Moving somatic gene editing to the clinic: routes to market access and reimbursement in Europe.

Somatic gene editing (SGE) holds great promise for making genetic therapy possible for many monogenic conditions very soon. Is our current system of European market authorization and reimbursement ready for the expected tsunami of gene therapies? At a recent workshop of the Netherlands ZonMw consortium on ethical, legal, and social implications of personalized medicine, we discussed the current possibilities for bringing new gene therapies to the clinic. In Europe, it is not yet clear whether the route via the European medicines agency as an advanced therapy medicinal product is the most appropriate for evaluation of highly personalized SGE applications, although this may optimally guarantee safety and effectiveness.

Hagiography by the Book: Bibliomancy and Early Modern Cultures of Compilation in Francisco Zumel's ().

This article probes the interplay of religious belief and early modern textual culture in Francisco Zumel's 1588 vita of Peter Nolasco. Like many hagiographers before and after, Zumel drew on earlier saint's lives to supply missing details; to choose his diverse set of sources, however, turned to bibliomancy, opening Laurentius Surius's hagiography collection De probatis sanctorum historiis at random. The intersection of divination and compilation constitutes not only a new and picturesque chapter in the story of early modern textuality, but also calls attention to the role of non-deliberative processes in reading and composition.

Comparison of nuisance parameters in pediatric versus adult randomized trials: a meta-epidemiologic empirical evaluation.

Background: We wished to compare the nuisance parameters of pediatric vs. adult randomized-trials (RCTs) and determine if the latter can be used in sample size computations of the former.

Methods: In this meta-epidemiologic empirical evaluation we examined meta-analyses from the Cochrane Database of Systematic-Reviews, with at least one pediatric-RCT and at least one adult-RCT.

Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis.

Background: Inexpensive medicines with a long history of use may currently be prescribed off-label for rare indications. Reimbursement is at the discretion of health insurance companies, and may be unpredictable. The example addressed was ephedrine as add-on treatment for myasthenia gravis.

Ephedrine treatment for autoimmune myasthenia gravis.

We studied the effect and safety of ephedrine as add-on treatment for patients with myasthenia gravis with acetylcholine receptor antibodies (AChR MG), who do not sufficiently respond to standard treatment. Four patients with AChR MG were included in a placebo-controlled, double-blind, and randomised, multiple crossover series of n-of-1 trials. Each n-of-1 trial consisted of 3 cycles, in which two 5-day intervention periods were followed by 2 days washout.

A systematic review to investigate the measurement properties of goal attainment scaling, towards use in drug trials.

Background: One of the main challenges for drug evaluation in rare diseases is the often heterogeneous course of these diseases. Traditional outcome measures may not be applicable for all patients, when they are in different stages of their disease. For instance, in Duchenne Muscular Dystrophy, the Six Minute Walk Test is often used to evaluate potential new treatments, whereas this outcome is irrelevant for patients who are already in a wheelchair.

Mothers' Views on Longer Storage of Neonatal Dried Blood Spots for Specific Secondary Uses.

Background: Neonatal dried blood spots (DBS) present a wealth of data. Currently, many countries discuss DBS storage, management and use. We collected data in the Netherlands on the awareness and views of an unheard stakeholder: mothers (-to-be).

Thinking with Crocodiles: An Iconic Animal at the Intersection of Early-Modern Religion and Natural Philosophy.

This paper seeks to explore how culturally and religiously significant animals could shape discourses in which they were deployed, taking the crocodile as its case study. Beginning with the textual and visual traditions linking the crocodile with Africa and the Middle East, I read sixteenth- and seventeenth-century travel narratives categorizing American reptiles as "crocodiles" rather than "alligators," as attempts to mitigate the disruptive strangeness of the Americas. The second section draws on Ann Blair's study of "Mosaic Philosophy" to examine scholarly debates over the taxonomic identity of the biblical Leviathan.

Ephedrine as add-on therapy for patients with myasthenia gravis: protocol for a series of randomised, placebo-controlled n-of-1 trials.

Introduction: Myasthenia gravis (MG), a rare neuromuscular disease, is often initially treated using acetylcholinesterase inhibitors. Patients who do not respond adequately depend on the use of corticosteroids or other immunosuppressive medication, but these may have serious side effects. Clinical observations suggest that ephedrine can diminish, postpone or even prevent the need for immunosuppressive therapy when added to acetylcholinesterase inhibitors or low-dose prednisone.

A genetic diagnosis of maturity-onset diabetes of the young (MODY): experiences of patients and family members.

Aims: Genetic testing for maturity-onset diabetes of the young (MODY) facilitates a correct diagnosis, enabling treatment optimization and allowing monitoring of asymptomatic family members. To date, the majority of people with MODY remain undiagnosed. To identify patients' needs and areas for improving care, this study explores the experiences of patients and family members who have been genetically tested for MODY.

Ephedrine for myasthenia gravis, neonatal myasthenia and the congenital myasthenic syndromes.

Background: Myasthenia is a condition in which neuromuscular transmission is affected by antibodies against neuromuscular junction components (autoimmune myasthenia gravis, MG; and neonatal myasthenia gravis, NMG) or by defects in genes for neuromuscular junction proteins (congenital myasthenic syndromes, CMSs). Clinically, some individuals seem to benefit from treatment with ephedrine, but its effects and adverse effects have not been systematically evaluated.

Objectives: To assess the effects and adverse effects of ephedrine in people with autoimmune MG, transient neonatal MG, and the congenital myasthenic syndromes.

Current and best practices of genetic testing for maturity onset diabetes of the young: views of professional experts.

Aims: Currently, many patients with maturity onset diabetes of the young (MODY) are undiagnosed or misdiagnosed with type 1 or 2 diabetes. This study aims to assess professional experts' views on factors which may influence the current practice of genetic testing for MODY and to explore next steps toward best practice.

Methods: Twelve semistructured interviews were conducted with professional experts.

Newborn screening for pompe disease? a qualitative study exploring professional views.

Background: Developments in enzyme replacement therapy have kindled discussions on adding Pompe disease, characterized by progressive muscle weakness and wasting, to neonatal screening. Pompe disease does not fit traditional screening criteria as it is a broad-spectrum phenotype disorder that may occur in lethal form in early infancy or manifest in less severe forms from infancy to late adulthood. Current screening tests cannot differentiate between these forms.

Population-based incidence and prevalence of facioscapulohumeral dystrophy.

Objective: To determine the incidence and prevalence of facioscapulohumeral muscular dystrophy (FSHD) in the Netherlands.

Methods: Using 3-source capture-recapture methodology, we estimated the total yearly number of newly found symptomatic individuals with FSHD, including those not registered in any of the 3 sources. To this end, symptomatic individuals with FSHD were available from 3 large population-based registries in the Netherlands if diagnosed within a 10-year period (January 1, 2001 to December 31, 2010).

Effects of a simple educational intervention in well-baby clinics on women's knowledge about and intake of folic acid supplements in the periconceptional period: a controlled trial.

Objective: To test the hypothesis that a concise intervention to promote the preconception use of folic acid (FA) supplements among mothers who visit a well-baby clinic (WBC) for the 6-month check-up of their youngest child is effective. Effectiveness was measured as intention to use or actual use of FA supplements before a next pregnancy among women who expected to be pregnant within 0-12 months.

Design: Controlled intervention study with independent samples of intervention and control mothers.

A decade of molecular genetic testing for MODY: a retrospective study of utilization in The Netherlands.

Genetic testing for maturity-onset diabetes of the young (MODY) may be relevant for treatment and prognosis in patients with usually early-onset, non-ketotic, insulin-sensitive diabetes and for monitoring strategies in non-diabetic mutation carriers. This study describes the first 10 years of genetic testing for MODY in The Netherlands in terms of volume and test positive rate, medical setting, purpose of the test and age of patients tested. Some analyses focus on the most prevalent subtype, HNF1A MODY.

Newborn screening for hunter disease: a small-scale feasibility study.

Hunter disease (Mucopolysaccharidosis type II, MPS II) is an X-linked lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase (IDS). Two main therapies have been reported for MPS II patients: enzyme-replacement therapy (ERT) and hematopoietic stem-cell transplantation (HSCT). Both treatment modalities have been shown to improve some symptoms, but the results with regard to cognitive functioning have been poor.

A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.

The European Union (EU) Council Recommendation on rare diseases urged the member states to implement national and EU collaborative actions to improve the health care of rare disease patients. Following this recommendation, the European Commission launched a tender on newborn screening (NBS) to report on current practices of laboratory testing, form a network of experts and provide guidance on how to further implement NBS screening in a responsible way, the latter of which was provided in an Expert Opinion document. After consultation of experts from EU member states, (potential) candidate member states and European Free Trade Association countries, in a consensus meeting in June 2011, 70 expert opinions were finalized.

Severely impaired health status at diagnosis of Pompe disease: a cross-sectional analysis to explore the potential utility of neonatal screening.

Since the introduction of enzyme replacement therapy for Pompe disease, awareness and early diagnosis have gained importance. Because the therapy is most effective when started early and methods for dried bloodspot screening for Pompe disease are currently being explored, neonatal screening is getting increased attention. The objective of this study was to investigate the gains that might be achieved with earlier diagnosis by neonatal screening.

Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 1. From blood spot to screening result.

In many European countries neonatal screening has been introduced over the last 50 years as an important public health programme. Depending on health care structure, available funds, local politics, input from professional groups, parent groups, and the general public this introduction has led to different approaches in the way the screening programmes have been set up, financed and governed. To get some insight about the current situation, in 2009 the European Union, via its EAHC agency, put out a call for a tender that was acquired by our project group.

Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 2. From screening laboratory results to treatment, follow-up and quality assurance.

In a survey conducted in 2010/2011 data from the 28 EU member states, four EU candidate states (Croatia, FYROM, Iceland, Turkey), three potential EU candidate states (Bosnia Herzegovina, Montenegro, Serbia), and two EFTA states (Norway and Switzerland) were collected. The status and function of newborn screening (NBS) programmes were investigated from the information to prospective parents and the public via confirmation of a positive screening result up to decisions on treatment. This article summarises the results from screening laboratory findings to start of treatment.

Public support for neonatal screening for Pompe disease, a broad-phenotype condition.

Background: Neonatal screening for Pompe disease has been introduced in Taiwan and a few U.S. states, while other jurisdictions including some European countries are piloting or considering this screening.

Population based epidemiology of amyotrophic lateral sclerosis using capture-recapture methodology.

Background: Variation in the incidence rate in epidemiological studies on amyotrophic lateral sclerosis (ALS) may be due to a small population size and under ascertainment of patients. The previously reported incidence decline in the elderly and a decrease in the male:female ratio in postmenopausal age groups have yet to be confirmed.

Methods: ALS epidemiology in a large population based register in The Netherlands was studied between 1 January 2006 and 31 December 2009, and applied capture-recapture methodology in separate age and gender groups to adjust for the number of unobserved patients.

Raising awareness of carrier testing for hereditary haemoglobinopathies in high-risk ethnic groups in the Netherlands: a pilot study among the general public and primary care providers.

Background: In the Netherlands no formal recommendations exist concerning preconceptional or antenatal testing for carriership of hereditary haemoglobinopathies. Those at highest risk may be unaware of the possibility of carrier screening. While universal newborn screening has recently been introduced, neither preconceptional nor antenatal carrier testing is routinely offered by health care services to the general public.