548 research outputs found

    A systematic review of moral reasons on orphan drug reimbursement

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    The number of market approvals of orphan medicinal products (OMPs) has been increasing steadily in the last 3 decades. While OMPs can offer a unique chance for patients suffering from rare diseases, they are usually very expensive. The growing number of approved OMPs increases their budget impact despite their low prevalence, making it pressing to find solutions to ethical challenges on how to fairly allocate scarce healthcare resources under this context. One potential solution could be to grant OMPs special status when considering them for reimbursement, meaning that they are subject to different, and less stringent criteria than other drugs. This study aims to provide a systematic analysis of moral reasons for and against such a special status for the reimbursement of OMPs in publicly funded healthcare systems from a multidisciplinary perspective.; With a systematic review of reasons, we identified 39 reasons represented in 243 articles (scientific and grey literature) for and against special status for the reimbursement of OMPs, then categorized them into nine topics. Taking a multidisciplinary perspective, we found that most articles came from health policy (n = 103) and health economics (n = 49). More articles took the position for a special status of OMPs (n = 97) than those against it (n = 31) and there was a larger number of reasons identified in favour (29 reasons) than against (10 reasons) this special status.; Results suggest that OMP reimbursement issues should be assessed and analysed from a multidisciplinary perspective. Despite the higher occurrence of reasons and articles in favour of a special status, there is no clear-cut solution for this ethical challenge. The binary perspective of whether or not OMPs should be granted special status oversimplifies the issue: both OMPs and rare diseases are too heterogeneous in their characteristics for such a binary perspective. Thus, the scientific debate should focus less on the question of disease prevalence but rather on how the important variability of different OMPs concerning e.g. target population, cost-effectiveness, level of evidence or mechanism of action could be meaningfully addressed and implemented in Health Technology Assessments

    Species-Specific and Distance-Dependent Dispersive Behaviour of Forisomes in Different Legume Species

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    Forisomes are giant fusiform protein complexes composed of sieve element occlusion (SEO) protein monomers, exclusively found in sieve elements (SEs) of legumes. Forisomes block the phloem mass flow by a Ca2+-induced conformational change (swelling and rounding). We studied the forisome reactivity in four different legume species—Medicago sativa, Pisum sativum, Trifolium pratense and Vicia faba. Depending on the species, we found direct relationships between SE diameter, forisome surface area and distance from the leaf tip, all indicative of a developmentally tuned regulation of SE diameter and forisome size. Heat-induced forisome dispersion occurred later with increasing distance from the stimulus site. T. pratense and V. faba dispersion occurred faster for forisomes with a smaller surface area. Near the stimulus site, electro potential waves (EPWs)—overlapping action (APs), and variation potentials (VPs)—were linked with high full-dispersion rates of forisomes. Distance-associated reduction of forisome reactivity was assigned to the disintegration of EPWs into APs, VPs and system potentials (SPs). Overall, APs and SPs alone were unable to induce forisome dispersion and only VPs above a critical threshold were capable of inducing forisome reactions

    The interlayer cohesive energy of graphite from thermal desorption of polyaromatic hydrocarbons

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    We have studied the interaction of polyaromatic hydrocarbons (PAHs) with the basal plane of graphite using thermal desorption spectroscopy. Desorption kinetics of benzene, naphthalene, coronene and ovalene at sub-monolayer coverages yield activation energies of 0.50 eV, 0.85 eV, 1.40 eV and 2.1 eV, respectively. Benzene and naphthalene follow simple first order desorption kinetics while coronene and ovalene exhibit fractional order kinetics owing to the stability of 2-D adsorbate islands up to the desorption temperature. Pre-exponential frequency factors are found to be in the range 101410^{14}-1021s110^{21} s^{-1} as obtained from both Falconer--Madix (isothermal desorption) analysis and Antoine's fit to vapour pressure data. The resulting binding energy per carbon atom of the PAH is 52±52\pm5 meV and can be identified with the interlayer cohesive energy of graphite. The resulting cleavage energy of graphite is 61±561\pm5~meV/atom which is considerably larger than previously reported experimental values.Comment: 8 pages, 4 figures, 2 table

    Microfluidic characterisation reveals broad range of SARS-CoV-2 antibody affinity in human plasma.

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    Funder: Herchel Smith FundFunder: St John’s College CambridgeFunder: Centre for Misfolding Diseases, CambridgeFunder: Swiss FCS and the Forschungskredit of the University of ZurichFunder: Frances and Augustus Newman FoundationFunder: BBRSCFunder: NOMIS FoundationThe clinical outcome of SARS-CoV-2 infections, which can range from asymptomatic to lethal, is crucially shaped by the concentration of antiviral antibodies and by their affinity to their targets. However, the affinity of polyclonal antibody responses in plasma is difficult to measure. Here we used microfluidic antibody affinity profiling (MAAP) to determine the aggregate affinities and concentrations of anti-SARS-CoV-2 antibodies in plasma samples of 42 seropositive individuals, 19 of which were healthy donors, 20 displayed mild symptoms, and 3 were critically ill. We found that dissociation constants, K d, of anti-receptor-binding domain antibodies spanned 2.5 orders of magnitude from sub-nanomolar to 43 nM. Using MAAP we found that antibodies of seropositive individuals induced the dissociation of pre-formed spike-ACE2 receptor complexes, which indicates that MAAP can be adapted as a complementary receptor competition assay. By comparison with cytopathic effect-based neutralisation assays, we show that MAAP can reliably predict the cellular neutralisation ability of sera, which may be an important consideration when selecting the most effective samples for therapeutic plasmapheresis and tracking the success of vaccinations

    Incidence and classification of pediatric diffuse parenchymal lung diseases in Germany

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    <p>Abstract</p> <p>Background</p> <p>Diffuse parenchymal lung diseases (DPLD) in children represent a rare and heterogeneous group of chronic pulmonary disorders. Despite substantial advances in genetics and pathomechanisms, these often lethal diseases are still under-diagnosed. This is due to the fact that (i) the incidence is low, and (ii) clinical presentation, (iii) disease classification and (iv) specific treatment options are largely unknown.</p> <p>Methods</p> <p>Here we systematically assessed the incidence, the presentation, the diagnostic yield and treatments of pediatric DPLD in Germany, using the Surveillance Unit for Rare Paediatric Disorders (ESPED).</p> <p>Results</p> <p>The incidence of DPLD was 1.32 new cases per 1 million of children per year. The majority of these children were diagnosed within the first year of life. Overall survival was 87%. Using centralized data entry and stratification tools, the patients were categorized into an advanced classification system based on diagnostic algorithms, including clinical presentations, genetics and/or histology. Combining molecular and clinical information, this survey provides an etiological overview and specific diagnostic recommendations for children with DPLD.</p> <p>Conclusions</p> <p>Standardized surveys and systematic classifications are valuable tools for the clinical handling of children with DPLD and aim to improve the disease understanding and the prognosis of these rare detrimental lung diseases.</p

    Diagnosis of obstructive coronary artery disease using computed tomography angiography in patients with stable chest pain depending on clinical probability and in clinically important subgroups: meta-analysis of individual patient data

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    OBJECTIVE: To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients. DESIGN: Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies. DATA SOURCES: Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative predictive values of CTA as a function of clinical pretest probability of obstructive CAD, analysed by a generalised linear mixed model; calculations were performed including and excluding non-diagnostic CTA results. The no-treat/treat threshold model was used to determine the range of appropriate pretest probabilities for CTA. The threshold model was based on obtained post-test probabilities of less than 15% in case of negative CTA and above 50% in case of positive CTA. Sex, angina pectoris type, age, and number of computed tomography detector rows were used as clinical variables to analyse the diagnostic performance in relevant subgroups. RESULTS: Individual patient data from 5332 patients from 65 prospective diagnostic accuracy studies were retrieved. For a pretest probability range of 7-67%, the treat threshold of more than 50% and the no-treat threshold of less than 15% post-test probability were obtained using CTA. At a pretest probability of 7%, the positive predictive value of CTA was 50.9% (95% confidence interval 43.3% to 57.7%) and the negative predictive value of CTA was 97.8% (96.4% to 98.7%); corresponding values at a pretest probability of 67% were 82.7% (78.3% to 86.2%) and 85.0% (80.2% to 88.9%), respectively. The overall sensitivity of CTA was 95.2% (92.6% to 96.9%) and the specificity was 79.2% (74.9% to 82.9%). CTA using more than 64 detector rows was associated with a higher empirical sensitivity than CTA using up to 64 rows (93.4% v 86.5%, P=0.002) and specificity (84.4% v 72.6%, P<0.001). The area under the receiver-operating-characteristic curve for CTA was 0.897 (0.889 to 0.906), and the diagnostic performance of CTA was slightly lower in women than in with men (area under the curve 0.874 (0.858 to 0.890) v 0.907 (0.897 to 0.916), P<0.001). The diagnostic performance of CTA was slightly lower in patients older than 75 (0.864 (0.834 to 0.894), P=0.018 v all other age groups) and was not significantly influenced by angina pectoris type (typical angina 0.895 (0.873 to 0.917), atypical angina 0.898 (0.884 to 0.913), non-anginal chest pain 0.884 (0.870 to 0.899), other chest discomfort 0.915 (0.897 to 0.934)). CONCLUSIONS: In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42012002780

    Coordinated optimization of visual cortical maps (II) Numerical studies

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    It is an attractive hypothesis that the spatial structure of visual cortical architecture can be explained by the coordinated optimization of multiple visual cortical maps representing orientation preference (OP), ocular dominance (OD), spatial frequency, or direction preference. In part (I) of this study we defined a class of analytically tractable coordinated optimization models and solved representative examples in which a spatially complex organization of the orientation preference map is induced by inter-map interactions. We found that attractor solutions near symmetry breaking threshold predict a highly ordered map layout and require a substantial OD bias for OP pinwheel stabilization. Here we examine in numerical simulations whether such models exhibit biologically more realistic spatially irregular solutions at a finite distance from threshold and when transients towards attractor states are considered. We also examine whether model behavior qualitatively changes when the spatial periodicities of the two maps are detuned and when considering more than 2 feature dimensions. Our numerical results support the view that neither minimal energy states nor intermediate transient states of our coordinated optimization models successfully explain the spatially irregular architecture of the visual cortex. We discuss several alternative scenarios and additional factors that may improve the agreement between model solutions and biological observations.Comment: 55 pages, 11 figures. arXiv admin note: substantial text overlap with arXiv:1102.335

    On species delimitation: Yet another lemur species or just genetic variation?

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    <p>Abstract</p> <p>Background</p> <p>Although most taxonomists agree that species are independently evolving metapopulation lineages that should be delimited with several kinds of data, the taxonomic practice in Malagasy primates (Lemuriformes) looks quite different. Several recently described lemur species are based solely on evidence of genetic distance and diagnostic characters of mitochondrial DNA sequences sampled from a few individuals per location. Here we explore the validity of this procedure for species delimitation in lemurs using published sequence data.</p> <p>Results</p> <p>We show that genetic distance estimates and <it>Population Aggregation Analysis </it>(PAA) are inappropriate for species delimitation in this group of primates. Intra- and interspecific genetic distances overlapped in 14 of 17 cases independent of the genetic marker used. A simulation of a fictive taxonomic study indicated that for the mitochondrial D-loop the minimum required number of individuals sampled per location is 10 in order to avoid false positives via PAA.</p> <p>Conclusions</p> <p>Genetic distances estimates and PAA alone should not be used for species delimitation in lemurs. Instead, several nuclear and sex-specific loci should be considered and combined with other data sets from morphology, ecology or behavior. Independent of the data source, sampling should be done in a way to ensure a quantitative comparison of intra- and interspecific variation of the taxa in question. The results of our study also indicate that several of the recently described lemur species should be reevaluated with additional data and that the number of good species among the currently known taxa is probably lower than currently assumed.</p