Pressure for drug development in lysosomal storage disorders – a quantitative analysis thirty years beyond the US orphan drug act

Background: Lysosomal storage disorders are a heterogeneous group of approximately 50 monogenically inherited orphan conditions. A defect leads to the storage of complex molecules in the lysosome, and patients develop a complex multisystemic phenotype of high morbidity often associated with premature death. More than 30 years ago the Orphan Drug Act of 1983 passed the United States legislation intended to facilitate the development of drugs for rare disorders. We directed our efforts in assessing which lysosomal diseases had drug development pressure and what distinguished those with successful development and approvals from diseases not treated or without orphan drug designation. Methods: Analysis of the FDA database for orphan drug designations through descriptive and comparative statistics. Results: Between 1983 and 2013, fourteen drugs for seven conditions received FDA approval. Overall, orphan drug status was designated 70 times for 20 conditions. Approved therapies were enzyme replacement therapies (N = 10), substrate reduction therapies (N = 1), small molecules facilitating lysosomal substrate transportation (N = 3). FDA approval was significantly associated with a disease prevalence higher than 0.5/100,000 (p = 0.00742) and clinical development programs that did not require a primary neurological endpoint (p = 0.00059). Orphan drug status was designated for enzymes, modified enzymes, fusion proteins, chemical chaperones, small molecules leading to substrate reduction, or facilitating subcellular substrate transport, stem cells as well as gene therapies. Conclusions: Drug development focused on more common diseases. Primarily neurological diseases were neglected. Small clinical trials with either somatic or biomarker endpoints were successful. Enzyme replacement therapy was the most successful technology. Four factors played a key role in successful orphan drug development or orphan drug designations: 1) prevalence of disease 2) endpoints 3) regulatory precedent, and 4) technology platform. Successful development seeded further innovation

Sex-specific risk factors for early mortality and survival after surgery of acute aortic dissection type a: a retrospective observational study

Results Women were older (70.7 years vs. 60.6 years; p <  0.001) and showed a higher logistic EuroSCORE I (31.0% vs. 19.7%, p <  0.001). In the male group, a higher portion of smokers (27.6% vs. 16.0%, p = 0.015) and intraoperatively, more complex procedures and longer cardiopulmonary bypass (CPB) (171 min vs. 149 min, p = 0.001) and cross-clamping times (94 min vs. 85 min, p = 0.018) occurred. 30-day mortality was 19.0% in the female and 16.5% in the male group (p = 0.545). Predictive for 30-day mortality in both genders was intraoperative blood transfusion, while in the female group chronic obstructive pulmonary disease (COPD), peripheral arterial disease and preoperative intubation were predictive. Preoperative cardiopulmonary resuscitation and duration of CPB time were predictors only in males. Averaged follow-up time was 5.2 years and survival did not differ between genders, even if it was stratified by age over 70 years. Conclusions This analysis demonstrated a similar and satisfactory survival in both genders after surgical treatment of AADA. Women and men differed significantly in age, unadjusted and adjusted risk factors and complexity of surgical treatment, but gender itself was no risk factor for mortality. These results suggest that the decision-making for surgical treatment should not depend on gender, but that accounting for sex-specific risk factors rather than common risk factors may help to improve the outcome in both genders

Rapid testing leads to the underestimation of the scrapie prevalence in an affected sheep and goat flock

To obtain a more detailed understanding of the prevalence of classical scrapie infections in a heavily affected German sheep flock (composed of 603 sheep and 6 goats), we analysed 169 sheep and 6 goats that carried the genotypes susceptible to the disease and that were therefore culled following discovery of the index case. The initial tests were performed using the Biorad TeSeE ELISA and reactive results were verified by official confirmatory methods (OIE-immunoblot and/or immunohistochemistry (IHC)) to demonstrate the deposition of scrapie-associated PrPSc in the brain stem (obex). This approach led to the discovery of 40 additional subclinically scrapie-infected sheep. Furthermore, peripheral lymphatic and nervous tissue samples of the 129 sheep and 6 goats with a negative CNS result were examined by IHC in order to identify any preclinical infections which had not already spread to the central nervous system (CNS). Using this approach we found 13 additional sheep with PrPSc depositions in the gut-associated lymph nodes (GALT) as well as in the enteric nervous system. Moreover, in most of these cases PrPSc was also deposited in the spleen and in the retropharyngeal and superficial cervical lymph nodes. Taken together, these results show a 30.3% infection prevalence in this scrapie-affected flock. Almost 7.4% of the infected animals harboured PrPSc exclusively in the peripheral lymphatic and nervous tissue and were therefore missed by the currently used testing strategy

Efficacy and outcome of expanded newborn screening for metabolic diseases - Report of 10 years from South-West Germany *

<p>Abstract</p> <p>Background</p> <p>National newborn screening programmes based on tandem-mass spectrometry (MS/MS) and other newborn screening (NBS) technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome.</p> <p>Methods</p> <p>In a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated.</p> <p>Results</p> <p>Optimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre-symptomatic start of treatment. Metabolic decompensation does not necessarily result in impairment of intellectual development, but there is a definite association between the two.</p> <p>Conclusions</p> <p>Physical and cognitive outcome in patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in phenylketonuria, used as a gold standard for NBS. Extended NBS entails many different interrelated variables which need to be carefully evaluated and optimized. More reports from different parts of the world are needed to allow a comprehensive assessment of the likely benefits, harms and costs in different populations.</p

Is total arch replacement associated with an increased risk after acute type A dissection?

Background The surgical strategy for acute type A aortic dissection (AADA) usually consists of reconstruction of the tear-lesion in the affected part of the ascending aorta. The optimal strategy either to replace the ascending aorta (AAR) or to replace the ascending aorta and the total aortic arch (TAAR) is still under debate. Our study compares the 30-day mortality between AAR and TAAR in AADA surgery. Results In 292 (86.1%) patients AAR and in 47 (13.9%) patients TAAR was performed for emergent AADA. Patients were older (P=0.049) in the AAR group. The median log Euro-SCORE was 25.5% (12.7; 41.7) for AAR and 19.7% (11.7; 32.2) for the TAAR patient cohort (P=0.12). Operative time, cardiopulmonary bypass- (CPB), cross-clamp- and ischemic time were significantly longer in the TAAR group (P<0.001). The overall 30-day mortality-rate was 17.7% (n=60) but was not significantly different between the two groups (P=0.27). Forty-nine (16.8%) patients died in the AAR and 11 patients (23.4%) in the TAAR group. After propensity-score matching, no difference in mortality was seen between the subgroups as well (P=0.44). Multivariable analysis identified the Euro-SCORE, long operation-time, postoperative dialysis and arrhythmia and administration of red blood cell concentrates as risk factors for 30-day mortality, but not for TAAR versus AAR. Conclusions The therapeutic goal in AADA surgery should be the complete restoration of the aorta to avoid further long-term complications and re-operations. Though 30-day mortality and postoperative co-morbidity for AAR are comparable to those in TAAR after treatment of AADA in our analysis, decision-making for the surgical strategy should weigh the operative risk of TAAR against the long-term outcome

Pediatric in-hospital emergencies: real life experiences, previous training and the need for training among physicians and nurses

Objective: Pediatric emergencies challenge professional teams by demanding substantial cognitive effort, skills and effective teamwork. Educational designs for team trainings must be aligned to the needs of participants in order to increase effectiveness. To assess these needs, a survey among physicians and nurses of a tertiary pediatric center in Germany was conducted, focusing on previous experience, previous training in emergency care, and individual training needs. Results: Fifty-three physicians and 75 nurses participated. Most frequently experienced emergencies were respiratory failure, resuscitation, seizure, shock/sepsis and arrhythmia. Resuscitations were perceived as being particularly precarious. Team collaboration and communication were major issues arising from previous emergency situations, but perceptions differed between physicians and nurses. Regarding previous training, physicians were accustomed to self-directed learning, whereas nurses usually attended practical courses. Both physicians and nurses rated themselves as having moderate levels of knowledge and skills for pediatric emergencies, though residents reported the significantly lowest preparedness. Both professions reported a high need for training of basic procedures and emergency algorithms, physicians even more than nurses

CAST constraints on the axion-electron coupling

In non-hadronic axion models, which have a tree-level axion-electron interaction, the Sun produces a strong axion flux by bremsstrahlung, Compton scattering, and axiorecombination, the "BCA processes." Based on a new calculation of this flux, including for the first time axio-recombination, we derive limits on the axion-electron Yukawa coupling gae and axion-photon interaction strength ga using the CAST phase-I data (vacuum phase). For ma <~ 10 meV/c2 we find ga gae < 8.1 × 10−23 GeV−1 at 95% CL. We stress that a next-generation axion helioscope such as the proposed IAXO could push this sensitivity into a range beyond stellar energy-loss limits and test the hypothesis that white-dwarf cooling is dominated by axion emission

The Genetic Landscape and Epidemiology of Phenylketonuria

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]–1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066−11G>A (IVS10−11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066−11G>A];[1066−11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.Fil: Hillert, Alicia. No especifíca;Fil: Anikster, Yair. No especifíca;Fil: Belanger Quintana, Amaya. No especifíca;Fil: Burlina, Alberto. No especifíca;Fil: Burton, Barbara K.. No especifíca;Fil: Carducci, Carla. No especifíca;Fil: Chiesa, Ana Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Christodoulou, John. No especifíca;Fil: Dordevic, Maja. No especifíca;Fil: Desviat, Lourdes R.. No especifíca;Fil: Eliyahu, Aviva. No especifíca;Fil: Evers, Roeland A.F.. No especifíca;Fil: Fajkusova, Lena. No especifíca;Fil: Feillet, Francois. No especifíca;Fil: Bonfim Freitas, Pedro E.. No especifíca;Fil: Gizewska, María. No especifíca;Fil: Gundorova, Polina. No especifíca;Fil: Karall, Daniela. No especifíca;Fil: Kneller, Katya. No especifíca;Fil: Kutsev, Sergey I.. No especifíca;Fil: Leuzzi, Vincenzo. No especifíca;Fil: Levy, Harvey L.. No especifíca;Fil: Lichter Koneck, Uta. No especifíca;Fil: Muntau, Ania C.. No especifíca;Fil: Namour, Fares. No especifíca;Fil: Oltarzewsk, Mariusz. No especifíca;Fil: Paras, Andrea. No especifíca;Fil: Perez, Belén. No especifíca;Fil: Polak, Emil. No especifíca;Fil: Polyakov, Alexander V.. No especifíca;Fil: Porta, Francesco. No especifíca;Fil: Rohrbach, Marianne. No especifíca;Fil: Scholl Bürgi, Sabine. No especifíca;Fil: Spécola, Norma. No especifíca;Fil: Stojiljkovic, Maja. No especifíca;Fil: Shen, Nan. No especifíca;Fil: Santana da Silva, Luiz C.. No especifíca;Fil: Skouma, Anastasia. No especifíca;Fil: van Spronsen, Francjan. No especifíca;Fil: Stoppioni, Vera. No especifíca;Fil: Thöny, Beat. No especifíca;Fil: Trefz, Friedrich K.. No especifíca;Fil: Vockley, Jerry. No especifíca;Fil: Yu, Youngguo. No especifíca;Fil: Zschocke, Johannes. No especifíca;Fil: Hoffmann, Georg F.. No especifíca;Fil: Garbade, Sven F.. No especifíca;Fil: Blau, Nenad. No especifíca