Leigh syndrome is the main clinical characteristic of PTCD3 deficiency

Mitochondrial translation defects are a continuously growing group of disorders showing a large variety of clinical symptoms including a wide range of neurological abnormalities. To date, mutations in PTCD3, encoding a component of the mitochondrial ribosome, have only been reported in a single individual with clinical evidence of Leigh syndrome. Here, we describe three additional PTCD3 individuals from two unrelated families, broadening the genetic and phenotypic spectrum of this disorder, and provide definitive evidence that PTCD3 deficiency is associated with Leigh syndrome. The patients presented in the first months of life with psychomotor delay, respiratory insufficiency and feeding difficulties. The neurologic phenotype included dystonia, optic atrophy, nystagmus and tonic-clonic seizures. Brain MRI showed optic nerve atrophy and thalamic changes, consistent with Leigh syndrome. WES and RNA-seq identified compound heterozygous variants in PTCD3 in both families: c.[1453-1G>C];[1918C>G] and c.[710del];[902C>T]. The functional consequences of the identified variants were determined by a comprehensive characterization of the mitochondrial function. PTCD3 protein levels were significantly reduced in patient fibroblasts and, consistent with a mitochondrial translation defect, a severe reduction in the steady state levels of complexes I and IV subunits was detected. Accordingly, the activity of these complexes was also low, and high-resolution respirometry showed a significant decrease in the mitochondrial respiratory capacity. Functional complementation studies demonstrated the pathogenic effect of the identified variants since the expression of wild-type PTCD3 in immortalized fibroblasts restored the steady-state levels of complexes I and IV subunits as well as the mitochondrial respiratory capacity. Additionally, minigene assays demonstrated that three of the identified variants were pathogenic by altering PTCD3 mRNA processing. The fourth variant was a frameshift leading to a truncated protein. In summary, we provide evidence of PTCD3 involvement in human disease confirming that PTCD3 deficiency is definitively associated with Leigh syndrome.© 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology

Risks in Antibiotic Substitution Following Medicine Shortage: A Health-Care Failure Mode and Effect Analysis of Six European Hospitals

Introduction: Medicine shortages result in great risk for the continuity of patient care especially for antimicrobial treatment, potentially enhancing resistance rates and having a higher economic impact. This study aims to identify, describe, assess, and assign risk priority levels to potential failures following substitution of antimicrobial treatment due to shortages among European hospitals. Furthermore, the study investigated the impact of corrective actions on risk reduction so as to provide guidance and improve future patient care. Methods: Health-care failure mode and effect analysis (HFMEA) was applied to hospitals in Austria (H-AT), Belgium (H-BE), Croatia (H-CR), Greece (H-GR), Spain (H-SP), and Serbia (H-SR). Multidisciplinary teams identified processes, failure modes, causes, and corrective actions related to antibiotic substitution following medicine shortages. Characteristics of study hospitals as well as severity, probability, and hazard scores (HSs) of failure modes/causes were analyzed using Microsoft Office Excel 2010 and IBM SPSS Statistics® via descriptive and inferential statistics. Results: Through HFMEA, 74 failure modes were identified, with 53 of these scoring 8 or above on the basis of assigned severity and probability for a failure. Severity of failure modes differed before and after corrective actions in H-CR, H-GR, and H-SR (p < 0.005). Their probability differed in all study hospitals (p < 0.005) when compared before and after corrective actions aimed to be implemented. The highest number of failure-mode causes was detected in H-CR (46) and the lowest in H-SP (16). Corrective actions can address failure modes and lower HSs; therein, all teams proposed the following: structuring communication among stakeholders, introducing electronic prescribing, strengthening pharmacists' involvement, and increasing effectiveness of the ward stock assessment. These proposed actions led to HS reductions up to 83%. Conclusion: There is a lack of structure in addressing risks associated with antibiotic substitution following shortages. Furthermore, lack of communication, data scarcity on availability of antibiotics, non-supportive information technology (IT) systems, and lack of internal substitution protocols hinder quick assessment of alternatives addressing patient needs. Nevertheless, the study shows that health-care professionals manage to secure optimal antimicrobial treatment for patients using available IT and human resources

GDF-15 is elevated in children with mitochondrial diseases and is induced by mitochondrial dysfunction

Background We previously described increased levels of growth and differentiation factor 15 (GDF-15) in skeletal muscle and serum of patients with mitochondrial diseases. Here we evaluated GDF-15 as a biomarker for mitochondrial diseases affecting children and compared it to fibroblast-growth factor 21 (FGF-21). To investigate the mechanism of GDF-15 induction in these pathologies we measured its expression and secretion in response to mitochondrial dysfunction. Methods We analysed 59 serum samples from 48 children with mitochondrial disease, 19 samples from children with other neuromuscular diseases and 33 samples from aged-matched healthy children. GDF-15 and FGF-21 circulating levels were determined by ELISA. Results Our results showed that in children with mitochondrial diseases GDF-15 levels were on average increased by 11-fold (mean 4046pg/ml, 1492 SEM) relative to healthy (350, 21) and myopathic (350, 32) controls. The area under the curve for the receiver-operating-characteristic curve for GDF-15 was 0.82 indicating that it has a good discriminatory power. The overall sensitivity and specificity of GDF-15 for a cut-off value of 550pg/mL was 67.8% (54.4%-79.4%) and 92.3% (81.5%-97.9%), respectively. We found that elevated levels of GDF-15 and or FGF-21 correctly identified a larger proportion of patients than elevated lev- els of GDF-15 or FGF-21 alone. GDF-15, as well as FGF-21, mRNA expression and protein secretion, were significantly induced after treatment of myotubes with oligomycin and that levels of expression of both factors significantly correlated. Conclusions Our data indicate that GDF-15 is a valuable serum quantitative biomarker for the diagnosis of mitochondrial diseases in children and that measurement of both GDF-15 and FGF-21 improves the disease detection ability of either factor separately. Finally, we demonstrate for the first time that GDF-15 is produced by skeletal muscle cells in response to mitochon- drial dysfunction and that its levels correlate in vitro with FGF-21 level

Prospective Risk Assessment of Medicine Shortages in Europe and Israel: Findings and Implications

Introduction: While medicine shortages are complex, their mitigation is more of a challenge. Prospective risk assessment as a means to mitigate possible shortages, has yet to be applied equally across healthcare settings. The aims of this study have been to: 1) gain insight into risk-prevention against possible medicine shortages among healthcare experts; 2) review existing strategies for minimizing patient-health risks through applied risk assessment; and 3) learn from experiences related to application in practice. Methodology: A semi-structured questionnaire focusing on medicine shortages was distributed electronically to members of the European Cooperation in Science and Technology (COST) Action 15105 (28 member countries) and to hospital pharmacists of the European Association of Hospital Pharmacists (EAHP) (including associated healthcare professionals). Their answers were subjected to both qualitative and quantitative analysis (Microsoft Office Excel 2010 and IBM SPSS Statistics®) with descriptive statistics based on the distribution of responses. Their proportional difference was tested by the chi-square test and Fisher's exact test for independence. Differences in the observed ordinal variables were tested by the Mann-Whitney or Kruskal-Wallis test. The qualitative data were tabulated and recombined with the quantitative data to observe, uncover and interpret meanings and patterns. Results: The participants (61.7%) are aware of the use of risk assessment procedures as a coping strategy for medicine shortages, and named the particular risk assessment procedure they are familiar with failure mode and effect analysis (FMEA) (26.4%), root cause analysis (RCA) (23.5%), the healthcare FMEA (HFMEA) (14.7%), and the hazard analysis and critical control point (HACCP) (14.7%). Only 29.4% report risk assessment as integrated into mitigation strategy protocols. Risk assessment is typically conducted within multidisciplinary teams (35.3%). Whereas 14.7% participants were aware of legislation stipulating risk assessment implementation in shortages, 88.2% claimed not to have reported their findings to their respective official institutions. 85.3% consider risk assessment a useful mitigation strategy. Conclusion: The study indicates a lack of systematically organized tools used to prospectively analyze clinical as well as operationalized risk stemming from medicine shortages in healthcare. There is also a lack of legal instruments and sufficient data confirming the necessity and usefulness of risk assessment in mitigating medicine shortages in Europe. © Copyright © 2020 Miljković, Godman, Kovačević, Polidori, Tzimis, Hoppe-Tichy, Saar, Antofie, Horvath, De Rijdt, Vida, Kkolou, Preece, Tubić, Peppard, Martinez, Yubero, Haddad, Rajinac, Zelić, Jenzer, Tartar, Gitler, Jeske, Davidescu, Beraud, Kuruc-Poje, Haag, Fischer, Sviestina, Ljubojević, Markestad, Vujić-Aleksić, Nežić, Crkvenčić, Linnolahti, Ašanin, Duborija-Kovačević, Bochenek, Huys and Miljković

Systematic Collaborative Reanalysis of Genomic Data Improves Diagnostic Yield in Neurologic Rare Diseases

Altres ajuts: Generalitat de Catalunya, Departament de Salut; Generalitat de Catalunya, Departament d'Empresa i Coneixement i CERCA Program; Ministerio de Ciencia e Innovación; Instituto Nacional de Bioinformática; ELIXIR Implementation Studies (CNAG-CRG); Centro de Investigaciones Biomédicas en Red de Enfermedades Raras; Centro de Excelencia Severo Ochoa; European Regional Development Fund (FEDER).Many patients experiencing a rare disease remain undiagnosed even after genomic testing. Reanalysis of existing genomic data has shown to increase diagnostic yield, although there are few systematic and comprehensive reanalysis efforts that enable collaborative interpretation and future reinterpretation. The Undiagnosed Rare Disease Program of Catalonia project collated previously inconclusive good quality genomic data (panels, exomes, and genomes) and standardized phenotypic profiles from 323 families (543 individuals) with a neurologic rare disease. The data were reanalyzed systematically to identify relatedness, runs of homozygosity, consanguinity, single-nucleotide variants, insertions and deletions, and copy number variants. Data were shared and collaboratively interpreted within the consortium through a customized Genome-Phenome Analysis Platform, which also enables future data reinterpretation. Reanalysis of existing genomic data provided a diagnosis for 20.7% of the patients, including 1.8% diagnosed after the generation of additional genomic data to identify a second pathogenic heterozygous variant. Diagnostic rate was significantly higher for family-based exome/genome reanalysis compared with singleton panels. Most new diagnoses were attributable to recent gene-disease associations (50.8%), additional or improved bioinformatic analysis (19.7%), and standardized phenotyping data integrated within the Undiagnosed Rare Disease Program of Catalonia Genome-Phenome Analysis Platform functionalities (18%)

Review and evaluation of the methodological quality of the existing guidelines and recommendations for inherited neurometabolic disorders

BACKGROUND: Inherited neurometabolic disorders (iNMDs) represent a group of almost seven hundred rare diseases whose common manifestations are clinical neurologic or cognitive symptoms that can appear at any time, in the first months/years of age or even later in adulthood. Early diagnosis and timely treatments are often pivotal for the favorable course of the disease. Thus, the elaboration of new evidence-based recommendations for iNMD diagnosis and management is increasingly requested by health care professionals and patients, even though the methodological quality of existing guidelines is largely unclear. InNerMeD-I-Network is the first European network on iNMDs that was created with the aim of sharing and increasing validated information about diagnosis and management of neurometabolic disorders. One of the goals of the project was to determine the number and the methodological quality of existing guidelines and recommendations for iNMDs. ----- METHODS: We performed a systematic search on PubMed, the National Guideline Clearinghouse (NGC), the Guidelines International Network (G-I-N), the Scottish Intercollegiate Guideline Network (SIGN) and the National Institute for Health and Care Excellence (NICE) to identify all the published guidelines and recommendations for iNMDs from January 2000 to June 2015. The methodological quality of the selected documents was determined using the AGREE II instrument, an appraisal tool composed of 6 domains covering 23 key items. ----- RESULTS: A total of 55 records met the inclusion criteria, 11 % were about groups of disorders, whereas the majority encompassed only one disorder. Lysosomal disorders, and in particular Fabry, Gaucher disease and mucopolysaccharidoses where the most studied. The overall methodological quality of the recommendation was acceptable and increased over time, with 25 % of the identified guidelines strongly recommended by the appraisers, 64 % recommended, and 11 % not recommended. However, heterogeneity in the obtained scores for each domain was observed among documents covering different groups of disorders and some domains like 'stakeholder involvement' and 'applicability' were generally scarcely addressed. ----- CONCLUSIONS: Greater efforts should be devoted to improve the methodological quality of guidelines and recommendations for iNMDs and AGREE II instrument seems advisable for new guideline development. The elaboration of new guidelines encompassing still uncovered disorders is badly needed

Phil Wiffen, Tommy Eriksson, Stein Bergan, Pascal Bonnabry, Ilko Getov, Cristina Garcia Yubero, Irene Kraemer, Paul Le Brun, Ged Lee, Carlo Polidori, Piera Polidori, Zdenka Šklubalová, Gunar Stemer, Hugo van der Kuy, Steven Williams

European Journal of Hospital Pharmacy (EJHP) is the only official journal of the European Association of Hospital Pharmacists (EAHP) and is committed to advancing the science, practice and profession of hospital pharmacy. As the premier communication platform for hospital pharmacists worldwide, EJHP is a major source for continuing education as well as updates on advances in the practice and standard of pharmaceutical care for patients. With peer reviewed papers, features, conference reports and more on topics covering all aspects of hospital pharmacy from both a scientific and practice perspective, the journal aims to highlight innovations and developments in pharmaceutical and biomedical sciences, promoting safe, efficacious and cost-effective pharmaceutical care for hospital pharmacists to practise

Editorial board of EUROPEAN JOURNAL OF HOSPITAL PHARMACY

Aims and scope European Journal of Hospital Pharmacy (EJHP) is the only official journal of the European Association of Hospital Pharmacists (EAHP) and is committed to advancing the science, practice and profession of hospital pharmacy. As the premier communication platform for hospital pharmacists worldwide, EJHP is a major source for continuing education as well as updates on advances in the practice and standard of pharmaceutical care for patients. With peer reviewed papers, features, conference reports and more on topics covering all aspects of hospital pharmacy from both a scientific and practice perspective, the journal aims to highlight innovations and developments in pharmaceutical and biomedical sciences, promoting safe, efficacious and cost-effective pharmaceutical care for hospital pharmacists to practise