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Background and Purpose: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by pervasive personality and behavioural disturbances with severe impact on patients and caregivers. In current clinical practice, treatment is based on nonpharmacological and pharmacological approaches. Unfortunately, trial-based evidence supporting symptomatic pharmacological treatment for the behavioural disturbances in FTD is scarce despite the significant burden this poses on the patients and caregivers., Method: The study examined drug management decisions for several behavioural disturbances in patients with FTD by 21 experts across European expert centres affiliated with the European Reference Network for Rare Neurological Diseases (ERN-RND)., Results: The study revealed the highest consensus on drug treatments for physical and verbal aggression, impulsivity and obsessive delusions. Antipsychotics (primarily quetiapine) were recommended for behaviours posing safety risks to both patients and caregivers (aggression, self-injury and self-harm) and nightly unrest. Selective serotonin reuptake inhibitors were recommended for perseverative somatic complaints, rigidity of thought, hyperphagia, loss of empathy and for impulsivity. Trazodone was specifically recommended for motor unrest, mirtazapine for nightly unrest, and bupropion and methylphenidate for apathy. Additionally, bupropion was strongly advised against in 10 out of the 14 behavioural symptoms, emphasizing a clear recommendation against its use in the majority of cases., Conclusions: The survey data can provide expert guidance that is helpful for healthcare professionals involved in the treatment of behavioural symptoms. Additionally, they offer insights that may inform prioritization and design of therapeutic studies, particularly for existing drugs targeting behavioural disturbances in FTD., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

In the past decade, next-generation sequencing (NGS) has revolutionised genetic diagnostics for rare neurological disorders (RND). However, the lack of standardised technical, interpretative, and reporting standards poses a challenge for ensuring consistent and high-quality diagnostics globally. To address this, the European Reference Network for Rare Neurological Diseases (ERN-RND) collaborated with the European Molecular Genetics Quality Network (EMQN) to establish an external quality assessment scheme for NGS-based diagnostics in RNDs. The scheme, initiated in 2021 with a pilot involving 29 labs and followed by a second round in 2022 with 42 labs, aimed to evaluate the performance of laboratories in genetic testing for RNDs. Each participating lab analysed genetic data from three hypothetical cases, assessing genotyping, interpretation, and clerical accuracy. Despite a majority of labs using exome or genome sequencing, there was considerable variability in gene content, sequencing quality, adherence to standards, and clinical guidance provision. Results showed that while most labs provided correct molecular diagnoses, there was significant variability in reporting technical quality, adherence to interpretation standards, reporting strategies, and clinical commentary. Notably, some labs returned results with the potential for adverse medical outcomes. This underscores the need for further harmonisation, guideline development, and external quality assessment in the evolving landscape of genomic diagnostics for RNDs. Overall, the experience with the scheme highlighted the generally good quality of participating labs but emphasised the imperative for ongoing improvement in data analysis, interpretation, and reporting to enhance patient safety., (© 2024. The Author(s).)

Background: For decades, early allogeneic stem cell transplantation (HSCT) has been used to slow neurological decline in metachromatic leukodystrophy (MLD). There is lack of consensus regarding who may benefit, and guidelines are lacking. Clinical practice relies on limited literature and expert opinions. The European Reference Network for Rare Neurological Diseases (ERN-RND) and the MLD initiative facilitate expert panels for treatment advice, but some countries are underrepresented. This study explores organizational and clinical HSCT practices for MLD in Europe and neighboring countries to enhance optimization and harmonization of cross-border MLD care., Methods: A web-based EUSurvey was distributed through the ERN-RND and the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Personal invitations were sent to 89 physicians (43 countries) with neurological/metabolic/hematological expertise. The results were analyzed and visualized using Microsoft Excel and IBM SPSS statistics., Results: Of the 30 countries represented by 42 respondents, 23 countries offer HSCT for MLD. The treatment is usually available in 1-3 centers per country (18/23, 78%). Most countries have no or very few MLD patients transplanted during the past 1-5 years. The eligibility criteria regarding MLD subtype, motor function, IQ, and MRI largely differ across countries., Conclusion: HSCT for MLD is available in most European countries, but uncertainties exist in Eastern and South-Eastern Europe. Applied eligibility criteria and management vary and may not align with the latest scientific insights, indicating physicians' struggle in providing evidence-based care. Interaction between local physicians and international experts is crucial for adequate treatment decision-making and cross-border care in the rapidly changing MLD field., (© 2024. The Author(s).)

Background and Purpose: Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey., Methods: The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe., Results: We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6 months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases., Conclusions: This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities., (© 2023. The Author(s).)

Background: Little is known about the costs of treating ataxia and whether treatment at a specialist ataxia centre affects the cost of care. The aim of this study was to investigate whether patients who attended specialist ataxia centres in three European countries reported differences in their health care use and costs compared with patients who did not attend a specialist ataxia centre. We compared mean resource use and health service costs per patient affected by ataxia in the United Kingdom, Italy and Germany over a 12-month period. Data were obtained from a survey distributed to people with ataxia in the three countries. We compared mean resource use for each contact type and costs, stratifying patients by whether they were currently attending a specialist ataxia centre or had never attended one., Results: Responses were received from 181 patients from the United Kingdom, 96 from Italy and 43 from Germany. Differences in the numbers of contacts for most types of health service use between the specialist ataxia centre and non-specialist ataxia centre groups were non-significant. In the United Kingdom the mean total cost per patient was €2209 for non-specialist ataxia centre patients and €1813 for specialist ataxia centre patients (P = 0.59). In Italy these figures were €2126 and €1971, respectively (P = 0.84). In Germany they were €2431 and €4087, respectively (P = 0.19). Inpatient stays made the largest contribution to total costs., Conclusions: Within each country, resource use and costs were broadly similar for specialist ataxia centre and non-specialist ataxia centre groups. There were differences between countries in terms of health care contacts and costs., (© 2023. The Author(s).)

Background: Progressive ataxias are rare and complex neurological disorders that represent a challenge for the clinicians to diagnose and manage them. This study explored the patient pathways of individuals attending specialist ataxia centres (SAC) compared with non-specialist settings. We investigated specifically how diagnosis was reached, the access to healthcare services, treatments, and care satisfaction. The focus of this study was on early intervention, coordination of treatment to understand the care provision in different countries., Methods: A patient survey was done in the UK, Germany and Italy to gather information about diagnosis and management of the ataxias in specialist (SAC) and non-specialist settings, utilisation of other primary and secondary health care services, and patients' satisfaction of received treatment., Results: Patients gave positive feedback about the role of SAC in understanding their condition, ways to manage their ataxia (p < 0.001; UK) and delivering care adapted to their needs (p < 0.001; UK), in coordinating referrals to other healthcare specialists, and in offering opportunities to take part in research studies. Similar barriers for patients were identified in accessing the SACs among the selected countries, UK, Germany, and Italy., Conclusions: This study provides crucial information about the ataxia patients care pathways in three European countries. Overall, the results showed a trend in patients' satisfaction being better in SAC compared to non-SAC. The outcomes can be used now for policy recommendations on how to improve treatment and care for people with these very rare and complex neurological diseases across Europe., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Splice-modulating antisense oligonucleotides (ASOs) offer treatment options for rare neurological diseases, including those with very rare mutations, where patient-specific, individualized ASOs have to be developed. Inspired by the development of milasen, the 1 Mutation 1 Medicine (1M1M) and Dutch Center for RNA Therapeutics (DCRT) aim to develop patient-specific ASOs and treat eligible patients within Europe and the Netherlands, respectively. Treatment will be provided under a named patient setting. Our initiatives benefited from regulatory advice from the European Medicines Agency (EMA) with regard to preclinical proof-of-concept studies, safety studies, compounding and measuring benefit and safety in treated patients. We here outline the most important considerations from these interactions and how we implemented this advice into our plan to develop and treat eligible patients within Europe., (© 2023 Aartsma-Rus et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

To evaluate the management of rare movement disorders (RMD) at the international level and identify care needs to be addressed, the Rare Movement Disorders Study Group of the International Parkinson and Movement Disorders Society (MDS) has conducted an exploratory survey. We sent an online survey to experts in Africa, Asia, Oceania and American continents following the classification of the MDS Regional Sections: Africa, Asia and Oceania (A&O), and Pan-America. We did not include Europe as the European Reference Network for Rare Neurological Diseases recently performed a similar care needs survey across European countries. We obtained responses from experts from 20 African, 26 A&O and 19 Pan-American countries. According to the respondents, only 55% of African countries had movement disorders experts, while these were present in 96% of A&O and 91% of Pan-American. Access to care for patients with RMD was stated difficult in 70% of African, 54% of A&O, and 65% of Pan-American countries. Africa was the region with greatest difficulties in accessing diagnostic tests. However, in Pan-America and A&O, large inequalities were observed between countries with quite variable access to therapeutic options such as deep brain stimulation. The survey results reflect wide variability in the management of RMD and provide evidence that a worldwide care-focused network is highly warranted. Scientific and medical organisations should raise awareness of deficits in managing RMD and care disparities among regions. The goals should be to facilitate the training of professionals, establish improvement strategies, and increase support and budgeting for these diseases., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest relevant to the topic of this manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Since the first European-wide evaluation of dystonia management in 2016, several efforts have been made to improve dystonia-care. One of these was the development of the Dystonia Disease Group as a part of the European Reference Network for Rare Neurological Diseases (ERN-RND) that implemented several initiatives based on the recommendations made in 2016., Aim: To evaluate the current state of dystonia management across Europe., Methods: Twenty-four countries were surveyed via 62 dystonia-experts from 44 ERN-RND-related centers., Results: Dystonia-experts for adult patients were available in all surveyed countries. However, almost half of the countries evaluated accessibility as merely 'satisfactory'. Access to genetic and neurophysiological testing was challenging to varying degrees in over half of countries. Main oral medications and botulinum toxin were available in all countries. Deep brain stimulation (DBS) was easily accessible in one-third of the countries. Dystonia research was conducted in 20/24 countries. Trainings on dystonia for general practitioners (GPs) were available in 11/24 countries. However, lack of trainings for other professionals was almost general. For pediatric dystonia, experts and specific training were available in over half of the countries., Conclusions: In this overview, we present the current state of dystonia management within ERN-RND. Management has slightly improved since 2016 in several fields, including diagnostics, availability of DBS, and research. The results highlight that future challenges in dystonia management are accessibility of experts, and diagnostic tools and treatments, education on adult and childhood dystonia, and optimization of referral pathways. These findings are important for improving dystonia care across Europe., (© 2022. The Author(s).)

People living with rare diseases (PLWRD) still face huge unmet needs, in part due to the fact that care systems are not sufficiently aligned with their needs and healthcare workforce (HWF) along their care pathways lacks competencies to efficiently tackle rare disease-specific challenges. Level of rare disease knowledge and awareness among the current and future HWF is insufficient. In recent years, many educational resources on rare diseases have been developed, however, awareness of these resources is still limited and rare disease education is still not sufficiently taken into account by some crucial stakeholders as academia and professional organizations. Therefore, there is a need to fundamentally rethink rare disease education and HWF development across the whole spectrum from students to generalists, specialists and experts, to engage and empower PLWRD, their families and advocates, and to work towards a common coherent and complementary strategy on rare disease education and training in Europe and beyond. Special consideration should be also given to the role of nurse coordinators in care coordination, interprofessional training for integrated multidisciplinary care, patient and family-centered education, opportunities given by digital learning and fostering of social accountability to enforce the focus on socially-vulnerable groups such as PLWRD. The strategy has to be developed and implemented by multiple rare disease education and training providers: universities, medical and nursing schools and their associations, professional organizations, European Reference Networks, patient organizations, other organizations and institutions dedicated to rare diseases and rare cancers, authorities and policy bodies., (© 2022. The Author(s).)

In the European Union (EU), rare diseases (RDs) are diseases that affect no more than 5 in 10,000 people. Due to their rarity, clinical expertise and quality-assured care structures are scarce, and research is more difficult compared to other diseases. However, these problems can be overcome by means of national and transnational RD care networks. Data and expertise are pooled in these networks.In the EU, the European Reference Networks (ERNs) for Rare and Complex Diseases cooperate across borders. Important services provided by ERNs using health data include diagnostic coding of RDs, conducting virtual cross-border case conferences, and establishing European registries that are used to measure and improve the quality of care. In ERNs, local data generation and documentation combine with network-wide data infrastructures. This paper describes the data-based services in and for RD healthcare networks: (1) diagnostic coding, (2) cross-border case conferences, and (3) ERN registries for RD patient care. The final section discusses the integration of the networks into national healthcare systems.In order to achieve the best possible benefit for SE patients, ERN activities and structures need to be better integrated into national healthcare systems. In Germany, the Medical Informatics Initiative and the German Reference Networks play a central role in this regard., (© 2022. The Author(s).)

Background and Purpose: Seven thousand rare diseases have been identified; most of them are of genetic origin. The diagnosis of a neurogenetic disease is difficult, and management and training programs are not well defined through Europe. To capture and assess care needs, the Neurogenetics Panel of the European Academy of Neurology (EAN) has performed an explorative survey., Methods: The survey covering multiple topics of neurogenetics was sent to all neurologists and neuropediatricians affiliated with the EAN practicing in Europe., Results: We collected answers from 239 members based in 40 European member states. Even though most of the responders were aware of neurogenetic diseases, when we came to amenability of carrying out a complete genetic diagnosis, almost one-third of the responders declared they were not happy with the current way of ordering genetic analyses in their countries. Furthermore, although single-gene analysis is diffusely present in Europe, whole exome and genome sequencing are not easily accessible, with considerable variabilities among countries. Almost 10% of the responders did not know if presymptomatic and prenatal diagnosis was available in their countries, and 47.3% were not aware of which newborn screening programs were available. Finally, 96.3% of responders declared that there is a need for education and training in neurogenetics., Conclusions: We believe that this survey may be of importance for all European stakeholders in neurogenetics in identifying key priorities, targeting areas to encourage education/travel fellowships, and educational seminars in the future, because this area will only accelerate, and diagnostic requirements will expand., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Antisense oligonucleotide (ASO) therapies present a promising disease-modifying treatment approach for rare neurological diseases (RNDs). However, the current focus is on "more common" RNDs, leaving a large share of RND patients still without prospect of disease-modifying treatments. In response to this gap, n-of-1 ASO treatment approaches are targeting ultrarare or even private variants. While highly attractive, this emerging, academia-driven field of ultimately individualized precision medicine is in need of systematic guidance and standards, which will allow global scaling of this approach. We provide here genetic, regulatory, and ethical perspectives for preparing n-of-1 ASO treatments and research programs, with a specific focus on the European context. By example of splice modulating ASOs, we outline genetic criteria for variant prioritization, chart the regulatory field of n-of-1 ASO treatment development in Europe, and propose an ethically informed classification for n-of-1 ASO treatment strategies and level of outcome assessments. To accommodate the ethical requirements of both individual patient benefit and knowledge gain, we propose a stronger integration of patient care and clinical research when developing novel n-of-1 ASO treatments: each single trial of therapy should inherently be driven to generate generalizable knowledge, be registered in a ASO treatment registry, and include assessment of generic outcomes, which allow aggregated analysis across n-of-1 trials of therapy.

Background: Congenital chloride diarrhoea [CLD] is a rare autosomal recessive disease caused by mutations in the solute family carrier 26 member 3 [SLC26A3] gene. Patients suffer from life-long watery diarrhoea and chloride loss. Inflammatory bowel disease [IBD] has been reported in individual patients with CLD and in scl26a3-deficient mice., Methods: We performed an international multicentre analysis to build a CLD cohort and to identify cases with IBD. We assessed clinical and genetic characteristics of subjects and studied the cumulative incidence of CLD-associated IBD., Results: In a cohort of 72 patients with CLD caused by 17 different SLC26A3 mutations, we identified 12 patients [17%] diagnosed with IBD. Nine patients had Crohn's disease, two ulcerative colitis and one IBD-unclassified [IBD-U]. The prevalence of IBD in our cohort of CLD was higher than the highest prevalence of IBD in Europe [p < 0.0001]. The age of onset was variable [13.5 years, interquartile range: 8.5-23.5 years]. Patients with CLD and IBD had lower z-score for height than those without IBD. Four of 12 patients had required surgery [ileostomy formation n = 2, ileocaecal resection due to ileocaecal valve stenosis n = 1 and colectomy due to stage II transverse colon cancer n = 1]. At last follow-up, 5/12 were on biologics [adalimumab, infliximab or vedolizumab], 5/12 on immunosuppressants [azathioprine or mercaptopurine], one on 5-ASA and one off-treatment., Conclusions: A substantial proportion of patients with CLD develop IBD. This suggests the potential involvement of SL26A3-mediated anion transport in IBD pathogenesis. Patients with CLD-associated IBD may require surgery for treatment failure or colon cancer., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe., (© 2021. The Author(s).)

Background & Aims: A diagnosis of celiac disease is made based on clinical, genetic, serologic, and duodenal morphology features. Recent pediatric guidelines, based largely on retrospective data, propose omitting biopsy analysis for patients with concentrations of IgA against tissue transglutaminase (IgA-TTG) >10-fold the upper limit of normal (ULN) and if further criteria are met. A retrospective study concluded that measurements of IgA-TTG and total IgA, or IgA-TTG and IgG against deamidated gliadin (IgG-DGL) could identify patients with and without celiac disease. Patients were assigned to categories of no celiac disease, celiac disease, or biopsy required, based entirely on antibody assays. We aimed to validate the positive and negative predictive values (PPV and NPV) of these diagnostic procedures., Methods: We performed a prospective study of 898 children undergoing duodenal biopsy analysis to confirm or rule out celiac disease at 13 centers in Europe. We compared findings from serologic analysis with findings from biopsy analyses, follow-up data, and diagnoses made by the pediatric gastroenterologists (celiac disease, no celiac disease, or no final diagnosis). Assays to measure IgA-TTG, IgG-DGL, and endomysium antibodies were performed by blinded researchers, and tissue sections were analyzed by local and blinded reference pathologists. We validated 2 procedures for diagnosis: total-IgA and IgA-TTG (the TTG-IgA procedure), as well as IgG-DGL with IgA-TTG (TTG-DGL procedure). Patients were assigned to categories of no celiac disease if all assays found antibody concentrations <1-fold the ULN, or celiac disease if at least 1 assay measured antibody concentrations >10-fold the ULN. All other cases were considered to require biopsy analysis. ULN values were calculated using the cutoff levels suggested by the test kit manufacturers. HLA typing was performed for 449 participants. We used models that considered how specificity values change with prevalence to extrapolate the PPV and NPV to populations with lower prevalence of celiac disease., Results: Of the participants, 592 were found to have celiac disease, 345 were found not to have celiac disease, and 24 had no final diagnosis. The TTG-IgA procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.934; the TTG-DGL procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.958. Based on our extrapolation model, we estimated that the PPV and NPV would remain >0.95 even at a disease prevalence as low as 4%. Tests for endomysium antibodies and HLA type did not increase the PPV of samples with levels of IgA-TTG ≥10-fold the ULN. Notably, 4.2% of pathologists disagreed in their analyses of duodenal morphology-a rate comparable to the error rate for serologic assays., Conclusions: In a prospective study, we validated the TTG-IgA procedure and the TTG-DGL procedure in identification of pediatric patients with or without celiac disease, without biopsy. German Clinical Trials Registry no.: DRKS00003854., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Climate change is already altering the magnitude and/or frequency of extreme events which will in turn affect plant fitness more than any change in the average. Although the fingerprint of anthropogenic warming in recent phenological records is well understood, the impacts of extreme events have been largely neglected. Thus, the temperature response of European phenological records to warm and cold spells was studied using the COST725 database. We restricted our analysis to the period 1951-2004 due to better spatial coverage. Warm and cold spells were identified using monthly mean ENSEMBLES temperature data on a 0.5° grid for Europe. Their phenological impact was assessed as anomalies from maps displaying mean onsets for 1930-1939. Our results clearly exhibit continental cold spells predominating in the period 1951-1988, especially during the growing season, whereas the period from 1989 onwards was mainly characterised by warm spells in all seasons. The impacts of these warm/cold spells on the onset of phenological seasons differed strongly depending on species, phase and timing. "False" phases such as the sowing of winter cereals hardly reacted to summer warm/cold spells; only the sowing of summer cereals mirrored spring temperature warm/cold spells. The heading dates of winter cereals did not reveal any consistent results probably due to fewer warm/cold spells identified in the relevant late spring months. Apple flowering and the harvest of winter cereals were the best indicators of warm/cold spells in early spring and summer, also being spatially coherent with the patterns of warm/cold spells.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Objective: To investigate the prescription pattern of antiemetic medications in 0- to 9-year-old children with infectious gastroenteritis in several industrialized countries during 2005., Study Design: We retrospectively retrieved data from 4 national and international databases (IMS MIDAS, IMS disease analyzer, WIdO databases)., Results: Between 2% and 23% of children with gastroenteritis (International Classification of Diseases code A08.X or A09) received prescriptions for antiemetic medications (United States, 23%; 95% CI, 15-31; Germany, 17%; 95% CI, 15-20; France, 17%; 95% CI, 14-19; Spain, 15%; 95% CI, 10-19; Italy, 11%; 95% CI, 7-16; Canada, 3%; 95% CI, 0-16; United Kingdom, 2%; 95% CI, 1-2). The antihistamines dimenhydrinate and diphenhydramine were most frequently used in Germany and Canada, whereas promethazine was prescribed preferentially in the United States. In France, Spain, and Italy, the dopamine receptor antagonist domperidone was preferred as antiemetic treatment. Ondansetron was used in a minor proportion of antiemetic prescriptions (Germany, Canada, Spain, and Italy, 0%; United States, 3%; United Kingdom, 6%)., Conclusion: Antiemetic drugs are frequently used in children with gastroenteritis. In different industrialized countries, prescription of antiemetic medication varies considerably. Ondansetron, the only drug with evidence-based antiemetic efficacy, plays a minor role among antiemetic prescriptions.

"Interventional ultrasound," defined as any diagnostic and therapeutic procedure performed under ultrasound guidance was first introduced in Europe, where its early development took place in Vienna, in Copenhagen, in Italy and in Switzerland. However, many of the applications of interventional ultrasound have been based on important pioneer work using other less-suitable needle guiding methods from the pre-ultrasound era. The European contributions to "interventional ultrasound" have especially been in the development of new puncture equipment, in the dissemination of various biopsy techniques, and draining procedures and, more recently, in the development of many different tissue-ablation techniques. The above contributions, which are outlined in this historical review, have, together with significant contributions from the rest of the world-not least from the United States and Japan-created a most efficient diagnostic as well as therapeutic tool for the benefit of our patients.

The history of interstitial brachytherapy of the prostate began in 1917 when Barringer inserted radium needles transperineally into the prostate, guided by a finger in the rectum. In 1952, Flocks et al. injected radioactive gold solution in prostatic cancer during open operation. In 1972, Whitmore et al. described retropubic Iodine-125 seed implantation through an open operation with pelvic lymph node dissection. The basis for ultrasound (US)-guided seed implantation was established in the late 1960s by Kratochwil's description of the first puncture transducer for one-dimensional US-guidance and Watanabe's pioneer work in prostatic screening. Our group performed the first punctures guided by static two-dimensional ultrasonic scanning (1969) and by dynamic ultrasound scanning (1974). During the 1970s, US-guided biopsies of almost all abdominal organs were performed and, in 1981, we introduced US-guided seed implantation of abdominal tumors and developed a technique for precise needle placement in the prostate guided by transrectal ultrasound. This was followed in 1983 by a technique for seed implantation guided by transrectal (transverse) ultrasonic scanning. That same year, Fornage described prostatic biopsy guided by transrectal longitudinal scanning. In 1990, we developed the seed implantation technique further by combining transverse and longitudinal scannings. In the late 1980s, Ragde from Seattle transferred the technique to the U.S., and since then, Ragde, Blasko, and others have treated numerous patients, refined the technique, taught many courses, and published extensively. They have obtained very promising prostate-specific antigen (PSA)-based results which compare favorably with radical prostatectomy and external beam radiation in the treatment of prostatic cancer.