Human rights & intellectual property for universal access to new essential medicines

This chapter illustrates how human rights principles can help governments, even those with the most modest budgets, scale-up universal access to expensive essential medicines. The key message is that governments have legally binding human rights obligations to immediately take steps to provide essential medicines. These steps include making a maximum of public resources available to finance essential medicines, particularly for vulnerable and marginalized groups, and using those resources efficiently. Crucially, using mechanisms to control medicines prices and, in the case of high priced patented medicines, the use of TRIPS flexibilities, is aligned with governments’ duties under human rights law to ensure access to essential medicines. Moreover, the right to health imposes duties on the international community of States and the pharmaceutical industry to respect and protect access to essential medicines

Practical Applications of the Flexibilities of the Agreement on Trade-Related Aspects of Intellectual Property Rights:Lessons beyond HIV for access to new essential medicines

Toegang tot dure geneesmiddelen is wereldwijd een steeds groter probleem aan het worden. De fabrikanten van geneesmiddelen vragen voor hun producten een hoge prijs ook als de productiekosten voor de betreffende middelen laag zijn. De hiv/aids crisis van de late negentiger jaren maakte duidelijk dat hoge geneesmiddelenprijzen vooral voor ontwikkelingslanden grote problemen opleverde. Daar stierven 8000 mensen per dag aan aids terwijl er levensreddende aidsgeneesmiddelen beschikbaar waren in rijke landen. Deze medicijnen kostten 15.000 euro per patiënt per jaar. De prijs stond niet in verhouding met de productiekosten die rond de 50 euro lagen. Hoe kan dit? Het antwoord ligt in de monopolie positie die de fabrikant heeft als gevolg van een patent. Een patent geeft de houder ervan het recht concurrenten van de markt te weren en dus zelf de prijs te bepalen. Om aids aan te pakken hebben internationale organisaties zoals de Wereldgezondheidsorganisatie en de Wereldhandelsorganisatie maatregelen genomen om ervoor te zorgen dat toegang tot goedkope geneesmiddelen van goede kwaliteit mogelijke werd, ook als deze gepatenteerd waren. Hierdoor zakte de prijs van aidsmedicijnen naar 80 Euro per patiënt per jaar. Het resultaat was indrukwekkend: miljoenen mensen kregen toegang tot levensreddende behandelingen. Dit proefschrift beschrijft de processen die geleid hebben tot beleids- en juridische veranderingen om de toegang tot medicijnen te verbeteren. De studie brengt in kaart hoe nationale overheden gebruik hebben gemaakt van flexibiliteiten in het patent recht en welke lessen we daaruit kunnen trekken voor de aanpak van hoge geneesmiddelenprijzen vandaag de dag

DNA methylation signatures of aggression and closely related constructs : A meta-analysis of epigenome-wide studies across the lifespan

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 x 10(-7); Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.Peer reviewe

Zika virus infection in pregnancy: a protocol for the joint analysis of the prospective cohort studies of the ZIKAlliance, ZikaPLAN and ZIKAction consortia

INTRODUCTION: Zika virus (ZIKV) infection in pregnancy has been associated with microcephaly and severe neurological damage to the fetus. Our aim is to document the risks of adverse pregnancy and birth outcomes and the prevalence of laboratory markers of congenital infection in deliveries to women experiencing ZIKV infection during pregnancy, using data from European Commission-funded prospective cohort studies in 20 centres in 11 countries across Latin America and the Caribbean. METHODS AND ANALYSIS: We will carry out a centre-by-centre analysis of the risks of adverse pregnancy and birth outcomes, comparing women with confirmed and suspected ZIKV infection in pregnancy to those with no evidence of infection in pregnancy. We will document the proportion of deliveries in which laboratory markers of congenital infection were present. Finally, we will investigate the associations of trimester of maternal infection in pregnancy, presence or absence of maternal symptoms of acute ZIKV infection and previous flavivirus infections with adverse outcomes and with markers of congenital infection. Centre-specific estimates will be pooled using a two-stage approach. ETHICS AND DISSEMINATION: Ethical approval was obtained at each centre. Findings will be presented at international conferences and published in peer-reviewed open access journals and discussed with local public health officials and representatives of the national Ministries of Health, Pan American Health Organization and WHO involved with ZIKV prevention and control activities

Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Human rights & intellectual property for universal access to new essential medicines

This chapter illustrates how human rights principles can help governments, even those with the most modest budgets, scale-up universal access to expensive essential medicines. The key message is that governments have legally binding human rights obligations to immediately take steps to provide essential medicines. These steps include making a maximum of public resources available to finance essential medicines, particularly for vulnerable and marginalized groups, and using those resources efficiently. Crucially, using mechanisms to control medicines prices and, in the case of high priced patented medicines, the use of TRIPS flexibilities, is aligned with governments’ duties under human rights law to ensure access to essential medicines. Moreover, the right to health imposes duties on the international community of States and the pharmaceutical industry to respect and protect access to essential medicines