major updates to the new consensus.
Abstract B45: Therapeutic potential of splicing in RMS: SRSF2 binding modulation controls MDM2 alternative splicing
Authors: Matias I. Montes, Daniel F. Comiskey, Safiya Khurshid, Dawn S. Chandler
Journal: Cancer Research (2020)

Abstract MDM2 undergoes complex alternative splicing and one of its spliced isoforms, MDM2-ALT1, comprised of coding exons 3 and 12, is highly expressed in pediatric rhabdomyosarcoma, and its expression correlates with a poor disease prognosis. MDM2-ALT1 expression is also upregulated under conditions of cellular genotoxic stress, and this alternative splicing is conserved in the mouse Mdm2 gene. Furthermore, previous research from our lab has reported that the splicing factors SRSF1, FUBP1, and PTBP1 are involved in this regulation; nevertheless, the way that MDM2 splicing is controlled is not entirely understood. In this work, we explore the role of the splicing factor SRSF2/SC35 in the alternative splicing of MDM2, hypothesizing that this factor acts as a positive regulator, in both human and mouse, facilitating the production of the full-length MDM2 mature transcript. This splicing factor has been reported to be mutated in several cancers, including myelodysplastic syndromes and rhabdomyosarcoma. Moreover, using a minigene system that mimics the endogenous Mdm2 splicing in response to UV and cisplatinum-induced DNA damage and the CRISPR-Cas9 technology, we show that mutations in SRSF2 predicted binding sites alter Mdm2 alternative splicing. The CRISPR-engineered mutant cells that express this splice isoform show increased proliferation in an Arf/p19 null context. On the other hand, we show that by using antisense oligonucleotides working as splice-switching molecules that target the SRSF2 binding sites in the MDM2 pre-mRNA, we are able to shift the expression of the MDM2 splice isoforms to drive p53 target gene expression in p53 wild-type cells. Furthermore, in an effort to understand better the effect of the MDM2-ALT1 isoform in carcinogenesis, we performed the CRISPR-Cas9 technique to generate a mouse model expressing the cancer-associated spliced isoform. We expect the mouse to be a cancer-sensitized model that will give rise to RMS tumors and provide a preclinical model for testing splice-switching oligonucleotide therapies. Citation Format: Matias I. Montes, Daniel F. Comiskey, Safiya Khurshid, Dawn S. Chandler. Therapeutic potential of splicing in RMS: SRSF2 binding modulation controls MDM2 alternative splicing [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B45.
5F 203-induced apoptosis involves oxidative stress and caspase activation in sensitive breast cancer cells
Authors: Lancelot McLean, Willie Davis, Lawrence Sowers, Eileen Brantley
Journal: Cancer Research (2008)

1448  2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) displays potent and selective anticancer activity against breast, ovarian and renal tumors and its lysylamide prodrug (Phortress, NSC 710305) has recently entered Phase I clinical trials in the United Kingdom. 5F 203 likely exhibits a unique mechanism of action, distinct from currently available anticancer drugs. It is metabolized by cytochrome P450 (CYP) 1A1 to electrophilic species, which can form DNA adducts in sensitive breast cancer cells. In this study, we further investigated the mechanism of anticancer action for 5F 203 in estrogen receptor positive (T47D) and estrogen receptor negative (MDA-MB-468) breast cancer cell lines. We sought to determine the role reactive oxygen species (ROS) and caspases play in mediating 5F 203-induced cytotoxicity and cell death. 5F 203 induced an increase in ROS and altered glutathione levels in sensitive breast cancer cells leading to oxidative DNA damage. Pretreatment with the antioxidant, N-acetylcysteine (NAC) attenuated 5F 203-induced cytotoxicity. Cytotoxicity was also partially reduced when cells were pretreated with the pancaspase inhibitor, z-VAD-fmk. 5F 203 activated caspases 3, 8 and 9 in a time-dependent manner suggesting that caspases are involved in 5F 203-induced cell death. These results suggest that the anticancer activity of 5F 203, in part, involves induction of intracellular ROS and caspase-mediated cell death in MDA-MB-468 and T47D breast cancer cells. Estrogen receptor status does not appear to determine the ability of 5F 203 to induce oxidative stress and caspase-mediated cell death in sensitive breast cancer cells.
Symptom Burden, Perceived Control, and Quality of Life Among Patients Living With Multiple Myeloma
Authors: Alexandra K. Zaleta, Melissa F. Miller, Julie S. Olson, Eva Y.N. Yuen, Thomas W. LeBlanc, Craig E. Cole, Shauna McManus, Joanne S. Buzaglo
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: New therapies for multiple myeloma (MM) have improved survival rates but often expose patients to heightened toxicities and prolonged treatment, leading to increasing complications and side effects. We evaluated the association between symptom burden, perceived control over illness, and quality of life (QoL) among a national sample of patients with MM. Methods: For this observational, cross-sectional study, we used data from the Cancer Experience Registry research initiative to examine symptom- and functioning-related concerns among 289 patients with MM across the illness trajectory. We applied hierarchical multiple linear regression analyses to explore associations between symptom burden and perceived control over illness with QoL indicators: depression, anxiety, and social satisfaction. Results: In our sample, 73% of participants with MM reported currently receiving treatment; 39% experienced relapse; 56% received 1 to 2 autologous transplants, 10% received ≥3 autologous transplants, and 4% received allogeneic and autologous transplants; 30% had not received a stem cell transplant. Average time since diagnosis was 4.4 years. The most highly endorsed concerns included eating and nutrition (61%), physical activity (59%), moving around (56%), fatigue (55%), pain (52%), and sleep (46%). Only 27% believed they had control over their disease, whereas 48% perceived having control over the physical side effects of MM. Approximately one-third of the variance in anxiety and depression and nearly two-thirds of variance in social satisfaction were explained by sociodemographic, clinical, and symptom burden variables. Perceived control over illness significantly predicted depression and anxiety, but not social satisfaction. Our results highlight substantial concern among patients with MM about physical symptoms and function. Additionally, greater symptom burden significantly accounted for poorer QoL, and lower perceived control over illness was linked to depression and anxiety. Conclusions: Patients with MM and survivors experience substantive long-term QoL issues. Together, these findings point to the critical need for comprehensive symptom management, integrated palliative care, and enhancement of social and emotional support for individuals with MM.
Abstract 15679: Effective and Functional Somatic Gene Transfer of mRNAs Into the Myocardium
Authors: David Wolfson, Jared Beyersdorf, Nam Kyun Kim, Michael Sayegh, Philip Santangelo, Hee Cheol Cho
Journal: Circulation (2019)

Background: Somatic gene transfer into the myocardium largely rely on recombinant viral vectors. Though effective, viral vectors require time-consuming subcloning, and may elicit adverse/catastroph...
Livedoid and Purpuric Skin Eruptions Associated With Coagulopathy in Severe COVID-19
Authors: Caren Droesch, Mytrang Hoang Do, Maria DeSancho, Eun-Ju Lee, Cynthia Magro, Joanna Harp
Journal: JAMA Dermatology (2020)

Between 2012 and 2017, overall Medicare reimbursements for PDT services in metropolitan regions increased by $1 601 015 (average annual growth rate [AAGR], 4.0%), with 19 219 (AAGR, 4.7%) additional claims; overall Medicare reimbursements for PDT services in nonmetropolitan regions increased by $122 076 (AAGR, 3.2%), with 1625 (AAGR, 3.9%) additional claims (Table 2).As of 2017, metropolitan counties accounted for 90.9% of Medicare reimbursements for PDT claims ($9 260 322 of $10 184 822).Discussion | In this study, we present data characterizing the trends in use, accessibility, and cost of PDT among the US Medicare population.Despite the consistent growth in the number of dermatologists offering PDT, the density of dermatologists providing PDT in nonmetropolitan counties is less than half of that in metropolitan counties in the most recent study year; this difference has widened from 2012 to 2017.With the incidence of NMSCs rising, PDT could be important for prevention and treatment of some NMSCs while maintaining low costs. 2Strategies leading to more dermatologists offering PDT, such as recent increases to reimbursements, may, therefore, ultimately lower Medicare expenditures on skin cancer treatment, especially in nonmetropolitan areas, where our study suggests that PDT access is particularly lacking.This study has several limitations.Our use of Medicare claims data precludes evaluation of PDT use for patients with commercial insurance.Likewise, while PDT is generally performed in outpatient settings, exclusion of institutional providers (such as hospitals) in the data set may limit our ability to capture all PDT services.Conclusions | We found that the use of PDT increased in both metropolitan and nonmetropolitan regions from
A Fibrosis‐Independent Hepatic Transcriptomic Signature Identifies Drivers of Disease Progression in Primary Sclerosing Cholangitis
Authors: Yevgeniy Gindin, Chuhan Chung, Zhaoshi Jiang, Jing Zhu Zhou, Jun Xu, Andrew N. Billin, Robert P. Myers, Zachary Goodman, Abdolamir Landi, Michael Houghton, Richard M. Green, Cynthia Levy, Kris V. Kowdley, Christopher L. Bowlus, Andrew J. Muir, Michael Trauner
Journal: Hepatology (2020)

Background and Aims Primary sclerosing cholangitis (PSC) is a heterogeneous cholangiopathy characterized by progressive biliary fibrosis. RNA sequencing of liver tissue from patients with PSC (n = 74) enrolled in a 96‐week clinical trial was performed to identify associations between biological pathways that were independent of fibrosis and clinical events. Approach and Results The effect of fibrosis was subtracted from gene expression using a computational approach. The fibrosis‐adjusted gene expression patterns were associated with time to first PSC‐related clinical event (e.g., cholangitis, hepatic decompensation), and differential expression based on risk groups and Ingenuity Pathway Analysis were performed. Baseline demographic data were representative of PSC: median age 48 years, 71% male, 49% with inflammatory bowel disease, and 44% with bridging fibrosis or cirrhosis. The first principle component (PC1) of RNA‐sequencing data accounted for 18% of variance and correlated with fibrosis stage ( ρ = −0.80; P &lt; 0.001). After removing the effect of fibrosis‐related genes, the first principle component was not associated with fibrosis ( ρ = −0.19; P = 0.11), and a semisupervised clustering approach identified two distinct patient clusters with differential risk of time to first PSC‐related event ( P &lt; 0.0001). The two groups had similar fibrosis stage, hepatic collagen content, and α‐smooth muscle actin expression by morphometry, Enhanced Liver Fibrosis score, and serum liver biochemistry, bile acids, and IL‐8 (all P &gt; 0.05). The top pathways identified by Ingenuity Pathway Analysis were eukaryotic translation inhibition factor 2 (eIF2) signaling and regulation of eIF4/p70S6K signaling. Genes involved in the unfolded protein response, activating transcription factor 6 ( ATF6 ) and eIF2 , were differentially expressed between the PSC clusters (down‐regulated in the high‐risk group by log‐fold changes of −0.18 [ P = 0.02] and −0.16 [ P = 0.02], respectively). Clinical events were enriched in the high‐risk versus low‐risk group (38% [12/32] vs. 2.4% [1/42], P &lt; 0.0001). Conclusions Removing the contribution of fibrosis‐related pathways uncovered alterations in the unfolded protein response, which were associated with liver‐related complications in PSC.
Over-Expression of Activation-Induced Cytidine Deaminase in TCL1 Mice Leads to the Development of IGHV-Mutated CLL Clones That Associate with More Aggressive Disease
Authors: Xiao J. Yan, Pablo Morande, Mei Qi, Ezra B Kolitz, Crystal D Grant, Gautam Nayyar, Pablo Oppezzo, Nicholas Chiorazzi
Journal: Blood (2017)
AB0066 THE JAK INHIBITOR (BARICITINIB) INHIBITS IFNΓ-INDUCED GLIOSTATIN EXPRESSION IN HUMAN FIBROBLAST-LIKE SYNOVIOCYTES
Authors: Yuji Joyo, Yuko Waguri-Nagaya, Yohei Kawaguchi, Yusuke Oguri, Masahiro Nozaki, Kiyofumi Asai
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The JAK/STAT signaling pathways mediate the production of many cytokines and growth factors related rheumatoid arthritis (RA) [1]. Baricitinib is a novel oral JAK inhibitor and it has demonstrated high efficacy in RA [2]. Gliostatin (GLS) is known to have angiogenic and arthritogenic activities. GLS was expressed in inflamed synovial tissues of patients with RA. In cultured fibroblast-like synoviocytes (FLSs), GLS expression was found to be up-regulated by inflammatory cytokines, such as IL-1β, TNFα [3]. GLS acted as a cytokine in FLSs, augmenting its own synthesis, and also induced the extracellular secretion of matrix metalloproteinase (MMP)-1, -3, -9, and -13 [4]. Therefore the suppression of GLS production might be an effective therapy in RA. The mechanism of the action of baricitinib had not been determined in fibroblast-like synoviocytes (FLSs). <h3>Objectives:</h3> The purpose of this study was to investigate the GLS production effect of interferon (IFN) γ and the inhibitory action of baricitinib in FLSs derived from patients with RA (RA-FLSs). <h3>Methods:</h3> RA-FLSs were cultured from synovial specimens of patients with RA and stimulated by IFNγ with or without treatment of baricitinib. The expression levels of GLS were determined using reverse transcription-polymerase chain reaction (RT-PCR), enzyme immunoassay and immunocytochemistry. <h3>Results:</h3> In cultured RA-FLSs, GLS mRNA and protein were significantly induced by stimulation with IFNγ and these GLS inductions were significantly suppressed by treatment of baricitinib in dose-dependent manners. <h3>Conclusion:</h3> Our data demonstrated that JAK/STAT activation play a pivotal role in IFNγ mediated GLS up-regulation in RA-FLSs. Suppression of GLS production in inflamed synovia has been suggested as one of the anti-inflammatory effects of baricitinib. <h3>References</h3> [1] Kawaguchi Y, et al. The Janus kinase inhibitor tofacitinib inhibits TNF-α-induced gliostatin expression in rheumatoid fibroblast-like synoviocytes. Clin Exp Rheumatol. 2018;36:559-567. [2] Vollenhoven R, et al. Safety and Efficacy of Baricitinib in Patients Receiving Conventional Synthetic Disease-Modifying Antirheumatic Drugs or Corticosteroids. Rheumatol Ther 2018; 5:525–536. [3] Ikuta K, et al. The Sp1 transcription factor is essential for the expression of gliostatin/thymidine phosphorylase in rheumatoid fibroblast-like synoviocytes. Arthritis Research &amp; Therapy 2012; 14:R87. [4] Tatematsu N, et al. Mithramycin has inhibitory effects on gliostatin and matrix metalloproteinase expression induced by gliostatin in rheumatoid fibroblast-like synoviocytes. Mod Rheumatol. 2018;28:495-505. <h3>Acknowledgement:</h3> This research was supported by Grand-in-Aid for Scientific Research(C)(26462309) from the Japan Society for the Promotion of Science. <h3>Disclosure of Interests:</h3> None declared