tbuckley/cabot-search huggingface dataset:
<i>Bmpr2</i> Mutant Rats Develop Pulmonary and Cardiac Characteristics of Pulmonary Arterial Hypertension
Authors: Aurélie Hautefort, Pedro Mendes-Ferreira, Jessica Sabourin, Grégoire Manaud, Thomas Bertero, Catherine Rucker-Martin, Marianne Riou, Rui Adão, Boris Manoury, Mélanie Lambert, Angèle Boet, Florence Lecerf, Valérie Domergue, Carmen Brás-Silva, Ana Maria Gomez, David Montani, Barbara Girerd, Marc Humbert, Fabrice Antigny, Frédéric Perros
Journal: Circulation (2019)

Monoallelic mutations in the gene encoding bone morphogenetic protein receptor 2 ( Bmpr2) are the main genetic risk factor for heritable pulmonary arterial hypertension (PAH) with incomplete penetrance. Several Bmpr2 transgenic mice have been reported to develop mild spontaneous PAH. In this study, we examined whether rats with the Bmpr2 mutation were susceptible to developing more severe PAH.The zinc finger nuclease method was used to establish rat lines with mutations in the Bmpr2 gene. These rats were then characterized at the hemodynamic, histological, electrophysiological, and molecular levels.Rats with a monoallelic deletion of 71 bp in exon 1 (Δ 71 rats) showed decreased BMPRII expression and phosphorylated SMAD1/5/9 levels. Δ 71 Rats develop age-dependent spontaneous PAH with a low penetrance (16%-27%), similar to that in humans. Δ 71 Rats were more susceptible to hypoxia-induced pulmonary hypertension than wild-type rats. Δ 71 Rats exhibited progressive pulmonary vascular remodeling associated with a proproliferative phenotype and showed lower pulmonary microvascular density than wild-type rats. Organ bath studies revealed severe alteration of pulmonary artery contraction and relaxation associated with potassium channel subfamily K member 3 (KCNK3) dysfunction. High levels of perivascular fibrillar collagen and pulmonary interleukin-6 overexpression discriminated rats that developed spontaneous PAH and rats that did not develop spontaneous PAH. Finally, detailed assessments of cardiomyocytes demonstrated alterations in morphology, calcium (Ca2+), and cell contractility specific to the right ventricle; these changes could explain the lower cardiac output of Δ 71 rats. Indeed, adult right ventricular cardiomyocytes from Δ 71 rats exhibited a smaller diameter, decreased sensitivity of sarcomeres to Ca2+, decreased [Ca2+] transient amplitude, reduced sarcoplasmic reticulum Ca2+ content, and short action potential duration compared with right ventricular cardiomyocytes from wild-type rats.We characterized the first Bmpr2 mutant rats and showed some of the critical cellular and molecular dysfunctions described in human PAH. We also identified the heart as an unexpected but potential target organ of Bmpr2 mutations. Thus, this new genetic rat model represents a promising tool to study the pathogenesis of PAH.
Treatment of a metabolic liver disease by in vivo genome base editing in adult mice
Authors: Lukas Villiger, Hiu Man Grisch-Chan, Helen Lindsay, Femke Ringnalda, Chiara B. Pogliano, Gabriella Allegri, Ralph Fingerhut, Johannes Häberle, Joao Matos, Mark D. Robinson, Beat Thöny, Gerald Schwank
Journal: Nature Medicine (2018)
Trusting the experience of the experienced athlete
Authors: Jermain Defoe
Journal: British Journal of Sports Medicine (2018)

When I was young I never used to go out, I never drunk, and I always had a good sleep. My Mum was strict with me and I always used to eat the right things leading up to games and stuff like that. As the years go on, you take these things to another level, and you understand your body a lot more. For me this isn’t something that has started now, but some players get to a certain point of their career and think ‘I have to start looking after myself’ and maybe that’s too late?

That is something they should be doing as soon as possible in their career. I mean now I literally do everything I can to help myself—Yoga, Pilates, I eat well, and I know how important sleep is too. You have to have a little bit of luck with injuries too, a lot of players I played with, from my generation, are not playing anymore. It’s not easy to keep playing at the top level and it is a challenge to keep competing in your 30s in elite football.

The culture in sport is completely different to when I started. When I first started playing, after training everyone used to sit in a big hot bath and that was it. Now there are ice baths, hot and cold contrast which is important, …
GMC should hold conflicts of interest register for all doctors, says McCartney
Authors: Gareth Iacobucci
Journal: BMJ (2018)

All UK doctors should be required to submit their declarations of interest to a public register held by the General Medical Council, the GP and former columnist for The BMJ Margaret McCartney has argued.

In a session focusing on doctors’ links to industry at the Royal College of General Practitioners conference in Glasgow on 5 October, McCartney said that while the medical regulator encouraged doctors to be transparent, it hadn’t yet …
Abstract 19525: Identifying Novel Phenotypes of Heart Failure Using Cluster Analysis of Clinical Variables
Authors: Yu Horiuchi, Shuzou Tanimoto, Mahbub Latif, Kevin Y Urayama, Taishi Okuno, Yu Sato, Kazuyuki Yahagi, Kota Komiyama, Jiro Aoki, Kazuhiro Hara, Kengo Tanabe
Journal: Circulation (2017)

Background: Heart failure (HF) is a heterogeneous syndrome. Although classification based on physical findings, biomarkers, echocardiogram or right-side catheterization are proposed, optimal subgro...
Letter to Editor: Response to AASLD Editorial/Message from the President
Authors: Ronald L. Koretz, Janus C. Jakobsen, Goran Hauser, Dimitrinka Nikolova, Christian Gluud
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. To the Editor: A commentary1 has criticized our systematic review regarding the use of direct‐acting agents (DAAs) in chronic hepatitis C.2 The following represents our major disagreements. Sustained virological response (SVR) is a nonvalidated surrogate outcome. The principles of evidence‐based medicine require that it be validated in randomized clinical trials (RCTs) by showing parallel benefits in clinical outcomes.3 This has never been accomplished. One RCT comparing pegylated interferon to no treatment in patients failing prior treatment found that more treated patients had SVRs (albeit a small percentage) but also died more often4; in this scenario, the surrogate failed to validate. We do agree that the RCTs to date were of relatively short duration and not designed to assess long‐term clinical outcomes, but no short‐term clinical benefits were observed. The cited “mounting evidence” consisted of observational studies (which are always limited by confounding). A comparison of treated and untreated patients cannot account for the reason(s) why treatment was or was not offered; untreated patients are often sicker. Patients who develop SVRs are at lower risk of progression,5 so comparing them to untreated participants adds selection bias. Comparing patients who do and do not develop SVRs shows that the SVR is a good prognostic sign, but this cannot provide any insight into treatment because all of the participants were treated. The six cited uncontrolled observational studies describing the use of DAAs for patients with decompensated liver disease (with or without transplantation) described many patients who had further episodes of liver failure; in the absence of untreated control groups, it is impossible to put these studies into perspective. Even alleged improvement may only represent better general care or natural history. The absence of blinding and the effects of marketing and bias make it impossible to assess quality of life. Because patients with SVRs may have hepatitis C virus RNA in peripheral blood mononuclear cells,5 transmission is still a theoretical possibility. It is ethical to call for RCTs to provide a scientific basis for the use of scarce resources. It may be unethical to expect health care systems to shift scarce resources from other interventions, particularly those with better evidence, to implement DAA therapy that has only been shown to improve surrogate outcomes and never been shown to improve morbidity or mortality.
SAT0528 Effectiveness of remission-induction therapy with concomitant cyclophosphamide and glucocorticoid for microscopic polyangiitis and granulomatosis with polyangiitis in japan: a propensity score matched analysis of two nationwide prospective cohort studies
Authors: H. Watanabe, K.-E. Sada, Y. Matsumoto, M. Harigai, H. Makino
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Although concomitant use of cyclophosphamide (CYC) with glucocorticoids (GC) is considered to be one of the standard remission-induction therapies for antineutrophil cytoplasmic antibody (ANCA) associated vasculitis over 30 years, there are few reports about clinical efficacy or effectiveness of CYC. <h3>Objectives</h3> To evaluate effectiveness and safety of concomitant CYC as remission induction therapy in Japanese patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) using data sets from two nationwide prospective cohort studies. <h3>Methods</h3> Newly diagnosed MPA and GPA patients treated with GC with or without CYC for remission-induction therapy were enrolled. The patients treated with other immunosuppressants or plasma exchange were excluded. A propensity score for the use of CYC was estimated using age, types of AAV, serum creatinine level, Birmingham Vasculitis Activity Score (BVAS), and initial GC dosage at baseline. After propensity score matching at 1:1, remission, overall survival, and end-stage renal disease (ESRD)-free survival rates, Vasculitis Damage Index (VDI), and incidence of serious infection within 6 months were compared between patients treated with and without concomitant CYC. <h3>Results</h3> Of enrolled 327 patients, concomitant CYC was used in 119 (36%) patients during the initial 3 weeks of treatment. After propensity score matching, 95 patients with concomitant CYC (CYC group) and 95 controls (non-CYC group) were selected. Demographics, baseline characteristics and treatments were balanced between the two groups except for myeloperoxidase ANCA positivity (<b>Table</b>). The remission within 6 months was achieved in 85% in both groups. The survival and ESRD-free survival rates were also similar between the two groups (log-rank test; p=0.77 and 1.0, respectively). Median VDI at the time of last observation did not differ between the two groups (CYC, 3 [interquartile {IQR}: 2–4]; non-CYC, 2 [IQR:1–3], p=0.26). The accumulated GC dosage of the CYC-group from 3 to 24 months was lower than the non-CYC group, the GC-related damage did not differ (CYC, 1 [IQR: 0–2]; non-CYC, 0 [IQR:0–2], p=0.69). <h3>Conclusions</h3> In Japanese patients with MPA and GPA, concomitant CYC could not show any benefits on clinical outcomes within 24 months. Dosage and treatment duration of CYC, as well as tapering methods of GC, could be confounding factors. Longer observation may be necessary to confirm the effectiveness of CYC as GC sparing agent. <h3>Disclosure of Interest</h3> None declared
Developments in molecular pathology testing for glioma
Authors: Ms Jodie Bance, Dr Ros Ganderton, Dr Shaoli Zhang, Mr Geoff Smith, Prof James Nicoll, Dr Mark Walker, Dr Mark Fabian, Dr Liz Hodges
Journal: Neuro-Oncology (2018)

Genetic analysis is now an integral part of glioma diagnosis and an essential aid to stratification of patient care (Louis et al., 2016). University Hospital Southampton is expanding its test repertoire to reflect these needs. The sensitive and specific technology of droplet digital PCR (ddPCR) can move Isocitrate Dehydrogenase (IDH) mutation testing away from current subjective immunohistochemistry (IHC) methodology. In a small study, 26 cases were tested by IHC, ddPCR and Sanger sequencing. Twenty cases were concordant for IDH R132H by IHC and ddPCR analysis, whilst three cases harboured the rarer IDH R132 or IDH2 variants, not evaluated by these two tests. However, three remaining IHC-IDH1 R132H negative cases were positive for IDH1 R132H by ddPCR, illustrating an improved sensitivity for IDH mutation testing using the digital PCR platform. Generic testing workflow for ddPCR, that meets ISO 15189 accreditation standards, facilitates a quick test work up for Single Nucleotide variant (SNV) mutation analysis. This can support clinical decision making vis-à-vis targeted therapy options and potential clinical trials entry. The use of microsatellite markers analysis provides an alternative method for the evaluation of 1p19q deletion characteristics. Investigation of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status using high resolution melt (HRM) brings this test in to our standard molecular laboratory workflow. Molecular testing for MGMT methylation status delivers results with fast turnaround time, supporting timely, evidence-based decisions for Temozolomide treatment. The PCR-based nature of these analyses have minimal tissue requirements and this suite of tests can be run on a single sample. Participation in the 100,000 genomes project is providing whole genome data with which to explore a ‘one stop shop’ approach to glioma molecular testing. In combination with DNA methylome analysis, we wish to evaluate the clinical utility of a pan-genome analysis for our glioma diagnostic and prognostic support service.
Abstract 12696: Transradial Approach to STEMI Intervention at Ohio State University: Clinical Results of a Protocol to Minimize Transradial D2B times
Authors: Quinn Capers, Ernest L Mazzaferri, Raymond D Magorien, Aaron Bagnola, Danielle Blais, Vincent Pompili
Journal: Circulation (2012)

Door to Balloon time (D2B) in PCI in STEMI is a major driver of clinical outcomes, with shorter D2B resulting in superior cardiac outcomes and long term survival. Cardiologists may be hesitant to p...
High Coronary Shear Stress in Patients With Coronary Artery Disease Predicts Myocardial Infarction
Authors: Arnav Kumar, Elizabeth W. Thompson, Adrien Lefieux, David S. Molony, Emily L. Davis, Nikita Chand, Stephane Fournier, Hee Su Lee, Jon Suh, Kimi Sato, Yi-An Ko, Daniel Molloy, Karthic Chandran, Hossein Hosseini, Sonu Gupta, Anastasios Milkas, Bill Gogas, Hyuk-Jae Chang, James K. Min, William F. Fearon, Alessandro Veneziani, Don P. Giddens, Spencer B. King, Bernard De Bruyne, Habib Samady
Journal: Journal of the American College of Cardiology (2018)
Circulating miRNA expression in glioblastoma patients &amp; its effect on cell migration
Authors: Ms Zenab Butt, Dr Vicky Jones, Dr Chris Smith, Dr Lisa Shaw
Journal: Neuro-Oncology (2018)

Glioblastoma Multiforme (GB) is the most common malignant human glioma and is currently incurable. Further understanding of the epigenetic mechanisms underpinning GB progression could facilitate earlier diagnosis and improve prognosis. MicroRNAs (miRNAs) are regions of RNA that reduce translation of proteins. Identifying dysregulated circulating miRNA(s) in sera could provide a potential biomarker for diagnosis, accessible through a blood test. GB and control sera supplied by Brain Tumour North West tissue bank was used to profile the circulating expression of miRNAs -20a, -34a, and -92a using quantitative PCR technology. The results were analysed according to age and sex, as well as overall comparison. MiRNA20a was reduced in GB samples as well as in 20–39 year-old (yo), 40–59 yo and male GB patients, but increased expression in GB patients aged 60 and over. MiRNA92a expression was reduced in 40-60yo GB patients however GB patients over the age of 60 showed an increased expression. MiRNA34a was reduced in GB patients overall, in both sexes and two out of three age groups (40–59, and 20–39 yo) when compared to age and sex matched control samples. The effect of miRNA 34a on cellular migration was analysed in human glioma and control human astrocyte cell lines by overexpression and knockdown. The cell lines were cultured in media containing pooled sera from GB patients, healthy individuals, standard fetal bovine serum and exosome depleted serum. Wound healing assays were performed to ascertain cell migration. Inhibition of miRNA 34a-5p significantly increased rate of migration in glioma cells cultured in human control sera. Acknowledgement should be made to Brain Tumour North West for providing the serum samples used in this study.
FRI0229 The validity of the omeract ultrasound definitions of gout elementary lesions in the diagnosis of gout
Authors: S.N. Christiansen, M. Østergaard, O. Slot, L. Terslev
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> The aim was to evaluate ultrasound (US) as a diagnostic tool for gout using the OMERACT US Working Group's 2015 US definitions for elementary lesions in gout using a) positive urate crystal microscopy or b) clinical diagnosis of gout blinded to the US assessment as gold standard for determining the sensitivity and specificity of each elementary lesion. <h3>Methods</h3> US examination (28 joints, 26 tendons) were performed in patients with clinically suspected gout. Joints were evaluated for the four OMERACT elementary lesions of gout (Double contour (DC), Tophus, Aggregates and Erosions) and tendons for aggregates and tophus. The lesions were registered as either present or absent for each patient. The US assessment was compared to 2 different gold standard references: 1) presence/absence of monosodium-urate (MSU) crystals by joint fluid microscopy and 2) the final clinical diagnosis based on the clinical assessment by a rheumatologist, blinded to US findings but not microscopy findings (table 1). <h3>Results</h3> 51 patients (44 males, 7 female), mean age of 62(30 – 89) years were included. 34 of these had a positive microscopy for MSU crystals whereas 15 patients had a negative microscopy and in 2 patients joint aspiration was not possible. Of the patients without positive microscopy 3 were clinically diagnosed as having gout by a US blinded assessor whereas 14 were diagnosed with other diseases. DC, tophus and aggregates were found to be statistically significantly more frequent in both patients with positive MSU microscopy and in patients with clinically diagnosed gout (p-values range from 0.003 to &lt;0.0001), compared to patients with negative MSU microscopy and other clinical diagnoses, respectively. All four elementary lesions were found to have high sensitivity (ranges from 0.74–0.88) for gout, both when MSU microscopy and when clinical diagnosis was used as gold standard reference. DC and aggregates had the highest sensitivities (0.85–0.88). Low specificity (0.33–0.64) was found for both aggregates and erosions, both when microscopy and clinical diagnosis was considered the gold standard. In contrast, DC and tophus showed high specificities for patients with microscopically proven gout (0.73 and 0.87, respectively) and particularly patients with clinically diagnosed gout (both 0.93). DC and tophi were also found to have high positive predictive values (PPV) for gout for patients with microscopically proven gout (0.88 and 0.93, respectively) and especially for patients with clinically diagnosed gout (both 0.97). In contrast negative predictive values (NPV) were relatively low for all lesions (ranges from 0.36–0.72). <h3>Conclusions</h3> The OMERACT US definitions of gout elementary lesions seem to be a valid tool for diagnosis of gout in clinical practice. Particularly, DC and tophi seem to have a high specificity and high PPV for the disease. <h3>Disclosure of Interest</h3> None declared
Bawa-Garba case: GMC failed in its job as a regulator
Authors: David J Nicholl
Journal: BMJ (2018)

Hadiza Bawa-Garba has won the right to practise medicine again.1 This is a landmark moment in patient safety—the General Medical Council (GMC) failed in its job as a regulator and confused the role of the criminal court with that of the supposedly arm’s length regulator the Medical Practitioners Tribunal (MPT). They have different roles, and the GMC should know this.

The …
Single dose of empagliflozin increases in vivo cardiac energy status in diabetic db/db mice
Authors: Desiree Abdurrachim, Emmy Manders, Klaas Nicolay, Eric Mayoux, Jeanine J Prompers
Journal: Cardiovascular Research (2018)

In the EMPA-REG OUTCOME trial, empagliflozin, a potent and specific inhibitor of the sodium glucose co-transporter 2, showed impressive benefits on cardiovascular outcome in patients with Type 2 diabetes.1 Empagliflozin reduced three-point primary composite outcome (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) by 14%, which was mainly attributed to a 38% relative risk reduction in cardiovascular death.1 A 35% relative risk reduction in hospitalization for heart failure and a 32% relative risk reduction in all-cause mortality was also reported.1 However, the underlying mechanisms explaining these beneficial outcomes are yet to be elucidated. Deprivation of cardiac energy, characterized by a decreased cardiac phosphocreatine-to-ATP ratio (PCr/ATP), has been proposed to play a major role in the development of heart failure.2 Empagliflozin increases plasma ketone body levels and it has therefore been hypothesized that a shift in energy substrate metabolism towards ketones or an increased availability of ketones as add-on fuel could explain the positive cardiovascular outcomes in the EMPA-REG study.3 To test the ‘fuel hypothesis’, we investigated whether an increase in plasma ketones by empagliflozin was accompanied by an increase in cardiac PCr/ATP. We administered a single dose of empagliflozin in fasting db/db mice, to simulate a situation in which plasma ketone levels are immediately increased. This acute experimental design allows investigating the effect of alterations in fuel availability on changes in cardiac PCr/ATP ratio without interference from other factors, such as cardiac remodelling after long-term treatment. Using 31P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), we measured in vivo cardiac PCr/ATP and function, respectively.
Abstract 19380: Cardiac Contractile Protein Expression of the Right Ventricle in End Stage Human Heart Failure
Authors: Yan R Su, Manuel Chuisa, David B Friedman, Tarek S Absi, Chee Lim, Thomas G Di Salvo
Journal: Circulation (2012)

Objectives: Little is known about right ventricular (RV) remodeling in human end-stage heart failure (HF). We sought to study RV contractile protein expression in HF. Methods: Western Blot (WB) analyses were performed on protein samples prepared from the RV and left ventricle (LV) free walls of 10 explanted human hearts (5 ischemic, ISC; 5 non-ischemic, N-ISC) and two normal (NOR) donor hearts. Tissues were homogenized in lysis buffer, subjected to electrophoresis gel separation and immune-blotted with antibodies against Myosin Heavy Chain 7 (MHC), Myosin Light Chain 3 (MLC), Troponin I type 3 (TNI), Tropomyosin 1 alpha (TRP), alpha Actinin-2 (ACT) and Desmin (DSM). GAPDH served as an internal loading control. The fluorescent intensity of reactive bands was detected by Li-Cor and band densities were quantified using Image Studio software. Results: We previously identified distinct RV and LV proteomic signatures in ISC in HF and confirmed these results by WB (Figure 1). In this study focused on the RV alone, we compared contractile protein expression in NOR, ISC and N-ISC RV (Figure 2). Expression of MHC and TNI was decreased and expression of MLC, TRP and DSM increased in both ISC and N-ISC RV compared to NOR. Expression of ACT was decreased in N-ISC RV but increased in ISC RV compared to NOR. Conclusions: RV contractile proteins exhibit distinctive expression patterns in human ISC and N-ISC HF compared to normal expression patterns in controls. In HF, RV expression of MLC and TRP is significantly increased and RV expression of MHC is significantly decreased. ACT RV expression is decreased only N-ISC HF.