tbuckley/cabot-search huggingface dataset:
Lipin 2/3 phosphatidic acid phosphatases maintain phospholipid homeostasis to regulate chylomicron synthesis
Authors: Peixiang Zhang, Lauren S. Csaki, Emilio Ronquillo, Lynn J. Baufeld, Jason Y. Lin, Alexis Gutierrez, Jennifer R. Dwyer, David N. Brindley, Loren G. Fong, Peter Tontonoz, Stephen G. Young, Karen Reue
Journal: Journal of Clinical Investigation (2018)

The lipin phosphatidic acid phosphatase (PAP) enzymes are required for triacylglycerol (TAG) synthesis from glycerol 3-phosphate in most mammalian tissues. The 3 lipin proteins (lipin 1, lipin 2, and lipin 3) each have PAP activity, but have distinct tissue distributions, with lipin 1 being the predominant PAP enzyme in many metabolic tissues. One exception is the small intestine, which is unique in expressing exclusively lipin 2 and lipin 3. TAG synthesis in small intestinal enterocytes utilizes 2-monoacylglycerol and does not require the PAP reaction, making the role of lipin proteins in enterocytes unclear. Enterocyte TAGs are stored transiently as cytosolic lipid droplets or incorporated into lipoproteins (chylomicrons) for secretion. We determined that lipin enzymes are critical for chylomicron biogenesis, through regulation of membrane phospholipid composition and association of apolipoprotein B48 with nascent chylomicron particles. Lipin 2/3 deficiency caused phosphatidic acid accumulation and mammalian target of rapamycin complex 1 (mTORC1) activation, which were associated with enhanced protein levels of a key phospholipid biosynthetic enzyme (CTP:phosphocholine cytidylyltransferase α) and altered membrane phospholipid composition. Impaired chylomicron synthesis in lipin 2/3 deficiency could be rescued by normalizing phospholipid synthesis levels. These data implicate lipin 2/3 as a control point for enterocyte phospholipid homeostasis and chylomicron biogenesis.
FRI0414 Evaluation of a novel multi-analyte assay for the detection of autoantibodies in the diagnosis of systemic sclerosis
Authors: P.L. Meroni, T. Schioppo, F. Ingegnoli, M.O. Borghi, J.L. Milo, C. Bentow, A. Seaman, G. Valentini, S. Vettori, P. Di Benedetto, V. Liakouli, R. Giacomelli, M. Mahler
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Systemic sclerosis (SSc) is a chronic autoimmune disease characterised by vascular changes and progressive fibrosis of skin and various internal organs. In SSc a variety of autoantibodies have been detected which are useful for the diagnosis and management of the disease. Some of these autoantibodies are well-established tools strongly associated with SSc (e.g. anti-centromere, anti-topoisomerase I, anti-RNA polymerase III). Other autoantibodies are less frequent and/or less-specific for SSc even if potentially useful to better assess disease subsets and prognosis. <h3>Objectives</h3> Our goal was to assess the frequency of SSc-related autoantibodies detected using a novel technology as well as to study the associations between these antibodies and clinical features in an Italian SSc cross sectional cohort. <h3>Methods</h3> Serum samples from 218 consecutive patients with SSc collected at three Italian sites were tested for a variety of autoantibodies (see table 1) using a novel fully automated system utilising bead-based immunoassays (research use only, Inova Diagnostics, San Diego, CA). The Italian cohort included: women 200 (92%), limited cutaneous SSc (lc-SSc) 166 (76%), patients with history of digital ulcers 91 (42%), calcinosis 46 (21%), lung fibrosis 84 (39%), heart involvement 38 (17.4%), pulmonary arterial hypertension 20 (9%), and esophageal involvement 138 (63.3%). <h3>Results</h3> The prevalence of antibodies is summarised in the table 1 below. Of note, anti-BICD2, anti-CENP-B, and anti-nucleosome antibodies were significantly associated with lc-SSc subtype (p=0.0237, p&lt;0.0001, p=0.0096, respectively), while anti-Ro60, anti-SSB, anti-Scl-70, and anti-DFS70 antibodies were significantly associated with the diffuse cutaneous SSc (dc-SSc) subtype (p=0.0102, p&lt;0.0001, p&lt;0.0001, and p=0.0032, respectively). When analysing all antibodies with multivariate analysis, SSc patients showed significant clustering based on antibody profile and clinical phenotype. <h3>Conclusions</h3> Autoantibodies identified via the novel system in this SSc cohort were found in the expected frequencies and also correlated to clinical features of the patients. The multiparameter approach combined with cluster analysis holds promise for a molecular and more precise stratification of SSc subsets. <h3>Disclosure of Interest</h3> None declared
Procedure volume and mortality after surgical lung biopsy in interstitial lung disease
Authors: Jolene H. Fisher, Shane Shapera, Teresa To, Theodore K. Marras, Andrea Gershon, Sharon Dell
Journal: European Respiratory Journal (2018)

Surgical volume-outcome relationships are well established but have not been studied in patients with interstitial lung disease (ILD) undergoing surgical lung biopsy (SLB). Our study objective was to determine if hospital SLB volume is associated with post-operative mortality in patients with ILD.A cohort study using administrative, population-based data from Ontario, Canada was performed in adults with ILD who underwent a SLB between 2001 and 2014. The association between yearly hospital SLB volume and 30-day post-operative mortality was assessed using multilevel logistic regression modelling.3057 surgical lung biopsies for ILD were performed during the study period with a median (interquartile range) yearly hospital volume of 73 (34-143) procedures. 30-day mortality was 7.1%, 20.2% and 1.9% in overall, nonelective and elective patients, respectively. Higher yearly hospital SLB volume was associated with lower odds of 30-day post-operative mortality after adjusting for patient characteristics (OR 0.84, 95% CI 0.73-0.97; p=0.02), with the association appearing stronger for nonelective versus elective procedures (OR 0.84, 95% CI 0.69-1.02; p=0.08 versus OR 0.94, 95% CI 0.74-1.18; p=0.57).Higher yearly hospital SLB volume was associated with lower post-operative mortality in patients with ILD, with the association appearing to be mainly driven by nonelective cases. SLB mortality was significantly higher for nonelective cases.
Gait speed and prognosis in patients with idiopathic pulmonary fibrosis: a prospective cohort study
Authors: Claire M. Nolan, Matthew Maddocks, Toby M. Maher, Winston Banya, Suhani Patel, Ruth E. Barker, Sarah E. Jones, Peter M. George, Paul Cullinan, William D-C. Man
Journal: European Respiratory Journal (2018)

The 4-m gait speed (4MGS), a simple physical performance measure and surrogate marker of frailty, consistently predicts adverse prognosis in older adults. We hypothesised that 4MGS could predict all-cause mortality and nonelective hospitalisation in patients with idiopathic pulmonary fibrosis (IPF).4MGS and lung function were measured at baseline in 130 outpatients newly diagnosed with IPF. Survival status and nonelective hospital admissions were recorded over 1 year. We assessed the predictive value of 4MGS (as a continuous variable and as a binary variable: slow versus preserved 4MGS) by calculating hazard ratios using Cox proportional regression, adjusting for potential confounding variables. Receiver operating characteristic curves assessed discrimination between the multivariable regression models and established prognostic indices.Continuous 4MGS and slow 4MGS were independent predictors of all-cause mortality (4MGS: HR 0.03, 95% CI 0.01-0.31; p=0.004; slow 4MGS: 2.63, 95% CI 1.01-6.87; p=0.049) and hospitalisation (4MGS: HR 0.02, 95% CI 0.01-0.14; p<0.001; slow 4MGS: 2.76, 95% CI 1.16-6.58; p=0.02). Multivariable models incorporating 4MGS or slow 4MGS had better discrimination for predicting mortality than either the gender, age and lung physiology index or Composite Physiologic Index.In patients with IPF, 4MGS is an independent predictor of all-cause mortality and nonelective hospitalisation.
David Oliver: Top healthcare words of 2018
Authors: David Oliver
Journal: BMJ (2018)

The Collins English Dictionary ’s top 10 words of 20181 included “plogging” (picking up litter while jogging), “VAR” (video assistant referee), and “floss” (a new dance craze). So, as The BMJ heads to the New Year, here’s my personal list of the top words of 2018 for UK health services. I’ve doubtless missed some, so please do post rapid responses or tweet your own suggestions.

It’s been good to see, for the first time in the NHS’s history, a draft workforce plan (technically, a “strategy”)—from Health Education England.2 It has its imperfections, but at least it’s a plan. And we’re eagerly expecting the launch of NHS England’s 10 year plan for the health service.3 Again, not everyone will be happy with its details, but a shift towards medium term plans beats short term, politically driven cycles. It’s a start.

To my mind,4 and …
Abstract 18520: Endogenous Cardiotonic Steroids in Salt- sensitive Hypertension
Authors: Estela S Estape, Ivette Torres-Negron, Olga V Fedorova, Claribel Gonzalez-Rodriguez, Lorena Gonzalez-Sepulveda, Alexei Y Bagrov, Wen Wei, Sandra Franqui, Ingrid Rodriguez-Rivera, Enid Garcia-Rivera, Fernando Santiago, Angel Lopez-Candales, Manuel Martinez-Maldonado
Journal: Circulation (2015)

Introduction: An endogenous inhibitor of Na,K-ATPase (CTS) is increased in Dahl salt-sensitive (DS) rats and in human cardiovascular pathologies. Hypothesis: Chronic hypertension is a major cause of CTS release which will not be corrected by treatment, and that effectively treated hypertensive patients (HT) will have increased plasma CTS, compared to ischemic stroke patients (STR) after thrombolytic treatment and controls ( CTL). Methods: Forty (40) subjects (age and sex matched) were recruited and grouped into three groups: STR (n = 13), HT (n = 13), and CTL (n = 14). Plasma was collected 1-2 days after diagnosis of ischemic stroke and thrombolytic treatment. CTS levels was determined in all groups by measuring the bufadienolide CTS marinobufagenin (MBG) using a fluoroimmunoassay. Fisher Exact test, Kruskal-Wallis test, and Mann-Whitney test with Bonferroni correction were used, when appropriate, to analyze all data. Results: Participants mean age was 61 ± 12 years; 56% were male. CTS levels within the normal range (200-400 pmoles/L) were found in 62% of the whole cohort. Median plasma CTS was significantly higher in HT as compared to CTL (437.6 vs. 326.8 pmoles/L, p= 0.018) and STR (437.6 vs. 286.9 pmoles/L, p=0.005). Blood pressure did not differ between HT and CTL groups (p&gt;0.05). Extreme CTS values (&gt; 1,000 pmoles/L) were observed in four HT and one CTL, despite normal BP. Conclusion: As predicted, HT patients had high CTS levels compared to CTL suggesting a strong relationship between hypertension and CTS. Plasma CTS may be lowered by thrombolytic but not anti-hypertension therapy. Further studies are required to define the role of CTS in human pathological states.
Discontinuation of adjuvant sunitinib due to adverse events in patients with high-risk renal cell carcinoma after nephrectomy: A combined analysis of phase III trials.
Authors: Somedeb Ball, Kyaw Zin Thein, Miguel Quirch, Nimesh Adhikari, Nicholas C. D'Cunha, Catherine Jones, Fred L. Hardwicke, Sanjay Awasthi, Lukman Tijani
Journal: Journal of Clinical Oncology (2018)

215 Background: Dysregulation in the vascular endothelial growth factor (VEGF) pathway has been implicated in the pathogenesis of renal cell carcinoma (RCC). Sunitinib is an oral VEGF receptor tyrosine kinase inhibitor and has been approved in the adjuvant treatment of high-risk RCC. However, there are significant adverse events, impacting patients’ quality of life, and leading to treatment discontinuation. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of high-grade toxicities and the rate of treatment discontinuation due to adverse events. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2018. Phase III RCTs which utilized adjuvant sunitinib in high risk RCC after nephrectomy and mentioned treatment interruption or discontinuation or dose reduction due to adverse events were included. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Fixed effects model was applied. Results: Two phase III RCTs with a total of 1866 patients were eligible. Studies utilized sunitinib versus placebo. The randomization ratio was 1:1 in both ASSURE and S-TRAC studies. The incidence of high-grade adverse events was 568 (60.5%) in sunitinib group versus 183 (19.6%) in placebo arm, with the relative risk of 3.10 (95% CI: 2.69 – 15.93, P &lt; 0.001). The reduction in dose was reported in 541 (57.9%) in study arm versus 86 (9.2%) in placebo group. The pooled RR for dose reduction was statistically significant at 6.28 (95% CI: 5.10 – 7.74, P &lt; 0.001). The treatment discontinuation rate was 27.9% higher with sunitinib than with placebo (RR - 4.14; 95% CI: 3.31 – 5.16, P &lt; 0.001). Conclusions: Our meta-analysis demonstrated that the rate of dose reduction, treatment discontinuation and the risk of grade 3 and 4 adverse events were notably high in sunitinib group. Timely recognition and proper supportive care are entailed in minimizing those adverse events which may ultimately improve patients’ quality of life and overall compliance.
An affinity-based approach to engineer laminin-presenting cell instructive microenvironments
Authors: Daniela Barros, Paula Parreira, Joana Furtado, Frederico Ferreira-da-Silva, Eduardo Conde-Sousa, Andrés J. García, M. Cristina L. Martins, Isabel Freitas Amaral, Ana Paula Pêgo
Journal: Biomaterials (2018)
Response by Kimura et al to Letters Regarding Article, “High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial”
Authors: Takeshi Kimura, Satoshi Iimuro, Isao Taguchi, Hiroshi Iwata, Teruo Inoue, Yasuo Ohashi, Ryozo Nagai
Journal: Circulation (2018)
Annals Story Slam - “The Wound Is the Place Where the Light Enters You”
Authors: Umberin Najeeb
Journal: Annals of Internal Medicine (2018)

Web Exclusives4 December 2018Annals Story Slam - “The Wound Is the Place Where the Light Enters You”FREEUmberin Najeeb, MDUmberin Najeeb, MDUniversity of Toronto and Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (U.N.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W18-0030 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - "The Wound Is the Place Where the Light Enters You" "'The Wound Is the Place Where the Light Enters You'," by Umberin Najeeb, MD (Duration 6:57)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: University of Toronto and Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (U.N.)Current Author Address: Umberin Najeeb, MD; e-mail, medicine.[email protected]ca. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 4 December 2018Volume 169, Issue 11Page: SS1 ePublished: 4 December 2018 Issue Published: 4 December 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.Loading ...
Abstract 19035: Machine Learning Predicts Mortality Better Than Biomarker Staging in Wild-type Cardiac Amyloidosis
Authors: Avinainder Singh, Hallie I Geller, Rodney H Falk
Journal: Circulation (2017)

Introduction: A biomarker-based staging system has recently been described for prognosis in wild-type transthyretin cardiac amyloidosis (ATTRwt). We validated this staging system in consecutive ATT...
Time series analysis of neoadjuvant chemotherapy and bevacizumab-treated breast carcinomas reveals a systemic shift in genomic aberrations
Authors: Elen Kristine Höglander, Silje Nord, David C. Wedge, Ole Christian Lingjærde, Laxmi Silwal-Pandit, Hedda vdL Gythfeldt, Hans Kristian Moen Vollan, Thomas Fleischer, Marit Krohn, Ellen Schlitchting, Elin Borgen, Øystein Garred, Marit M. Holmen, Erik Wist, Bjørn Naume, Peter Van Loo, Anne-Lise Børresen-Dale, Olav Engebraaten, Vessela Kristensen
Journal: Genome Medicine (2018)

Chemotherapeutic agents such as anthracyclines and taxanes are commonly used in the neoadjuvant setting. Bevacizumab is an antibody which binds to vascular endothelial growth factor A (VEGFA) and inhibits its receptor interaction, thus obstructing the formation of new blood vessels. A phase II randomized clinical trial of 123 patients with Her2-negative breast cancer was conducted, with patients treated with neoadjuvant chemotherapy (fluorouracil (5FU)/epirubicin/cyclophosphamide (FEC) and taxane), with or without bevacizumab. Serial biopsies were obtained at time of diagnosis, after 12 weeks of treatment with FEC ± bevacizumab, and after 25 weeks of treatment with taxane ± bevacizumab. A time course study was designed to investigate the genomic landscape at the three time points when tumor DNA alterations, tumor percentage, genomic instability, and tumor clonality were assessed. Substantial differences were observed with some tumors changing mainly between diagnosis and at 12 weeks, others between 12 and 25 weeks, and still others changing in both time periods. In both treatment arms, good responders (GR) and non-responders (NR) displayed significant difference in genomic instability index (GII) at time of diagnosis. In the combination arm, copy number alterations at 25 loci at the time of diagnosis were significantly different between the GR and NR. An inverse aberration pattern was also observed between the two extreme response groups at 6p22-p12 for patients in the combination arm. Signs of subclonal reduction were observed, with some aberrations disappearing and others being retained during treatment. Increase in subclonal amplification was observed at 6p21.1, a locus which contains the VEGFA gene for the protein which are targeted by the study drug bevacizumab. Of the 13 pre-treatment samples that had a gain at VEGFA, 12 were responders. Significant decrease of frequency of subclones carrying gains at 17q21.32-q22 was observed at 12 weeks, with the peak occurring at TMEM100, an ALK1 receptor signaling-dependent gene essential for vasculogenesis. This implies that cells bearing amplifications of VEGFA and TMEM100 are particularly sensitive to this treatment regime. Taken together, these results suggest that heterogeneity and subclonal architecture influence the response to targeted treatment in combination with chemotherapy, with possible implications for clinical decision-making and monitoring of treatment efficacy. NCT00773695 . Registered 15 October 2008
Clinical and research implications of serum versus plasma potassium measurements
Authors: Lauren B. Cooper, Gianluigi Savarese, Juan‐Jesus Carrero, Barna Szabo, Tomas Jernberg, Åsa Jonsson, Catarina Dahlbom, Ulf Dahlström, Anders Larson, Lars H. Lund
Journal: European Journal of Heart Failure (2018)
68Ga-PSMA PET/CT Urachus Metastases in Recurrent Prostate Cancer With Very Low PSA Level
Authors: Maëlle Le Thiec, Daniela Rusu, Vincent Fleury, Francoise Kraeber-Bodéré, Caroline Rousseau
Journal: Clinical Nuclear Medicine (2018)

Abstract Peritoneal carcinomatosis in prostate cancer is extremely rare and has been described in only few cases with high PSA level, androgen deprivation, or in symptomatic patients. To date, 2 cases of 68 Ga-PSMA PET positive peritoneal metastases have been reported. We report a case of urachus metastases showed on 68 Ga-PSMA PET/CT performed for biochemical recurrence with a very low PSA level at 0.50 ng/mL.
Abstract 20228: Nicotinamide Riboside Improves Autophagic Flux and Prevents Doxorubicin-Induced Cardiac Injury
Authors: Dong Zheng, Yi Zhang, Tianqing Peng
Journal: Circulation (2017)

Introduction: Doxorubicin is widely used as a first-line chemotherapeutic drug for various malignancies. However, doxorubicin causes severe cardiotoxicity. Recent studies report that autophagic flu...
Association of Hospital Surgical Aortic Valve Replacement Quality With 30-Day and 1-Year Mortality After Transcatheter Aortic Valve Replacement
Authors: Harun Kundi, Jeffrey J. Popma, Kamal R. Khabbaz, Louis M. Chu, Jordan B. Strom, Linda R. Valsdottir, Changyu Shen, Robert W. Yeh
Journal: JAMA Cardiology (2018)

Hospital outcomes for transcatheter aortic valve replacement (TAVR) may be dependent on the quality of evaluation, personnel, and procedural and postprocedural care common to patients undergoing cardiac surgery.We sought to assess whether those hospitals with better patient outcomes for surgical aortic valve replacement (SAVR) subsequently achieved better TAVR outcomes after launching TAVR programs.This national cohort included US patients 65 years and older. The analysis used the Centers for Medicare and Medicaid Services' Medicare Provider and Review data collected between January 1, 2010, and September 29, 2015. Only hospitals performing at least 1 SAVR prior to September 1, 2011, and performing at least 1 TAVR after this date were included in the analysis. Data analysis was completed from June 2018 to August 2018.Isolated aortic valve replacements.Hospital risk-adjusted 30-day mortality for SAVR in the pre-TAVR period was used as a surrogate for SAVR quality. Thirty-day and 1-year TAVR mortality rates were examined after stratification by quartile of baseline hospital risk-adjusted SAVR mortality.A total of 51 924 TAVR procedures were performed in 519 hospitals, of which 19 798 were performed at hospitals in quartile 1 (the lowest risk-adjusted SAVR mortality rate), 7663 were performed in quartile 2, 10 180 were performed in quartile 3, and 14 283 were performed in quartile 4 (the highest risk-adjusted SAVR mortality rate). Observed mortality rates at 30 days consistently increased with increasing baseline hospital SAVR risk-adjusted mortality (quartile 1, 917 patients [4.6%]; quartile 2, 381 [5.0%]; quartile 3, 521 [5.1%]; quartile 4, 800 [5.6%]; P < .001). The same pattern was observed in 1-year mortality (quartile 1, 3359 [17.0%]; quartile 2, 1337 [17.5%]; quartile 3, 1852 [18.2%]; quartile 4, 2652 [18.6%]; P < .001). After multivariable analysis, compared with the lowest quartile of SAVR mortality, undergoing TAVR at a hospital with higher baseline SAVR mortality continued to be associated with higher 30-day mortality (odds ratios: quartile 2, 1.02 [95% CI, 0.87-1.21]; quartile 3, 1.13 [95% CI, 1.02-1.26]; quartile 4, 1.23 [95% CI, 1.07-1.40]; P = .02) and 1-year mortality (hazard ratios: quartile 2, 1.04 [95% CI, 0.92-1.17]; quartile 3, 1.14 [95% CI, 1.02-1.28]; quartile 4, 1.16 [95% CI, 1.05-1.28]; P = .02).Hospitals with higher SAVR mortality rates also had higher short-term and long-term TAVR mortality after initiating TAVR programs. Quality of cardiac surgical care may be associated with a hospital's performance with new structural heart disease programs.