Wilson and Jungner Revisited: Are Screening Criteria Fit for the 21st Century?

Driven by technological innovations, newborn screening (NBS) panels have been expanded and the development of genomic NBS pilot programs is rapidly progressing. Decisions on disease selection for NBS are still based on the Wilson and Jungner (WJ) criteria published in 1968. Despite this uniform reference, interpretation of the WJ criteria and actual disease selection for NBS programs are highly variable. A systematic literature search [PubMED search “Wilson” AND “Jungner”; last search 16.07.22] was performed to evaluate the applicability of the WJ criteria for current and future NBS programs and the need for adaptation. By at least two reviewers, 105 publications (systematic literature search, N = 77; manual search, N = 28) were screened for relevant content and, finally, 38 publications were evaluated. Limited by the study design of qualitative text analysis, no statistical evaluation was performed, but a structured collection of reported aspects of criticism and proposed improvements was instead collated. This revealed a set of general limitations of the WJ criteria, such as imprecise terminology, lack of measurability and objectivity, missing pediatric focus, and absent guidance on program management. Furthermore, it unraveled specific aspects of criticism on clinical, diagnostic, therapeutic, and economical aspects. A major obstacle was found to be the incompletely understood natural history and phenotypic diversity of rare diseases prior to NBS implementation, resulting in uncertainty about case definition, risk stratification, and indications for treatment. This gap could be closed through the systematic collection and evaluation of real-world evidence on the quality, safety, and (cost-)effectiveness of NBS, as well as the long-term benefits experienced by screened individuals. An integrated NBS public health program that is designed to continuously learn would fulfil these requirements, and a multi-dimensional framework for future NBS programs integrating medical, ethical, legal, and societal perspectives is overdue

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

Konsumstau, höhere Energiepreise, lockere Geldpolitik: Droht nach Corona die große Inflation?

Markus Demary, Institut der deutschen Wirtschaft, Köln, geht davon aus, dass die höheren Inflationsraten auf vorübergehende Effekte zurückzuführen sind. Auch die Konjunkturprogramme hätten bisher nicht inflationär gewirkt. Zudem könnte nach vielen Jahren niedriger Inflation ein Anstieg der Inflationserwartungen auch als Zeichen einer sich erholenden Wirtschaft gewertet werden. Timo Wollmershäuser, ifo Institut, zeigt, dass der Preisauftrieb 2021 zum größten Teil auf außergewöhnlich niedrige Preise im Jahr 2020 zurückzuführen ist. Allerdings könne auch ein gewisser Teil des Preisschubs durch einen beschleunigten Preisanstieg, insbesondere bei Energie, Nahrungsmitteln und in einigen Dienstleistungsbereichen, erklärt werden. Die Inflationsrate dürfte somit im Durchschnitt des Jahres 2021 bei etwa 3% und 2022 bei durchschnittlich 2 bis 2,5% liegen. Auch Gerit Vogt, Bundesverband der Deutschen Volksbanken und Raiffeisenbanken, sieht die aktuelle Entwicklung stark durch Sonderfaktoren, wie das Auslaufen der Mehrwertsteuersenkung Ende 2020, beeinflusst. Mittelfristig sei eine Beruhigung wahrscheinlich, aber es könne nicht ausgeschlossen werden, dass der Preisauftrieb in den kommenden Jahren, unter anderem aufgrund des demografischen Wandels, stärker zunehmen werde. Nach Ansicht von Gertud R. Traud und Stefan Mütze, Helaba Landesbank Hessen-Thüringen, ist kurzfristig keine übermäßig starke Inflation zu erwarten. Mittelfristig dürften allerdings strukturelle Faktoren zu höheren Preisen führen. Zudem dürften auch konjunkturelle Aspekte und die Bekämpfung des Klimawandels zu mehr Inflation beitragen. Insgesamt seien die preistreibenden Effekte zwar in der Überzahl, aber es drohe vermutlich nicht die ganz große Inflation. Thomas Mayer, Flossbach von Storch Research Institute, verweist darauf, dass eine ungezügelte Geldvermehrung sehr oft zu Inflation geführt hat. Die Ausweitung der Geldmenge, gerade im Zuge der Corona-Pandemie, habe einen erheblichen Geldüberhang zur Folge. Dass die Kaufkraft des Geldes fallen müsse, wenn es mehr Geld als käufliche Dinge gibt, leuchte jedem ein. Pascal Seiler, ETH Zürich, untersucht am Beispiel der Schweiz, wie sich das durch die Pandemie veränderte Konsumverhalten auf die Messung der Inflation ausgewirkt hat. Die Inflation wurde im ersten Pandemiejahr tendenziell unter- und am aktuellen Rand eher überschätzt. Lukas Haffert, Universität Zürich, Nils Redeker, Jacques Delors Centre, und Tobias Rommel, Hochschule für Politik, Technische Universität München, zeigen auf Basis einer repräsentativen Umfrage, dass die deutsche Erinnerung an die Weimarer Republik von einem weitgreifenden Missverständnis geprägt ist: Nur wenige Deutsche wissen, dass das Preisniveau während der Weltwirtschaftskrise sank. Stattdessen verbindet fast die Hälfte der Befragten die Massenarbeitslosigkeit der frühen 1930er Jahre mit massiven Preissteigerungen

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

Neurological outcome in long‐chain hydroxy fatty acid oxidation disorders

Abstract Objective This study aims to elucidate the long‐term benefit of newborn screening (NBS) for individuals with long‐chain 3‐hydroxy‐acyl‐CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiency, inherited metabolic diseases included in NBS programs worldwide. Methods German national multicenter study of individuals with confirmed LCHAD/MTP deficiency identified by NBS between 1999 and 2020 or selective metabolic screening. Analyses focused on NBS results, confirmatory diagnostics, and long‐term clinical outcomes. Results Sixty‐seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived, but four with MTP deficiency (14.8%) died during the study period. Despite NBS and early treatment neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%), hepatopathy (32%), retinopathy (17%), and/or neuropathy (22%) occurred. Hospitalization rates were high (up to a mean of 2.4 times/year). Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447). Achievement of dietary goals decreased with age, from 75% in the first year of life to 12% at age 10, and consensus group recommendations on dietary management were often not achieved. Interpretation While NBS and early treatment result in improved (neonatal) survival, they cannot reliably prevent long‐term morbidity in screened individuals with LCHAD/MTP deficiency, highlighting the urgent need of better therapeutic strategies and the development of disease course‐altering treatment