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. They included the need to develop case definitions for all disorders screened for to facilitate assessment and international outcome studies. Decision whether a screening program should be performed can be based on screening criteria updated from the traditional Wilson and Jungner (1968) criteria, relating to disease, treatment, test and cost. The interest of the child should be central in the assessment of pros and cons. A European NBS body should assess evidence on (new) screening candidate disorders. For rare conditions, best level evidence should be used. The health system should ensure treatment to cases diagnosed by screening, controlled and revised by follow-up outcome studies. Screening methodology should aim to avoid unintended findings, such as mild forms and carrier status information, as much as possible. Activities to improve NBS in Europe, such as training and scientific evaluation, could benefit from collaboration at EU level and beyond.The European Union (EU) Council Recommendation¹ on Rare Diseases (9 June 2009)² identified rare diseases (ie, a life-threatening or chronically debilitating condition affecting not more than five in 10 000 persons in the community) as a public health concern and highlighted the need for public health actions, promoting the development of research on rare disorders and the improvement of the health care of rare disease patients. Following this recommendation, the European Commission launched a tender on neonatal screening (=newborn screening, NBS) in July 2009 (http://ec.europa.eu/eahc/health/tenders_H09C2.html) in order to (1) report on the practices of neonatal screening for rare disorders implemented in all the member states, including number of centers, estimate the number of infants screened and the number of disorders included in the NBS, as well as reasons for the selection of these disorders, (2) to identify types of medical management and follow-up implemented in the member states, (3) to establish a network of experts analyzing the information and formulating a final opinion containing recommendations on best practices, and recommending a core panel of NBS conditions that could be included in all MS practices, and (4) to develop a decision-making matrix that could be used by member states'' programs to systematically expand (or contract) screening mandates.The focus of the tender activities was on NBS by using laboratory testing techniques (blood spot screening). All reports are available on the internet (http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64).To get some insight into the current practices (points 1 and 2 above), an online survey was compiled and filled out by EU member states, (potential) member states and European Free Trade Association countries – in total 40 countries. Apart from the final report, available on the internet, the current practices are summarized in two journal articles: the first publication addresses the steps in screening programmes from blood spot to screening result³ and the second publication addresses the steps from screening laboratory results to treatment, follow-up and quality assurance.⁴As a third part of the activity and work methodology requested by the tender specifications, a European Union Network of Experts on Newborn Screening (EUNENBS) had to be constituted. Criteria for the inclusion of experts in EUNENBS (http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64) include that all member states'' authorities should be represented in the network. Each countries'' competent authorities were invited to identify their experts to represent the country at the workshops in 2010 and 2011. Further experts represent European professional and scientific organizations involved in NBS, the representative of the US Secretary''s Advisory Committee on Heritable Disorders in Newborns and Children, additional fields of expertise (eg, ethics) and patient organizations. The list of EUNENBS members is available as Appendix 1 of the Expert Opinion document (http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64). Most EUNENBS members have a background in health policy making, health technology assessment (HTA) and/or coordinating screening programs, many are involved in the service delivery of NBS in pediatrics, laboratory medicine and genetics. The task of EUNENBS was to supervise the work of the tender and participate in the revision of the tender deliverables, including the Expert Opinion document. The EUNENBS members have provided informally their input and advice without implying any obligation or commitment of their national authorities or organizations. Working documents were prepared reviewing most relevant scientific literature on the development of NBS policy and submitted to EUNENBS to stimulate the discussion during its meeting held on 6–7 December 2010, where the future of NBS was discussed in a workshop. Conclusions were integrated in a draft of the Expert Opinion document that was circulated by e-mail on 9 March 2011 to the membership of EUNENBS and to European Union Committee of Experts on Rare Diseases members from the Candidate and European Economic Area/European Free Trade Association countries inviting comments. This consultation ended on 6 April 2011. The preparation of the second draft, integrating the suggestions received, took place until 6 May 2011. Before the consensus meeting on 20 and 21 June 2011 in Luxembourg, the document was circulated for a second consultation, which took place from 11 to 27 May 2011, and amended considering the comments received. The Expert Opinion document was endorsed by the Boards of the International Society for Neonatal Screening and the European Society of Human Genetics in August and October 2011.Experiences from other countries have served as useful sources, although their applicability may need to be checked against information from EU countries and agreement needs to be sought with EUNENBS. This article presents the 70 Expert Opinions, resulting from the debate among the EUNENBS members with respect to the elements that are part of a system to evaluate the quality and ethical aspects of neonatal screening in the light of available literature, as well as the proposal for a decision matrix. We furthermore provide a brief discussion.     

Risk factors associated with fatal influenza,Romania, October 2009 – May 2011

Background

Limited data are available from Central and Eastern Europe on risk factors for severe complications of influenza. Such data are essential to prioritize prevention and treatment resources and to adapt influenza vaccination recommendations.

Objectives

To use sentinel surveillance data to identify risk factors for fatal outcomes among hospitalized patients with severe acute respiratory infections (SARI) and among hospitalized patients with laboratory-confirmed influenza.

Methods

Retrospective analysis of case-based surveillance data collected from sentinel hospitals in Romania during the 2009/2010 and 2010/2011 winter influenza seasons was performed to evaluate risk factors for fatal outcomes using multivariate logistic regression.

Results

During 2009/2010 and 2010/2011, sentinel hospitals reported 661 SARI patients of which 230 (35%) tested positive for influenza. In the multivariate analyses, infection with influenza A(H1N1)pdm09 was the strongest risk factor for death among hospitalized SARI patients (OR: 6·6; 95% CI: 3·3–13·1). Among patients positive for influenza A(H1N1)pdm09 virus infection (n = 148), being pregnant (OR: 7·1; 95% CI: 1·6–31·2), clinically obese (OR: 2·9;95% CI: 1·6–31·2), and having an immunocompromising condition (OR: 3·7;95% CI: 1·1–13·4) were significantly associated with fatal outcomes.

Conclusion

These findings are consistent with several other investigations of risk factors associated with influenza A(H1N1)pdm09 virus infections. They also support the more recent 2012 recommendations by the WHO Strategic Advisory Group of Experts on Immunization (SAGE) that pregnant women are an important risk group for influenza vaccination. Ongoing sentinel surveillance can be useful tool to monitor risk factors for complications of influenza virus infections during each influenza season, and pandemics as well.     

Improving test properties for neonatal cystic fibrosis screening in the Netherlands before the nationwide start by May 1st 2011

When new technical possibilities arise in health care, often attunement is needed between different actors from the perspectives of research, health care providers, patients, ethics and policy. For cystic fibrosis (CF) such a process of attunement in the Netherlands started in a committee of the Health Council on neonatal screening in 2005. In the balancing of pros and cons according to Wilson and Jungner criteria, the advantages for the CF patient were considered clear, even though CF remains a severe health problem with treatment. Nevertheless, screening was not started then, mainly since the specificity of the tests available at that time was considered too low. Many healthy infants would have been referred for sweat testing and much uncertainty would arise in their parents. Also the limited sensitivity for immigrants and the detection of less severe phenotypes and carriers were considered problematic. The Health Council recommended a pilot screening project which was subsequently performed in some provinces, leading to a 4-step protocol: IRT, PAP, screening for a CFTR mutation panel, and sequencing of the CFTR gene. This would lead to the identification of 23 cases of classical CF, two infants with less severe forms and 12 carriers per year in the Netherlands. Thus many CF patients can be diagnosed early, while limiting the number of referrals, the number of infants with less severe forms diagnosed and the number of carriers identified. Technical solutions were found to limit the ethical problems. A nationwide program using this four step protocol started by 1 May 2011.     

Laparoscopic low anterior resection with total mesorectal excision for rectal cancer

Rectal resections are the only treatment with curative intent currently accepted world wide. When performed in elective circumstances, laparoscopic rectal excision is technically feasible in surgical approach of mid-rectal cancer in a considerable number of patients. There are many benefits of the laparoscopic approach to rectal resection such as short hospitalization, less pain, less postoperative complications and improved quality of life. However, one mandatory condition in laparoscopic resection of rectum includes complete excision of the rectum and mesorectum, generally ensuring a minimal distal margin of 2cm and circumferential radial clearance before performing a coloanal anastomosis. Here, we present a laparoscopic approach for rectal cancer treatment consisting in a wide resection of the rectum, including the entire fascia with the enclosed mesentery of the rectum.     

Formulation of Natural Oil Nano-Emulsions for the Topical Delivery of Clofazimine,Artemisone and Decoquinate

Purpose

The aim of this study was to formulate nano-emulsions comprising natural oils and the active pharmaceutical ingredients (APIs) clofazimine (CLF), artemisone (ATM) and decoquinate (DQ) in order to determine effectiveness of the nano-emulsions for topical delivery of the APIs. The APIs alone do not possess suitable physicochemical properties for topical drug delivery.

Methods

Nano-emulsions were formulated with olive and safflower oils encapsulating the APIs. Skin diffusion and tape stripping studies were performed. By using the lactate dehydrogenase (LDH) assay, in vitro toxicity studies were carried out on immortalized human keratinocytes (HaCaT) cell line to determine cytotoxicities due to the APIs and the nano-emulsions incorporating the APIs.

Results

The nano-emulsions were effective in delivering the APIs within the stratum corneum-epidermis and the epidermis-dermis, were non-cytotoxic towards HaCaT cell lines (p <?0.05) and inhibited Mycobacterium tuberculosis in vitro.

Conclusion

Natural oil nano-emulsions successfully deliver CLF, ATM and DQ and in principle could be used as supplementary topical treatment of cutaneous tuberculosis (CTB).

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Graphical Abstract ?

     

The Impact of Dysphagia on Mortality of Nursing Home Residents: Results From the nutritionDay Project

Objectives

Dysphagia is a frequent finding in nursing home residents. The aim of this study is to evaluate the association of dysphagia and mortality in nursing home residents and identify further risk factors for mortality in residents with dysphagia.

Short‐term splenic impact of single‐strand DNA functionalized multi‐walled carbon nanotubes intraperitoneally injected in rats

In recent years, a great deal of studies have focused on the possible toxicity of carbon nanotubes (CNT), as a result of their potential applications in the field of nanotechnologies. The investigation of spleen toxicity is part of the carbon nanotubes‐induced toxicity assessment. In this study, we investigated the possible toxic effects of CNT on the rat spleen, after intraperitoneally (i.p.) administration of a single dose [1.5 ml; 2 mg multi‐walled (MW) CNT per body weight (bw)] of multi‐walled carbon nanotubes (exterior diameter 15–25 nm, interior diameter 10–15 nm, surface 88 m² g^–1) functionalized 1:1 with single‐strand DNA (ss‐DNA‐MWCNT, 270 mg l^–1). CNT functionalization with DNA determines a stable dispersion in the body fluids. For the detection of carbon nanotubes in the spleen, Raman spectroscopy, histopathologic examination, confocal microscopy and transmission electron microscopy (TEM) were performed at different time points (1, 6, 24, 48 and 144 h) after MWCNT administration. The dynamics of oxidative stress parameters (malondialdehyde, protein carbonyls and reduced glutathione), along with nitrosative stress parameters (nitric oxide, inducible NO synthase), the pro‐inflammatory cytokines [interleukin‐(IL)‐1β] and the number of cells expressing caspase 3 and proliferating cell nuclear antigen (PCNA) were assessed. Our results indicate that, after i.p. administration, MWCNT translocate progressively in the spleen, with a peak of concentration after 48 h, and determine lymphoid hyperplasia and an increase in the number of cells which undergo apoptosis, in parallel with the enhancement of the mitosis in the white pulp and with transient alterations of oxidative stress and inflammation that need further investigations for a longer period of monitoring. Copyright © 2013 John Wiley & Sons, Ltd.