tbuckley/cabot-search huggingface dataset:
The feared postdilation complication in caustic esophageal stenosis: combined endoscopic and surgical treatment
Authors: Vitor Massaro Takamatsu Sagae, Igor Braga Ribeiro, Alberto Machado da Ponte Neto, Sergio Eiji Matuguma, Spencer Cheng, Marcos Eduardo Lera dos Santos, Eduardo Guimarães Hourneaux de Moura
Journal: Endoscopy (2021)

Esophageal stricture is a major complication after caustic ingestion. When the ingestion is associated with a suicide attempt, the damage is typically worse because a large amount is ingested [1]. Endoscopic dilation is the go-to for initial treatment, with surgical treatment being reserved for refractory cases. The success rate of dilation ranges from 40 % to 90 % [2] [3]. Perforation is a complication with high morbidity and mortality that can occur during the dilation procedure, ranging from 0 to 32 % of cases [4] [5]. We describe a case of esophageal perforation during dilation and how it was treated with a combined endoscopic and surgical procedure.
Randomized phase II trial of olaparib + pembrolizumab versus olaparib alone as maintenance therapy in metastatic pancreatic cancer patients with germline BRCA1 or BRCA2 (g<i>BRCA</i>1/2+) mutations: SWOG S2001.
Authors: Vincent Chung, Katherine A Guthrie, Michael J. Pishvaian, Andrew M. Lowy, Elena Gabriela Chiorean, Mai T. Duong, Eileen Mary O'Reilly, Philip Agop Philip
Journal: Journal of Clinical Oncology (2021)

TPS447 Background: Olaparib was approved in 2019 as maintenance therapy for g BRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression free survival (mPFS) with olaparib compared to placebo (7.4 versus 3.8 months) for g BRCA1/2+ mPDA pts following either stable disease/response on first-line platinum chemotherapy. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Several clinical studies in solid tumors have shown preliminary efficacy with the combination of PARP plus immune checkpoint inhibitors. Based upon these data, SWOG S2001 aims to further improve the PFS of g BRCA1/2+ mPDA pts. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in October 2020. mPDA pts with gBRCA1/2 mutations identified with standard of care germline genetic testing will be eligibleif no progression after receiving 4 to 6 months of platinum chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin). Zubrod performance status (PS) 0 or 1 pts are eligible. Pts will be stratified according to first line chemotherapy, PS 0 versus 1, and disease status after first-line treatment. The primary objective of this study is to evaluate the PFS of mPDA pts treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha=0.10, this design requires 78 evaluable pts to be accrued over 3 years. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Support:NIH/NCI grants U10CA180888 and U10CA180819. Clinical trial information: TBD.
Inducibility, but not stability, of atrial fibrillation is increased by NOX2 overexpression in mice
Authors: Alexandra S Mighiu, Alice Recalde, Klemen Ziberna, Ricardo Carnicer, Jakub Tomek, Gil Bub, Alison C Brewer, Sander Verheule, Ajay M Shah, Jillian N Simon, Barbara Casadei
Journal: Cardiovascular Research (2021)

Abstract Aims Gp91-containing NADPH oxidases (NOX2) are a significant source of myocardial superoxide production. An increase in NOX2 activity accompanies atrial fibrillation (AF) induction and electrical remodelling in animal models and predicts incident AF in humans; however, a direct causal role for NOX2 in AF has not been demonstrated. Accordingly, we investigated whether myocardial NOX2 overexpression in mice (NOX2-Tg) is sufficient to generate a favourable substrate for AF and further assessed the effects of atorvastatin, an inhibitor of NOX2, on atrial superoxide production and AF susceptibility. Methods and results NOX2-Tg mice showed a 2- to 2.5-fold higher atrial protein content of NOX2 compared with wild-type (WT) controls, which was associated with a significant (twofold) increase in NADPH-stimulated superoxide production (2-hydroxyethidium by HPLC) in left and right atrial tissue homogenates (P = 0.004 and P = 0.019, respectively). AF susceptibility assessed in vivo by transoesophageal atrial burst stimulation was modestly increased in NOX2-Tg compared with WT (probability of AF induction: 88% vs. 69%, respectively; P = 0.037), in the absence of significant alterations in AF duration, surface ECG parameters, and LV mass or function. Mechanistic studies did not support a role for NOX2 in promoting electrical or structural remodelling, as high-resolution optical mapping of atrial tissues showed no differences in action potential duration and conduction velocity between genotypes. In addition, we did not observe any genotype difference in markers of fibrosis and inflammation, including atrial collagen content and Col1a1, Il-1β, Il-6, and Mcp-1 mRNA. Similarly, NOX2 overexpression did not have consistent effects on RyR2 Ca2+ leak nor did it affect PKA or CaMKII-mediated RyR2 phosphorylation. Finally, treatment with atorvastatin significantly inhibited atrial superoxide production in NOX2-Tg but had no effect on AF induction in either genotype. Conclusion Together, these data indicate that while atrial NOX2 overexpression may contribute to atrial arrhythmogenesis, NOX2-derived superoxide production does not affect the electrical and structural properties of the atrial myocardium.
Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial
Authors: François Quénet, Dominique Elias, Lise Roca, Diane Goéré, Laurent Ghouti, Marc Pocard, Olivier Facy, Catherine Arvieux, Gérard Lorimier, Denis Pezet, Frédéric Marchal, Valeria Loi, Pierre Meeus, Beata Juzyna, Hélène de Forges, Jacques Paineau, Olivier Glehen, Pascale MARIANI, Cécile BRIGAND, Jean-Marc BEREDER, Simon MSIKA, Guillaume PORTIER, Patrick RAT
Journal: The Lancet Oncology (2021)
SAT0215 Diagnostic value of synovial fluid analysis in pigmented villonodular synovitis (pvs)-a proposal of diagnostic criteria
Authors: I Zimmermann-Górska, M Puszczewicz, G Bia³kowska-Puszczewicz
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> PVS is an idiopathic lesion that affects the synovial lining joints, tendons, sheats, and bursea through the production of tumour-like growths. Diagnosis of PVS is difficult. Arthroscopy and biopsy together with microscopic examination is usually a base. According to our experience, cytologic features of synovial fluid is a very useful diagnostic tool in PVS. <h3>Objectives</h3> Synovial fluid (SF) from the joints of 14 patients with biopsy-proven PVS were examined. Moreover in all the patients features of the disease were confirmed in surgical specimes. <h3>Methods</h3> Synovial fluids were divided into three samples, for physicochemical analysis, bacteriological and cytologic findings and placed in sterile tubes. For cytological examination MMG staining was used. <h3>Results</h3> SF analysis had revealed an inflammatory character of effusions. In all the cases synovial fluids were bloody and fragments of synovial villi in their sediments were observed as well as multinucleated giant cells, pseudomalignant cells, macrophages with phagocytized hemosiderin, foam cells an a few synoviocytes. Moreover the fat crystals were seen, under polarised light. <h3>Conclusion</h3> Cytological features of synovial fluid in PVS are in parallel with results of microscopic examination of joint tissues. In our opinion SF analysis should be the first step in the diagnostic procedure in PVS. We propose the cytologic criteria: Major the presence of bloody fluid with fragments of synovial villi in sediment macrophages containing hemosiderin pseudomalignant cells Minor multinucleated giant cells foam cells fat crystals The diagnosis of PVS can be establish if all major and at least one minor criteria are fulfilled.
Temporal Trends and Clinician Variability in Potassium Monitoring of Healthy Young Women Treated for Acne With Spironolactone
Authors: John S. Barbieri, David J. Margolis, Arash Mostaghimi
Journal: JAMA Dermatology (2021)

Although recent studies and guideline recommendations indicate that potassium level monitoring is of low usefulness for healthy young women being treated for acne with spironolactone, little is known about whether these recommendations have been implemented in clinical practice.To evaluate trends in rates of potassium level monitoring among young women treated for acne with spironolactone and clinician variability in monitoring practices.This retrospective cohort study was conducted between January 1, 2008, and June 30, 2019, using data from the Optum deidentified Clinformatics Data Mart database. Participants comprised 108 547 healthy female patients aged 12 to 45 years who were treated for acne with spironolactone.The primary outcome was the proportion of women who received a test for baseline potassium level and the proportion of women whose potassium levels were monitored in the first 180 days of being treated for acne with spironolactone. For clinicians who had prescribed at least 5 courses of spironolactone, the percentage of clinicians who ordered baseline potassium testing or monitoring and the percentage of clinicians who always monitored potassium were compared between 2008 and 2015 vs between 2016 and 2018.For 108 547 women included in this cohort study, the mean (SD) age at the start of treatment was 30.7 (8.6) years, and the mean (SD) course duration was 159 (218) days. Between 2008 and 2018, the percentage of women whose potassium levels were monitored within 180 days of starting spironolactone by all clinicians decreased from 41.4% to 38.5%, with a decrease from 48.9% to 41.0% among dermatologists and from 39.7% to 37.7% among internists but with an increase from 71.4% to 75.4% among advanced practice clinicians (ie, nurse practitioners and physician assistants). The proportion of dermatologists who always monitored potassium decreased from 10.6% between 2008 and 2015 to 4.2% between 2016 and 2018. There was no significant difference in the proportion of internists who always monitored potassium from 2008 to 2015 (15.8%) vs from 2016 to 2018 (17.7%).Despite increasing evidence and guidelines supporting the elimination of potassium monitoring among healthy young women treated for acne with spironolactone, the present study findings suggest that potassium monitoring remains common, with substantial variability in clinician practices. There is a need for future implementation and dissemination research to understand underlying factors for this variation and to develop strategies to address this practice gap.
THU0224 SKIN PROTEOME INVESTIGATION IN CUTANEOUS LUPUS ERYTHEMATOSUS (CLE) REVEALS NOVEL UNIQUE DISEASE PATHWAYS
Authors: T. Niewold, K. Popovic-Silwerfeldt, J. Lehman, A. Meves, C. Charlesworth, B. Madden, A. Hayry, A. Antovic, I. E. Lundberg, M. Wahren-Herlenius, E. Svenungsson, V. Oke
Journal: Annals of the Rheumatic Diseases (2020)

Background: Cutaneous lupus erythematosus (CLE) is an autoimmune disease. It can be limited to the skin or be one of manifestations of systemic LE (SLE). The typical histopathologic pattern in CLE/SLE is interface dermatitis, which can also be observed in dermatomyositis (DM). While LE may affect any organ system, DM most commonly affect muscles and skin. Objectives: The aim of this study was to investigate the whole proteome of skin inflammatory foci in the cohort of CLE and DM patients in a comparatory, hypothesis-free manner and identify disease-unique molecular mechanisms. Methods: CLE (n=6), DM (n=5) patients and controls (n=6) were recruited at diagnosis or disease exacerbation. Skin biopsies were acquired, examined by a pathologist and selected inflammatory foci were laser micro-dissected. The total protein content was analyzed by mass-spectrometry, further analysis was performed by string-db.org platform. Certain proteomic findings were confirmed by immunohistochemistry (IHC). Results: CLE infiltrates were more protein rich in comparison to DM lesions. There ratio of 5x upregulated proteins in LE/DM was 60, while ratio for DM/LE was 13. Our results confirmed high abundance of (IFN)-regulated proteins both in CLE and DM, including: IFIT, MX and OAS families. Proteins expressed differentially in CLE covered complement proteins (C1b), including membrane attack complex (MAC) (C5, C6, C7, C8A and B) and complement regulators (CFHR1, CFHR2, CFHR5), as well as regulators of coagulation: thrombospondin 2 (THBS2), thrombin (F2), fibrinogen (F12) and annexin A3 (ANXA3). Importantly, we identified interleukin (IL) -16 as the only detectable and highly abundant cytokine in the CLE lesions and confirmed this finding by IHC. Conclusion: Conclusions Our data confirm evidence on IFN-regulated processes in CLE/SLE. Importantly, we identified IL-16 as a novel cytokine most strongly upregulated locally in the skin lesions. Moreover, we identified activation of MAC, complement regulating proteins as well as involvement of coagulation/fibrinolysis system. The study brings information on novel pathways involved in the inflammatory foci of the skin lesions in CLE patients. Our findings are of interest in further search of new therapeutic targets. Disclosure of Interests: : Timothy Niewold: None declared, Karin Popovic-Silwerfeldt: None declared, Julia Lehman: None declared, Alexander Meves: None declared, Cristine Charlesworth: None declared, Benjamin Madden: None declared, Aliisa Hayry: None declared, Aleksandra Antovic: None declared, Ingrid E. Lundberg Grant/research support from: Bristol Meyer Squibb, Corbus Pharmaceuticals, Inc and Astra Zeneca, Marie Wahren-Herlenius: None declared, Elisabet Svenungsson: None declared, Vilija Oke: None declared
Progress on pivotal role and application of exosome in lung cancer carcinogenesis, diagnosis, therapy and prognosis
Authors: Ming-Yue Li, Li-Zhong Liu, Ming Dong
Journal: Molecular Cancer (2021)

Abstract Lung cancer is often diagnosed at an advanced stage and has a poor prognosis. Conventional treatments are not effective for metastatic lung cancer therapy. Although some of molecular targets have been identified with favorable response, those targets cannot be exploited due to the lack of suitable drug carriers. Lung cancer cell-derived exosomes (LCCDEs) receive recent interest in its role in carcinogenesis, diagnosis, therapy, and prognosis of lung cancer due to its biological functions and natural ability to carry donor cell biomolecules. LCCDEs can promote cell proliferation and metastasis, affect angiogenesis, modulate antitumor immune responses during lung cancer carcinogenesis, regulate drug resistance in lung cancer therapy, and be now considered an important component in liquid biopsy assessments for detecting lung cancer. Therapeutic deliverable exosomes are emerging as promising drug delivery agents specifically to tumor high precision medicine because of their natural intercellular communication role, excellent biocompatibility, low immunogenicity, low toxicity, long blood circulation ability, biodegradable characteristics, and their ability to cross various biological barriers. Several studies are currently underway to develop novel diagnostic and prognostic modalities using LCCDEs, and to develop methods of exploiting exosomes for use as efficient drug delivery vehicles. Current status of lung cancer and extensive applicability of LCCDEs are illustrated in this review. The promising data and technologies indicate that the approach on LCCDEs implies the potential application of LCCDEs to clinical management of lung cancer patients.
The versatility of liver X receptors in T cell homeostasis: Location, location, location!
Authors: Truong San Phan, Thomas Brunner
Journal: The Journal of Experimental Medicine (2021)

Nuclear receptors control the transcriptional program of target cells and thereby their phenotype and activities. Two complementary studies by Micheals et al. (https://doi.org/10.1084/jem.20201311) and Chan et al. (https://doi.org/10.1084/jem.20200318) published in JEM uncover the cell type–specific expression and role of the nuclear receptors liver X receptors in the regulation of T cell homeostasis and function.
Asthma, ECMO and eosinophils
Authors: Tom McLellan, Chinmay Patvardhan, Doris Rassl, Huw Steven Jenkins, Martin Knolle, Muhunthan Thillai
Journal: Thorax (2021)

A man in his 30s, with a history of mild childhood asthma only, went to his local hospital with difficulty in breathing. His presentation was preceded by 6 days of worsening breathlessness, wheeze and cough. He had been using his mother’s salbutamol inhaler and received oral amoxicillin in the community. He was hypertensive, tachycardic and had a respiratory rate of 32 breaths/min. He could not complete sentences, peak flow measurement or lie flat. Chest auscultation revealed diffuse polyphonic wheeze. Arterial blood gas (ABG) while receiving fraction of inspired oxygen (FiO2) 40% revealed pH 7.32, PaO2 9.7 kPa, PaCO2 6.7 kPa. He had a blood eosinophil count of 0.5×109/L, serum C-reactive protein of 30 mg/L with normal renal and liver profiles. His chest radiograph (figure 1A) revealed clear lung fields with no pneumothorax or consolidation. He was treated with nebulised bronchodilators, intravenous broad-spectrum antibiotics, magnesium, hydrocortisone and aminophylline before transfer to the high dependency unit.



Figure 1 
(A) Presentation chest radiograph. (B) CT thorax, day 1 extracorporeal membrane oxygenation (ECMO) treatment. (C) Summary of antibiotic and steroid therapy, change in blood eosinophil and bronchoalveolar lavage (BAL) % and ECMO sweep requirements (necessary to clear CO2). Shaded area is time spent on ECMO. Key: MP, methylprednisolone; Vc, vancomycin (D). Eosinophil-rich BAL.



Over 48 hours, there was an improvement and treatments were gradually weaned but on day 3 there was a respiratory deterioration associated with a PaCO2 of 7.6 kPa requiring intubation. Treatment was augmented with a ketamine infusion and inhaled sevoflurane. Despite optimum ventilation strategies, 4 hours after intubation there was severe gas trapping requiring manual decompression, low tidal volumes and a rising arterial PaCO2. A referral to the local extracorporeal membrane oxygenation (ECMO) centre was made.

On our arrival, the patient was in ventilatory failure with severe gas trapping. Pre-ECMO …
Asthma prescribing according to Arg16Gly beta-2 genotype: a randomised trial in adolescents
Authors: Tom Ruffles, Christina J. Jones, Colin Palmer, Steve Turner, Jonathan Grigg, Roger Tavendale, Fiona Hogarth, Petra Rauchhaus, Kristina Pilvinyte, Romanie Hannah, Helen Smith, Roberta Littleford, Brian Lipworth, Somnath Mukhopadhyay
Journal: European Respiratory Journal (2021)

Introduction The A allele of rs1042713 (Arg16 amino acid) in the β 2 -adrenoreceptor is associated with poor response to long-acting β 2 -agonist (LABA) in young people with asthma. Our aim was to assess whether the prescribing of second-line controller with LABA or a leukotriene receptor antagonist according to Arg16Gly genotype would result in improvements in Pediatric Asthma-Related Quality of Life Questionnaire (PAQLQ). Methods We performed a pragmatic randomised controlled trial (RCT) via a primary care clinical research network covering England and Scotland. We enrolled participants aged 12–18 years with asthma taking inhaled corticosteroids. 241 participants (mean± sd age 14.7±1.91 years) were randomised (1:1) to receive personalised care (genotype directed prescribing) or standard guideline care. Following a 4-week run-in participants were followed for 12 months. The primary outcome measure was change in PAQLQ. Asthma control, asthma exacerbation frequency and healthcare utilisation were secondary outcomes. Results Genotype-directed prescribing resulted in an improvement in PAQLQ compared to standard care (0.16, 95% CI 0.00–0.31; p=0.049), although this improvement was below the pre-determined clinical threshold of 0.25. The AA genotype was associated with a larger improvement in PAQLQ with personalised versus standard care (0.42, 95% CI 0.02–0.81; p=0.041). Conclusion This is the first RCT demonstrating that genotype-driven asthma prescribing is associated with a significant improvement in a clinical outcome compared to standard care. Adolescents with the AA homozygous genotype benefited most. The potential role of such β 2 -adrenoceptor genotype directed therapy in younger and more severe childhood asthma warrants further exploration.
Now is not the time to change GP contract, leaders agree
Authors: Abi Rimmer
Journal: BMJ (2021)

The BMA and NHS England have agreed that only minor changes will be made to the GP contract in England from April this year. In addition, there will be funding increases for practices and primary care network staff, the BMA said, giving practices the support and stability necessary to focus on their response to the pandemic.

In 2019, the BMA’s England GP committee and NHS England agreed a five year contract framework,1 with further changes to be negotiated annually and …
Memory-Altering Drugs: Shifting the Paradigm of Informed Consent
Authors: Evelyn M. Tenenbaum, Brian Reese
Journal: The American Journal of Bioethics (2007)

Henry et al. (2007) favor pursuing research with propranolol as a method for treating post-traumatic stress disorder (PTSD). As part of their argument, the authors recommend that “adequate” informe...
Engineering biopharmaceutical formulations to improve diabetes management
Authors: Caitlin L. Maikawa, Andrea I. d’Aquino, Rayhan A. Lal, Bruce A. Buckingham, Eric A. Appel
Journal: Science Translational Medicine (2021)

Insulin was first isolated almost a century ago, yet commercial formulations of insulin and its analogs for hormone replacement therapy still fall short of appropriately mimicking endogenous glycemic control. Moreover, the controlled delivery of complementary hormones (such as amylin or glucagon) is complicated by instability of the pharmacologic agents and complexity of maintaining multiple infusions. In this review, we highlight the advantages and limitations of recent advances in drug formulation that improve protein stability and pharmacokinetics, prolong drug delivery, or enable alternative dosage forms for the management of diabetes. With controlled delivery, these formulations could improve closed-loop glycemic control.