Postauthorization safety study of betaine anhydrous

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013–2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0–9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation

Long-term effects of medical management on growth and weight in individuals with urea cycle disorders

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Beschreibung des Bake-Hardening-Effektes bei modernen Karosseriestählen

Die Zielstellung der vorgestellten Arbeiten ist die Erarbeitung von Grundlagen zur gezielten Einstellung von Werkstoffverfestigungen in der Blechumformung. Die Untersuchungen finden im Rahmen der Innovationsallianz "Green Carbody Technologies", Verbundprojekt 2 - Performance Presswerk (InnoCaT2), Teilvorhaben: Verfahrens-, Werkzeug- und Anlagenentwicklung und -optimierung unter ressourcenrelevanten Gesichtspunkten, Teilprojekt 2.1.1: Ausnutzung und Verbesserung der Bake-Hardening- und Work-Hardening-Effekte statt. Das Umformvermögen der Werkstoffe soll bei verschiedenartigen Beanspruchungen (Lastpfaden) unter Berücksichtigung der Festigkeitsanforderungen an die Bauteile sowie der Verformungsreserven bei einer Crashbeanspruchung betrachtet werden. Zu berücksichtigen sind dabei sowohl die Werkstoffverfestigungen während des Umformvorganges (Work-Hardening) als auch während einer anschließenden Wärmebehandlung im KTL-Prozess (Bake-Hardening). Dazu ist es erforderlich, das Werkstoffverhalten umfassend experimentell zu ermitteln und spezifische, unter realen Prozessbedingungen ermittelte Kennwerte für unterschiedliche Simulationsprogramme detailliert zur Verfügung zu stellen. Ziel dabei ist es, die benannten Effekte bereits bei der Bauteilauslegung bewusst zu nutzen und somit ein bisher nicht aktiv genutztes Potenzial zur effizienten Nutzung von Ressourcen auszuschöpfen

Colonization of newly forming Arctic sea ice by meiofauna: a case study for the future Arctic?

Global warming has led to a strong deterioration of the Arctic sea ice cover. Ice thickness, age and coverage have been strongly declining in recent years. Brine channels that form in sea ice when seawater freezes represent a unique habitat for bacteria, algae, proto- and small metazoans. We hypothesized that the loss of multi-year ice and the more prevalent formation of first-year ice even in central regions of the Arctic will lead to changes in the Arctic sea ice meiofauna community composition. We therefore analysed the sea ice meiofauna community composition of three different ice types sampled in summer and autumn 2007. Young, thin ice of few cm thickness was typified by taxa of pelagic origin or with good swimming abilities (ciliates, pelagic foraminifera, rotifers and platyhelminthes). Harpacticoid copepods and nematodes with poor swimming abilities were prevalent in older, thicker (>0.5 m) first- and multi-year ice. Brash ice—which was likely a mix of older broken ice, slush and pancake ice—was characterized by a high abundance of platyhelminthes and rotifers. An experimental analysis of colonization efficiencies of artificial thin ice also revealed that species with poor swimming ability are less successful to colonize newly forming thin ice. We conclude that observed and predicted changes in the ice formation regime will likely result in changes in the composition of Arctic sea ice communities. We predict negative effects particularly for species with low dispersal capacities like harpacticoid copepods and endemic nematodes, as these are less successful in colonizing newly forming thin ice

WISDOM GPR subsurface investigations in the Atacama desert during the SAFER rover operation simulation

SAFER (Sample Acquisition Field Experiment with a Rover) is a field trial that occured from 7th to 13th October 2013 in the Atacama desert, Chile. This trial was designed to gather together scientists and engineers in a context of a real spatial mission with a rover. This is ESA's opportunity to validate operations procedures for the ExoMars 2018 mission, since a rover, provided by Astrium, was equipped with three ExoMars payload instruments, namely the WISDOM (Water Ice Subsurface Deposits Observations on Mars) Ground Penetrating Radar, PANCAM (Panoramic Camera) and CLUPI (Close-UP Imager), and was used to experiment the real context of a Martian rover mission. The test site was located close to the Paranal ESO's Observatory (European Southern Observatorys) while the operations were conducted in the Satellite Applications Catapult remote Center in Harwell, UK. The location was chosen for its well-known resemblance with Mars' surface and its arid dryness. To provide the best from this trial, geologists, engineers and instrumentation scientists teams collaborated by processing and analyzing the data, planning in real time the next trajectories for the Bridget rover, as well as the sites of interest for WISDOM subsurface investigations. This WISDOM GPR has been designed to define the geological context of the ExoMars 2018 landing site by characterizing the shallow subsurface in terms of electromagnetic properties and structures. It will allow to lead the drill to locations of potential exobiologocal interest. WISDOM is a polarimetric step frequency radar operating from 0.5GHz to 3GHz, which allows a vertical resolution of a few centimeters over a few meters depth. Provided with a DEM (Digital Elevation Model) and a low-resolution map to assist the team with the rover's operations, several soudings with WISDOM were done over the area. The WISDOM data allowed, in collaboration with the SCISCYS team, to map the electromagnetic contrasts into the subsurface underneath the rover path and to get a 3D representation. WISDOM data were also used to assess the most promising locations for drilling operations by identifying the interfaces and the scatterers embedded in the subsurface and retrieving their depths. We present the results derived from WISDOM data acquired over the SAFER trial site to characterize the shallow subsurface of the area in terms of geology and electromagnetic properties. The quantitative results are compared with the characteristics of the samples removed from the site during drilling operations. The SAFER team carries on the cooperation in order to take the best from all instruments put together

Maternal Vitamin B12 Deficiency Detected by Newborn Screening&mdash;Evaluation of Causes and Characteristics

Vitamin B12 deficiency, mostly of maternal origin in newborns, is a well-treatable condition but can cause severe neurologic sequelae in infants. Early detection of vitamin B12 deficiency allows the pre-symptomatic treatment of affected children. This evaluation assesses the characteristics of maternal vitamin B12 deficiency detected by newborn screening. In a prospective single-center study, a systematic screening strategy for vitamin B12 deficiency using a combination of two second-tier strategies was applied. In addition to confirmatory diagnostics in children, the systematic work-up of vitamin B12 status was also performed for their mothers. Maternal characteristics were assessed including ethnic origin, diet, and vitamin supplementation during pregnancy. For affected mothers, a work-up by internal medicine was recommended. In total, 121 mother&ndash;infant couples were analyzed. 66% of mothers adhered to a balanced diet including meat. The cause of maternal vitamin B12 deficiency was unknown in 56% of cases, followed by dietary causes in 32%, and organic causes in 8%. All mothers following a vegan diet and most mothers with a vegetarian diet took vitamin preparations during pregnancy, whereas only 55.8% of mothers with a balanced diet took folic acid or other vitamins. Maternal vitamin B12, folic acid, and homocysteine levels were significantly correlated with the child&rsquo;s folic acid levels, and with homocysteine, methylmalonic, and methylcitric acid levels in first and second NBS dried blood spots. Most children had normal blood counts and showed normocytosis. Although 36.7% of mothers showed anemia, only one presented with macrocytosis. Adherence to vitamin supplementation in pregnancy is low despite the recommendation for supplementation of folic acid. Ideally, the evaluation of mothers for vitamin B12 levels and appropriate therapy should be initiated in early pregnancy. In infants detected through newborn screening, the multidisciplinary assessment and therapy of both children and mothers should be performed

Collaborative evaluation study on 18 candidate diseases for newborn screening in 1.77 million samples

Analytical and therapeutic innovations led to a continuous but variable extension of newborn screening (NBS) programmes worldwide. Every extension requires a careful evaluation of feasibility, diagnostic (process) quality and possible health benefits to balance benefits and limitations. The aim of this study was to evaluate the suitability of 18 candidate diseases for inclusion in NBS programmes. Utilising tandem mass spectrometry as well as establishing specific diagnostic pathways with second-tier analyses, three German NBS centres designed and conducted an evaluation study for 18 candidate diseases, all of them inherited metabolic diseases. In total, 1 777 264 NBS samples were analysed. Overall, 441 positive NBS results were reported resulting in 68 confirmed diagnoses, 373 false-positive cases and an estimated cumulative prevalence of approximately 1 in 26 000 newborns. The positive predictive value ranged from 0.07 (carnitine transporter defect) to 0.67 (HMG-CoA lyase deficiency). Three individuals were missed and 14 individuals (21%) developed symptoms before the positive NBS results were reported. The majority of tested candidate diseases were found to be suitable for inclusion in NBS programmes, while multiple acyl-CoA dehydrogenase deficiency, isolated methylmalonic acidurias, propionic acidemia and malonyl-CoA decarboxylase deficiency showed some and carnitine transporter defect significant limitations. Evaluation studies are an important tool to assess the potential benefits and limitations of expanding NBS programmes to new diseases

Impact of the SARS-CoV-2 pandemic on the health of individuals with intoxication-type metabolic diseases—Data from the E-IMD consortium

The SARS-CoV-2 pandemic challenges healthcare systems worldwide. Within inherited metabolic disorders (IMDs) the vulnerable subgroup of intoxication-type IMDs such as organic acidurias (OA) and urea cycle disorders (UCD) show risk for infection-induced morbidity and mortality. This study (observation period February 2020 to December 2021) evaluates impact on medical health care as well as disease course and outcome of SARS-CoV-2 infections in patients with intoxication-type IMDs managed by participants of the European Registry and Network for intoxication type metabolic diseases Consortium (E-IMD). Survey's respondents managing 792 patients (n = 479 pediatric; n = 313 adult) with intoxication-type IMDs (n = 454 OA; n = 338 UCD) in 14 countries reported on 59 (OA: n = 36; UCD: n = 23), SARS-CoV-2 infections (7.4%). Medical services were increasingly requested (95%), mostly alleviated by remote technologies (86%). Problems with medical supply were scarce (5%). Regular follow-up visits were reduced in 41% (range 10%–50%). Most infected individuals (49/59; 83%) showed mild clinical symptoms, while 10 patients (17%; n = 6 OA including four transplanted MMA patients; n = 4 UCD) were hospitalized (metabolic decompensation in 30%). ICU treatment was not reported. Hospitalization rate did not differ for diagnosis or age group (p = 0.778). Survival rate was 100%. Full recovery was reported for 100% in outpatient care and 90% of hospitalized individuals. SARS-CoV-2 impacts health care of individuals with intoxication-type IMDs worldwide. Most infected individuals, however, showed mild symptoms and did not require hospitalization. SARS-CoV-2-induced metabolic decompensations were usually mild without increased risk for ICU treatment. Overall prognosis of infected individuals is very promising and IMD-specific or COVID-19-related complications have not been observed

Postauthorization safety study of betaine anhydrous

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013–2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0–9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation