tbuckley/cabot-search huggingface dataset:
A Randomized Trial Comparing Disease Activity Measures for the Assessment and Prediction of Response in Rheumatoid Arthritis Patients Initiating Certolizumab Pegol
Authors: Jeffrey R. Curtis, Melvin Churchill, Alan Kivitz, Ahmed Samad, Laura Gauer, Leon Gervitz, Willem Koetse, Jeffrey Melin, Yusuf Yazici
Journal: Arthritis & Rheumatology (2015)

The aim of the Patient/Physician Reported Efficacy Determination In Clinical Practice Trial (PREDICT; ClinicalTrials identifier NCT01255761) was to compare the patient-reported Routine Assessment of Patient Index Data 3 (RAPID-3) instrument with the investigator-based Clinical Disease Activity Index (CDAI) for assessing certolizumab pegol (CZP) treatment response in rheumatoid arthritis patients at 12 weeks and to predict the treatment response at week 52 using the data from week 12 (coprimary end points).Patients received 400 mg of CZP at weeks 0, 2, and 4 (loading dose), followed by 200 mg every 2 weeks thereafter. Patients were randomized 1:1 to assessment with the RAPID-3 or the CDAI. Responder classification was performed at week 12; treatment response was defined as a score of ≤6 or a 20% improvement over baseline on the RAPID-3 or a score of ≤10 or a 20% improvement over baseline on the CDAI. Long-term treatment success was defined as a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) of ≤3.2 at week 52. Comparisons were made for the coprimary end points using noninferiority methods. Patients with improvement of <1 on the CDAI score or with no improvement on the RAPID-3 score at week 12 or patients with high levels of disease activity (CDAI score >22 or RAPID-3 score >12) at 2 consecutive visits were withdrawn from the study.Patients had longstanding disease (mean 8.9 years) and high levels of disease activity (mean scores of 6.3 on the DAS28-ESR, 16.1 on the RAPID-3, and 40.2 on the CDAI). Previous anti-tumor necrosis factor therapy had failed in 55.5% of them. At week 12, a total of 64.7% (by RAPID-3) and 76.4% (by CDAI) of the patients were classified as responders (difference of -11.9% [95% confidence interval -18.4%, -5.3%]). At week 52, a total of 31.5% (by RAPID-3) and 32.3% (by CDAI) of the responders achieved a low level of disease activity on the DAS28-ESR (difference of -1.3% [95% confidence interval -9.3%, 6.6%]).The CDAI classified more patients as CZP responders at week 12 than did the RAPID-3. Although these outcome measures were not statistically comparable, the positive predictive value for low disease activity at week 52 was similar. As these tools cover differing domains of therapy response, further evaluation for clinical disease activity assessments and treatment decisions is needed.
Abstract 3089: CDKN2A and p53 status predicts response to CDK4/6 inhibition in melanoma
Authors: Claire A. Martin, Laura Kirby, Stephen Wong, Grant A. McArthur, Karen E. Sheppard
Journal: Cancer Research (2015)

Abstract The p16-CyclinD1-CDK4-RB pathway regulates G1-S cell cycle transition. This pathway is deregulated in 90% of melanomas, through amplification or increased expression of CDK4 or Cyclin D1 (CCND1), or reduced expression of the CDK inhibitor p16INK4A (CDKN2A). To explore if CDK4 may be a viable target for the treatment of human melanoma we screened a panel of melanoma cell lines with the highly selective CDK4/6 inhibitor PD-0332991 (PD-991). A majority of cell lines were found to be sensitive to PD-991, although there was a distinct population of resistant cell lines. In sensitive melanoma cell lines, treatment with PD-991 resulted in loss of hyperphosphorylated RB and a concomitant G0/G1 cell cycle arrest. Treated cells displayed an enlarged flattened morphology and an increase in SA-β-galactosidase staining compared to vehicle controls, indicative of cellular senescence. RB-null cell lines were resistant to CDK4/6 inhibition, and did not display cell cycle arrest or senescence. Expression and mutational analysis was performed to identify additional genomic predictors of sensitivity and resistance. Loss of CDKN2A/p16 correlated with sensitivity to PD-991 (p&amp;lt;0.02), and this was confirmed at the level of protein expression. Mutation of p53 and the corresponding low expression of p53 targets p21 and MDM2 correlated with resistance (p&amp;lt;0.0001). There was no increase in p53 transcriptional targets or evidence of apoptosis in response to PD-991 treatment of sensitive cells, and senescence occurs in both p53 WT and mutant cells, indicating that this response does not require functional p53. However, in p53 WT cells, combination treatment with PD-991 and the p53 pathway activator Nutlin3a results in increased sensitivity to PD-991 compared to treatment with PD-991 alone. This additive effect is not observed in p53 mutant cells, suggesting there is a functional role for WT p53 in the response to PD-991. Conclusions: These preliminary data identify RB, p16 and p53 as predictors of response to PD-991, and support further evaluation of CDK4/6 inhibitors in melanoma. Citation Format: Claire A. Martin, Laura Kirby, Stephen Wong, Grant A. McArthur, Karen E. Sheppard. CDKN2A and p53 status predicts response to CDK4/6 inhibition in melanoma. [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 3089. doi:10.1158/1538-7445.AM2015-3089
Abstract 15280: Functional Interactions of the Osteogenic-Related Transcription Factors Runx2, Vdr and Nfkb to Regulate the Transcription of Osteopontin (opn) During Cardiac Calcification in Mice
Authors: Ann-Kathrin Sowa, Frank J. Kaiser, Juliana Eckhold, Lars C. Doehring, Heribert Schunkert, Jeanette Erdmann, Zouhair Aherrahrou
Journal: Circulation (2011)

Introduction: Cardiovascular calcification is prevalent in coronary artery diseases (CAD) enhancing morbidity and mortality in western countries. Mice were used as model for dystrophic cardiac calc...
Plume temperature and force of fluticasone propionate/formoterol pMDI compared with fluticasone propionate/salmeterol pMDI
Authors: Baljinder Johal, John Tuohy, Jonathan Marshall
Journal: European Respiratory Journal (2014)

Background:   Aerosol inhaler characteristics such as low plume temperature and high force may result in greater impaction of drug in the mouth and throat and reduced lung deposition. 1  This study compared plume temperature and force of two ICS/LABA combination products: fluticasone propionate/formoterol 125/5μg (FP/FORM;   flutiform   ® ) and fluticasone propionate/salmeterol 125/25μg (FP/SAL; Seretide ® ), delivered via metered-dose inhalers.   Methods:   Inhalers were held in a fixed device and operated according to manufacturers9 instructions. A thermal imaging video camera, operating at 30 frames per second, recorded plume temperature from the side of the device. The same test rig, with a copper disc attached to a sensitive load cell measured plume force over a range of distances 25mm to 95mm from the device.   Results:   At 25mm the FP/FORM plume was +6 o C, while that of the FP/SAL plume was -38 o C. The FP/SAL plume was colder over a longer distance. The force of the FP/SAL plume was greater than that of the FP/FORM device at all distances measured: mean force recorded for FP/SAL was 218.0mN compared to 104.0mN for FP/FORM.   Conclusion:   The FP/SAL plume was considerably colder than the FP/FORM plume particularly over shorter distances. The FP/SAL plume was more forceful, approximately twice that of the FP/FORM device. These differences may be due to different types of HFA propellant with different boiling points, the excipients in each formulation, and actuator geometry. The plume characteristics of the FP/FORM device may facilitate lung deposition and lessen impaction in the throat.  1 Gabrio BJ. Int J Pharm 1999;186:3-12  Sponsor: Mundipharma Research Ltd.
Abstract 1489: Mechanisms Underlying Cardioprotective Effects Of Glucagon-like Peptide-1 In Ischemia-reperfusion Injury
Authors: Kiwon Ban, Judith Hoefer, Steffen S Bolz, Daniel J Drucker, Mansoor Husain
Journal: Circulation (2007)

Background : GLP-1 is a member of the gut incretin hormone family, and a GLP-1 receptor agonist (exendin-4) is approved for the treatment of Type-II diabetes. Studies in man post-MI, and in rat and dog models suggest that GLP-1 is cardioprotective. However, the mechanisms underlying the effects of structurally diverse GLP-1 peptides in the heart have not been fully elucidated.

Methods & Results: GLP-1(7–36) (i.e. GLP-1), its cleavage product GLP(9–36), and the degradation-resistant GLP-1R agonist exendin-4 were examined in 30 min of global ischemia followed by 40 min of reperfusion (I/R) in Langendorff isolated heart preparations from both wild-type (WT) and GLP-1 receptor knockout (GLP-1R−/−) mice. In WT mice, recovery of left ventricular developed pressure (LVDP) following I/R was higher in GLP-1 pre-infused hearts than in untreated controls (79±9 vs. 42±1%; p<0.01). Pre-treatment with 5 nM but not with 0.3~3 nM exendin-4 also protected the heart from I/R injury. Although pre-infusion of GLP(9–36) induced lower recovery than untreated controls (21.4±1%), post-infusion of either GLP(9–36) or GLP-1 augmented functional recovery to a similar extent (59.1±6% and 53.3±6%). Surprisingly, the cardioprotective effects of pre- and post-treatments with both molecular forms of GLP-1 were detected in studies with GLP-1R−/− hearts (80.1±6% and 55.8±8). Of note, both GLP-1 and GLP(9–36) treatments also demonstrated potent vasodilatory effects, as manifested by increased coronary flow rates in isolated hearts and increased diameters of pre-constricted mesenteric arteries isolated from both WT and GLP-1R−/− mice. The cardioprotective effects on isolated hearts and vasodilatory effects on isolated mesenteric arteries, induced by GLP-1 was blunted by co-treatment with a dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor, that blocked conversion of GLP-1 to GLP(9–36). Increased cGMP release in the coronary effluents was also observed following addition of GLP-1 and GLP(9–36) to hearts isolated from WT and GLP-1R−/− mice.

Summary: These data expand the complexity of GLP-1 biology by illustrating that the beneficial effects of GLP-1 in I/R injury are mediated in part by GLP(9–36) via a NO/cGMP-dependent vasodilatory effect that is independent of the known GLP-1R.
Efficacy of Tocilizumab in Conventional Treatment–Refractory Adult‐Onset Still's Disease: Multicenter Retrospective Open‐Label Study of Thirty‐Four Patients
Authors: Francisco Ortiz‐Sanjuán, Ricardo Blanco, Vanesa Calvo‐Rio, Javier Narvaez, Esteban Rubio Romero, Alejandro Olivé, Santos Castañeda, Adela Gallego Flores, M. Victoria Hernández, Cristina Mata, Inmaculada Ros Vilamajo, Walter Alberto Sifuentes Giraldo, Miguel A. Caracuel, Mercedes Freire, Catalina Gómez Arango, José Llobet, Sara Manrique Arija, Carlos Marras, Concepción Moll‐Tuduri, Chamaida Plasencia‐Rodriguez, Rosa Roselló, Ana Urruticoechea, Maria L. Velloso‐Feijoo, Jordi del Blanco, M. Carmen González‐Vela, Javier Rueda‐Gotor, Trinitario Pina, Javier Loricera, Miguel A. González‐Gay
Journal: Arthritis & Rheumatology (2014)

Adult-onset Still's disease (AOSD) is frequently refractory to standard therapy. Tocilizumab (TCZ) has demonstrated efficacy in single cases and in small series of patients with AOSD. The aim of this multicenter study was to assess the efficacy of TCZ in patients with AOSD refractory to conventional treatment.This was a retrospective open-label study of TCZ treatment in 34 patients with AOSD who had experienced an inadequate response to corticosteroids and at least 1 standard synthetic immunosuppressive drug and also, in many cases, biologic agents.The mean ± SD age of the patients (8 men and 26 women) was 38.7 ± 16.1 years. The median duration of AOSD before TCZ was initiated was 4.2 years (interquartile range [IQR] 1-9 years). The initial dosages of intravenous TCZ were 8 mg/kg every 4 weeks in 22 patients, 4 mg/kg every 4 weeks in 2 patients, and 8 mg/kg every 2 weeks in 10 patients. TCZ treatment resulted in rapid and maintained improvement in both clinical and laboratory parameters. After 1 year of TCZ therapy, the incidence of joint manifestations had decreased from 97.1% at baseline to 32.4%, the incidence of both cutaneous manifestations and fever had decreased from 58.8% to 5.9%, and the incidence of lymphadenopathy had decreased from 29.4% to 0%. A dramatic reduction in laboratory markers of inflammation, including the C-reactive protein level, the erythrocyte sedimentation rate, and the ferritin level, was achieved. The median dosage of prednisone was also reduced, from 13.8 mg/day (IQR 5-45) at the initiation of TCZ to 2.5 mg/day (IQR 0-30) at 12 months. After a median followup of 19 months (IQR 12-31 months), only 2 patients required permanent discontinuation of TCZ therapy because of severe infections.TCZ treatment was associated with rapid and maintained clinical and laboratory improvement in patients with AOSD refractory to standard treatment. However, joint manifestations seem to be more refractory to treatment compared with systemic manifestations.
TCT-427 Second generation devices for renal denervation give better renal blood flow when compared with 1st generation catheters
Authors: Waleed Kadro, Maya Turkmani, Hussam Rahim, Cathy John, Zaid Zaki, Gina Pietro, Amr Alkarmi, Fares Alahdab
Journal: Journal of the American College of Cardiology (2014)
Response to Letter Regarding Article, “The ERG–APLNR Axis Controls Pulmonary Venule Endothelial Proliferation in Pulmonary Veno-Occlusive Disease”
Authors: Christopher Lathen, Yu Zhang, Jennifer Chow, Martanday Singh, Grace Lin, Vishal Nigam, Yasser A. Ashraf, Jason X. Yuan, Ivan M. Robbins, Patricia A. Thistlethwaite
Journal: Circulation (2015)
Commitment: the consistency of clinicians and the use of legal standards
Authors: C W Lidz, E P Mulvey, P S Appelbaum, S Cleveland
Journal: American Journal of Psychiatry (1989)

The reliability and validity of the application of legal criteria for commitment were investigated as part of a larger study. Evaluations of 411 patients by 96 different clinicians showed good interrater reliability for assessment of dangerousness and committability. A strong relationship between ratings of committability and ratings of dangerousness suggests that clinicians were conforming to the logic of the commitment law. Discrepant cases involved patients who desired voluntary admission or whose commitment was completed elsewhere. Results suggest fair application of commitment standards but that two issues of statutory interpretation confused participating clinicians.
Abstract 16004: The Prognostic Value of Automatically Detected Early Repolarization - A Focus on Hispanics
Authors: Philip Aagaard
Journal: Circulation (2014)

Introduction: Early repolarization (ER) associated with sudden cardiac death is based on the presence of &gt;1mm J-point elevations in inferior and/or lateral leads with horizontal/downsloping ST-segments. Automated ECG readings of early repolarization (AER) obtained in clinical practice, on the other hand, are defined by ST segment elevation (ascending/upsloping ST-segments) in addition to J-point elevation. Nonetheless, such automated readings may cause alarm. Methods: We therefore assessed the prevalence and prognostic significance of AER in 238,456 individuals aged 18-75 years. The study was performed at a tertiary medical center serving a racially diverse urban population with a large proportion of Hispanics (43%). The first recorded ECG of each individual during 2000-2012 was included. Patients with ventricular paced rhythm or acute coronary syndrome at the time of acquisition were excluded from the analysis. All automated ECG interpretations were reviewed for accuracy by a board certified cardiologist. The primary endpoint was death during a median follow up of 8.0±2.6 years. Results: AER was present in 3,450 (1.6%) subjects. The prevalence varied significantly with race: African Americans 2.2%, Caucasians 0.9%, and Hispanics 1.5% (p&lt;0.01), and sex: male 2.4% vs. female 0.6% (p&lt;0.001). In a Cox-proportional Hazards model (Figure 1) controlling for age, smoking status, heart rate, QTc, systolic blood pressure, LDL-cholesterol, BMI, and CAD, there was no significant difference in mortality regardless of race or sex (RR 0.98 (95% CI: 0.89-1.07). This was true even if J-waves were present. Conclusion: The prevalence of AER in Hispanics was intermediate to that of African Americans and Caucasians. This ECG finding was not associated with an increased risk of death, regardless of race or sex, and should not trigger additional diagnostic testing.
Control of allergen-induced inflammation and hyperresponsiveness by the metalloproteinase ADAMTS-12
Authors: Geneviève Paulissen, Mehdi El Hour, Natacha Rocks, Maud Guéders, Fabrice Bureau, Jean-Michel Foidart, Carlos Lopez-Otin, Agnès Noel, Didier Cataldo
Journal: European Respiratory Journal (2011)

Background: ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) constitute a family of endopeptidases related to matrix metalloproteinases (MMPs). These proteinases have been largely implicated in tissue remodelling associated to pathological processes. ADAMTS-12 has been identified as an asthma-associated gene in a human genome screening program.

Objective: To investigate potential roles of ADAMTS-12 in experimental models of asthma.

Methods: In our study, two different in vivo protocols of allergen-induced asthma were applied to the recently generated Adamts-12 -deficient mice, and corresponding wild-type mice.

Results: The results obtained provide evidence for a protective effect of this enzyme against bronchial inflammation and hyperresponsiveness. In the absence of Adamts-12 , challenge with allergens (ovalbumin and house dust mite) led to exacerbated eosinophilic inflammation in the bronchoalveolar lavage fluid (BALF) and in lung tissue, along with airway dysfunction assessed by increased airway responsiveness following methacholine exposure. Furthermore, mast cells counts, ST2 receptor, and IL-33 levels were higher in the lungs of allergen-challenged Adamts-12 -deficient mice.

Conclusion: The present study provides the first experimental evidence for a contribution of ADAMTS-12 as a key mediator in asthma, interfering with immunological processes leading to inflammation and airway hyperresponsiveness.
Abstract 17686: Appropriate Use and Clinical Impact of Early Echocardiograms in Hospitalized Patients
Authors: Anca Chiriac, Ana Kadkhodayan, Sorin V Pislaru, Eric Dailey, Tamara Buechler, James Newman, Patricia Pellikka
Journal: Circulation (2014)

Introduction: Transthoracic echocardiography (TTE) is a versatile tool for investigating cardiac function in hospitalized patients, but it was recently suggested that only a fraction of the studies result in an active change in management. The importance of early inpatient TTE to guide management and rule out important alternative pathology has not been previously investigated. The opinion of the referring provider has never been systematically surveyed. Hypothesis: Appropriate use (AU) of TTE in hospitalized patients has significant implications for patient care, even without resulting in direct alterations in management. Methods: We conducted a prospective review of 546 consecutive echocardiograms performed within 72 hours of hospital admission. An electronic survey consisting of 6 questions pertinent to rationale for TTE and consequences to patient care was sent to physicians. AU was independently determined by two investigators blinded to survey results and clinical outcomes, with differences adjudicated by a third independent investigator. Results: Of 546 TTEs included in this study, 526 (96%) were appropriate, 2% inappropriate, and 2% uncertain. Although only 48% of responders actively changed management after TTE results, 97% thought the TTE answered their clinical question. At least one new medication change occurred in 190 (35%) patients. Moreover, 95% of physicians would do another TTE in a similar situation, either to guide cardiac therapy, rule out contributing cardiac pathology, or support their current therapeutic plan. Only 5% of responders would not order another TTE if given a similar presentation in the future. Furthermore, our study uncovered a high incidence of unexpected findings (33% of TTEs), ranging from new decrease in LV systolic function, new valvular dysfunction, to pericardial effusion and new aortic aneurysm. These findings have significant clinical implications for the individual patient. Conclusions: Most early inpatient TTEs at our institution were appropriate and answered a specific clinical question important for management decisions. Even those not directly altering the acute therapeutic strategy impacted clinical course. A large number of significant incidental findings were recorded.
An Outbreak of Hepatitis C Virus Infections among Outpatients at a Hematology/Oncology Clinic
Authors: Alexandre Macedo de Oliveira, Kathryn L. White, Dennis P. Leschinsky, Brady D. Beecham, Tara M. Vogt, Ronald L. Moolenaar, Joseph F. Perz, Thomas J. Safranek
Journal: Annals of Internal Medicine (2005)

Approximately 2.7 million persons in the United States have chronic hepatitis C virus (HCV) infection. Health care-associated HCV transmission can occur if aseptic technique is not followed. The authors suspected a health care-associated HCV outbreak after the report of 4 HCV infections among patients at the same hematology/oncology clinic.To determine the extent and mechanism of HCV transmission among clinic patients.Epidemiologic analysis through a cohort study.Hematology/oncology clinic in eastern Nebraska.Patients who visited the clinic from March 2000 through December 2001.HCV infection status, relevant medical history, and clinic-associated exposures. Bivariate analysis and logistic regression were used to identify risk factors for HCV infection.Of 613 clinic patients contacted, 494 (81%) underwent HCV testing. The authors documented infection in 99 patients who lacked previous evidence of HCV infection; all had begun treatment at the clinic before July 2001. Hepatitis C virus genotype 3a was present in all 95 genotyped samples and presumably originated from a patient with chronic hepatitis C who began treatment in March 2000. Infection with HCV was statistically significantly associated with receipt of saline flushes (P < 0.001). Shared saline bags were probably contaminated when syringes used to draw blood from venous catheters were reused to withdraw saline solution. The clinic corrected this procedure in July 2001.The delay between outbreak and investigation (>1 year) may have contributed to an underestimate of cases.This large health care-associated HCV outbreak was related to shared saline bags contaminated through syringe reuse. Effective infection-control programs are needed to ensure high standards of care in outpatient care facilities, such as hematology/oncology clinics.
Book dispelling immunisation myths is available
Authors: C. Essex, P. Tuohy, M. Hunter
Journal: BMJ (1995)

EDITOR,—Neil Simpson and colleagues report that the rate of non-immunisation among children in their area is 0.33% and describe the reasons why some parents refused immunisation.1 We wish to describe the situation in New Zealand.

Until recently the childhood immunisation rate in New Zealand was thought to be low relative to that in many other developed countries (New Zealand does not have a national immunisation register to give accurate overall figures). A small study in 1992 showed that less …