tbuckley/cabot-search huggingface dataset:
Randomized Outpatient Trial of Single- and Dual-Hormone Closed-Loop Systems That Adapt to Exercise Using Wearable Sensors
Authors: Jessica R. Castle, Joseph El Youssef, Leah M. Wilson, Ravi Reddy, Navid Resalat, Deborah Branigan, Katrina Ramsey, Joseph Leitschuh, Uma Rajhbeharrysingh, Brian Senf, Samuel M. Sugerman, Virginia Gabo, Peter G. Jacobs
Journal: Diabetes Care (2018)

Automated insulin delivery is the new standard for type 1 diabetes, but exercise-related hypoglycemia remains a challenge. Our aim was to determine whether a dual-hormone closed-loop system using wearable sensors to detect exercise and adjust dosing to reduce exercise-related hypoglycemia would outperform other forms of closed-loop and open-loop therapy.Participants underwent four arms in randomized order: dual-hormone, single-hormone, predictive low glucose suspend, and continuation of current care over 4 outpatient days. Each arm included three moderate-intensity aerobic exercise sessions. The two primary outcomes were percentage of time in hypoglycemia (<70 mg/dL) and in a target range (70-180 mg/dL) assessed across the entire study and from the start of the in-clinic exercise until the next meal.The analysis included 20 adults with type 1 diabetes who completed all arms. The mean time (SD) in hypoglycemia was the lowest with dual-hormone during the exercise period: 3.4% (4.5) vs. 8.3% (12.6) single-hormone (P = 0.009) vs. 7.6% (8.0) predictive low glucose suspend (P < 0.001) vs. 4.3% (6.8) current care where pre-exercise insulin adjustments were allowed (P = 0.49). Time in hypoglycemia was also the lowest with dual-hormone during the entire 4-day study: 1.3% (1.0) vs. 2.8% (1.7) single-hormone (P < 0.001) vs. 2.0% (1.5) predictive low glucose suspend (P = 0.04) vs. 3.1% (3.2) current care (P = 0.007). Time in range during the entire study was the highest with single-hormone: 74.3% (8.0) vs. 72.0% (10.8) dual-hormone (P = 0.44).The addition of glucagon delivery to a closed-loop system with automated exercise detection reduces hypoglycemia in physically active adults with type 1 diabetes.
Abstract 12512: Combination of Global Longitudinal Strain and Late Gadolinium Enhancement Predicts Improvement of Systolic Function After Aortic Valve Replacement in Patients With Severe Aortic Stenosis
Authors: Tsuyoshi Fujimiya, Masumi Iwai-Takano, Takashi Igarashi, Shinya Takase, Hitoshi Yokoyama
Journal: Circulation (2016)

Introduction: Myocardial fibrosis correlates with post-operative prognosis in patients with severe aortic stenosis (AS). There were a few reports that global longitudinal strain (GLS) by echocardiography decreased and correlated with myocardial fibrosis and/or late gadolinium enhancement (LGE) by MRI in patients with AS. However, it remains unclear whether GLS and LGE are possible to predict improvement of myocardial function after aortic valve replacement (AVR). Hypothesis: The combination of GLS and LGE identify the systolic dysfunction including myocardial fibrosis in severe AS, and predicts the improvement of systolic function after AVR. Methods: In 27 patients with severe AS before AVR, we examined GLS by 2D speckle tracking echocardiography and LGE by MRI for assessment of myocardial fibrosis, i.e., LGEcore(g): &gt;mean of normal area +5SD, LGEgray(g): mean of normal area +2~5SD, and LGEcore+gray(g): LGEcore+LGEgray. In addition, fibrosis index (FI, %), as the percentage of fibrosis in myocardial specimen, was calculated in 11 patients. We evaluated the relationship among the GLS, the LGEs and the FI. Moreover, at 1 year after AVR, we assessed which indices in pre-operative period related to the improvement of GLS. Results: The mean values of indices were: GLS -15.6±0.9%, LGEcore 5.0±1.3g (4.5±1.2%), LGEgray 12.5±1.9g (11.5±1.4%), LGEcore+gray 17.5±3.0g (16.1±2.4%) and FI 7.1±1.4%. The FI related with the GLS (R=0.60, P&lt;0.05), the LGEcore (R=0.58, P&lt;0.05), and the LGEcore+gray (R=0.54, P&lt;0.05). On the other hand, the GLS related to the LGEcore (R=0.50, P&lt;0.05), LGEgray (R=0.52, P&lt;0.05) and the LGEcore+gray (R=0.60, P&lt;0.01). After AVR, the GLS was significantly improved (-15.0±1.2 to -18.6±1.1%, P&lt;0.05). The LGE core before AVR was significantly smaller in the improvement group (GLS≥-19.0%) than the un-improvement group (GLS&lt;-19.0%) (1.3±0.4 vs 7.1±2.5g, P&lt;0.05). Conclusions: In patients with severe AS, GLS before AVR related with the mild to severe myocardial fibrosis. Moreover, the patients with severe fibrosis did not show the improvement of GLS in follow-up period. The combination of GLS and LGE will identify the potential systolic dysfunction including myocardial fibrosis, and predicts the improvement of systolic function after AVR.
P372Heparin binding copolymer reverses the anticoagulant activity of low molecular weight heparins: safety and efficacy data in rats
Authors: J Miklosz, B Kalaska, K Kaminski, K Szczubialka, D Pawlak, M Nowakowska, A Mogielnicki
Journal: Cardiovascular Research (2018)

parameters of heart biomechanics and main arteries kinetics (carotid, radial, ulnaris, posterior tibia, arch of foot arteries), which characterized speed, acceleration, capacity and work in each phase of heart cycle in systole and diastole, and also the periods of dominance of outflow over inflow.For that we used by doppler-ultrasound and sphygmography.We analyzed the peak speed direct blood flow, blood flow volume.We valued the contribute to the circulation of the premature contraction and first post-extrasystolic contraction.The volume of cardiac output and transmitral blood flow were measured by echocardiography.We identified the moment of extrasysyoles' appearance by using apex-cardiography and ECG.We classified extrasystoles in accordance to the moment of their appearance in cardio cycle.We have identified: Extrasysoles before the mitral valve opening.Extrasystoles in rapid ventricular filling phase before the transmitral blood flow peak.Extrasystoles in rapid ventricular filling phase after the transmitral blood flow peak.Extrasystoles in slow ventricular filling phase.Results: and conclusion.The main role in hemodynamic and kinetics changes play the time of extrasystole appearance in cardio cycle and the ability of the first post-extrasystolic contruction to reestablish an adequate resulting blood flow.If there's a patient with multifocal atherosclerosis in main arteries the sharp increase of hemodynamic and kinetic parameters of arteries increase deformation of vascular wall.The maximums of these parameters are revealed in first post-extrasystolic contruction in case of extrasystoles before the mitral valve opening and before the transmitral peak flow.In atrial fibrillation the main danger are the first ventricular contractions after the maximum time pauses.It causes the significant increase of cardiac output, arteries diameter as well as non-stability of atheromas and mural thrombus fragmentation with high embolism probability.
Ledipasvir/sofosbuvir with or without ribavirin for 8 or 12 weeks for the treatment of HCV genotype 4 infection: results from a randomised phase III study in Egypt
Authors: Gamal Shiha, Gamal Esmat, Mohamed Hassany, Reham Soliman, Mohamed Elbasiony, Rabab Fouad, Aisha Elsharkawy, Radi Hammad, Wael Abdel-Razek, Talaat Zakareya, Kathryn Kersey, Benedetta Massetto, Anu Osinusi, Sophia Lu, Diana M Brainard, John G McHutchison, Imam Waked, Wahid Doss
Journal: Gut (2018)

We evaluated the efficacy and safety of ledipasvir/sofosbuvir alone and with ribavirin for 8 and 12 weeks in Egyptian patients with and without cirrhosis, who were infected with hepatitis C virus (HCV) genotype 4, including those who had failed previous treatment with sofosbuvir regimens.In this open-label, multicentre, phase III study, treatment-naive patients were randomised to receive 8 or 12 weeks of ledipasvir/sofosbuvir±ribavirin. Interferon treatment-experienced patients were randomised to receive 12 weeks of ledipasvir/sofosbuvir±ribavirin, while sofosbuvir-experienced or ledipasvir/sofosbuvir-experienced patients received 12 weeks of ledipasvir/sofosbuvir+ribavirin. Randomisation was stratified by cirrhosis status. The primary endpoint was sustained virological response 12 weeks post-treatment (SVR12).We enrolled 255 patients from four centres in Egypt. Among treatment-naive patients, SVR12 rates were 95% and 90% for those receiving 8 weeks of ledipasvir/sofosbuvir alone and with ribavirin, respectively, and 98% for those receiving 12 weeks of ledipasvir/sofosbuvir both alone and with ribavirin. Among interferon-experienced patients, SVR rates were 94% for those receiving 12 weeks of ledipasvir/sofosbuvir and 100% for those receiving 12 weeks of ledipasvir/sofosbuvir plus ribavirin. All patients previously treated with sofosbuvir regimens who received ledipasvir/sofosbuvir plus ribavirin achieved SVR12. The most common adverse events, headache and fatigue, were more common among patients receiving ribavirin.Among non-cirrhotic treatment-naive patients with HCV genotype 4, 8 weeks of ledipasvir/sofosbuvir±ribavirin was highly effective. Twelve weeks of ledipasvir/sofosbuvir±ribavirin was highly effective regardless of presence of cirrhosis or prior treatment experience, including previous treatment with sofosbuvir or ledipasvir/sofosbuvir.NCT02487030.
A new prognostic model identifies patients aged 80 years and older with diffuse large B‐cell lymphoma who may benefit from curative treatment: A multicenter, retrospective analysis by the Spanish GELTAMO group
Authors: Emilia Pardal, Eva Díez Baeza, Queralt Salas, Tomás García, Juan M. Sancho, Encarna Monzón, José M. Moraleda, Raúl Córdoba, Fátima de la Cruz, José A. Queizán, María J. Rodríguez, Belén Navarro, José A. Hernández, Rosana Díez, María Vahi, María C. Viguria, Miguel Canales, María J. Peñarrubia, Tomás J. González‐López, Santiago Montes‐Moreno, Eva González‐Barca, Dolores Caballero, Alejandro Martín
Journal: American Journal of Hematology (2018)

The means of optimally managing very elderly patients with diffuse large B-cell lymphoma (DLBCL) has not been established. We retrospectively analyzed 252 patients aged 80-100 years, diagnosed with DLBCL or grade 3B follicular lymphoma, treated in 19 hospitals from the GELTAMO group. Primary objective was to analyze the influence of the type of treatment and comorbidity scales on progression-free survival (PFS) and overall survival (OS). One hundred sixty-three patients (63%) were treated with chemotherapy that included anthracyclines and/or rituximab, whereas 15% received no chemotherapeutic treatment. With a median follow-up of 44 months, median PFS and OS were 9.5 and 12.5 months, respectively. In an analysis restricted to the 205 patients treated with any kind of chemotherapy, comorbidity scales did not influence the choice of treatment type significantly. Independent factors associated with better PFS and OS were: age < 86 years, cumulative illness rating scale (CIRS) score < 6, intermediate risk (1-2) R-IPI, and treatment with R-CHOP at full or reduced doses. We developed a prognostic model based on the multivariate analysis of the 108 patients treated with R-CHOP-like: median OS was 45 vs. 12 months (P = .001), respectively, for patients with 0-1 vs. 2-3 risk factors (age > 85 years, R-IPI 3-5 or CIRS > 5). In conclusion, treatment with R-CHOP-like is associated with good survival in a significant proportion of patients. We have developed a simple prognostic model that may aid the selection patients who could benefit from a curative treatment, although it needs to be validated in larger series.
Type I interferons in tuberculosis: Foe and occasionally friend
Authors: Lúcia Moreira-Teixeira, Katrin Mayer-Barber, Alan Sher, Anne O’Garra
Journal: The Journal of Experimental Medicine (2018)

Tuberculosis remains one of the leading causes of mortality worldwide, and, despite its clinical significance, there are still significant gaps in our understanding of pathogenic and protective mechanisms triggered by Mycobacterium tuberculosis infection. Type I interferons (IFN) regulate a broad family of genes that either stimulate or inhibit immune function, having both host-protective and detrimental effects, and exhibit well-characterized antiviral activity. Transcriptional studies have uncovered a potential deleterious role for type I IFN in active tuberculosis. Since then, additional studies in human tuberculosis and experimental mouse models of M. tuberculosis infection support the concept that type I IFN promotes both bacterial expansion and disease pathogenesis. More recently, studies in a different setting have suggested a putative protective role for type I IFN. In this study, we discuss the mechanistic and contextual factors that determine the detrimental versus beneficial outcomes of type I IFN induction during M. tuberculosis infection, from human disease to experimental mouse models of tuberculosis.
SWOG S1115: Randomized phase II trial of selumetinib (AZD6244; ARRY 142886) hydrogen sulfate (NSC-748727) and MK-2206 (NSC-749607) vs. mFOLFOX in pretreated patients (Pts) with metastatic pancreatic cancer.
Authors: Vincent M. Chung, Shannon L McDonough, Philip Agop Philip, Dana Backlund Cardin, Andrea Wang-Gillam, Laifong Hui, Andrew M. Lowy, Katherine Guthrie, Charles David Blanke, Howard S. Hochster
Journal: Journal of Clinical Oncology (2015)

4119 Background: Over 90% of pancreatic cancers (PC) have mutant KRAS that is at present not druggable. Activating mutations lead to signaling through RAF/MEK/ERK and PI3K/AKT/mTOR pathways leading to cell growth, proliferation and survival. Pre-clinical data suggest that simultaneously blockade of these pathways is effective in treating KRASmutant tumors. Our trial evaluated this novel, molecularly targeted treatment approach in pancreatic cancer versus mFOLFOX chemotherapy. Methods: 113 pts (PS 0-1) with metastatic PC failing gemcitabine-based therapy were randomized to MK-2206 135 mg weekly plus selumetinib 100 mg daily (MS) or mFOLFOX6 (without bolus 5FU) every 2 weeks. Overall survival (OS) was the primary endpoint with secondary objectives evaluating toxicities, objective tumor response and progression free survival (PFS). Results: Pt characteristics and results are in the table. 34 pts had grade 3 toxicities in the MS arm vs. 19 in the mFOLFOX arm. The most common grade 3 toxicities in the MS arm include rash, mucositis, dehydration and fatigue while for mFOLFOX arm, hematologic toxicities, fatigue, nausea and vomiting. In the MS arm vs. mFOLFOX, there were 0 vs 3 pts with a partial response and 8 vs 9 pts with stable disease, respectively. Shorter survival was observed in the MS arm (median OS 4.0 vs 7.5 mos, hazard ratio (HR) 1.46, 95% CI 0.90-2.38; median PFS 2 mos for each, HR 1.43, 95% CI 0.93-2.20). Approximately 50% of the patients on the mFOLFOX arm went on to receive additional therapy as compared to 30% on the MS arm. Conclusions: MS did not improve OS in pts who previously failed gemcitabine chemotherapy. Collected tissue will be analyzed for potential biomarkers. Clinical trial information: NCT01658943. mFOLFOX (n=60) AZD-6244 + MK-2206 (n=53) AGE (median, years) 66.0 68.7 SEX Females 39 65% 23 43% PERFORMANCE STATUS 0 27 45% 22 42% 1 33 55% 31 58% DURATION OF GEMCITABINE BASED THERAPY ≤ 4 months 22 37% 20 38% LIVER METASTASES Yes 39 65% 38 72% NUMBER OFF PROTOCOL TREATMENT DUE TO: Adverse Event (AE) 6 13 Refusal unrelated to AE 8 2 Progression/relapse 37 36 MEDIAN SURVIVAL (months) Progression-free 2.0 2.0 Overall 7.5 4.0
Abstract 11884: MRI and ICDs or Pacemakers After Magnsafe
Authors: Steve Mason, Allison Tonkin, Jeffrey S Osborn, Jon-David Ethington, Jeffrey L Anderson, Ritesh Dhar, T J Bunch, Donald L Lappé, Viet T Le, Kirk U Knowlton
Journal: Circulation (2016)

Introduction: The MagnaSafe registry was a prospective study that examined cardiac implantable electronic devices (CIED) parameter changes when exposed to non-thoracic MRI scanning. This registry data showed that MRI scans in patients with a CIED can be performed safely. Ongoing real-word data that encompasses newer CIED technologies are required to further understand outcomes of non-MRI conditional CIED parameters after exposure to 1.5 Tesla extra-thoracic MRI. These data are especially pertinent as the REPLACE trial showed a 4% (without leads) and 15% (with leads) risk of major complications with upgrade to a MRI conditional device. Methods: We prospectively examined 152 patients with either a pacemaker or ICD who underwent MR imaging between 2-12-2014 date and 3-15-2016 dates using a General Electric 1.5 Tesla model Optima MR450w scanner. Ambient temperature was set at 19 ° C. Pacing modes during MRI were 0D0 for intrinsic rates &gt;40 and D00 for rates ≤40. All patients were cleared prior to scan by both Radiology and Cardiology per our in-house developed standard protocol with pre- and post-MRI CIED interrogation. Primary outcomes were death, generator or lead failure. Secondary outcomes were a battery voltage loss of &gt;0.04 V, decrease in P wave voltage of &gt;50% and R wave voltage of &gt;25%, a threshold increase of &gt;0.5 V, and an impedance change of &gt;50 Ω. Results: 181 scans were performed in 50(28%) patients with pacemakers and 131(72%) patients with ICDs. A summary of vendor and device type is listed. No patients experienced a primary or secondary outcome, regardless of whether the device was MRI-conditional. By design, each patients underwent a post MRI device interrogation there were no parameter changes seen or device complications. Conclusions: Real-world ongoing device surveillance at Intermountain Medical Center using the MagnaSafe registry approach and endpoint to demonstrate that 1.5 Tesla extra-thoracic MRI scanning is safe in patients with all forms of CIED, regardless of whether the device was MRI conditional.. This data extend to newer Bi-V technologies and lead designs as well as subcutaneous ICDs. This data continue to support that clinically-indicated MRI tests need not be withheld in patients with CIEDs.
Abstract 20869: Preservation of Transplant Organ Function and Recipient Survival With Thrombin-Targeted Perfluorocarbon Nanoparticles Perfused Ex Vivo
Authors: Chandu Vemuri, Ara Upadhya, Batool Arif, J Jia, Joe Gaut, Pam Manning, Y Lin, Samuel Wickline, William Chapman
Journal: Circulation (2016)

Introduction:  Methods to improve functionality of excised organs harvested for transplant could extend the time available for selection and implantation and enhance transplant opportunities for millions of potential organ recipients. For proof of concept, we elected to test kidney preservation with use of methods that could be applicable to all other tissues such as the heart, liver and lungs.   Hypothesis:  We hypothesized that perfusion of explanted allografts with thrombin-targeted perfluorocarbon nanoparticles (PFC-NP) could attenuate organ inflammation, prevent ischemic injury by inhibiting microvascular thrombosis, and thereby improve graft function.   Methods:  Male Lewis rats underwent left renal explantation followed by perfusion with 0.3 ml of untargeted PFC-NP (N=4), 0.3 ml thrombin-targeted PFC NP functionalized with the anti-thrombin molecule PPACK (phenylalanine-proline-arginine-chloromethylketone), an irreversible thrombin inhibitor, (N=4) or standard perfusate (N=3). Kidneys then underwent 60 minutes of warm ischemia and 6 hours of cold incubation, followed by transplantation into recipients and native nephrectomy. Blood was collected at 48 hours post-transplant and the animals were euthanized. Kidney biopsies were processed for blinded histologic analysis. A survival experiment was then performed using the protocol as above in Male Lewis rats with standard perfusate (N=3), empty nanoparticle (N=3) and PFC-PPACK (N=6).   Results:  Serum Cr at 48 hrs was substantially improved for the PPACK PFC NP groups as compared to control groups: 6.3 vs 5.2 vs 1.9 mg/dl for control, PFC-NP, and PPACK NP (p   Conclusions:  Nanoparticles targeted to thrombin preserved explanted organ function in a syngeneic transplant model and extended survival, offering a simple approach for preserving tissue integrity under conditions of even extreme prolonged ischemia.
Symptom relief does not reflect reduced clinical events in heart failure: a report from the ATLAS study
Authors: Kristian Anton Thygesen, P.W. Armstrong, J.G.F. Cleland, J.D. Horowitz, B.M. Massie, M. Packer, P.A. Poole-Wilson, L. Rydén, B. Uretsky
Journal: European Journal of Heart Failure (1999)
Autism-associated neuroligin-4 mutation selectively impairs glycinergic synaptic transmission in mouse brainstem synapses
Authors: Bo Zhang, Ozgun Gokce, W. Dylan Hale, Nils Brose, Thomas C. Südhof
Journal: The Journal of Experimental Medicine (2018)

In human patients, loss-of-function mutations of the postsynaptic cell-adhesion molecule neuroligin-4 were repeatedly identified as monogenetic causes of autism. In mice, neuroligin-4 deletions caused autism-related behavioral impairments and subtle changes in synaptic transmission, and neuroligin-4 was found, at least in part, at glycinergic synapses. However, low expression levels precluded a comprehensive analysis of neuroligin-4 localization, and overexpression of neuroligin-4 puzzlingly impaired excitatory but not inhibitory synaptic function. As a result, the function of neuroligin-4 remains unclear, as does its relation to other neuroligins. To clarify these issues, we systematically examined the function of neuroligin-4, focusing on excitatory and inhibitory inputs to defined projection neurons of the mouse brainstem as central model synapses. We show that loss of neuroligin-4 causes a profound impairment of glycinergic but not glutamatergic synaptic transmission and a decrease in glycinergic synapse numbers. Thus, neuroligin-4 is essential for the organization and/or maintenance of glycinergic synapses.
Evolution of Genome Architecture in Archaea: Spontaneous Generation of a New Chromosome in Haloferax volcanii
Authors: Darya Ausiannikava, Laura Mitchell, Hannah Marriott, Victoria Smith, Michelle Hawkins, Kira S Makarova, Eugene V Koonin, Conrad A Nieduszynski, Thorsten Allers
Journal: Molecular Biology and Evolution (2018)

The common ancestry of archaea and eukaryotes is evident in their genome architecture. All eukaryotic and several archaeal genomes consist of multiple chromosomes, each replicated from multiple origins. Three scenarios have been proposed for the evolution of this genome architecture: 1) mutational diversification of a multi-copy chromosome; 2) capture of a new chromosome by horizontal transfer; 3) acquisition of new origins and splitting into two replication-competent chromosomes. We report an example of the third scenario: the multi-origin chromosome of the archaeon Haloferax volcanii has split into two elements via homologous recombination. The newly generated elements are bona fide chromosomes, because each bears "chromosomal" replication origins, rRNA loci, and essential genes. The new chromosomes were stable during routine growth but additional genetic manipulation, which involves selective bottlenecks, provoked further rearrangements. To the best of our knowledge, rearrangement of a naturally evolved prokaryotic genome to generate two new chromosomes has not been described previously.
Establishment of persistent functional remission of HBV and HDV infection following REP 2139 and pegylated interferon alpha 2a therapy in patients with chronic HBV/HDV co-infection: 18 month follow-up results from the REP 301-LTF study
Authors: M. Bazinet, V. Pantea, V. Cebotarescu, L. Cojuhari, P. Jimbei, A. Vaillant
Journal: Journal of Hepatology (2018)