The consequences of greater net price transparency for innovative medicines in Europe: Searching for a consensus

The merits of greater or lesser net price transparency (NPT) has been a topic for discussion for many years across business and industry in general. However, in the past few years, the debate on NPT of innovative medicines has intensified, with organisations such as the United Nations (UN), the World Health Organization (WHO) and the Organisation for Economic Co-operation and Development (OECD) leading calls for greater transparency in the pharmaceutical sector, specifically focused on prices. In May 2019 the World Health Assembly (WHA) approved a resolution to support the greater public disclosure of prices and research and development (R&D) costs for both medicines and other health products supported by several European and non-European governments. To contribute to the international debate on the transparency of medicine prices in Europe, Merck Sharp & Dohme (MSD) asked Charles River Associates (CRA) to curate a panel of experts to develop evidence on the impact of greater NPT of innovative medicines. Professor Walter Van Dyck1 and Professor Massimo Riccaboni2 were asked by CRA to lead this research, supported by a wider panel of 10 experts from a range of European markets. A structured literature review was first conducted to summarise the theoretical consequences of greater NPT. This was supplemented with a survey of national payers and payer experts3 from a range of European markets. This was used as pre-read information for an expert advisory board of 12 economic and health economic experts representing 12 countries selected to give a range of market sizes, national income and payer approaches. The debate and the consensus reached by the advisory board have been summarised in this report. In addition, a computational model has been developed by two key investigators to provide new, empirical evidence to illustrate the impact of NPT on different European markets

Neuropsychosocial profiles of current and future adolescent alcohol misusers

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models1 can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers2 in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence3. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms4. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention

PET/CT imaging of pancreatic carcinoma targeting the “cancer integrin” αvβ6

Purpose!#!Fluorine-18 fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG PET/CT) is the standard for staging aggressive non-Hodgkin lymphoma (NHL). Limited data from prospective studies is available to determine whether initial staging by FDG PET/CT provides treatment-relevant information of bone marrow (BM) involvement (BMI) and thus could spare BM biopsy (BMB).!##!Methods!#!Patients from PETAL (NCT00554164) and OPTIMAL>60 (NCT01478542) with aggressive B-cell NHL initially staged by FDG PET/CT and BMB were included in this pooled analysis. The reference standard to confirm BMI included a positive BMB and/or FDG PET/CT confirmed by targeted biopsy, complementary imaging (CT or magnetic resonance imaging), or concurrent disappearance of focal FDG-avid BM lesions with other lymphoma manifestations during immunochemotherapy.!##!Results!#!Among 930 patients, BMI was detected by BMB in 85 (prevalence 9%) and by FDG PET/CT in 185 (20%) cases, for a total of 221 cases (24%). All 185 PET-positive cases were true positive, and 709 of 745 PET-negative cases were true negative. For BMB and FDG PET/CT, sensitivity was 38% (95% confidence interval [CI]: 32-45%) and 84% (CI: 78-88%), specificity 100% (CI: 99-100%) and 100% (CI: 99-100%), positive predictive value 100% (CI: 96-100%) and 100% (CI: 98-100%), and negative predictive value 84% (CI: 81-86%) and 95% (CI: 93-97%), respectively. In all of the 36 PET-negative cases with confirmed BMI patients had other adverse factors according to IPI that precluded a change of standard treatment. Thus, the BMB would not have influenced the patient management.!##!Conclusion!#!In patients with aggressive B-cell NHL, routine BMB provides no critical staging information compared to FDG PET/CT and could therefore be omitted.!##!Trial registration!#!NCT00554164 and NCT01478542

What Should Be Done with Pernkopf’s Anatomical Illustrations? A Commentary from the Medical University of Vienna

Thanks to a recent donation by Elsevier, the Medical University of Vienna now holds in its collections the known existing original paintings for Eduard Pernkopf's Atlas of Topographic and Applied Human Anatomy. This atlas is widely considered a pinnacle of the art of anatomical illustration. However, it is severely tainted by its historical origins. Pernkopf was a high-ranking National Socialist and co-responsible for the expulsion of hundreds of Jewish scientists and students from the university. Also, the Vienna Institute of Anatomy, which Pernkopf headed, received during the war the bodies of at least 1377 people executed by the regime, many for their political views or acts of resistance, including at least seven Jewish victims. Although it is impossible to individually identify the people used for the atlas, it is to be assumed that a considerable number of the paintings produced during and after the war are based on the bodies of these victims. Against this background, and out of respect for the victims, use of Pernkopf's atlas in medical teaching and training should be — wherever possible without compromising medical outcomes — reduced to a minimum. Given the strong variability of human anatomy, even the most detailed anatomical illustrations cannot replace teaching and training in the dissection room. As the experience at the Medical University of Vienna and elsewhere demonstrates, Pernkopf's atlas is far from irreplaceable. In keeping with the stipulations of the contract of donation, the Medical University of Vienna considers the Pernkopf originals primarily as historical artifacts, which will support the investigation and teaching of this dark chapter of the history of medicine in Austria, out of responsibility towards the victims. Table of Contents image credit: Medical University of Vienna, MUW-AD-003250-5-ABB-35

The Chemokine RANTES Is More than a Chemoattractant: Characterization of Its Effect on Human Eosinophil Oxidative Metabolism and Morphology in Comparison with IL-5 and GM-CSF

Eosinophils were shown to play a major role in the allergic inflammatory process leading to the clinical symptoms of atopic dermatitis. Only selected cytokines are capable of inducing a chemotactic response in eosinophils. In particular, the chemokine RANTES was recently shown to be a potent eosinophil chemotaxin. To examine the role of RANTES in eosinophil activation, we investigated the effect of RANTES and other chemokines on morphology and oxidative metabolism of highly purified eosinophils of normal nonatopic blood donors by assessment of functional as well as morphologic criteria. RANTES, and, to a lesser extent, MIP-1α significantly induced the production of reactive oxygen species by human eosinophils, whereas MCP-1, MIP-1β, and interleukin (IL)-8/NAP-1 had no significant effects. RANTES stimulated only a subpopulation of the normal eosinophils. With the exception of IL-8, none of the cytokines tested had any significant effect on polymorphonuclear neutrophilic granulocytes.. By scanning electron microscopy, RANTES induced characteristic changes that were completely abrogated in the presence of cytochalasin B. Based on functional and ultrastructural assays significant extracellular but not intracellular H2O2 production was detected and completely inhibited by cytochalasin B. Separation of eosinophils by discontinous density gradients revealed the existence of two hypodense eosinophil populations, one which showed significantly reduced responses upon stimulation with RANTES. RANTES-induced production of reactive oxygen species was almost completely inhibited by staurosporine, wortmannin, or pertussis toxin. Based on these data it is evident that RANTES represents a potent eosinophil-specific activator of oxidative metabolism. Besides its chemotactic activity on T cells and eosinophils, therefore, RANTES may be involved in the functional activation of eosinophils in the skin of patients with atopic dermatitis

Induction of Intercellular Adhesion Molecule 1 (ICAM-1) Expression in Normal Human Eosinophils by Inflammatory Cytokines

Intercellular adhesion molecule-1 (ICAM-1) functions as a ligand for lymphocyte function-associated antigen-1 (LFA-1), and thereby plays a crucial role in mediating cell-cell interactions in inflammatory reactions. Human eosinophils represent important effector cells in allergic skin diseases. To gain more insight into the capacity of eosinophils to physically interact with LFA-1-positive inflammatory leukocytes, in the present study ICAM-1 expression in eosinophils was investigated. Using fluorescence-activated cell sorter analysis, it could be shown that highly purified (⩾95%) eosinophils from peripheral blood of non-atopic individuals do not constitutively express ICAM-1 molicules. However, stimulation of eosinophil with interferon gamma (IFNγ), tumor-necrosis factor alpha (TNFα), or interleukin 3 (IL-3) markedly upregulated ICAM-1 surface expression in a time-and dose-dependent manner. Cytokine-induced ICAM-1 expression in human eosinophils was corroborated by Northern blot analysis. Accordingly, unstimulated eosinophils did not express significant amounts of ICAM-1 mRNA, but ICAM-1 mRNA expression could be markedly induced in these cells upon stimulation with IFNγ plus TNFα. The combination of TNFα with either IFNγ, IL-3, IL-5, or granulocyte/macrophage colony-stimulating factor (GM-CSF) increased ICAM-1 expression in a synergistic fashion, whereas IL-5 or GM-CSF by itself did not induce ICAM-1 expression. Cytokine-induced ICAM-1 expression was specific, because IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, C5a, and platelet-activating factor did not significantly affect eosinophil ICAM-1 surface expression. In summary, these studies indicated that eosinophils may be activated to express the adhesion molecule ICAM-1 surface expression. In summary, these studies indicated that eosinophils may be activated to express the adhesion molecule ICAM-1 upon stimulation with selected inflammatory cytokines, which may allow adhesion-mediated crosstalk between eosinophils and LFA-1-positive cells. In addition, these data demonstrate for the first time a role for IL-3, IL-5, and GM-CSF in regulation of ICAM-1 expression in human cells

Angiogenic factors in plasma of brain tumour patients.

Angiopoiesis and angiopoietic growth factors are of considerable importance in the development and progression of intracranial tumours. However, knowledge of the plasma detectability of distinct angiogenic factors in patients with brain tumour is very limited. This study evaluates the plasma concentrations of the angiogenic factors angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF) and platelet-derived growth factor BB (PDGF-BB) in patients with brain tumour