tbuckley/cabot-search huggingface dataset:
Abstract 19708: Pre-Hospital Initiation of Therapeutic Hypothermia Associated With Better Survival and Neurologic Outcome in a Broad Population of Patients in North Carolina
Authors: Meena P Rao, Matthew Dupre, Carolina Hansen, Sarah Milford-Beland, Lisa Monk, Clark Tyson, David A Pearson, Robert D Nelson, Brent Meyers, James G Jollis, Christopher B Granger
Journal: Circulation (2014)

Introduction: Out-of-hospital cardiac arrest (OHCA) has less than 10% hospital survival. While therapeutic hypothermia resulted in a 16%-24% improvement in neurologic outcome in patients with ventricular fibrillation (VF) in prior trials, recent trials have not shown benefit of pre-hospital initiation hypothermia or of hospital cooling to 33 vs 36 degrees. Methods: We studied patients who suffered OHCA in North Carolina from 2012-2013 captured in the CARES database as part of the Heart Rescue Project. To limit selection bias, we excluded patients without return of spontaneous circulation after arrest and without intubation in the field as they may have regained consciousness. Results: 847 patients were included in the analysis of pre-hospital hypothermia. The patients that received pre-hospital hypothermia had more bystander initiated CPR (p-value &lt; 0.45). Pre-hospital hypothermia was associated with a significant increase in survival to hospital discharge (OR 1.55, 95% CI 1.03-2.32) and neurologic outcome at discharge (OR 1.56 95% CI 1.01-2.40). When looking at arrest types, the significant association was seen after VF arrest (figure). 537 patients survived to hospital admission and included in the analysis of in-hospital hypothermia. Patients who received hospital hypothermia were younger, had more VF, more witnessed arrest and more pre-hospital hypothermia. Hypothermia showed a non-significant trend toward better survival to discharge. Conclusions: The association between pre-hospital hypothermia after VF arrest and improved survival, in light of randomized data showing no effect, may be due to confounding or to a greater likelihood of in-hospital hypothermia in this group. The trend in better outcome using in-hospital hypothermia is consistent with a benefit from temperature management. These findings suggest the need for ongoing efforts to understand the value of hypothermia in context of other efforts to improve survival from cardiac arrest.
Abstract 644: Impact of conjugation site on pharmacokinetics and off-target toxicity of site-specific antibody drug conjugates
Authors: Dangshe Ma, Fang Jin, Frank Barletta, George Hu, Nathan Tumey, Haige Zhang, Tao He, Eric Sousa, Manoj Charti, Kiran Khadke, Judy Lucas, Darren Ferguson, Christoper Brown, Weijun Ma, Scott Gatto, William Brady, Edmund Graziani, Hans-Peter Gerber, Puja Sapra, Lioudmila Tchistikova
Journal: Cancer Research (2015)

Abstract Site-specific conjugation of toxic payload to antibody yields homogeneous ADCs resulting in improved therapeutic index over conventional conjugation. To understand the role of conjugation site on pharmacokinetics, off-target toxicity, cysteine(cys) was engineered into a humanized anti-IL13Rα2 antibody, hAB08, at various sites within the IgG1/k constant domains. Single cys mutants L443C and Q347C with DAR 2, and double cys mutants K392C+L443C, L443C/kK183C and Q347C/kK183C with DAR 4 were conjugated using auristatin 0101 via maleimidocapronic - valine-citruline-p-aminobenzyloxycarbonyl (vc, cleavable linker). All cys mutants and their conjugates maintained their binding properties compared to parental hAb08. Cysteine substitution sites were selected based on conjugation efficiency and in vitro stability. In vivo efficacy was evaluated in mouse xenograph tumor models. Pharmacokinetics (PK) and off target toxicity (TOX) were assessed in both mouse and rat in vivo studies. Our data demonstrate that that all site specific conjugates show improved in vitro stability, comparable or better in vivo efficacy in mice xenograph models and in vivo stability (ratio of ADC-AUC/Ab-AUC) compared to conventional conjugates. However PK and off-target toxicity of antibody drug conjugates had been significantly impacted by conjugation site and animal species. L443 mutants show higher ADC-AUC, lower clearance and longer half life than Q347 mutants in mice while a reverse TK behavior was observed in rat. All site specific conjugates show higher dose tolerance and less off-target toxicity relative to conventional conjugates in rat. This off-target toxicity improvement depends on sites of conjugation. The L443 mutants exhibited a better off-target TOX profile relative to Q347 mutants. Taken together, site-specific conjugation improved in vivo efficacy and off-target toxicity relative to conventionally conjugated ADC. PK differences and off-target toxicity improvements depend on conjugation sites and animal species. Note: This abstract was not presented at the meeting. Citation Format: Dangshe Ma, Fang Jin, Frank Barletta, George Hu, Nathan Tumey, Haige Zhang, Tao He, Eric Sousa, Manoj Charti, Kiran Khadke, Judy Lucas, Darren Ferguson, Christoper Brown, Weijun Ma, Scott Gatto, William Brady, Edmund Graziani, Hans-Peter Gerber, Puja Sapra, Lioudmila Tchistikova. Impact of conjugation site on pharmacokinetics and off-target toxicity of site-specific antibody drug conjugates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 644. doi:10.1158/1538-7445.AM2015-644
Harmonising Outcome Measures for Eczema (HOME).Report from the First International Consensus Meeting (HOME 1), 24 July 2010, Munich, Germany
Authors: J. Schmitt, H. Williams
Journal: British Journal of Dermatology (2010)

Current clinical research in eczema (atopic dermatitis) is hampered by a profusion of outcome measures, most of which have not been developed or tested adequately. The first Harmonising Outcome Measures for Eczema meeting (HOME 1) was an exploratory meeting to determine whether there was sufficient interest and enthusiasm in the international scientific community to form a collaborative group to define a minimum set of core outcomes for future eczema (atopic dermatitis) research. The meeting was open to all participants of the 6th Georg Rajka Symposium/International Symposium on Atopic Dermatitis/New Trends in Allergy VII meeting in Munich, 22-24 July 2010. Approximately 40 individuals attended. Prior to the meeting, an international Delphi exercise was performed to develop consensus-based sets of core outcome domains for eczema for 'controlled trials' and 'clinical recordkeeping'. The results of this Delphi exercise were presented at the meeting and critically discussed by the attendees. The constructive group discussion identified several important issues for future eczema outcomes research such as the degree to which patients and carers can be involved and the importance of involving colleagues from countries not represented at the meeting. In summary, this exploratory meeting indicated a genuine interest in the academic eczema community to form an international multiprofessional group dedicated to harmonizing outcomes research in eczema. The group decided to continue collaboratively with the HOME initiative.
A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis
Authors: Ayalew Tefferi, Terra L. Lasho, Kebede H. Begna, Mrinal M. Patnaik, Darci L. Zblewski, Christy M. Finke, Rebecca R. Laborde, Emnet Wassie, Lauren Schimek, Curtis A. Hanson, Naseema Gangat, Xiaolin Wang, Animesh Pardanani
Journal: New England Journal of Medicine (2015)

Current drugs for myeloproliferative neoplasm-associated myelofibrosis, including Janus kinase (JAK) inhibitors, do not induce complete or partial remissions. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase reverse transcriptase.We sought to obtain preliminary information on the therapeutic activity and safety of imetelstat in patients with high-risk or intermediate-2-risk myelofibrosis. Imetelstat was administered as a 2-hour intravenous infusion (starting dose, 9.4 mg per kilogram of body weight) every 1 to 3 weeks. The primary end point was the overall response rate, and the secondary end points were adverse events, spleen response, and independence from red-cell transfusions.A total of 33 patients (median age, 67 years) met the eligibility criteria; 48% had received prior JAK inhibitor therapy. A complete or partial remission occurred in 7 patients (21%), with a median duration of response of 18 months (range, 13 to 20+) for complete responses and 10 months (range, 7 to 10+) for partial responses. Bone marrow fibrosis was reversed in all 4 patients who had a complete response, and a molecular response occurred in 3 of the 4 patients. Response rates were 27% among patients with a JAK2 mutation versus 0% among those without a JAK2 mutation (P=0.30) and 32% among patients without an ASXL1 mutation versus 0% among those with an ASXL1 mutation (P=0.07). The rate of complete response was 38% among patients with a mutation in SF3B1 or U2AF1 versus 4% among patients without a mutation in these genes (P=0.04). Responses did not correlate with baseline telomere length. Treatment-related adverse events included grade 4 thrombocytopenia (in 18% of patients), grade 4 neutropenia (in 12%), grade 3 anemia (in 30%), and grade 1 or 2 elevation in levels of total bilirubin (in 12%), alkaline phosphatase (in 21%), and aspartate aminotransferase (in 27%).Imetelstat was found to be active in patients with myelofibrosis but also had the potential to cause clinically significant myelosuppression. (Funded by Geron; ClinicalTrials.gov number, NCT01731951.).
Rebuttal from Authors re: Axel Heidenreich. Identification of High-Risk Prostate Cancer: Role of Prostate-Specific Antigen, PSA Doubling Time and PSA Velocity. Eur Urol 2008;54:976–7
Authors: Stacy Loeb, Anna Kettermann, Luigi Ferrucci, Patricia Landis, E. Jeffrey Metter, H. Ballentine Carter
Journal: European Urology (2008)
Abstract 16029: Periprocedural Change of the Index of Microcirculatory Resistance in Patients Treated With Elective Stenting
Authors: Tadashi Murai, Taishi Yonetsu, Tetsumin Lee, Kenji Koura, Takamitsu Takagi, Toshiyuki Iwai, Tsunekazu Kakuta
Journal: Circulation (2011)

BACKGROUND Recently, an index of microcirculatory resistance (IMR) was developed that is based on combined measurements of distal coronary pressure and thermodilution-derived mean transit time. Thi...
Abstract 4328: Integrated Network and Microarray Analysis to Identify New Biomarkers of Heart Failure after Myocardial Infarction
Authors: Yvan Devaux, Céline Yvorra, Mélanie Vausort, Céline Jeanty, Francisco Azuaje, Daniel Wagner
Journal: Circulation (2008)

Purpose : A significant proportion of acute myocardial infarction (MI) patients develop heart failure (HF). Early identification of patients at risk of developing HF after MI would be a major breakthrough. An approach combining the power of biological information networks and the precision of microarray analysis was undertaken to identify new biomarkers of HF. Methods : Since angiogenesis may be related to MI and HF, a protein-protein interaction (PPI) network was constructed by first extracting from the Entrez-Gene database a set of genes relevant to angiogenesis and MI. These genes were used as inputs to retrieve annotated interactions from the Human Protein Reference Database. Potential biomarkers were identified by network analysis. Gene expression profiles of blood cells taken at the time of MI in two groups of 16 patients (high ejection fraction (EF) at 1 month, EF≥45% and low EF at 1 month, EF≤40%) were obtained using oligonucleotide microarrays containing 25,000 genes and compared by Statistical Analysis of Microarrays (SAM). Prediction models based on machine learning were used to classify low and high EF patients. Results : SAM identified 525 genes differentially expressed between patients with high and low EF (fold-change ≥1.3). The PPI network included 556 nodes (proteins) and 686 edges (interactions). A network clustering algorithm identified 53 proteins highly specialized in growth and regulation processes. Out of these, 38 were found differentially expressed by SAM. Further filtering reported 3 genes as the optimal biomarker set: Vascular Endothelial Growth Factor B (VEGFB), Placental Growth Factor (PGF), both pro-angiogenic, and the anti-angiogenic protein Thrombospondin-1 (THBS1). Prediction models reported areas under the receiver operating characteristic curve (AUC) of 0.82 for this biomarker set. Conclusion : The classification performances achieved with the 3 biomarkers stresses the prognostic value of genes involved in angiogenesis. The network-based approach allowed us to identify powerful biomarkers, which could not be identified by applying standard gene expression data analysis only. Therefore, combined network and microarray analysis allows a systematic and less biased approach to biomarker discovery.
Abstract 11567: The Transcription Cofactor Eya4 Regulates Age-dependent Adverse Cardiac Physiology
Authors: Tatjana Williams, Moritz Hundertmark, Jost Schonberger, Peter Nordbeck, Sabine Voll, Martin Czolbe, Vera Pekarek, Oliver Ritter
Journal: Circulation (2012)

Introduction: We identified a mutation in the human transcription cofactor Eya4 (E193) to cause terminal heart failure preceded by sensorineural hearing loss. Eya proteins lack DNA-binding and nuclear translocation sequences and therefore must interact with real transcription factors, including Six family members. The cyclin-dependent kinase inhibitor p27kip1 (p27), one of the few known Eya-Six targets expressed in the heart has been shown to inhibit hypertrophic growth in adult cardiomyocytes. We hypothesize that Eya4/Six1 regulates targets relevant to sustain normal cardiac function via p27. Methods and results: We examined the correlation of Eya4 and the mutant E193 overexpression upon p27 in permanent mammalian cell lines and primary cardiac myocytes. Westernblot analysis demonstrated that an overexpression of Eya4 led to a significant suppression of p27, whereas E193 had no effect on p27 levels; knockdown of Eya4 via siRNA exerted opposing effects. Promoter studies using a p27 promoter fragment inclu...
Enlargement of the Prostate. Its History, Anatomy, Etiology, Pathology, Clinical Causes, Symptoms, Diagnosis, Prognosis, Treatment; Technique of Operations, and After-Treatment.
Authors: John B. Deaver, Leon Herman
Journal: JAMA (1923)

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Application CAT questionnaire of the treatment of patients with COPD
Authors: Miroslav Ilic, Ivan Kopitovic, Biljana Zvezdin, Nikolina Tomasevic, Ljiljana Vitas
Journal: European Respiratory Journal (2013)

CAT is a new, simple questionnaire, designed to provide reliable insight into the control of the health status of patients with COPD.  The aim of the study was to determine how the results of CAT questionnaire correlated with clinical characteristics and lung function parameters in order to obtain quick and safe indicator of the course and treatment of COPD.  Method: Study included 200 patients (randomized accident) who have been diagnosed with COPD. Over a period of three months (2011), including patients who are appearing for the first time, as well as those that have occurred up exam. Each patient prior to the examination and spirometry given CAT questionnaire to fill it independently.  Results. There were 54 (25.7 %) patients had CAT 10, p = 0.041. Patients were evaluated as worsening of 56 (31.1%), 78.6% of them (44/56) belonged to the CAT>10, p = 0673. Patients were evaluated as no change in their health status, 23.1% of 52 had CAT>10.  Conclusion: Serial application of CAT questionnaire in GP and pulmonary specialists as a field test at regular intervals, along with spirometry is extremely useful for the assessment of disease severity, treatment and therapeutic response.
Abstract 357: Novel Gain of Function SCN5A Mutation Causes Familial Atrial Fibrillation
Authors: Julie Rutberg, Hai Huang, Robert Lemery, Anthony Tang, David Birnie, Martin Green, B. Khanh Lam, Robert Roberts, Mohamed Chahine, Michael Gollob
Journal: Circulation (2007)

Background : Few genetic etiologies are known for familial or sporadic cases of atrial fibrillation, which is the most common arrhythmia in older adults. We report a mother and son, both with atrial fibrillation, who were found to have a novel mutation in the sodium channel gene, SCN5A. Case History: The proband, a 50 year old male, first developed paroxysmal atrial fibrillation following orthopedic surgery. At age 57, he presented with increasing fatigue and shortness of breath and was found to have chronic atrial fibrillaion. Cardiac testing found no evidence of ischemia, normal left ventricular function and mild left atrial dilation. His mother had paroxysmal atrial fibrillation, diagnosed at age 63, and a history of well-controlled hypertension and palpitations. Her atrial fibrillation was initially controlled by sotalol, but worsening symptoms led to a change to amiodarone at age 83. Her echo showed mild biatrial enlargement. ECGs for the proband and his mother have never demonstrated conduction system disease, long QT, or a Brugada pattern. Methods and Results: Genomic DNA isolated from blood lymphocytes was screened using direct sequencing techniques. Genes previously reported to be associated with atrial fibrillation, KCNA5, GJA5 and KCNQ1, were screened and no mutations were found. In the sodium channel gene, SCN5A, a novel missense mutation was identified (c. 1493K&gt;R) in both the proband and his mother, but not in an unaffected sibling or in the proband’s 2 asymptomatic offspring. The mutation is in a highly conserved lysine residue in the voltage-gated sodium channel gene family. Functional studies recorded macroscopic sodium currents from tsA201 cells expressing both the wild-type (Nav1.5/WT) and mutant channel (Nav1.5/K1493R). The mutant channel exhibited fast activation and inactivation kinetics and an increase in current density. No effect on steady-state activation and inactivation were observed, however, current deactivation was faster in mutant Nav1.5/K1493R as compared to the WT channels. Conclusions: This is the first report of an inherited SCN5A mutation in familial atrial fibrillation. Functional studies suggest a ’gain-of-function’ effect of the identified Nav1.5/K1493R mutation.
Qualitative study on patients with stroke
Authors: A. F Bisset, R. Chesson
Journal: BMJ (1995)

Mental Health Act 1983 would be a standard course of action if he or she refused voluntary admission.It is wrong to suggest that if such a patient took an overdose his or her refusal of treatment while distressed should be considered to be valid.In most cases of self poisoning presenting to casualty departments the history is scanty, the patient is uncooperative, and treatment is needed immediately.If fleeting refusals of treatment were to be honoured many lives would negligently be lost; this is not what English law requires of doctors.The common law allows doctors to act in the best interests of patients if they do not have the capacity to consent.
Abstract 2955: Increased Luminal Diameter With Drug-eluting Versus Bare-metal Stenting Of The Piglet Ductus Arteriosus
Authors: Kyong-Jin Lee, Aleksander Hinek, Claudia Almeida, Rajiv Chaturvedi, Lee Benson
Journal: Circulation (2007)

Introduction: Maintaining ductus arteriosus (DA) patency by stent implantation may be advantageous in congenital heart disease management algorithms. Rapamycin, an immuno-suppressant drug, has anti-proliferative properties, inhibits smooth muscle cell (SMC) migration and may deter intimal hyperplasia occurring during spontaneous closure and post stent implantation of the DA. Methods: 16 Yorkshire piglets (age 7–11 days old, weight 2.2– 4.9 kg) underwent stent implantation of the DA (rapamycin-eluting (n = 8), bare metal (n = 8) stents, (3.5 mm diameter) and were sacrificed at 2, 4 and 6 weeks. Dissected DA were analyzed for SMC and extracellular matrix components (elastin, collagen and glycosaminoglycans). External diameter, wall thickness and lumen diameter were analyzed by morphometric software. DA-derived SMC were isolated and cultured for 7 days in the presence or absence of 100mM of rapamycin. Cellular proliferation rates were assessed by proliferative antigen Ki-67 detection and [ 3 H]-thymidine incorporation. Specific antibodies to elastin, collagen type I, and chondroitin sulfate-containing glycosaminoglycans were analyzed. Results: Rapamycin-eluting stents significantly inhibited neointimal formation compared with bare metal stents at 4 and 6 weeks resulting in larger luminal diameters (p&lt;0.001). The in vitro studies demonstrated rapamycin-treated cultures of the DA-derived SMC had 50% lower proliferation rates (p&lt;0.001). Conclusions : Rapamycin has anti-proliferative actions on the DA. Drug-eluting stents may be a more efficient tool for prolonging patency of the DA in neonates palliated for future correctional surgery.