tbuckley/cabot-search huggingface dataset:
Cost-Related Medication Nonadherence and Spending on Basic Needs Following Implementation of Medicare Part D
Authors: Jeanne M. Madden
Journal: JAMA (2008)

Cost-related medication nonadherence (CRN) has been a persistent problem for individuals who are elderly and disabled in the United States. The impact of Medicare prescription drug coverage (Part D) on CRN is unknown.To estimate changes in CRN and forgoing basic needs to pay for drugs following Part D implementation.In a population-level study design, changes in study outcomes between 2005 and 2006 before and after Medicare Part D implementation were compared with historical changes between 2004 and 2005. The community-dwelling sample of the nationally representative Medicare Current Beneficiary Survey (unweighted unique n = 24,234; response rate, 72.3%) was used, and logistic regression analyses were controlled for demographic characteristics, health status, and historical trends.Self-reports of CRN (skipping or reducing doses, not obtaining prescriptions) and spending less on basic needs to afford medicines.The unadjusted, weighted prevalence of CRN was 15.2% in 2004, 14.1% in 2005, and 11.5% after Part D implementation in 2006. The prevalence of spending less on basic needs was 10.6% in 2004, 11.1% in 2005, and 7.6% in 2006. Adjusted analyses comparing 2006 with 2005 and controlling for historical changes (2005 vs 2004) demonstrated significant decreases in the odds of CRN (ratio of odds ratios [ORs], 0.85; 95% confidence interval [CI], 0.74-0.98; P = .03) and spending less on basic needs (ratio of ORs, 0.59; 95% CI, 0.48-0.72; P < .001). No significant changes in CRN were observed among beneficiaries with fair to poor health (ratio of ORs, 1.00; 95% CI, 0.82-1.21; P = .97), despite high baseline CRN prevalence for this group (22.2% in 2005) and significant decreases among beneficiaries with good to excellent health (ratio of ORs, 0.77; 95% CI, 0.63-0.95; P = .02). However, significant reductions in spending less on basic needs were observed in both groups (fair to poor health: ratio of ORs, 0.60; 95% CI, 0.47-0.75; P < .001; and good to excellent health: ratio of ORs, 0.57; 95% CI, 0.44-0.75; P < .001).In this survey population, there was evidence for a small but significant overall decrease in CRN and forgoing basic needs following Part D implementation. However, no net decrease in CRN after Part D was observed among the sickest beneficiaries, who continued to experience higher rates of CRN.
Introducing CCR Perspectives in Drug Approval
Authors: James L. Abbruzzese
Journal: Clinical Cancer Research (2011)

In this issue of Clinical Cancer Research, we are pleased to introduce a new feature titled CCR Perspectives in Drug Approval. This feature will incorporate the popular Report from the FDA but will evolve to include perspectives from other regulatory groups addressing broad topics that affect the drug approval process, as well as discussions of how national regulatory bodies are approaching the challenges inherent in evaluating the value of novel anticancer therapies.Fundamental scientific discoveries that contribute to a deeper understanding of oncogenesis and the identification of novel targets that may lead to the development of new drugs and other therapeutic strategies for cancer therapy continue to emerge at an ever-increasing pace. It is clear that the drug approval process must also evolve to accommodate our increasingly detailed understanding of cancer. In addition to this scientific revolution, drug evaluation and approval is now an international endeavor, with various criteria for drug approval being established across the globe. Even greater complexity is added when one considers the escalating costs of novel anticancer treatments, and the fact that many of these agents may extend survival only very slightly for patients with a short overall life expectancy. Thus, assessing the value of new cancer treatments is very difficult and at times very controversial.Ultimately, our goal is to provide a scientific/scholarly forum for communicating these challenging issues to the oncology community. To lead off the CCR Perspectives in Drug Approval feature, Peter Littlejohns and colleagues of the National Institute for Health and Clinical Excellence (NICE) will describe the Institute's role in assessing the value of new cancer treatments in England and Wales. We hope our readership will find these articles useful, and would be happy to receive any feedback on this new feature.
Increased Expression of Vascular Endothelial Growth Factor in Kidney Leads to Progressive Impairment of Glomerular Functions
Authors: Enqi Liu, Masatoshi Morimoto, Shuji Kitajima, Tomonari Koike, Ying Yu, Hideo Shiiki, Michio Nagata, Teruo Watanabe, Jianglin Fan
Journal: Journal of the American Society of Nephrology (2007)

Vascular endothelial growth factor (VEGF) is an important mediator in maintaining normal kidney functions. In addition, several lines of evidence suggest that upregulation of VEGF in glomeruli may be associated with or cause renal dysfunction such as diabetic nephropathy. For elucidation of the pathologic consequences of high levels of VEGF in glomeruli, transgenic (Tg) rabbits that express human VEGF(165) isoform in both kidney and liver under the control of the human alpha-1-antitrypsin promoter were generated and characterized. With the use of heterozygous Tg rabbits and their littermates aged 8 to 55 wk, renal functions and structures were investigated. Compared with control rabbits, Tg rabbits exhibited progressive proteinuria with increased GFR at the early stage and decreased GFR at the later stage. Histologic examinations revealed that Tg rabbit kidneys were characterized by considerable glomerular hypertrophy as a result of increased proliferation of both glomerular capillaries and mesangial cells accompanied by prominent podocyte hypertrophy. With increasing age starting from 20 wk, Tg rabbit kidneys showed prominent formation of microaneurysms and capillary proliferation at the vascular pole area. At a later stage (55 wk), many glomeruli showed sclerosis and tuft collapse with the formation of glomerular cysts on a background of tubular atrophy and interstitial fibrosis. This study provides the first evidence that increased expression of VEGF in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria, suggesting that VEGF exerts multiple effects on the glomerular pathophysiologic processes.
<i>KIR</i>and<i>HLA</i>Genotypes Are Associated with Disease Progression and Survival following Autologous Hematopoietic Stem Cell Transplantation for High-Risk Neuroblastoma
Authors: Jeffrey M. Venstrom, Junting Zheng, Nabila Noor, Karen E. Danis, Alice W. Yeh, Irene Y. Cheung, Bo Dupont, Richard J. O'Reilly, Nai-Kong V. Cheung, Katharine C. Hsu
Journal: Clinical Cancer Research (2009)

NK cells exhibit cytotoxicity against neuroblastoma. Gene polymorphisms governing NK cell function, therefore, may influence prognosis. Two highly polymorphic genetic loci instrumental in determining NK cell responses encode the NK cell killer immunoglobulin-like receptors (KIR) and their class I human leukocyte antigen (HLA) ligands. We hypothesized that patients with a "missing ligand" KIR-HLA compound genotype may uniquely benefit from autologous hematopoietic stem cell transplantation (HSCT).One hundred sixty-nine patients treated with autologous HSCT for stage IV neuroblastoma underwent KIR and HLA genotyping. Patients were segregated according to the presence or absence of HLA ligands for autologous inhibitory KIR. Univariate and multivariate analyses were done for overall and progression-free survival.Sixty-four percent of patients lacked one or more HLA ligands for inhibitory KIR. Patients lacking a HLA ligand had a 46% lower risk of death [hazard ratio, 0.54; 95% confidence interval (95% CI), 0.35-0.85; P = 0.007] and a 34% lower risk of progression (hazard ratio, 0.66; 95% CI, 0.44-1.0; P = 0.047) at 3 years compared with patients who possessed all ligands for his/her inhibitory KIR. Among all KIR-HLA combinations, 16 patients lacking the HLA-C1 ligand for KIR2DL2/KIR2DL3 experienced the highest 3-year survival rate of 81% (95% CI, 64-100). Survival was more strongly associated with "missing ligand" than with tumor MYCN gene amplification.KIR-HLA immunogenetics represents a novel prognostic marker for patients undergoing autologous HSCT for high-risk neuroblastoma.
Mortality in Patients with HIV-1 Infection Starting Antiretroviral Therapy in South Africa, Europe, or North America: A Collaborative Analysis of Prospective Studies
Authors: Andrew Boulle, Michael Schomaker, Margaret T. May, Robert S. Hogg, Bryan E. Shepherd, Susana Monge, Olivia Keiser, Fiona C. Lampe, Janet Giddy, James Ndirangu, Daniela Garone, Matthew Fox, Suzanne M. Ingle, Peter Reiss, Francois Dabis, Dominique Costagliola, Antonella Castagna, Kathrin Ehren, Colin Campbell, M. John Gill, Michael Saag, Amy C. Justice, Jodie Guest, Heidi M. Crane, Matthias Egger, Jonathan A. C. Sterne
Journal: PLoS Medicine (2014)

High early mortality in patients with HIV-1 starting antiretroviral therapy (ART) in sub-Saharan Africa, compared to Europe and North America, is well documented. Longer-term comparisons between settings have been limited by poor ascertainment of mortality in high burden African settings. This study aimed to compare mortality up to four years on ART between South Africa, Europe, and North America.Data from four South African cohorts in which patients lost to follow-up (LTF) could be linked to the national population register to determine vital status were combined with data from Europe and North America. Cumulative mortality, crude and adjusted (for characteristics at ART initiation) mortality rate ratios (relative to South Africa), and predicted mortality rates were described by region at 0-3, 3-6, 6-12, 12-24, and 24-48 months on ART for the period 2001-2010. Of the adults included (30,467 [South Africa], 29,727 [Europe], and 7,160 [North America]), 20,306 (67%), 9,961 (34%), and 824 (12%) were women. Patients began treatment with markedly more advanced disease in South Africa (median CD4 count 102, 213, and 172 cells/µl in South Africa, Europe, and North America, respectively). High early mortality after starting ART in South Africa occurred mainly in patients starting ART with CD4 count <50 cells/µl. Cumulative mortality at 4 years was 16.6%, 4.7%, and 15.3% in South Africa, Europe, and North America, respectively. Mortality was initially much lower in Europe and North America than South Africa, but the differences were reduced or reversed (North America) at longer durations on ART (adjusted rate ratios 0.46, 95% CI 0.37-0.58, and 1.62, 95% CI 1.27-2.05 between 24 and 48 months on ART comparing Europe and North America to South Africa). While bias due to under-ascertainment of mortality was minimised through death registry linkage, residual bias could still be present due to differing approaches to and frequency of linkage.After accounting for under-ascertainment of mortality, with increasing duration on ART, the mortality rate on HIV treatment in South Africa declines to levels comparable to or below those described in participating North American cohorts, while substantially narrowing the differential with the European cohorts. Please see later in the article for the Editors' Summary.
Impaired nitric oxide bioavailability and <scp>l</scp>-arginine–reversible endothelial dysfunction in adults with falciparum malaria
Authors: Tsin W. Yeo, Daniel A. Lampah, Retno Gitawati, Emiliana Tjitra, Enny Kenangalem, Yvette R. McNeil, Christabelle J. Darcy, Donald L. Granger, J. Brice Weinberg, Bert K. Lopansri, Ric N. Price, Stephen B. Duffull, David S. Celermajer, Nicholas M. Anstey
Journal: The Journal of Experimental Medicine (2007)

Severe falciparum malaria (SM) is associated with tissue ischemia related to cytoadherence of parasitized erythrocytes to microvascular endothelium and reduced levels of NO and its precursor, l-arginine. Endothelial function has not been characterized in SM but can be improved by l-arginine in cardiovascular disease. In an observational study in Indonesia, we measured endothelial function using reactive hyperemia–peripheral arterial tonometry (RH-PAT) in 51 adults with SM, 48 patients with moderately severe falciparum malaria (MSM), and 48 controls. The mean RH-PAT index was lower in SM (1.41; 95% confidence interval [CI] = 1.33–1.47) than in MSM (1.82; 95% CI = 1.7–2.02) and controls (1.93; 95% CI = 1.8–2.06; P &amp;lt; 0.0001). Endothelial dysfunction was associated with elevated blood lactate and measures of hemolysis. Exhaled NO was also lower in SM relative to MSM and controls. In an ascending dose study of intravenous l-arginine in 30 more patients with MSM, l-arginine increased the RH-PAT index by 19% (95% CI = 6–34; P = 0.006) and exhaled NO by 55% (95% CI = 32–73; P &amp;lt; 0.0001) without important side effects. Hypoargininemia and hemolysis likely reduce NO bioavailability. Endothelial dysfunction in malaria is nearly universal in severe disease, is reversible with l-arginine, and likely contributes to its pathogenesis. Clinical trials in SM of adjunctive agents to improve endothelial NO bioavailability, including l-arginine, are warranted.
Positive inotropic effect of insulin-like growth factor-1 on normal and failing cardiac myocytes
Authors: S Kinugawa
Journal: Cardiovascular Research (1999)

Objective: The acute administration of growth hormone (GH) or insulin-like growth factor-1 (IGF-1) improves cardiac performance, possibly contributing to the beneficial effects of GH therapy on heart failure (HF). GH can induce the production of IGF-1 and thus the actions of GH may be mediated through its IGF-1 induction. However, these effects have not yet been demonstrated in failing hearts and the cellular basis of GH or IGF-1-induced inotropic effects remains unknown. We examined the direct effects of GH and IGF-1 on the contractile function and intracellular calcium ([Ca2+]i) homeostasis in normal and failing myocytes. Methods: To determine whether GH and IGF-1 have a direct effect on myocardial contractility and whether the GH/IGF-1-induced effect was the results of changes in Ca2+ activation, cell shortening and [Ca2+]i transient were simultaneously measured in the left ventricular myocyte preparations, isolated from normal and rapid pacing-induced HF dogs. Results: Basal shortening of HF myocytes was reduced by 64% (p<0.01). In normal and HF myocytes, GH (0.4–40×10−3 IU/ml) had no effect on either cell shortening or [Ca2+]i transients. In normal myocytes, IGF-1 exerted a positive inotropic effect in a time- and dose-dependent manner (25–500 ng/ml), associated with a parallel increase of [Ca2+]i transient amplitude. IGF-1 increased the shortening magnitude in normal (121±5% increase from baseline, p<0.05) and HF (118±4% increase from baseline, p<0.05) myocytes. It also increased [Ca2+]i transient amplitude in normal and HF cells by 124±4 and 125±7%, respectively. The percent increase of cell shortening and [Ca2+]i transient amplitude was comparable between normal and HF myocytes. Furthermore, IGF-1 did not shift the trajectory of the relaxation phase in the phase-plane plots of cell length vs. [Ca2+]i, indicating that it did not change myofilament Ca2+ sensitivity. Conclusions: In both normal and HF conditions, IGF-1 exerted an acute direct positive inotropic effect in adult cardiac myocytes by increasing the availability of [Ca2+]i to the myofilaments, possibly explaining the beneficial effect of GH on HF.
The Innate Mononuclear Phagocyte Network Depletes B Lymphocytes through Fc Receptor–dependent Mechanisms during Anti-CD20 Antibody Immunotherapy
Authors: Junji Uchida, Yasuhito Hamaguchi, Julie A. Oliver, Jeffrey V. Ravetch, Jonathan C. Poe, Karen M. Haas, Thomas F. Tedder
Journal: The Journal of Experimental Medicine (2004)

Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin's lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined because human mechanistic studies are limited. Proposed mechanisms include antibody-, effector cell–, and complement-dependent cytotoxicity, the disruption of CD20 signaling pathways, and the induction of apoptosis. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti–mouse CD20 monoclonal antibodies representing all four immunoglobulin G isotypes. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion used both FcγRI- and FcγRIII-dependent pathways, whereas B cells were not eliminated in FcR common γ chain–deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or natural killer cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components. That the innate monocyte network depletes B cells through FcγR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies.
Authors’ response to letter to the editor concerning our SKUP<sup>3</sup>trial
Authors: Nanna Browaldh, Danielle Friberg
Journal: Thorax (2013)

In contrast, the Canadian data related to arrhythmias requiring hospital admission in the last 6 months. 1 Third, the cardiovascular and renal comorbidity exclusion criteria in UPLIFT were not used in major longterm COPD trials evaluating LABAS±ICS, such as the landmark TOwards a Revolution in COPD Health study, which had no specific cardiovascular or renal comorbidity exclusion criteria. 4 In our view, the efficacy/safety profile of a COPD medication can only be determined if those patients who are at greatest risk of serious adverse events are studied.If this has not been done, then failing to list the characteristics of patients who were excluded from trial participation in the medication data sheet is unsatisfactory.We propose that the tiotropium data sheet 5 is amended to state that the favourable efficacy/safety profile of tiotropium HandiHaler estab-
Forecasting the Effects of Obesity and Smoking on U.S. Life Expectancy
Authors: Susan T. Stewart, David M. Cutler, Allison B. Rosen
Journal: New England Journal of Medicine (2009)

Although increases in obesity over the past 30 years have adversely affected the health of the U.S. population, there have been concomitant improvements in health because of reductions in smoking. Having a better understanding of the joint effects of these trends on longevity and quality of life will facilitate more efficient targeting of health care resources.For each year from 2005 through 2020, we forecasted life expectancy and quality-adjusted life expectancy for a representative 18-year-old, assuming a continuation of past trends in smoking (based on data from the National Health Interview Survey for 1978 through 1979, 1990 through 1991, 1999 through 2001, and 2004 through 2006) and past trends in body-mass index (BMI) (based on data from the National Health and Nutrition Examination Survey for 1971 through 1975, 1988 through 1994, 1999 through 2002, and 2003 through 2006). The 2003 Medical Expenditure Panel Survey was used to examine the effects of smoking and BMI on health-related quality of life.The negative effects of increasing BMI overwhelmed the positive effects of declines in smoking in multiple scenarios. In the base case, increases in the remaining life expectancy of a typical 18-year-old are held back by 0.71 years or 0.91 quality-adjusted years between 2005 and 2020. If all U.S. adults became nonsmokers of normal weight by 2020, we forecast that the life expectancy of an 18-year-old would increase by 3.76 life-years or 5.16 quality-adjusted years.If past obesity trends continue unchecked, the negative effects on the health of the U.S. population will increasingly outweigh the positive effects gained from declining smoking rates. Failure to address continued increases in obesity could result in an erosion of the pattern of steady gains in health observed since early in the 20th century.
Right ventricular function in adults with repaired tetralogy of Fallot assessed with cardiovascular magnetic resonance imaging
Authors: Periklis A. Davlouros, Philip J. Kilner, Tim S. Hornung, Wei Li, Jane M. Francis, James C.C. Moon, Gillian C. Smith, Tri Tat, Dudley J. Pennell, Michael A. Gatzoulis
Journal: Journal of the American College of Cardiology (2002)
Functional analysis of Arabidopsis immune-related MAPKs uncovers a role for MPK3 as negative regulator of inducible defences
Authors: Nicolas Frei dit Frey, Ana Victoria Garcia, Jean Bigeard, Rim Zaag, Eduardo Bueso, Marie Garmier, Stéphanie Pateyron, Marie-Ludivine de Tauzia-Moreau, Véronique Brunaud, Sandrine Balzergue, Jean Colcombet, Sébastien Aubourg, Marie-Laure Martin-Magniette, Heribert Hirt
Journal: Genome biology (2014)

Abstract Background Mitogen-activated protein kinases (MAPKs) are key regulators of immune responses in animals and plants. In Arabidopsis , perception of microbe-associated molecular patterns (MAMPs) activates the MAPKs MPK3, MPK4 and MPK6. Increasing information depicts the molecular events activated by MAMPs in plants, but the specific and cooperative contributions of the MAPKs in these signalling events are largely unclear. Results In this work, we analyse the behaviour of MPK3 , MPK4 and MPK6 mutants in early and late immune responses triggered by the MAMP flg22 from bacterial flagellin. A genome-wide transcriptome analysis reveals that 36% of the flg22-upregulated genes and 68% of the flg22-downregulated genes are affected in at least one MAPK mutant. So far MPK4 was considered as a negative regulator of immunity, whereas MPK3 and MPK6 were believed to play partially redundant positive functions in defence. Our work reveals that MPK4 is required for the regulation of approximately 50% of flg22-induced genes and we identify a negative role for MPK3 in regulating defence gene expression, flg22-induced salicylic acid accumulation and disease resistance to Pseudomonas syringae. Among the MAPK -dependent genes, 27% of flg22-upregulated genes and 76% of flg22-downregulated genes require two or three MAPKs for their regulation. The flg22-induced MAPK activities are differentially regulated in MPK3 and MPK6 mutants, both in amplitude and duration, revealing a highly interdependent network. Conclusions These data reveal a new set of distinct functions for MPK3, MPK4 and MPK6 and indicate that the plant immune signalling network is choreographed through the interplay of these three interwoven MAPK pathways.