tbuckley/cabot-search huggingface dataset:
The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications
Authors: James D. McFadyen, Hannah Stevens, Karlheinz Peter
Journal: Circulation Research (2020)

The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing global pandemic has presented a health emergency of unprecedented magnitude. Recent clinical data has highlighted that coronavirus disease 2019 (COVID-19) is associated with a significant risk of thrombotic complications ranging from microvascular thrombosis, venous thromboembolic disease, and stroke. Importantly, thrombotic complications are markers of severe COVID-19 and are associated with multiorgan failure and increased mortality. The evidence to date supports the concept that the thrombotic manifestations of severe COVID-19 are due to the ability of SARS-CoV-2 to invade endothelial cells via ACE-2 (angiotensin-converting enzyme 2), which is expressed on the endothelial cell surface. However, in patients with COVID-19 the subsequent endothelial inflammation, complement activation, thrombin generation, platelet, and leukocyte recruitment, and the initiation of innate and adaptive immune responses culminate in immunothrombosis, ultimately causing (micro)thrombotic complications, such as deep vein thrombosis, pulmonary embolism, and stroke. Accordingly, the activation of coagulation (eg, as measured with plasma D-dimer) and thrombocytopenia have emerged as prognostic markers in COVID-19. Given thrombotic complications are central determinants of the high mortality rate in COVID-19, strategies to prevent thrombosis are of critical importance. Several antithrombotic drugs have been proposed as potential therapies to prevent COVID-19-associated thrombosis, including heparin, FXII inhibitors, fibrinolytic drugs, nafamostat, and dipyridamole, many of which also possess pleiotropic anti-inflammatory or antiviral effects. The growing awareness and mechanistic understanding of the prothrombotic state of COVID-19 patients are driving efforts to more stringent diagnostic screening for thrombotic complications and to the early institution of antithrombotic drugs, for both the prevention and therapy of thrombotic complications. The shifting paradigm of diagnostic and treatment strategies holds significant promise to reduce the burden of thrombotic complications and ultimately improve the prognosis for patients with COVID-19.
The 14-3-3ζ–c-Src–integrin-β3 complex is vital for platelet activation
Authors: Chuanbin Shen, Ming Liu, Runjia Xu, Gan Wang, June Li, Pingguo Chen, Wenjing Ma, James Mwangi, Qiumin Lu, Zilei Duan, Zhiye Zhang, Fatima Zohra Dahmani, Daniel Thomas Mackeigan, Heyu Ni, Ren Lai
Journal: Blood (2020)
Bmi-1-induced miR-27a and miR-155 promote tumor metastasis and chemoresistance by targeting RKIP in gastric cancer
Authors: Yaqing Li, Zhenfeng Tian, Ying Tan, Guoda Lian, Shangxiang Chen, Shaojie Chen, Jiajia Li, Xuanna Li, Kaihong Huang, Yinting Chen
Journal: Molecular Cancer (2020)

Abstract Background We previously reported an inverse relationship between B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and Raf kinase inhibitory protein (RKIP), which is associated with the prognosis of gastric cancer (GC). In this study, we further explored the microRNA (miRNA) regulatory mechanism between Bmi-1 and RKIP. Methods Microarray analysis was first carried out to identify miRNA profiles that were differentially expressed in cells overexpressing Bmi-1. Then, miRNAs that could regulate RKIP were identified. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to measure the expression of Bmi-1, miR-155, miR-27a and RKIP. RKIP was confirmed as a target of miR-27a and miR-155 through luciferase reporter assays, qRT-PCR and Western blotting. The effects of the Bmi-1/miR-27a/RKIP and Bmi-1/miR-155/RKIP axes on tumor growth, proliferation, migration, invasion, colony-formation ability, metastasis and chemoresistance were investigated both in vitro and in vivo. Results The downregulation of RKIP by Bmi-1 occurred at the protein but not mRNA level. This indicates probable posttranscriptional regulation. miRNA expression profiles of cells with ectopic expression of Bmi-1 were analyzed and compared to those of control cells by microarray analysis. A total of 51 upregulated and 72 downregulated miRNAs were identified. Based on publicly available algorithms, miR-27a and miR-155 were predicted, selected and demonstrated to target RKIP. Bmi-1, miR-27a and miR-155 are elevated in human GC and associated with poor prognosis of GC, while RKIP is expressed at lower levels in GC and correlated with good prognosis. Then, in vitro tests shown that in addition to regulating RKIP expression via miR-27a and miR-155, Bmi-1 was also able to regulate the migration, invasion, proliferation, colony-formation ability and chemosensitivity of GC cells through the same pathway. Finally, the in vivo test showed similar results, whereby the knockdown of the Bmi-1 gene led to the inhibition of tumor growth, metastasis and chemoresistance through miR-27a and miR-155. Conclusions Bmi-1 was proven to induce the expression of miR-27a and miR-155 and thus promote tumor metastasis and chemoresistance by targeting RKIP in GC. Overall, miR-27a and miR-155 might be promising targets for the screening, diagnosis, prognosis, treatment and disease monitoring of GC.
How to make an alternative plastic gown during the personal protective equipment shortage due to the COVID-19 pandemic
Authors: Tsutomu Nishida, Norihiro Suzuki, Yuji Ono, Junzo Shimizu, Dai Nakamatsu, Kengo Matsumoto, Masashi Yamamoto
Journal: Endoscopy (2020)

Prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has led to a shortage of personal protective equipment (PPE) since the end of 2019, when SARS-CoV-2 was identified in Wuhan, China. Quickly manufactured alternative PPE is in high demand worldwide. We show how to make an alternative long-sleeve plastic gown for use as PPE, the Toyonaka Poly Gown, using a plastic trash bag. We thank all staff and doctors at Toyonaka Municipal Hospital.
Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa
Authors: Chandy C. John, Robert O. Opoka, Teresa S. Latham, Heather A. Hume, Catherine Nabaggala, Phillip Kasirye, Christopher M. Ndugwa, Adam Lane, Russell E. Ware
Journal: New England Journal of Medicine (2020)

Hydroxyurea has proven safety, feasibility, and efficacy in children with sickle cell anemia in sub-Saharan Africa, with studies showing a reduced incidence of vaso-occlusive events and reduced mortality. Dosing standards remain undetermined, however, and whether escalation to the maximum tolerated dose confers clinical benefits that outweigh treatment-related toxic effects is unknown.
US hospitals must publish price lists after losing court challenge
Authors: Owen Dyer
Journal: BMJ (2020)

The American Hospital Association and several other US hospital associations have lost a legal challenge against a proposed Trump administration rule requiring hospitals to publish price lists of their common services and procedures.

A US district court in Washington found that the rule, drafted last year by President Trump’s health department, did not exceed the agency’s authority or impose an undue regulatory burden on the hospital industry. The judge, Carl Nichols, also rejected the American Hospital Association’s argument that publishing prices negotiated with insurers could actually drive them up.1

The ruling was “a resounding victory for President Trump,” said the US health secretary, Alex Azar. “With today’s decision, we will continue …
Rate and Risk Factors Associated With Prolonged Opioid Use After Surgery
Authors: Oluwadolapo D. Lawal, Justin Gold, Amala Murthy, Rupam Ruchi, Egle Bavry, Anne L. Hume, Adam K. Lewkowitz, Todd Brothers, Xuerong Wen
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Prolonged opioid use after surgery may be associated with opioid dependency and increased health care use. However, published studies have reported varying estimates of the magnitude of prolonged opioid use and risk factors associated with the transition of patients to long-term opioid use. <h3>Objectives</h3> To evaluate the rate and characteristics of patient-level risk factors associated with increased risk of prolonged use of opioids after surgery. <h3>Data Sources</h3> For this systematic review and meta-analysis, a search of MEDLINE, Embase, and Google Scholar from inception to August 30, 2017, was performed, with an updated search performed on June 30, 2019. Key words may include<i>opioid analgesics, general surgery, surgical procedures, persistent opioid use,</i>and<i>postoperative pain</i>. <h3>Study Selection</h3> Of 7534 articles reviewed, 33 studies were included. Studies were included if they involved participants 18 years or older, evaluated opioid use 3 or more months after surgery, and reported the rate and adjusted risk factors associated with prolonged opioid use after surgery. <h3>Data Extraction and Synthesis</h3> The Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed. Two reviewers independently assessed and extracted the relevant data. <h3>Main Outcomes and Measures</h3> The weighted pooled rate and odds ratios (ORs) of risk factors were calculated using the random-effects model. <h3>Results</h3> The 33 studies included 1 922 743 individuals, with 1 854 006 (96.4%) from the US. In studies with available sex and age information, participants were mostly female (1 031 399; 82.7%) and had a mean (SD) age of 59.3 (12.8) years. The pooled rate of prolonged opioid use after surgery was 6.7% (95% CI, 4.5%-9.8%) but decreased to 1.2% (95% CI, 0.4%-3.9%) in restricted analyses involving only opioid-naive participants at baseline. The risk factors with the strongest associations with prolonged opioid use included preoperative use of opioids (OR, 5.32; 95% CI, 2.94-9.64) or illicit cocaine (OR, 4.34; 95% CI, 1.50-12.58) and a preoperative diagnosis of back pain (OR, 2.05; 95% CI, 1.63-2.58). No significant differences were observed with various study-level factors, including a comparison of major vs minor surgical procedures (pooled rate: 7.0%; 95% CI, 4.9%-9.9% vs 11.1%; 95% CI, 6.0%-19.4%;<i>P</i> = .20). Across all of our analyses, there was substantial variability because of heterogeneity instead of sampling error. <h3>Conclusions and Relevance</h3> The findings suggest that prolonged opioid use after surgery may be a substantial burden to public health. It appears that strategies, such as proactively screening for at-risk individuals, should be prioritized.
<i>NRAS</i>Status Determines Sensitivity to SHP2 Inhibitor Combination Therapies Targeting the RAS–MAPK Pathway in Neuroblastoma
Authors: Ivette Valencia-Sama, Yagnesh Ladumor, Lynn Kee, Teresa Adderley, Gabriella Christopher, Claire M. Robinson, Yoshihito Kano, Michael Ohh, Meredith S. Irwin
Journal: Cancer Research (2020)

Survival for high-risk neuroblastoma remains poor and treatment for relapsed disease rarely leads to long-term cures. Large sequencing studies of neuroblastoma tumors from diagnosis have not identified common targetable driver mutations other than the 10% of tumors that harbor mutations in the anaplastic lymphoma kinase (ALK) gene. However, at neuroblastoma recurrence, more frequent mutations in genes in the RAS-MAPK pathway have been detected. The PTPN11-encoded tyrosine phosphatase SHP2 is an activator of the RAS pathway, and we and others have shown that pharmacologic inhibition of SHP2 suppresses the growth of various tumor types harboring KRAS mutations such as pancreatic and lung cancers. Here we report inhibition of growth and downstream RAS-MAPK signaling in neuroblastoma cells in response to treatment with the SHP2 inhibitors SHP099, II-B08, and RMC-4550. However, neuroblastoma cell lines harboring endogenous NRASQ61K mutation (which is commonly detected at relapse) or isogenic neuroblastoma cells engineered to overexpress NRASQ61K were distinctly resistant to SHP2 inhibitors. Combinations of SHP2 inhibitors with other RAS pathway inhibitors such as trametinib, vemurafenib, and ulixertinib were synergistic and reversed resistance to SHP2 inhibition in neuroblastoma in vitro and in vivo. These results suggest for the first time that combination therapies targeting SHP2 and other components of the RAS-MAPK pathway may be effective against conventional therapy-resistant relapsed neuroblastoma, including those that have acquired NRAS mutations. SIGNIFICANCE: These findings suggest that conventional therapy-resistant, relapsed neuroblastoma may be effectively treated via combined inhibition of SHP2 and MEK or ERK of the RAS-MAPK pathway.
Histone Deacetylase Inhibitors Downregulate CCR4 Expression and Decrease Mogamulizumab Efficacy in CCR4-Positive Mature T-Cell Lymphomas
Authors: Akihiro Kitadate, Sho Ikeda, Fumito Abe, Naoto Takahashi, Norio Shimizu, Kosei Matsue, Hiroyuki Tagawa
Journal: Blood (2017)
Evaluation of Prescription Drug Monitoring Program Integration With Hospital Electronic Health Records by US County-Level Opioid Prescribing Rates
Authors: A. Jay Holmgren, Nate C. Apathy
Journal: JAMA Network Open (2020)

This cross-sectional study assesses the level of electronic health record (EHR) and prescription drug monitoring program integration in hospitals in US counties with vs without high opioid prescribing rates.
Response to: ‘Incidence of severe COVID-19 in a Spanish cohort of 1037 patients with rheumatic diseases treated with biologics and JAK-inhibitors’ by Jovani<i>et al</i>
Authors: Kristin M D’Silva, Naomi Serling-Boyd, Rachel Wallwork, Tiffany Hsu, Jeffrey A Sparks, Zachary S Wallace
Journal: Annals of the Rheumatic Diseases (2020)

We appreciate the comments by Jovani et al 1 in response to our manuscript evaluating the outcomes among a cohort of patients with rheumatic diseases and COVID-19.2 We commend the authors for sharing the experience of their patients during the COVID-19 pandemic and would like to reply to some of the queries they posed to us.

First, Jovani et al wondered why we included age in our multivariable models if we matched on age. This was done because continuous age was matched over a range (±5 years). To further address any potential differences in ages between the study groups (which was minimal), we included age in our multivariable models. Notably, adjusting for age did not change our findings when comparing adjusted to unadjusted models.

Second, the authors questioned why lymphopaenia and troponin levels were not included in the multivariable models. These laboratory changes may be a result of infection that occurred after the exposure of interest (COVID-19 infection). As such, they should not be adjusted for in models because they may be on the causal pathway between the exposure and outcome (eg, mechanical ventilation …
Ubiquitination of PPAR-gamma by pVHL inhibits ACLY expression and lipid metabolism, is implicated in tumor progression
Authors: Kyung Hee Noh, Hyun Mi Kang, Wonbeak Yoo, Yoohong Min, Daehun Kim, Mijin Kim, Sihyung Wang, Jung Hwa Lim, Cho-Rok Jung
Journal: Metabolism (2020)
Gastrointestinal Stromal Tumor: Challenges and Opportunities for a New Decade
Authors: César Serrano, Suzanne George
Journal: Clinical Cancer Research (2020)

Gastrointestinal stromal tumor (GIST) provides a paradigm to evaluate new molecularly targeted therapies and to identify structural and functional mechanisms for drug response and resistance. Drug development in GIST has successfully exploited the high reliance on KIT/PDGFRA oncogenic signaling as a therapeutic vulnerability. The recent arrival of avapritinib and ripretinib to the GIST arena has aimed to further improve on precision kinase inhibition and address tumor heterogeneity in imatinib-resistant GIST. The two main clinical challenges for the forthcoming years entail tumor eradication in patients with early-stage GIST, and maximization of tumor response in late-stage disease. To succeed, we will need to better understand the mechanisms behind adaptation to KIT inhibition and apoptosis evasion, tumor evolution after successive lines of treatment, and to explore clinically novel creative therapeutic strategies, with the overarching goal to tackle the intrinsic oncogenic complexity while minimizing adverse events.
Bench‐to‐Bedside Lessons Learned: Commercialization of an Acellular Nerve Graft
Authors: Mary Kasper, Curt Deister, Florence Beck, Christine E. Schmidt
Journal: Advanced Healthcare Materials (2020)

Abstract Peripheral nerve injury can result in debilitating outcomes including loss of function and neuropathic pain. Although nerve repair research and therapeutic development are widely studied, translation of these ideas into clinical interventions has not occurred at the same rate. At the turn of this century, approaches to peripheral nerve repair have included microsurgical techniques, hollow conduits, and autologous nerve grafts. These methods provide satisfactory results; however, they possess numerous limitations that can prevent effective surgical treatment. Commercialization of Avance, a processed nerve allograft, sought to address limitations of earlier approaches by providing an off‐the‐shelf alternative to hollow conduits while maintaining many proregenerative properties of autologous grafts. Since its launch in 2007, Avance has changed the landscape of the nerve repair market and is used to treat tens of thousands of patients. Although Avance has become an important addition to surgeon and patient clinical options, the product's journey from bench to bedside took over 20 years with many research and commercialization challenges. This article reviews the events that have brought a processed nerve allograft from the laboratory bench to the patient bedside. Additionally, this review provides a perspective on lessons and considerations that can assist in translation of future medical products.
Socioeconomic and Demographic Characteristics of US Adults Who Purchase Prescription Drugs From Other Countries
Authors: Young-Rock Hong, Juan M. Hincapie-Castillo, Zhigang Xie, Richard Segal, Arch G. Mainous
Journal: JAMA Network Open (2020)

Little is known about the current use of imported drugs and the factors associated with individual purchase of medications outside the US.To evaluate the proportion of the US adult population that purchases medications in other countries and the patient factors associated with the behavior.This retrospective cross-sectional study used data from the 2015-2017 National Health Interview Survey. The study sample included 61 238 individuals 18 years or older who reported use of prescribed medication by a physician or other practitioner. Data analysis was performed in November 2019.Self-reported experience of purchasing prescription drugs from countries outside the US in the past 12 months. Internet use behaviors for health care included searches for health information and filling of a prescription online. Medication-taking behaviors included skipping or delaying filling a prescription and using alternative therapies to save money. Survey design-adjusted analysis was used to estimate and compare characteristics between those who purchased medications outside the US and those did not. Multivariable logistic regression was fitted to examine the association of medication purchases with internet use and medication-taking behavior factors.Among 61 238 US adults taking prescription medications (mean [SD] age, 50.5 [18.5] years; 56.5% female; 70.8% white), the estimated prevalence of purchasing of medication outside the US was 1.5% (95% CI, 1.4%-1.7%; 2.3 million US individuals). Those who purchased medications outside the US were more likely to be older (age >64 years; adjusted odds ratio [aOR], 1.68; 95% CI, 1.24-2.29), to be from Hispanic (aOR, 1.70; 95% CI, 1.23-2.35) or immigrant populations (aOR, 3.20; 95% CI, 2.44-4.20), and to have higher educational attainment (bachelor's degree; aOR, 1.79; 95% CI, 1.27-2.54), lower family income (low income; aOR, 1.41; 95% CI, 1.06-1.87), and lack of insurance (aOR, 3.14; 95% CI, 2.33-4.21). Data analyses indicated that online health information-seeking behavior (aOR, 1.62; 95% CI, 1.33-1.98) or use of an online pharmacy (aOR, 2.30; 95% CI, 1.83-2.90) was associated with a greater likelihood of medication purchases outside the US. Individuals who skipped medications (aOR, 3.86; 95% CI, 3.05-4.88) or delayed filling a prescription (aOR, 4.04, 95% CI, 3.23-5.06) also had higher odds of purchasing medication outside the US.The findings suggest that patients are not using prescription purchases outside the US to meet their medication needs. However, monitoring to promote safe administration of medications imported into the US should be continued.
Covid-19: RCGP apologises for covid-19 “lifestyle” event title
Authors: Abi Rimmer
Journal: BMJ (2020)

The Royal College of General Practitioners has apologised for the title of an online event that seemed to describe covid-19 as a lifestyle disease.The event, which took place on Saturday 27 June, was called "Covid-19: A lifestyle disease and the vital role GPs have in beating it."Many doctors raised concerns with the title on social media.Taking to Twitter, Helen Salisbury, a GP and columnist for The BMJ, said, "Lifestyle implies choice and to link this to covid is offensive.The things that have led people to die in great numbers-age, sex, ethnicity, poverty, diabetes, and obesity-are not choices.Very poor judgement." 1 Natalie Silvey, an anaesthetic registrar, said on Twitter, "A lifestyle disease?I am absolutely astonished that [the RCGP] have described covid-19 as such and are running such an event.I am almost lost for words." 2 Nisreen Alwan, a public health consultant, tweeted, "Covid-19 is not a lifestyle disease, because poverty, high risk key worker jobs, crowded accommodation, access to healthcare, zero hour contracts, and having no sick pay are not 'lifestyles.'This is bad." 3The RCGP issued an apology on Twitter and deleted its tweets referring to the title of the conference."The RCGP does not consider [covid-19] to be a lifestyle disease.We recognise that the title of today's conference could be misleading, and we apologise for any offence caused.The purpose of the conference is to support GPs to give appropriate lifestyle advice for patients," the college said on Twitter.Commenting on the issue, Martin Marshall, chair of the RCGP, reiterated the college's apology."GPs are on the frontline of tackling this terrible virus and we have lost many patients and colleagues to it.To suggest it is a lifestyle disease is wrong," he said."The purpose of the conference was to support GPs to offer lifestyle advice to patients generally, and by all accounts it was a productive meeting that more than 500 delegates attended."Marshall added, "The title and course description was misjudged and misleading, and we issued a clarification as soon as it was brought to our attention.This error should not have happened, and our sincere apologies go to our members and to our patients and communities who have been directly affected.We send our condolences to those who have been bereaved as a result of covid-19."1 Salisbury H. Twitter.
Ebola: DRC’s 10th outbreak is declared over
Authors: Jacqui Wise
Journal: BMJ (2020)

The World Health Organization has declared the end of the Ebola epidemic in the eastern Democratic Republic of the Congo, although it warned that maintaining strong surveillance and response systems would be critical to containing potential flare ups.

Many of the public health measures that successfully ended the Ebola outbreak are the same that are now essential for stopping covid-19, including finding, isolating and testing for cases, and carrying out contact tracing.

The outbreak, declared in North Kivu on 1 …