ECFS standards of care on CFTR-related disorders: Identification and care of the disorders.

This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted.

ECFS standards of care on CFTR-related disorders: Towards a comprehensive program for affected individuals.

After three publications defining an updated guidance on the diagnostic criteria for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (pwCFTR-RDs), establishing its relationship to CFTR-dysfunction and describing the individual disorders, this fourth and last paper in the series addresses some critical challenges facing health care providers and pwCFTR-RD. Topics included are: 1) benefits and obstacles to collect data from pwCFTR-RD are discussed, together with the opportunity to integrate them into established CF-registries; 2) the potential of infants designated CRMS/CFSPID to develop a CFTR-RD and how to communicate this information; 3) a description of the challenges in genetic counseling, with particular regard to phenotypic variability, unknown long-term evolution, CFTR testing and pregnancy termination 4) a proposal for the assessment of potential barriers to the implementation and dissemination of the produced documents to health care professionals involved in the care of pwCFTR-RD and a process to monitor the implementation of the CFTR-RD recommendations; 5) clinical trials investigating the efficacy of CFTR modulators in CFTR-RD and how endpoints and outcomes might be adapted to the heterogeneity of these disorders.

ECFS standards of care on CFTR-related disorders: Updated diagnostic criteria.

This paper is the first in a series providing updated guidance on the definition, evaluation and management of people with a Cystic Fibrosis Transmembrane conductance Regulator (CFTR)-Related Disorder (CFTR-RD). The need for this update relates to more precise characterisation of CFTR gene variants and improved assessment of CFTR protein dysfunction. The exercise is co-ordinated by the European CF Society Standards of Care Committee and Diagnostic Network Working Group and involves stakeholder engagement. This first paper was produced by a core group using an extensive literature review and papers graded for their quality. Subsequent wider stakeholder agreement was achieved. The definition of a CFTR-RD remains "a clinical condition with evidence of CFTR protein dysfunction that does not fulfil the diagnostic criteria for CF". Clearer guidance on CFTR dysfunction and relevant CFTR variants will be provided. Thresholds for clinical presentations are presented and the paradigm that pathobiological processes may be evident in more than one organ is agreed. In this paper we reflect on the early patient journey, highlighting that CF specialists as well as other relevant specialists should be involved in the care of people with a CFTR-RD.

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

SARS-CoV-2 and Burkholderia cenocepacia infection in a patient with Cystic Fibrosis: An unfavourable conjunction?

The effects of the concomitant infection by COVID-19 and Burkholderia cepacia (Bc) in CF are not known. We describe the case of a 34 years woman with CF, colonized by Bc and found SARS-CoV2 positive. In the first hospital week she suffered acute respiratory failure and chest imaging showed interstitial involvement and multiple thickenings. She was treated with antibiotics, dexamethasone, remdesivir and heparin, with gradual improvement and discharge at day 20th. The reciprocal role of SARS-CoV-2 and Bc, their potential interactions and the contribution of the individual therapies to the favourable outcome are unclear. It is debatable whether it was SARS-CoV2 that triggered a Bc pulmonary exacerbation or if the chronic Bc infection facilitated the development of a COVID-19 more aggressive than usually seen in CF. If the latter hypothesis were confirmed by similar cases, Bc colonization should be regarded as a risk factor for severe COVID-19 expression in CF.

The local microbiome after pediatric bladder augmentation: intestinal segments and the native urinary bladder host similar mucosal microbiota.

INTRODUCTION: Next-generation sequencing (NGS) techniques have provided novel insights into the microbiome of the urinary bladder (UB). In children after bladder augmentation using either ileum (ileocystoplasty, ICP) or colon (colocystoplasty, CCP), the fate of the mucosal microbiome introduced into the urinary tract remains unknown. OBJECTIVE: The aim was to compare the mucosal microbiome of the native UB vs the augmented intestinal segment (IS) using NGS. STUDY DESIGN: Twelve children after bladder augmentation (ICP n = 6, CCP n = 6) were included. Biopsies were taken during routine postoperative cystoscopy from the native UB and the IS. Specimens underwent whole-genome DNA extraction, 16S rRNA gene amplification, NGS, and Quantitative Insights Into Microbial Ecology (QIIME) data analysis. Downstream statistical data analyses were performed in Calypso. RESULTS: Patients' median age at the time of surgery was 11 years (6-17 years), and the median interval between augmentation and sampling was 7 years (4-13 years). α-Diversity (Shannon diversity index) was not significantly different between IS vs UB, ICP vs CCP, and male vs female. No general differences in the overall bacterial pattern (ß-diversity) were found between IS, UB, ICP, and CCP groups. The groups overlapped in principal coordinate analysis (PCoA) and non-metric multidimensional scaling (NMDS) analysis (Figure). Age at sampling had a statistically significant influence on ß-diversity at the genus level. Corynebacterium, Pseudoxanthomonas, Lactobacillus, Flavobacterium, and Micrococcus were the most dominating taxa detected over all samples. There was an obvious dominance of the genus Corynebacterium in the samples taken from the UB and IS in both ICP and CCP patients. Limitations of this study include the relatively small number of patients. CONCLUSION: After bladder augmentation, the native UB and augmented ISs (ICP and CCP) host similar microbiota despite their distinct differences of originating mucosal anatomy.

Large-scale individual thyroid monitoring following nuclear accidents by means of non-spectrometric devices.

In order to properly respond to an emergency caused by an accident in a nuclear power plant with a spread of radionuclides in the atmosphere, we propose a field procedure to perform a large-scale individual thyroid monitoring of internal contamination due to inhalation of 131I, by means of non-spectrometric equipment, in particular dose rate meters. Specific attention is paid to the individual monitoring of children, because of the very high radiosensitivity of the child's thyroid to the carcinogenic effects of ionising radiation. The device performance was evaluated by measuring mock iodine sources provided in the Child and Adult Thyroid Monitoring After Reactor Accident (CAThyMARA) intercomparison and, just for a scintillator dose rate meter, by means of 60 s acquisitions of healthy volunteers' thyroids. All the devices showed a remarkable accuracy in quantification of equivalent 131I activity in the thyroids of persons of all ages. The selected scintillator dose rate meter showed detection limit values resulting in a maximum committed equivalent dose to thyroid HT, assuming an acute 131I inhalation occurred five days before the measurement, equal to 10 mSv (related to five-year-old children). Considering the level of HT values associated with the calculated detection limit activities, the proposed procedure has a significant sensitivity to be used for fast internally thyroid monitoring in nuclear or radiological emergencies, allowing daily monitoring a large amount of individuals.

EURADOS work on internal dosimetry.

European Radiation Dosimetry Group (EURADOS) Working Group 7 is a network on internal dosimetry that brings together researchers from more than 60 institutions in 21 countries. The work of the group is organised into task groups that focus on different aspects, such as development and implementation of biokinetic models (e.g. for diethylenetriamine penta-acetic acid decorporation therapy), individual monitoring and the dose assessment process, Monte Carlo simulations for internal dosimetry, uncertainties in internal dosimetry, and internal microdosimetry. Several intercomparison exercises and training courses have been organised. The IDEAS guidelines, which describe - based on the International Commission on Radiological Protection's (ICRP) biokinetic models and dose coefficients - a structured approach to the assessment of internal doses from monitoring data, are maintained and updated by the group. In addition, Technical Recommendations for Monitoring Individuals for Occupational Intakes of Radionuclides have been elaborated on behalf of the European Commission, DG-ENER (TECHREC Project, 2014-2016, coordinated by EURADOS). Quality assurance of the ICRP biokinetic models by calculation of retention and excretion functions for different scenarios has been performed and feedback was provided to ICRP. An uncertainty study of the recent caesium biokinetic model quantified the overall uncertainties, and identified the sensitive parameters of the model. A report with guidance on the application of ICRP biokinetic models and dose coefficients is being drafted at present. These and other examples of the group's activities, which complement the work of ICRP, are presented.

EURADOS-IDEAS GUIDELINES (VERSION 2) FOR THE ESTIMATION OF COMMITTED DOSES FROM INCORPORATION MONITORING DATA.

Dose assessment after intakes of radionuclides requires application of biokinetic and dosimetric models and assumptions about factors influencing the final result. In 2006, a document giving guidance for such assessment was published, commonly referred to as the IDEAS Guidelines. Following its publication, a working group within the European networks CONRAD and EURADOS was established to improve and update the IDEAS Guidelines. This work resulted in Version 2 of the IDEAS Guidelines, which was published in 2013 in the form of a EURADOS report. The general structure of the original document was maintained; however, new procedures were included, e.g. the direct dose assessment method for (3)H or special procedure for wound cases applying the NCRP wound model. In addition, information was updated and expanded, e.g. data on dietary excretion of U, Th, Ra and Po for urine and faeces or typical and achievable values for detection limits for different bioassay measurement techniques.

IFRD1 gene polymorphisms are associated with nasal polyposis in cystic fibrosis patients.

BACKGROUND: Nasal polyposis (NP) is an inflammatory disease of the upper nasal airways frequently present in CF patients. Interferon-Related Developmental Regulator 1 (IFRD1) gene was reported as a possible modifier of CF lung disease severity. Three IFRD1 SNPs were analyzed to investigate a possible effect on the development of NP in CF patients. METHODS AND PATIENTS: The DNA of 143 patients with CF (40 with and 103 without NP) was purified from peripheral blood samples. IFRD1 SNPs (rs7817, rs3807213, rs6968084) were genotyped by restriction enzyme analysis. RESULTS: The T allele of the common polymorphisms rs7817 and the rs7817-rs3807213 haplotype were associated with NP (p = 0.002 and 0.004, respectively). CONCLUSIONS: These results showed the association of the IFRD1-rs7817 polymorphism with NP in CF patients.

Medical consensus, guidelines, and position papers: a policy for the ECFS.

The terms consensus, guideline and position paper are sometimes employed as if they were interchangeable, but the purpose of such documents and the robustness of advice vary as the evidence base does not have the same depth in each. The Board of the European Cystic Fibrosis Society deemed it to be helpful to provide a short commentary on the definition of these terms, on their interconnections and on how ECFS considers them in documents endorsed by the society.

Loss of autonomy of hospitalized elderly patients: does hospitalization increase disability?

AIM: The study of the determinants of loss of autonomy during hospitalization may be valuable in the identification of the most effective interventions and to achieve better outcomes. The aim of this study was to describe changes in the level of autonomy of the elderly admitted to the hospital at the entrance and at discharge in relation to a rehabilitation program. METHODS: Prospective observational study conducted at the INRCA Geriatric Hospital of Ancona. The study included patients aged 65 years and over, daily admitted to INRCA Hospital of Ancona between September and December 2010. Criteria for inclusion were age ≥ 65 years, length of stay > 24 hours and signed informed consent. Patients admitted for less than 24 hours or in day hospital or day surgery were excluded from the beginning. A total of 1266 elderly patients were recruited in the period. From this sample, 74 people who died during hospitalization were excluded. At the time of hospitalization (within 24 hours) and at discharge, patients were evaluated with the Barthel Index (BI), the Rankin scale, and a short assessment of cognitive status derived from the Mini Mental State Examination (MMSE). RESULTS: Referring to 1192 subjects who participated to the study, the mean age was 82.13 years ±7.39, age range between 65 and 100 years. The average BI was 56.6±36.16 (SD) (median value =60) at admission and 63.84±34.7 (SD) (median value=70) at discharge. The average Rankin score at admission was 2.63±1.5 (SD) (median value=3). CONCLUSION: Patients presented better score of the BI at discharge and this figure was associated to the implementation of a rehabilitation treatment. Hospitalization of the elderly patient in a suitable environment, such as a geriatric hospital, contrary to some theories highlighting only the negative aspects of removal from the living environment, can be a measure of benefit for the reduction of disability and the recovery of compromised activities along and after the acute event. The collection of data on the level of autonomy of the subjects before and after hospitalization can be a useful element for clinical evaluation in a geriatric hospital.

Postoperative emesis after laparoscopic pyloromyotomy in infantile hypertrophic pyloric stenosis.

AIM: This study aimed to determine the causes of postoperative emesis (PE) in neonates with infantile hypertrophic pyloric stenosis (IHPS) after laparoscopic pyloromyotomy (LP). METHODS: Retrospective review of the hospital database for infants with IHPS managed between 2000 and 2010 was performed. Relevant data were collected from the clinical records in the Medocs(®) system and used for statistical analysis. RESULTS: During the 10-year period, 95 patients with IHPS were identified and 43 (36 boys and seven girls) fulfilled the inclusion criteria. PE occurred in 21 infants (48.8%), of which nine presented with manifestations of enteric infections, with confirmed diagnosis in four. PE was significantly higher in the fast track feeding protocol (FTFP) group 12/15 compared with the conventional slow feeding protocol (CSFP) group 8/21 (p = 0.019). Gastro-oesophageal reflux (GER) confirmed by 24-h impedance monitoring was responsible for PE in three. Operative revision for suspected incomplete pyloromyotomy was performed in five infants. However, incomplete myotomy could only be confirmed in two infants during surgery. CONCLUSION: Postoperative emesis in IHPS after LP requires careful evaluation as it can be a result of enteric viral infections, aggressive feeding protocols or GER. Decisions to perform reoperations for incomplete myotomy after LP due to PE are challenging.