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Find video protocols related to scientific articles indexed in Pubmed.
Violation of the 12/23 rule of genomic V(D)J recombination is common in lymphocytes.
Genome Res.
PUBLISHED: 11-03-2014
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V(D)J genomic recombination joins single gene segments to encode an extensive repertoire of antigen receptor specificities in T and B lymphocytes. This process initiates with double-stranded breaks adjacent to conserved recombination signal sequences that contain either 12 or 23 nucleotide spacer regions. Only recombination between signal sequences with unequal spacers result in productive coding genes, a phenomenon known as the '12/23 rule'. Here we present two novel genomic tools that allow the capture and analysis of immune locus rearrangements from whole thymic and splenic tissues using second generation sequencing. Further, we provide strong evidence that the 12/23 rule of genomic recombination is frequently violated under physiological conditions resulting in unanticipated hybrid recombinations in ~10% of Tcra excision circles. Hence, we demonstrate that strict adherence to the 12/23 rule is intrinsic neither to recombination signal sequences nor to the catalytic process of recombination and propose that non-classical excision circles are liberated during the formation of antigen receptor diversity.
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Epitope Specificity Delimits the Functional Capabilities of Vaccine-Induced CD8 T Cell Populations.
J. Immunol.
PUBLISHED: 10-27-2014
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Despite progress toward understanding the correlates of protective T cell immunity in HIV infection, the optimal approach to Ag delivery by vaccination remains uncertain. We characterized two immunodominant CD8 T cell populations generated in response to immunization of BALB/c mice with a replication-deficient adenovirus serotype 5 vector expressing the HIV-derived Gag and Pol proteins at equivalent levels. The Gag-AI9/H-2K(d) epitope elicited high-avidity CD8 T cell populations with architecturally diverse clonotypic repertoires that displayed potent lytic activity in vivo. In contrast, the Pol-LI9/H-2D(d) epitope elicited motif-constrained CD8 T cell repertoires that displayed lower levels of physical avidity and lytic activity despite equivalent measures of overall clonality. Although low-dose vaccination enhanced the functional profiles of both epitope-specific CD8 T cell populations, greater polyfunctionality was apparent within the Pol-LI9/H-2D(d) specificity. Higher proportions of central memory-like cells were present after low-dose vaccination and at later time points. However, there were no noteworthy phenotypic differences between epitope-specific CD8 T cell populations across vaccine doses or time points. Collectively, these data indicate that the functional and phenotypic properties of vaccine-induced CD8 T cell populations are sensitive to dose manipulation, yet constrained by epitope specificity in a clonotype-dependent manner.
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Complex TCR repertoire dynamics underlie the CD8+ T-cell response to HIV-1.
J. Virol.
PUBLISHED: 10-17-2014
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Although CD8(+) T-cells are important for the control of HIV-1 in vivo, the precise correlates of immune efficacy remain unclear. In this study, we conducted a comprehensive analysis of viral sequence variation and T-cell receptor (TCR) repertoire composition across multiple epitope specificities in a group of antiretroviral treatment-naïve individuals chronically infected with HIV-1. A negative correlation was detected between changes in antigen-specific TCR repertoire diversity and CD8(+) T-cell response magnitude, reflecting clonotypic expansions and contractions related to alterations in cognate viral epitope sequences. These patterns were independent of the individual, evidenced by discordant clonotype-specific evolution against different epitopes in single subjects. Moreover, long-term asymptomatic HIV-1 infection was characterized by evolution of the TCR repertoire in parallel with viral replication. Collectively, these data suggest a continuous bidirectional process of adaptation between HIV-1 and virus-specific CD8(+) T-cell clonotypes orchestrated at the TCR/antigen interface.
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Tetramer-enrichment reveals presence of phenotypically diverse hepatitis C virus specific CD8+ T cells in chronic infection.
J. Virol.
PUBLISHED: 10-17-2014
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Virus-specific CD8(+) T cells are rarely detectable ex vivo by conventional methods during chronic hepatitis C virus (HCV) infection. In this study, however, we were able to detect and characterize HCV-specific CD8(+) T cells in all chronically genotype 1a infected, HLA-A*02:01(+) patients analyzed by performing major histocompatibility complex (MHC) class I tetramer enrichment. Two thirds of these enriched HCV-specific CD8(+) T-cell populations displayed an effector-memory phenotype whereas, surprisingly, one third displayed a naïve-like phenotype despite ongoing viral replication. CD8(+) T cells with an effector-memory phenotype could not expand in vitro, suggesting exhaustion of these cells. Interestingly, some of the naïve-like CD8(+) T cells proliferated vigorously upon in vitro priming, whereas others did not. These differences were linked to the corresponding viral sequences in the respective patients. Indeed, naïve-like CD8(+) T cells from patients with consensus sequence in the corresponding T-cell epitope did not expand in vitro. In contrast, in patients displaying sequence variations, we were able to induce HCV-specific CD8(+) T-cell proliferation, which may indicate infection with a variant virus. Collectively, these data reveal the presence of phenotypically and functionally diverse HCV-specific CD8(+) T cells at very low frequencies that are detectable in all chronically infected patients despite viral persistence.
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Cyclic Penta- and Hexaleucine Peptides without N-Methylation Are Orally Absorbed.
ACS Med Chem Lett
PUBLISHED: 10-09-2014
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Development of peptide-based drugs has been severely limited by lack of oral bioavailability with less than a handful of peptides being truly orally bioavailable, mainly cyclic peptides with N-methyl amino acids and few hydrogen bond donors. Here we report that cyclic penta- and hexa-leucine peptides, with no N-methylation and five or six amide NH protons, exhibit some degree of oral bioavailability (4-17%) approaching that of the heavily N-methylated drug cyclosporine (22%) under the same conditions. These simple cyclic peptides demonstrate that oral bioavailability is achievable for peptides that fall outside of rule-of-five guidelines without the need for N-methylation or modified amino acids.
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?-cell-specific CD8 T cell phenotype in type 1 diabetes reflects chronic autoantigen exposure.
Diabetes
PUBLISHED: 09-25-2014
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Autoreactive CD8 T cells play a central role in the destruction of pancreatic islet ?-cells that leads to type 1 diabetes, yet the key features of this immune-mediated process remain poorly defined. In this study, we combined high definition polychromatic flow cytometry with ultrasensitive peptide-human leukocyte antigen class I (pHLAI) tetramer staining to quantify and characterize ?-cell-specific CD8 T cell populations in patients with recent onset type 1 diabetes and healthy controls. Remarkably, we found that ?-cell-specific CD8 T cell frequencies in peripheral blood were similar between subject groups. In contrast to healthy controls, however, patients with newly diagnosed type 1 diabetes displayed hallmarks of antigen-driven expansion uniquely within the ?-cell-specific CD8 T cell compartment. Molecular analysis of selected ?-cell-specific CD8 T cell populations further revealed highly skewed oligoclonal T cell receptor (TCR) repertoires comprising exclusively private clonotypes. Collectively, these data identify novel and distinctive features of disease-relevant CD8 T cells that inform the immunopathogenesis of type 1 diabetes.
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Translational diffusion of cyclic peptides measured using pulsed-field gradient NMR.
J Phys Chem B
PUBLISHED: 09-15-2014
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Cyclic peptides are increasingly being recognized as valuable templates for drug discovery or design. To facilitate efforts in the structural characterization of cyclic peptides, we explore the use of pulse-field gradient experiments as a convenient and noninvasive approach for characterizing their diffusion properties in solution. We present diffusion coefficient measurements of five cyclic peptides, including dichC, SFTI-1, cVc1.1, kB1, and kB2. These peptides range in size from six to 29 amino acids and have various therapeutically interesting activities. We explore the use of internal standards, such as dioxane and acetonitrile, to evaluate the hydrodynamic radius from the diffusion coefficient, and show that 2,2-dimethyl-2-silapentane-5-sulfonic acid, a commonly used chemical shift reference, can be used as an internal standard to avoid spectral overlap issues and simplify data analysis. The experimentally measured hydrodynamic radii correlate with increasing molecular weight and in silico predictions. We further applied diffusion measurements to characterize the self-association of kB2 and showed that it forms oligomers in a concentration-dependent manner, which may be relevant to its mechanism of action. Diffusion coefficient measurements appear to have broad utility in cyclic peptide structural biology, allowing for the rapid characterization of their molecular shape in solution.
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Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised, placebo-controlled trial.
Lancet Respir Med
PUBLISHED: 09-08-2014
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The effectiveness of intermittent montelukast for wheeze in young children is unclear. We aimed to assess whether intermittent montelukast is better than placebo for treatment of wheeze in this age group. Because copy numbers of the Sp1-binding motif in the arachidonate 5-lipoxygenase (ALOX5) gene promoter (either 5/5, 5/x, or x/x, where x does not equal 5) modifies response to montelukast in adults, we stratified by this genotype.
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A Recombinant Modified Vaccinia Ankara Vaccine Encoding Epstein-Barr Virus (EBV) Target Antigens: A Phase I Trial in UK Patients with EBV-Positive Cancer.
Clin. Cancer Res.
PUBLISHED: 08-14-2014
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Epstein-Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses.
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Lipoprotein-apheresis reduces circulating microparticles in individuals with familial hypercholesterolemia.
J. Lipid Res.
PUBLISHED: 08-13-2014
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Lipoprotein-apheresis (apheresis) removes LDL-cholesterol in patients with severe dyslipidemia. However, reduction is transient, indicating that the long-term cardiovascular benefits of apheresis may not solely be due to LDL removal. Microparticles (MPs) are submicron vesicles released from the plasma membrane of cells. MPs, particularly platelet-derived MPs, are increasingly being linked to the pathogenesis of many diseases. We aimed to characterize the effect of apheresis on MP size, concentration, cellular origin, and fatty acid concentration in individuals with familial hypercholesterolemia (FH). Plasma and MP samples were collected from 12 individuals with FH undergoing routine apheresis. Tunable resistive pulse sensing (np200) and nanoparticle tracking analysis measured a fall in MP concentration (33 and 15%, respectively; P < 0.05) pre- to post-apheresis. Flow cytometry showed MPs were predominantly annexin V positive and of platelet (CD41) origin both pre- (88.9%) and post-apheresis (88.4%). Fatty acid composition of MPs differed from that of plasma, though apheresis affected a similar profile of fatty acids in both compartments, as measured by GC-flame ionization detection. MP concentration was also shown to positively correlate with thrombin generation potential. In conclusion, we show apheresis nonselectively removes annexin V-positive platelet-derived MPs in individuals with FH. These MPs are potent inducers of coagulation and are elevated in CVD; this reduction in pathological MPs could relate to the long-term benefits of apheresis.
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MR1-restricted MAIT cells display ligand discrimination and pathogen selectivity through distinct T cell receptor usage.
J. Exp. Med.
PUBLISHED: 07-21-2014
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Mucosal-associated invariant T (MAIT) cells express a semi-invariant T cell receptor (TCR) that detects microbial metabolites presented by the nonpolymorphic major histocompatibility complex (MHC)-like molecule MR1. The highly conserved nature of MR1 in conjunction with biased MAIT TCR? chain usage is widely thought to indicate limited ligand presentation and discrimination within a pattern-like recognition system. Here, we evaluated the TCR repertoire of MAIT cells responsive to three classes of microbes. Substantial diversity and heterogeneity were apparent across the functional MAIT cell repertoire as a whole, especially for TCR? chain sequences. Moreover, different pathogen-specific responses were characterized by distinct TCR usage, both between and within individuals, suggesting that MAIT cell adaptation was a direct consequence of exposure to various exogenous MR1-restricted epitopes. In line with this interpretation, MAIT cell clones with distinct TCRs responded differentially to a riboflavin metabolite. These results suggest that MAIT cells can discriminate between pathogen-derived ligands in a clonotype-dependent manner, providing a basis for adaptive memory via recruitment of specific repertoires shaped by microbial exposure.
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Observational study to characterise 24-hour COPD symptoms and their relationship with patient-reported outcomes: results from the ASSESS study.
Respir. Res.
PUBLISHED: 07-14-2014
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BackgroundFew studies have investigated the 24-hour symptom profile in patients with COPD or how symptoms during the 24-hour day are inter-related. This observational study assessed the prevalence, severity and relationship between night-time, early morning and daytime COPD symptoms and explored the relationship between 24-hour symptoms and other patient-reported outcomes.MethodsThe study enrolled patients with stable COPD in clinical practice. Baseline night-time, early morning and daytime symptoms (symptom questionnaire), severity of airflow obstruction (FEV1), dyspnoea (modified Medical Research Council Dyspnoea Scale), health status (COPD Assessment Test), anxiety and depression levels (Hospital Anxiety and Depression Scale), sleep quality (COPD and Asthma Sleep Impact Scale) and physical activity level (sedentary, moderately active or active) were recorded.ResultsThe full analysis set included 727 patients: 65.8% male, mean¿±¿standard deviation age 67.2¿±¿8.8 years, % predicted FEV1 52.8¿±¿20.5%.In each part of the 24-hour day, >60% of patients reported experiencing ¿1 symptom in the week before baseline. Symptoms were more common in the early morning and daytime versus night-time (81.4%, 82.7% and 63.0%, respectively). Symptom severity was comparable for each period assessed. Overall, in the week before baseline, 56.7% of patients had symptoms throughout the whole 24-hour day (3 parts of the day); 79.9% had symptoms in ¿2 parts of the 24-hour day. Symptoms during each part of the day were inter-related, irrespective of disease severity (all p¿<¿0.001).Early morning and daytime symptoms were associated with the severity of airflow obstruction (p¿<¿0.05 for both). Night-time, early morning and daytime symptoms were all associated with worse dyspnoea, health status and sleep quality, and higher anxiety and depression levels (all p¿<¿0.001 versus patients without symptoms in each corresponding period). In each part of the 24-hour day, there was also an association between symptoms and a patient¿s physical activity level (p¿<¿0.05 for each period).ConclusionsMore than half of patients experienced COPD symptoms throughout the whole 24-hour day. There was a significant relationship between night-time, early morning and daytime symptoms. In each period, symptoms were associated with worse patient-reported outcomes, suggesting that improving 24-hour symptoms should be an important consideration in the management of COPD.
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Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies.
Expert Opin Investig Drugs
PUBLISHED: 07-07-2014
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The discovery of new antiobesity agents has attracted considerable interest over the past decade, but many of the investigational agents that have advanced into human clinical trials have shown unacceptable adverse events and/or efficacy profiles.
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Cost-effectiveness of the LABA/LAMA dual bronchodilator indacaterol/glycopyrronium in a Swedish healthcare setting.
Respir Med
PUBLISHED: 07-02-2014
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Indacaterol/glycopyrronium (IND/GLY) is a once-daily inhaled fixed-dose combination of indacaterol (IND), a long-acting ?2-adrenergic agonist (LABA), and glycopyrronium (GLY), a long-acting muscarinic antagonist (LAMA) for use as maintenance treatment to relieve symptoms of chronic obstructive pulmonary disease (COPD) in adults.
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Interstitial lung disease: raising the index of suspicion in primary care.
NPJ Prim Care Respir Med
PUBLISHED: 07-02-2014
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Interstitial lung disease (ILD) describes a group of diseases that cause progressive scarring of the lung tissue through inflammation and fibrosis. The most common form of ILD is idiopathic pulmonary fibrosis, which has a poor prognosis. ILD is rare and mainly a disease of the middle-aged and elderly. The symptoms of ILD-chronic dyspnoea and cough-are easily confused with the symptoms of more common diseases, particularly chronic obstructive pulmonary disease and heart failure. ILD is infrequently seen in primary care and a precise diagnosis of these disorders can be challenging for physicians who rarely encounter them. Confirming a diagnosis of ILD requires specialist expertise and review of a high-resolution computed tomography scan (HRCT). Primary care physicians (PCPs) play a key role in facilitating the diagnosis of ILD by referring patients with concerning symptoms to a pulmonologist and, in some cases, by ordering HRCTs. In our article, we highlight the importance of prompt diagnosis of ILD and describe the circumstances in which a PCP's suspicion for ILD should be raised in a patient presenting with chronic dyspnoea on exertion, once more common causes of dyspnoea have been investigated and excluded.
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Exploring the role of quantitative feedback in inhaler technique education: a cluster-randomised, two-arm, parallel-group, repeated-measures study.
NPJ Prim Care Respir Med
PUBLISHED: 06-11-2014
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Feedback is a critical component of any educational intervention. When it comes to feedback associated with inhaler technique education, there is a lack of knowledge on its role or its potential to solve the major issue of poor inhaler technique.
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Refinement of indicators and criteria in a quality tool for assessing quality in primary care in Canada: a Delphi panel study.
Fam Pract
PUBLISHED: 05-21-2014
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Primary care is the cornerstone of the health care system and increasingly countries are developing indicators for assessing quality in primary care practices. The 'Quality Tool', developed in Ontario, Canada, provides a framework for assessing practices and consists of indicators and criteria. The purpose of this study was to validate the indicators and simplify the Quality Tool.
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Improving on nature: making a cyclic heptapeptide orally bioavailable.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 05-16-2014
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The use of peptides in medicine is limited by low membrane permeability, metabolic instability, high clearance, and negligible oral bioavailability. The prediction of oral bioavailability of drugs relies on physicochemical properties that favor passive permeability and oxidative metabolic stability, but these may not be useful for peptides. Here we investigate effects of heterocyclic constraints, intramolecular hydrogen bonds, and side chains on the oral bioavailability of cyclic heptapeptides. NMR-derived structures, amide H-D exchange rates, and temperature-dependent chemical shifts showed that the combination of rigidification, stronger hydrogen bonds, and solvent shielding by branched side chains enhances the oral bioavailability of cyclic heptapeptides in rats without the need for N-methylation.
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Fluticasone propionate/formoterol fumarate in fixed-dose combination for the treatment of asthma.
Expert Rev Respir Med
PUBLISHED: 05-06-2014
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A new combination inhaler containing fluticasone, a potent inhaled corticosteroid (ICS), and formoterol, a long-acting ?-agonist (LABA) with rapid onset and sustained bronchodilator effect, has been approved for treatment of persistent asthma in patients ?12 years of age requiring combination ICS-LABA therapy. The fluticasone/formoterol combination, delivered via pressurized metered-dose inhaler and available in three dose strengths, has demonstrated a good safety and tolerability profile in trials of up to 1 year. The efficacy of fluticasone/formoterol is greater than that of fluticasone or formoterol alone and noninferior to that of fluticasone/salmeterol and budesonide/formoterol in tightly controlled 8-12-week clinical trials. Advantages of the fluticasone/formoterol combination aerosol include rapid onset of bronchodilation, an attribute preferred by patients, and emission of a high fine-particle fraction that is consistent at different flow rates, which may aid consistency of delivery (given patient variability in inhalation maneuvers) and provide real-life benefits.
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Systems medicine approaches for the definition of complex phenotypes in chronic diseases and ageing. From concept to implementation and policies.
Curr. Pharm. Des.
PUBLISHED: 03-12-2014
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Chronic diseases are diseases of long duration and slow progression. Major NCDs (cardiovascular diseases, cancer, chronic respiratory diseases, diabetes, rheumatologic diseases and mental health) represent the predominant health problem of the Century. The prevention and control of NCDs are the priority of the World Health Organization 2008 Action Plan, the United Nations 2010 Resolution and the European Union 2010 Council. The novel trend for the management of NCDs is evolving towards integrative, holistic approaches. NCDs are intertwined with ageing. The European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has prioritised NCDs. To tackle them in their totality in order to reduce their burden and societal impact, it is proposed that NCDs should be considered as a single expression of disease with different risk factors and entities. An innovative integrated health system built around systems medicine and strategic partnerships is proposed to combat NCDs. It includes (i) understanding the social, economic, environmental, genetic determinants, as well as the molecular and cellular mechanisms underlying NCDs; (ii) primary care and practice-based interprofessional collaboration; (iii) carefully phenotyped patients; (iv) development of unbiased and accurate biomarkers for comorbidities, severity and follow up of patients; (v) socio-economic science; (vi) development of guidelines; (vii) training; and (viii) policy decisions. The results could be applicable to all countries and adapted to local needs, economy and health systems. This paper reviews the complexity of NCDs intertwined with ageing. It gives an overview of the problem and proposes two practical examples of systems medicine (MeDALL) applied to allergy and to NCD co-morbidities (MACVIA-LR, Reference Site of the European Innovation Partnership on Active and Healthy Ageing).
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Quality standards for real-world research. Focus on observational database studies of comparative effectiveness.
Ann Am Thorac Soc
PUBLISHED: 02-25-2014
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Real-world research can use observational or clinical trial designs, in both cases putting emphasis on high external validity, to complement the classical efficacy randomized controlled trials (RCTs) with high internal validity. Real-world research is made necessary by the variety of factors that can play an important a role in modulating effectiveness in real life but are often tightly controlled in RCTs, such as comorbidities and concomitant treatments, adherence, inhalation technique, access to care, strength of doctor-caregiver communication, and socio-economic and other organizational factors. Real-world studies belong to two main categories: pragmatic trials and observational studies, which can be prospective or retrospective. Focusing on comparative database observational studies, the process aimed at ensuring high-quality research can be divided into three parts: preparation of research, analyses and reporting, and discussion of results. Key points include a priori planning of data collection and analyses, identification of appropriate database(s), proper outcomes definition, study registration with commitment to publish, bias minimization through matching and adjustment processes accounting for potential confounders, and sensitivity analyses testing the robustness of results. When these conditions are met, observational database studies can reach a sufficient level of evidence to help create guidelines (i.e., clinical and regulatory decision-making).
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Complementing the randomized controlled trial evidence base. Evolution not revolution.
Ann Am Thorac Soc
PUBLISHED: 02-25-2014
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Observational studies and pragmatic trials can complement classical randomized controlled trials (RCTs) by providing data more relevant to the circumstances under which medicine is routinely practiced, thereby providing practical guidance for clinicians. The bearing of RCT findings on day-to-day practice can be weighted and the data more meaningfully interpreted by practicing clinicians if evidence is integrated from a variety of different study designs and methodologies. The advent of observational studies and pragmatic trials, often referred to as "real-life studies," has met with a degree of cynicism, but their role and value is gaining widespread recognition and support among clinicians. This article discusses where observational studies and pragmatic trials have utility, namely: in addressing clinical questions that are unanswered and/or unanswerable by RCTs; in testing new hypotheses and possible license extensions; and in helping to differentiate between available therapies for a given indication. Moreover, it seeks to highlight how the different approaches fit within a conceptual framework of evidence relevant to clinical practice, a step-change in the traditional view of medical evidence.
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Integrating evidence for managing asthma in patients who smoke.
Allergy Asthma Immunol Res
PUBLISHED: 02-17-2014
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Cigarette smoking among asthma patients is associated with worsening symptoms and accelerated decline in lung function. Smoking asthma is also characterized by increased levels of neutrophils and macrophages, and greater small airway remodeling, resulting in increased airflow obstruction and impaired response to corticosteroid therapy. As a result, smokers are typically excluded from asthma randomized controlled trials (RCTs). The strict inclusion/exclusion criteria used by asthma RCTs limits the extent to which their findings can be extrapolated to the routine care asthma population and to reflect the likely effectiveness of therapies in subgroups of particular clinical interest, such as smoking asthmatics. The inclusion of smokers in observational asthma studies and pragmatic trials in asthma provides a way of assessing the relative effectiveness of different treatment options for the management of this interesting clinical subgroup. Exploratory studies of possible treatment options for smoking asthma suggest potential utility in: prescribing higher-dose ICS; targeting the small airways of the lungs with extra-fine particle ICS formulations; targeting leukotreines, and possibly also combinations of these options. However, further studies are required. With the paucity of RCT data available, complementary streams of evidence (those from RCTs, pragmatic trials and observational studies) need to be combined to help guide judicious prescribing decisions in smokers with asthma.
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Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma?
NPJ Prim Care Respir Med
PUBLISHED: 02-14-2014
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Despite current guidelines and the range of available treatments, over a half of patients with asthma continue to suffer from poor symptomatic control and remain at risk of future worsening. Although a number of non-pharmacological measures are crucial for good clinical management of asthma, new therapeutic controller medications will have a role in the future management of the disease. Several long-acting anticholinergic bronchodilators are under investigation or are available for the treatment of respiratory diseases, including tiotropium bromide, aclidinium bromide, glycopyrronium bromide, glycopyrrolate and umeclidinium bromide, although none is yet licensed for the treatment of asthma. A recent Phase III investigation demonstrated that the once-daily long-acting anticholinergic bronchodilator tiotropium bromide improves lung function and reduces the risk of exacerbation in patients with symptomatic asthma, despite the use of inhaled corticosteroids (ICS) and long-acting ?2-agonists (LABAs). This has prompted the question of what the rationale is for long-acting anticholinergic bronchodilators in asthma. Bronchial smooth muscle contraction is the primary cause of reversible airway narrowing in asthma, and the baseline level of contraction is predominantly set by the level of 'cholinergic tone'. Patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, possibly as a result of elevated cholinergic activity, which anticholinergic compounds are known to reduce. Further, anticholinergic compounds may also have anti-inflammatory properties. Thus, evidence suggests that long-acting anticholinergic bronchodilators might offer benefits for the maintenance of asthma control, such as in patients failing to gain control on ICS and a LABA, or those with frequent exacerbations.
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Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort.
Lancet Respir Med
PUBLISHED: 02-13-2014
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Patterns of health-care use and comorbidities present in patients in the period before diagnosis of chronic obstructive pulmonary disease (COPD) are unknown. We investigated these factors to inform future case-finding strategies.
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White matter NAA/Cho and Cho/Cr ratios at MR spectroscopy are predictive of motor outcome in preterm infants.
Radiology
PUBLISHED: 01-31-2014
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To determine (a) whether diffuse white matter injury of prematurity is associated with an increased choline (Cho)-to-creatine (Cr) ratio and a reduced N-acetylaspartate (NAA)-to-Cho ratio and whether these measures can be used as biomarkers of outcome and (b) if changes in peak area metabolite ratios at magnetic resonance (MR) spectroscopy are associated with changes in T2 and fractional anisotropy (FA) at MR imaging.
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Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey.
NPJ Prim Care Respir Med
PUBLISHED: 01-30-2014
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Asthma is one of the most common chronic diseases in the world, and previous studies have reported low levels of control. Recent developments in the availability and use of online sources of information about asthma might add to patients' knowledge and help improve control.
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Physician surveillance of influenza: collaboration between primary care and public health.
Can Fam Physician
PUBLISHED: 01-24-2014
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Influenza-like illness (ILI) is a global and national concern. The surveillance of ILI requires collaborative efforts from many diverse settings, including primary care clinics.
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Current evidence and future research needs for FeNO measurement in respiratory diseases.
Respir Med
PUBLISHED: 01-12-2014
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Although not yet widely implemented, fraction of exhaled nitric oxide (FeNO) has emerged in recent years as a potentially useful biomarker for the assessment of airway inflammation both in undiagnosed patients with non-specific respiratory symptoms and in those with established airway disease. Research to date essentially suggests that FeNO measurement facilitates the identification of patients exhibiting T-helper cell type 2 (Th2)-mediated airway inflammation, and effectively those in whom anti-inflammatory therapy, particularly inhaled corticosteroids (ICS), is beneficial. In some studies, FeNO-guided management of patients with established airway disease is associated with lower exacerbation rates, improvements in adherence to anti-inflammatory therapy, and the ability to predict risk of future exacerbations or decline in lung function. Despite these data, concerns regarding the applicability and utility of FeNO in clinical practice still remain. This article reviews the current evidence, both supportive and critical of FeNO measurement, in the diagnosis and management of asthma and other inflammatory airway diseases. It additionally provides suggestions regarding the practical application of FeNO measurement: how it could be integrated into routine clinical practice, how its utility could be assessed and its true value to both clinicians and patients could be established. Although some unanswered questions remain, current evidence suggests that FeNO is potentially a valuable tool for improving the personalised management of inflammatory airway diseases.
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Comparing the effectiveness of small-particle versus large-particle inhaled corticosteroid in COPD.
Int J Chron Obstruct Pulmon Dis
PUBLISHED: 01-01-2014
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Small airway changes and dysfunction contribute importantly to airway obstruction in chronic obstructive pulmonary disease (COPD), which is currently treated with inhaled corticosteroids (ICS) and long-acting bronchodilators at Global initiative for Obstructive Lung Disease (GOLD) grades 2-4. This retrospective matched cohort analysis compared effectiveness of a representative small-particle ICS (extrafine beclomethasone) and larger-particle ICS (fluticasone) in primary care patients with COPD.
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Management of COPD in the UK primary-care setting: an analysis of real-life prescribing patterns.
Int J Chron Obstruct Pulmon Dis
PUBLISHED: 01-01-2014
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Despite the availability of national and international guidelines, evidence suggests that chronic obstructive pulmonary disease (COPD) treatment is not always prescribed according to recommendations. This study evaluated the current management of patients with COPD using a large UK primary-care database.
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Adjunctive treatment with oral AKL1, a botanical nutraceutical, in chronic obstructive pulmonary disease.
Int J Chron Obstruct Pulmon Dis
PUBLISHED: 01-01-2014
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The objective of this pilot trial was to evaluate the safety and efficacy of AKL1, a patented botanical formulation containing extracts of Picrorhiza kurroa, Ginkgo biloba, and Zingiber officinale, as add-on therapy for patients with chronic obstructive pulmonary disease (COPD) and chronic cough.
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Switching patients from other inhaled corticosteroid devices to the Easyhaler(®): historical, matched-cohort study of real-life asthma patients.
J Asthma Allergy
PUBLISHED: 01-01-2014
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To investigate the clinical and cost effectiveness of switching real-life asthma patients from other types of inhalers to the Easyhaler(®) (EH) for the administration of inhaled corticosteroids (ICS).
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Detection of airflow limitation using a handheld spirometer in a primary care setting.
Respirology
PUBLISHED: 01-01-2014
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Early diagnosis of chronic obstructive pulmonary disease (COPD) in primary care settings is difficult to achieve chiefly due to lack of availability of spirometry. This study estimated the prevalence of airflow limitation among chronic smokers using a handheld spirometer in this setting.
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Long-term, randomized safety study of MP29-02 (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in an advanced delivery system) in subjects with chronic rhinitis.
J Allergy Clin Immunol Pract
PUBLISHED: 01-01-2014
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MP29-02 is a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate (FP) in an advanced delivery system for the treatment of seasonal allergic rhinitis.
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Clinical and cost effectiveness of switching asthma patients from fluticasone-salmeterol to extra-fine particle beclometasone-formoterol: a retrospective matched observational study of real-world patients.
Prim Care Respir J
PUBLISHED: 11-05-2013
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Efficacy trials suggest that extra-fine particle beclometasone dipropionate-formoterol (efBDP-FOR) is comparable to fluticasone propionate-salmeterol (FP-SAL) in preventing asthma exacerbations at a clinically equivalent dosage. However, switching from FP-SAL to efBDP-FOR has not been evaluated in real-world asthma patients.
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Types, frequency and impact of asthma triggers on patients lives: a quantitative study in five European countries.
J Asthma
PUBLISHED: 11-04-2013
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Abstract Objective: To identify the types, frequency and impact of asthma triggers and the relationship to asthma control among adults with asthma in Europe. Methods: Adults with self-reported physician-diagnosed asthma receiving maintenance asthma treatment and self-reported exposure to known asthma triggers completed an online questionnaire; a subset completed a diary over 3-4 weeks. Information on asthma control (Asthma Control Test™ [ACT]), asthma triggers, frequency of exposure and behaviours in response or to avoid asthma triggers and the perceived impact on daily life was captured. A post-hoc analysis evaluated the impact of high trigger burden on the frequency of severe asthma exacerbations, hospitalisations and days lost at work/study. Results: A total of 1202 adults participated and 177 completed the diary. Asthma was uncontrolled for the majority (76%) of participants and most (52%) reported exposure to 6-15 asthma triggers. As trigger burden increased, behavioural changes to manage trigger exposure had a significantly increased impact on daily life (p?16) were more likely to report uncontrolled asthma than those with a low trigger burden (1-5). Participants with a high trigger burden had previously experienced on average two more severe asthma attacks during a lifetime (p?16 different triggers) experience more severe asthma attacks than those reporting lower trigger burdens.
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Challenges of COPD diagnosis.
Expert Opin Med Diagn
PUBLISHED: 10-08-2013
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Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide and this burden is predicted to increase unless exposure to risk factors is addressed. Diagnosis of COPD is a challenge: COPD is underdiagnosed and frequently misdiagnosed for asthma or other respiratory conditions. Although spirometry is only one parameter for establishing a clinical diagnosis of COPD, lack of routine spirometry is a key cause of COPD misdiagnosis. Differential diagnosis from asthma is essential because the treatment strategies for, and progression and outcomes of, the two conditions vary greatly.
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Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD.
Prim Care Respir J
PUBLISHED: 10-01-2013
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While the pharmacological management of chronic obstructive pulmonary disease (COPD) has evolved from the drugs used to treat asthma, the treatment models are different and the two diseases require clear differential diagnosis in order to determine the correct therapeutic strategy. In contrast to the almost universal requirement for anti-inflammatory treatment of persistent asthma, the efficacy of inhaled corticosteroids (ICS) is less well established in COPD and their role in treatment is limited. There is some evidence of a preventive effect of ICS on exacerbations in patients with COPD, but there is little evidence for an effect on mortality or lung function decline. As a result, treatment guidelines recommend the use of ICS in patients with severe or very severe disease (forced expiratory volume in 1 second <50% predicted) and repeated exacerbations. Patients with frequent exacerbations - a phenotype that is stable over time - are likely to be less common among those with moderate COPD (many of whom are managed in primary care) than in those with more severe disease. The indiscriminate use of ICS in COPD may expose patients to an unnecessary increase in the risk of side-effects such as pneumonia, osteoporosis, diabetes and cataracts, while wasting healthcare spending and potentially diverting attention from other more appropriate forms of management such as pulmonary rehabilitation and maximal bronchodilator use. Physicians should carefully weigh the likely benefits of ICS use against the potential risk of side-effects and costs in individual patients with COPD.
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Modulation of adipose tissue thermogenesis as a method for increasing energy expenditure.
Bioorg. Med. Chem. Lett.
PUBLISHED: 09-02-2013
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There is a renewed interest in the role of adipose tissue in energy utilization and thermogenesis and its potential application in the treatment of metabolic disorders such as obesity and diabetes. The last few years have seen the identification of brown adipose tissue capable of metabolic activation in adult humans, the possibility of recruiting beige adipocytes to increase energy expenditure, and the implication of molecules such as FGF21 and irisin in inducing increases in energy expenditure in adipose tissue. The translation of these findings into human trials to deliver safe, efficacious medicines remains a challenge.
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Fellowships in international emergency medicine in the USA: a comparative survey of program directors and fellows perspectives on the curriculum.
Postgrad Med J
PUBLISHED: 08-20-2013
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Experts have proposed core curriculum components for international emergency medicine (IEM) fellowships. This study examined perceptions of program directors (PDs) and fellows on whether IEM fellowships cover these components, whether their perspectives differ and the barriers preventing fellowships from covering them.
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Efficacy versus effectiveness trials: informing guidelines for asthma management.
Curr Opin Allergy Clin Immunol
PUBLISHED: 08-02-2013
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Randomized controlled trials, known as efficacy trials and long considered the gold standard for evidence-based asthma guidelines, are designed to test whether interventions have a benefit for selective patient populations under ideal conditions. The goal of pragmatic trials and observational studies instead is to understand real-life efficacy, known as effectiveness. This review summarizes the strengths and limitations of efficacy and effectiveness trials, results of recent effectiveness trials in asthma and initiatives promoting effectiveness research.
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Using fractional exhaled nitric oxide (FeNO) to diagnose steroid-responsive disease and guide asthma management in routine care.
Clin Transl Allergy
PUBLISHED: 07-19-2013
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Fractional exhaled nitric oxide (FeNO) is a surrogate marker of eosinophilic airway inflammation and good predictor of corticosteroid response.Aim: To evaluate how FeNO is being used to guide primary care asthma management in the United Kingdom (UK) with a view to devising practical algorithms for the use of FeNO in the diagnosis of steroid-responsive disease and to guide on-going asthma management.
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Modelling blood flow and metabolism in the piglet brain during hypoxia-ischaemia: simulating brain energetics.
Adv. Exp. Med. Biol.
PUBLISHED: 07-16-2013
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We have developed a computational model to simulate hypoxia-ischaemia (HI) in the neonatal piglet brain. It has been extended from a previous model by adding the simulation of carotid artery occlusion and including pH changes in the cytoplasm. Here, simulations from the model are compared with near-infrared spectroscopy (NIRS) and phosphorus magnetic resonance spectroscopy (MRS) measurements from two piglets during HI and short-term recovery. One of these piglets showed incomplete recovery after HI, and this is modelled by considering some of the cells to be dead. This is consistent with the results from MRS and the redox state of cytochrome-c-oxidase as measured by NIRS. However, the simulations do not match the NIRS haemoglobin measurements. The model therefore predicts that further physiological changes must also be taking place if the hypothesis of dead cells is correct.
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Modelling blood flow and metabolism in the piglet brain during hypoxia-ischaemia: simulating pH changes.
Adv. Exp. Med. Biol.
PUBLISHED: 07-16-2013
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We describe the extension of a computational model of blood flow and metabolism in the piglet brain to investigate changes in neonatal intracellular brain pH during hypoxia-ischemia (HI). The model is able to simulate near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS) measurements obtained from HI experiments conducted in piglets. We adopt a method of using (31)P-MRS data to estimate of intracellular pH and compare measured pH and oxygenation with their modelled counterparts. We show that both NIRS and MRS measurements are predicted well in the new version of the model.
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A new-generation continuous glucose monitoring system: improved accuracy and reliability compared with a previous-generation system.
Diabetes Technol. Ther.
PUBLISHED: 06-18-2013
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Use of continuous glucose monitoring (CGM) systems can improve glycemic control, but widespread adoption of CGM utilization has been limited, in part because of real and perceived problems with accuracy and reliability. This study compared accuracy and performance metrics for a new-generation CGM system with those of a previous-generation device.
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The future of peptide-based drugs.
Chem Biol Drug Des
PUBLISHED: 05-23-2013
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The suite of currently used drugs can be divided into two categories - traditional small molecule drugs with typical molecular weights of <500 Da but with oral bioavailability, and much larger biologics typically >5000 Da that are not orally bioavailable and need to be delivered via injection. Due to their small size, conventional small molecule drugs may suffer from reduced target selectivity that often ultimately manifests in human side-effects, whereas protein therapeutics tend to be exquisitely specific for their targets due to many more interactions with them, but this comes at a cost of low bioavailability, poor membrane permeability, and metabolic instability. The time has now come to reinvestigate new drug leads that fit between these two molecular weight extremes, with the goal of combining advantages of small molecules (cost, conformational restriction, membrane permeability, metabolic stability, oral bioavailability) with those of proteins (natural components, target specificity, high potency). This article uses selected examples of peptides to highlight the importance of peptide drugs, some potential new opportunities for their exploitation, and some difficult challenges ahead in this field.
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Hypocalcaemia after an Occult Calcium Channel Blocker Overdose: A Case Report and Literature Review.
Basic Clin. Pharmacol. Toxicol.
PUBLISHED: 05-16-2013
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Hypocalcaemia is a rare complication of calcium channel blocker overdose, having been reported only once previously (J Toxicol Clin Toxicol, 1992, 30, 309). In this article, we report a case of a 37-year-old woman who developed hypocalcaemia after a verapamil overdose, review the literature and propose a mechanism for this rare finding.
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Exploitation, akrasia, and Goldilocks: how many pounds for flesh for medical uses?
Med Law Rev
PUBLISHED: 05-14-2013
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Modest reforms to the present system of the giving of body parts for therapy and research are being put on the table (for example, by the Nuffield Council on Bioethics and the Human Fertilisation and Embryology Authority). These potentially presage a move to a system where (greater) material incentives could be offered in the future (and this is certainly how such initial reforms will be perceived by objectors). At present, however, the diverse rationales for constraints on both payments being offered in themselves, and to specific levels of payments, are both confused and consistently conflated. Greater clarity in the application of both concepts and terminology will provide a sounder foundation for deliberation of potential reforms in areas where demand is pressing and substantial suffering very real.
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Loss of population data sources when health systems are not responsible for geographically defined populations: implications of the Health and Social Care Act of 2012 in England.
Evid Based Med
PUBLISHED: 05-03-2013
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Biomedical health services and health systems research require timely, complete, accurate and accessible data relating to geographical populations in order to facilitate needs assessment and planning of medical care, new medicines and technology. The international trend towards competition and privatisation has largely proceeded as if data generation were immune to market fragmentation and loss of universal coverage. By examining recent reforms to the English National Health Service, the authors show that this is not the case. Routine and population data are products of administrative systems and the nature, completeness and quality of data available to clinical and public health researchers are substantially impaired by market reforms.
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Design and synthesis of diazatricyclodecane agonists of the G-protein-coupled receptor 119.
J. Med. Chem.
PUBLISHED: 04-19-2013
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A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1?3,7?]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Löffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the "agonist conformation" as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules.
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A UK-based cost-utility analysis of indacaterol, a once-daily maintenance bronchodilator for patients with COPD, using real world evidence on resource use.
Appl Health Econ Health Policy
PUBLISHED: 03-27-2013
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Chronic Obstructive Pulmonary Disease (COPD) is a chronic, progressive disease that is not curable. However, there are effective treatments available. In the UK, long-acting bronchodilators are first-line treatments for COPD patients requiring maintenance therapy, and there are several options available. The aim of this study is to establish, from the UK National Health Service (NHS) perspective, the cost-effectiveness profile of indacaterol, the first once-daily long-acting beta2-agonist (LABA), compared with tiotropium and salmeterol, in patients with moderate to severe COPD. In assessing the cost-effectiveness of COPD therapies, this study has the advantage of using real world evidence on the resource use associated with COPD management across the spectrum of the disease.
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InternationaL cross-sectIonAl and longItudinal assessment on aSthma cONtrol in European adult patients--the LIAISON study protocol.
BMC Pulm Med
PUBLISHED: 03-15-2013
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According to international guidelines, the goal of asthma management is to achieve and maintain control of the disease, which can be assessed using composite measures. Prospective studies are required to determine how these measures are associated with asthma outcomes and/or future risk. The InternationaL cross-sectIonAl and longItudinal assessment on aSthma cONtrol (LIAISON) observational study has been designed to evaluate asthma control and its determinants, including components of asthma management.
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Characteristics of patients preferring once-daily controller therapy for asthma and COPD: a retrospective cohort study.
Prim Care Respir J
PUBLISHED: 03-06-2013
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Patient preference is an important factor when choosing an inhaler device for asthma or chronic obstructive pulmonary disease (COPD).
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Clinically relevant effect of a new intranasal therapy (MP29-02) in allergic rhinitis assessed by responder analysis.
Int. Arch. Allergy Immunol.
PUBLISHED: 02-18-2013
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It is unclear what constitutes a clinically meaningful response for allergic rhinitis (AR) outcomes. The objectives of these post hoc analyses were (1) to define a clinically meaningful response using novel efficacy analyses (including a responder analysis), and (2) to compare the efficacy of MP29-02 [a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP)] with commercially available FP, AZE and placebo in seasonal AR (SAR) patients, using these novel analyses.
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Real-life comparison of beclometasone dipropionate as an extrafine- or larger-particle formulation for asthma.
Respir Med
PUBLISHED: 02-12-2013
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Beclometasone dipropionate is an inhaled corticosteroid (ICS) available in both extrafine and larger-particle hydrofluoroalkane formulations. Extrafine beclometasone has greater small airway distribution and inhalation technique tolerance than larger-particle beclometasone; therefore, its use may be associated with improved asthma outcomes at population levels. The study objective was to compare real-life effectiveness of extrafine and larger-particle beclometasone.
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Asthma outcomes and costs of therapy with extrafine beclomethasone and fluticasone.
J. Allergy Clin. Immunol.
PUBLISHED: 02-06-2013
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Characteristics of inhaled corticosteroids (ICSs) differ, but data comparing the real-life effectiveness of various ICSs for asthma are lacking.
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Effect of montelukast for treatment of asthma in cigarette smokers.
J. Allergy Clin. Immunol.
PUBLISHED: 02-04-2013
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Many asthmatic patients are unable to quit cigarettes; therefore information is needed on treatment options for smokers. This study evaluates 10 mg/d montelukast and 250 ?g of fluticasone propionate twice daily, each compared with placebo, in patients with self-reported active smoking (unable to quit) and asthma.
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Outcomes following neonatal patent ductus arteriosus ligation done by pediatric surgeons: a retrospective cohort analysis.
J. Pediatr. Surg.
PUBLISHED: 01-20-2013
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Patent Ductus Arteriosus (PDA) ligation in premature infants is an urgent procedure performed by some but not all pediatric surgeons. Proficiency in PDA ligation is not a requirement of Canadian pediatric surgery training. Our purpose was to determine the outcomes of neonatal PDA ligation done by pediatric surgeons.
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Improving clinical reality in chronic obstructive pulmonary disease economic modelling : development and validation of a micro-simulation approach.
Pharmacoeconomics
PUBLISHED: 01-19-2013
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Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible disease responsible for the deaths of 3 million people worldwide in 2005, and predicted to be the third leading cause of death worldwide by 2030. Many COPD models developed to date have followed a Markov structure, in which patients or populations can move between defined health states over successive time periods or cycles. In COPD, health states are typically based on disease severity defined solely by lung function, as described by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. These current modelling methods may restrict the ability to reflect the disease progression/clinical pathway or clinical practice.
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Improving knowledge and process for international emergency medicine fellowship applicants: a call for a uniform application.
Emerg Med Int
PUBLISHED: 01-17-2013
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Background. There are currently 34 International Emergency Medicine (IEM) fellowship programs. Applicants and programs are increasing in number and diversity. Without a standardized application, applicants have a difficulty approaching programs in an informed and an organized method; a streamlined application system is necessary. Objectives. To measure fellows knowledge of their programs curricula prior to starting fellowship and to determine what percent of fellows and program directors would support a universal application system. Methods. A focus group of program directors, recent, and current fellows convened to determine the most important features of an IEM fellowship application process. A survey was administered electronically to a convenience sample of 78 participants from 34 programs. Respondents included fellowship directors, fellows, and recent graduates. Results. Most fellows (70%) did not know their programs curriculum prior to starting fellowship. The majority of program directors and fellows support a uniform application service (81% and 67%, resp.) and deadline (85% for both). A minority of program directors (35%) and fellows (30%) support a formal match. Conclusions. Program directors and fellows support a uniform application service and deadline, but not a formalized match. Forums for disseminating IEM fellowship information and for administering a uniform application service and deadline are currently in development to improve the process.
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Impact of night-time symptoms in COPD: a real-world study in five European countries.
Int J Chron Obstruct Pulmon Dis
PUBLISHED: 01-01-2013
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Sleep quality is often poor in patients with chronic obstructive pulmonary disease (COPD). A cross-sectional European survey investigated the prevalence of night-time symptoms in COPD to evaluate the level of disconnect between physician and patient perceptions of the presence of night-time symptoms, and to compare the characteristics of patients with and without night-time symptoms.
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Planning for interprofessional change in primary health care: exploring the use of the Interprofessional Resource Centre.
Adv Med Educ Pract
PUBLISHED: 01-01-2013
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Resources to support change are needed for solo practitioners who are transitioning to family health teams (FHTs) which involve multiple health disciplines working together to provide team-based care.
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Clonotype and repertoire changes drive the functional improvement of HIV-specific CD8 T cell populations under conditions of limited antigenic stimulation.
J. Immunol.
PUBLISHED: 12-30-2011
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Persistent exposure to cognate Ag leads to the functional impairment and exhaustion of HIV-specific CD8 T cells. Ag withdrawal, attributable either to antiretroviral treatment or the emergence of epitope escape mutations, causes HIV-specific CD8 T cell responses to wane over time. However, this process does not continue to extinction, and residual CD8 T cells likely play an important role in the control of HIV replication. In this study, we conducted a longitudinal analysis of clonality, phenotype, and function to define the characteristics of HIV-specific CD8 T cell populations that persist under conditions of limited antigenic stimulation. Ag decay was associated with dynamic changes in the TCR repertoire, increased expression of CD45RA and CD127, decreased expression of programmed death-1, and the emergence of polyfunctional HIV-specific CD8 T cells. High-definition analysis of individual clonotypes revealed that the Ag loss-induced gain of function within HIV-specific CD8 T cell populations could be attributed to two nonexclusive mechanisms: 1) functional improvement of persisting clonotypes; and 2) recruitment of particular clonotypes endowed with superior functional capabilities.
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Incentives for organ donation: proposed standards for an internationally acceptable system.
Am. J. Transplant.
PUBLISHED: 12-17-2011
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Incentives for organ donation, currently prohibited in most countries, may increase donation and save lives. Discussion of incentives has focused on two areas: (1) whether or not there are ethical principles that justify the current prohibition and (2) whether incentives would do more good than harm. We herein address the second concern and propose for discussion standards and guidelines for an acceptable system of incentives for donation. We believe that if systems based on these guidelines were developed, harms would be no greater than those to todays conventional donors. Ultimately, until there are trials of incentives, the question of benefits and harms cannot be satisfactorily answered.
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A single autoimmune T cell receptor recognizes more than a million different peptides.
J. Biol. Chem.
PUBLISHED: 11-18-2011
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The T cell receptor (TCR) orchestrates immune responses by binding to foreign peptides presented at the cell surface in the context of major histocompatibility complex (MHC) molecules. Effective immunity requires that all possible foreign peptide-MHC molecules are recognized or risks leaving holes in immune coverage that pathogens could quickly evolve to exploit. It is unclear how a limited pool of <10(8) human TCRs can successfully provide immunity to the vast array of possible different peptides that could be produced from 20 proteogenic amino acids and presented by self-MHC molecules (>10(15) distinct peptide-MHCs). One possibility is that T cell immunity incorporates an extremely high level of receptor degeneracy, enabling each TCR to recognize multiple peptides. However, the extent of such TCR degeneracy has never been fully quantified. Here, we perform a comprehensive experimental and mathematical analysis to reveal that a single patient-derived autoimmune CD8(+) T cell clone of pathogenic relevance in human type I diabetes recognizes >one million distinct decamer peptides in the context of a single MHC class I molecule. A large number of peptides that acted as substantially better agonists than the wild-type "index" preproinsulin-derived peptide (ALWGPDPAAA) were identified. The RQFGPDFPTI peptide (sampled from >10(8) peptides) was >100-fold more potent than the index peptide despite differing from this sequence at 7 of 10 positions. Quantification of this previously unappreciated high level of CD8(+) T cell cross-reactivity represents an important step toward understanding the system requirements for adaptive immunity and highlights the enormous potential of TCR degeneracy to be the causative factor in autoimmune disease.
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Structural basis of diverse peptide accommodation by the rhesus macaque MHC class I molecule Mamu-B*17: insights into immune protection from simian immunodeficiency virus.
J. Immunol.
PUBLISHED: 11-14-2011
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The MHC class I molecule Mamu-B*17 has been associated with elite control of SIV infection in rhesus macaques, akin to the protective effects described for HLA-B*57 in HIV-infected individuals. In this study, we determined the crystal structures of Mamu-B*17 in complex with eight different peptides corresponding to immunodominant SIV(mac)239-derived CD8(+) T cell epitopes: HW8 (HLEVQGYW), GW10 (GSHLEVQGYW), MW9 (MHPAQTSQW), QW9 (QTSQWDDPW), FW9 (FQWMGYELW), MF8 (MRHVLEPF), IW9 (IRYPKTFGW), and IW11 (IRYPKTFGWLW). The structures reveal that not only P2, but also P1 and P3, can be used as N-terminal anchor residues by Mamu-B*17-restricted peptides. Moreover, the N-terminal anchor residues exhibit a broad chemical specificity, encompassing basic (H and R), bulky polar aliphatic (Q), and small (T) residues. In contrast, Mamu-B*17 exhibits a very narrow preference for aromatic residues (W and F) at the C terminus, similar to that displayed by HLA-B*57. Flexibility within the whole peptide-binding groove contributes to the accommodation of these diverse peptides, which adopt distinct conformations. Furthermore, the unusually large pocket D enables compensation from other peptide residues if P3 is occupied by an amino acid with a small side chain. In addition, residues located at likely TCR contact regions present highly flexible conformations, which may impact TCR repertoire profiles. These findings provide novel insights into the structural basis of diverse peptide accommodation by Mamu-B*17 and highlight unique atomic features that might contribute to the protective effect of this MHC I molecule in SIV-infected rhesus macaques.
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Aurora kinase A-specific T-cell receptor gene transfer redirects T lymphocytes to display effective antileukemia reactivity.
Blood
PUBLISHED: 10-24-2011
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Aurora kinase A (AURKA) is overexpressed in leukemias. Previously, we demonstrated that AURKA-specific CD8(+) T cells specifically and selectively lysed leukemia cells, indicating that AURKA is an excellent target for immunotherapy. In this study, we examined the feasibility of adoptive therapy using redirected T cells expressing an HLA-A*0201-restricted AURKA(207-215)-specific T-cell receptor (TCR). Retrovirally transduced T cells recognized relevant peptide-pulsed but not control target cells. Furthermore, TCR-redirected CD8(+) T cells lysed AURKA-overexpressing human leukemic cells in an HLA-A*0201-restricted manner, but did not kill HLA-A*0201(+) normal cells, including hematopoietic progenitors. In addition, AURKA(207-215)-specific TCR-transduced CD4(+) T cells displayed target-responsive Th1 cytokine production. Finally, AURKA(207-215)-specific TCR-transduced CD8(+) T cells displayed antileukemia efficacy in a xenograft mouse model. Collectively, these data demonstrate the feasibility of redirected T cell-based AURKA-specific immunotherapy for the treatment of human leukemia.
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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.