Search

European CF Society Neonatal Screening Working Group (ECFS NSWG): Sabine Renner , Max Zeyda , Elke de Wachter , Luc Regal , Felix Votava, Andrea Holubova, Marianne Skov , Tessa Morgan, Paul Bregeaut , Loretta O'Grady, Ines Bucci , Stefano Pantano , Simonetta Simonetti, Domenica De Venuto, Donatello Salvatore, Nicola Perrotti, Mimma Caloiero, Giuseppe Castaldo, Antonella Tosco, Francesca Righetti, Giovanna Pisi, Fiorella Battistini, Antonio Angeloni, Giuseppe Cimino, Giovanni Fiocchi, Antonella Angiolillo, Michela Cassanello, Luisella Alberti, Laura E Claut, Raffaele Badolato, Enza Pavanello, Benedetta Fabrizzi, Elisabetta Bignamini, Anna Cardillo, Mariangela Lombardo, Letizia Cocciadiferro, Lisa Termini, Daniela Dolce, Vito Terlizzi, Anna Tamanini, Francesca Pauro, Giancarlo la Marca, Elina Aleksejeva, Dita Gaidule-Logina, Stoika Fustik, Violeta Anastasovska, Marelle Bouva, Alastair Reid, Jennifer Cundick, Emma Lundman, Egil Bakkeheim, Katarzyna Zybert, Mariusz Oltarzewski, Laura Vilarinho, Victoria Sherman, Elena Kondratyeva, Sarah Smith, Gordana Vilotijevic Dautovic, Maria Knapkova, Zuzana Mydlova, Rosa Mª López, Valle Velasco, Felicitas Díaz Flores, Cristóbal Colón Mejeras, Eva Sl Pedersen, Ugur Ozcelik, Bulent Karadag, Halyna Makukh, Moat Stuart. European CF Society Neonatal Screening Working Group (ECFS NSWG): INSA - Laura Vilarinho Background: The aim of this study was to record the current status of newborn bloodspot screening (NBS) for CF across Europe and assess performance. Methods: Survey of representatives of NBS for CF programmes across Europe. Performance was assessed through a framework developed in a previous exercise. Results: In 2022, we identified 22 national and 34 regional programmes in Europe. Barriers to establishing NBS included cost and political inertia. Performance was assessed from 2019 data reported by 21 national and 21 regional programmes. All programmes employed different protocols, with IRT-DNA the most common strategy. Six national and 11 regional programmes did not use DNA analysis. Conclusions: Integrating DNA analysis into the NBS protocol improves PPV, but at the expense of increased carrier and CFSPID recognition. Some programmes employ strategies to mitigate these outcomes. Programmes should constantly strive to improve performance but large datasets are needed to assess outcomes reliably. Highlights: In 2022, newborn bloodspot screening (NBS) for CF is undertaken in 30 European countries, 26 of them are national programmes; Some programmes are still not achieving ECFS standards. Compared to 2014, there is an improvement in sensitivity but a deterioration in achieving a sufficient PPV; There continues to be a wide variety of approaches, but the majority of national programmes are now using DNA analysis as a 2nd tier; This survey demonstrates areas of good practice, but there is considerable scope for improvement in the quality of NBS for CF across Europe; The framework of the 20 parameters to calculate the 8 key outcomes should be part of any annual report of a CF NBS programme, and thus improve future surveys. The survey was funded by the European CF Society info:eu-repo/semantics/publishedVersion

Subglacial lakes may form beneath ice sheets and ice caps, given the availability of water and appropriate bedrock and surface topography to capture the water. On a regional scale, these lakes can modulate the freshwater output to the ocean by acting as reservoirs that may periodically drain and recharge. Several such active subglacial lakes have been documented under the Antarctic ice sheet, while only a few are observed under the Greenland ice sheet. The small size of the hydrologically active subglacial lakes in Greenland compared to those in Antarctica, puts additional demands on our mapping capabilities to resolve in great detail the evolving surface topography over these lakes to document their temporal behavior. Here, we explore the potential of combining CryoSat-2 swath data and high resolution DEMs generated from TanDEM-X scenes and ArcticDEM strips to improve our knowledge of the evolution of four active subglacial lake sites previously documented in the literature. We find that the DEM data complement each other well in terms of time and resolution and thus provide new information about the subglacial lake activity, though the small size of the collapse basins is challenging for CS2, and we are only able to derive useful CS2 data for the two largest of the four investigated lakes. Based on these data sets we can e.g. conclude that the collapse basin at Flade Isblink was actually as deep as 95 m when it formed, which is 30 m deeper than previously documented. We also present evidence of a new active subglacial lake in Southwest Greenland.

Introduction Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that has demonstrated clinical benefits in phase 3 trials. We report results from a real-world study (BRIO) to assess the effectiveness of ivacaftor in people with cystic fibrosis (pwCF) in France. Methods BRIO was an observational study conducted at 35 centers in France. Both pwCF initiating ivacaftor treatment and those already taking ivacaftor were included and prospectively followed for 24 months. The primary objective was to evaluate the effect of ivacaftor on percent predicted forced expiratory volume in 1 s (ppFEV1); secondary objectives were evaluating the effect of ivacaftor on clinical effectiveness, healthcare resource utilization (HCRU), and safety. Results A total of 129 pwCF were enrolled; 58.9% were aged

Le dépistage néonatal (DNN) de la mucoviscidose a permis une prise en charge multidisciplinaire très précoce des nourrissons et a amélioré le pronostic de cette maladie. Il a connu, en une vingtaine d’années, un développement international spectaculaire. Les performances du DNN national français, réalisé depuis 2002, répondent aux exigences des standards européens en termes de valeur prédictive positive et de sensibilité. Nous pouvons noter, en particulier, un nombre très faible de cas en attente de conclusion, un pourcentage très élevé de tests de la sueur réalisés et d’identification des mutations du gène cystic fibrosis transmembrane conductance regulator (CFTR), un ratio important de cas de mucoviscidose par rapport aux cas de diagnostics non conclus, ainsi qu’une stratégie efficace pour repérer les faux-négatifs. Une nouvelle organisation du DNN français a été mise en place. Il est donc capital de maintenir l’efficacité du processus ainsi mis en place, du nouveau-né en maternité jusqu’au diagnostic dans des centres de ressources et de compétences de la mucoviscidose, avec le recueil exhaustif des données et leur validation.

In previous work, participants with a G970R mutation in cystic fibrosis transmembrane conductance regulator (CFTR) (c.2908G>C) had numerically lower sweat chloride responses during ivacaftor treatment than participants with other CFTR gating mutations. The objective of this substudy was to characterize the molecular defect of the G970R mutation in vitro and assess the benefit of ivacaftor in participants with this mutation. This substudy assessed sweat chloride, spirometry findings, and nasal potential difference on and off ivacaftor treatment in three participants with a G970R/F508del genotype. Intestinal organoids derived from rectal biopsy specimens were used to assess ivacaftor response ex vivo and conduct messenger RNA splice and protein analyses. No consistent or meaningful trends were observed between on-treatment and off-treatment clinical assessments. Organoids did not respond to ivacaftor in forskolin-induced swelling assays; no mature CFTR protein was detected in Western blots. Organoid RNA analysis demonstrated that 3 novel splice variants were created by G970R-CFTR: exon 17 truncation, exons 13-15 and 17 skipping, and intron 17 retention. Functional and molecular analyses indicated that the c.2908G>C mutation caused a cryptic splicing defect. Organoids lacked an ex vivo response with ivacaftor and supported identification of the mechanism underlying the CFTR defect caused by c.2908G>C. Analysis of CFTR mutations indicated that cryptic splicing was a rare cause of mutation misclassification in engineered cell lines. This substudy used organoids as an alternative in vitro model for mutations, such as cryptic splice mutations that cannot be fully assessed using cDNA expressed in recombinant cell systems. ispartof: CTS-Clinical and Translational Science vol:14 issue:2 pages:656-663 ispartof: location:United States status: published

Background Tezacaftor/ivacaftor is a CFTR modulator approved to treat people with cystic fibrosis (pwCF) who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function mutation (F/RF). This randomized, double-blind, placebo-controlled Phase 3 study evaluated the efficacy, safety, tolerability, and pharmacokinetics (PK) of tezacaftor/ivacaftor in participants ≥12 years of age heterozygous for the F508del-CFTR mutation and a minimal function mutation (F/MF), which produces no CFTR protein or a protein unresponsive to tezacaftor/ivacaftor in vitro. Methods Participants were randomized 1:1 to receive tezacaftor/ivacaftor or placebo for 12 weeks. The primary endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) between the tezacaftor/ivacaftor and placebo groups through week 12. Key secondary endpoints included absolute change from baseline in CF Questionnaire-Revised respiratory domain scores and the number of pulmonary exacerbations through week 12 and the absolute change from baseline in body mass index at week 12. A prespecified interim analysis (IA) for futility was conducted when approximately 50% of a planned enrollment of 300 participants reached week 12 of the study. Results At the time of the IA, 83 participants were randomized to tezacaftor/ivacaftor and 85 to placebo; 165 participants completed treatment. The study failed to demonstrate that tezacaftor/ivacaftor significantly improved ppFEV1 or any of the key secondary endpoints and was terminated for futility. The safety profile and PK parameters of tezacaftor/ivacaftor were similar to those reported in prior studies in participants ≥12 years of age with CF. Conclusions Tezacaftor/ivacaftor did not show a clinically meaningful benefit in participants with F/MF genotypes but was generally safe and well tolerated, consistent with the safety profile reported in other Phase 3 studies (NCT02516410).

OBJECTIVE To characterize the phenotypic expression of children with conductance regulator-related metabolic syndrome (CRMS)/cystic fibrosis screen positive inconclusive diagnosis (CFSPID) designation after positive newborn screening, reassign labeling if applicable and better define these children's prognosis. METHODS A multicenter cohort with CRMS/CFSPID designation was matched with cystic fibrosis (CF)-diagnosed cohort. Cohorts were prospectively compared on baseline characteristics, cumulative data and when they reached 6 to 7 years at endpoint assessment. RESULTS Compared to infants with CF (n = 63), the CRMS/CFSPID cohort (n = 63) had initially lower immunoreactive trypsinogen (IRT) and sweat chloride (SC) values, delayed visits, less symptoms, and better nutritional status; during follow-up, they had fewer hospitalizations, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus identification, CF comorbidities, and treatment burden. At endpoint assessment, they presented a milder pulmonary phenotype on Brody computed tomography scores (0.0[0.0; 2.0] vs 13[2.0; 31.0]; P

International audience

Resume Le depistage neonatal (DNN) de la mucoviscidose, grâce a une prise en charge multidisciplinaire tres precoce des nourrissons, est optimal en termes de pronostic pour les patients. Depuis 20 ans, il a connu une expansion internationale spectaculaire. Les performances du DNN national francais realise depuis 2002 sont en accord avec les standards europeens pour la valeur predictive positive (0,31 pour un minimum de 0,30) et la specificite (0,95 pour un minimum de 0,95) ; nous soulignons le nombre tres faible de cas non conclus, un pourcentage tres eleve de test de la sueur realises (95,5 %) et d’identification des mutations (96,6 %), un ratio de cas de mucoviscidose par rapport aux cas de diagnostic incertain de 6,3:1, ainsi qu’une strategie efficace pour reperer les faux negatifs. Une nouvelle organisation du DNN francais vient de se mettre en place, il est capital de maintenir l’efficacite du processus, du nouveau-ne en maternite jusqu’au diagnostic dans des centres de reference ou de competences de la mucoviscidose avec un recueil exhaustif des donnees et leur validation. Par ailleurs, une proposition de changement d’algorithme introduisant le dosage du polypeptide d’activation pancreatique est soumise aux nouvelles instances du DNN. L’annonce d’un diagnostic positif reste difficile et peu standardisee, si bien qu’une plateforme de simulation est en cours de mise en place. Nous detaillons ici les bonnes pratiques et les difficultes de realisation du test de la sueur, avec les seuils de chlorures recemment redefinis, ainsi que les modalites du conseil genetique.

Antibiotic eradication treatment is the standard-of-care for cystic fibrosis (CF) patients with early Pseudomonas aeruginosa (Pa)-infection; however, evidence from placebo-controlled trials is limited.This double-blind, placebo-controlled trial randomised CF patients7 years (N = 51) with early Pa-infection to tobramycin inhalation solution (TOBI 300 mg) or placebo (twice daily) for 28 days with an optional cross-over on Day 35. Primary endpoint was proportion of patients having throat swabs/sputum free of Pa on Day 29.On Day 29, 84.6% patients in the TOBI versus 24.0% in the placebo group were Pa-free (p 0.001). At the end of the cross-over period, 76.0% patients receiving TOBI in the initial 28 days were Pa-free compared to 47.8% receiving placebo initially. Adverse events were consistent with the TOBI safety profile with no differences between TOBI and placebo.TOBI was effective in eradicating early Pa-infection with a favourable safety profile in young CF patients.NCT01082367.

International audience; Background: Phase 3 trials have demonstrated the safety and efficacy of lumacaftor-ivacaftor (LUMA-IVA) in patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation and percent predicted forced expiratory volume in 1 s (ppFEV1) between 40 and 90. Marketing authorizations have been granted for patients at all levels of ppFEV1.Methods: To evaluate the safety and effectiveness of LUMA-IVA over the first year of treatment in patients with ppFEV1

International audience; Background: Major issues of newborn screening (NBS) for CF are the assessment of disease liability of variants and of the penetrance of clinical CF, notably in inconclusive diagnosis. The penetrance of CF is defined as the risk of a particular genotype to lead to a CF phenotype.Methods: We aimed to get insight into the penetrance of CF for fifteen CFTR variants: 5 frequent CF-causing and 10 classified as of varying clinical consequence (VCC) or associated with a CFTR-related disorder (CFTR-RD) in CFTR2 or CFTR-France databases. The penetrance was approached by: (1) comparison of variant allelic frequencies in CF patients (CFTR2) and in the general population; (2) estimation of the likelihood of a positive NBS test for the 14 compound heterozygous with F508del and the F508del homozygous genotypes, defined as the ratio of detected/expected number of neonates with a given genotype in the 2002-2017 period.Results: A full penetrance was observed for severe CF-causing variants. Five variants were more frequently found in the general population than in CF patients: TG11T5, TG12T5, TG13T5, L997F and R117H;T7. The likelihood of a positive NBS test was 0.03% for TG11T5, 0.3% for TG12T5, 1.9% for TG13T5, 0.6% for L997F, 11.7% for D1152H, and 17.8% for R117H;T7. Penetrance varied greatly for variants with discrepant classification between CFTR2 and CFTR-France: 5.1% for R117C, 12.3% for T338I, 43.5% for D110H and 52.6% for L206W.Conclusion: These results illustrate the contribution of genetics population data to assess the disease liability of variants for diagnosis and genetic counselling purposes.

Summary Background As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs. Methods We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy. Eligible patients had cystic fibrosis, were older than 10 years, and had newly diagnosed diabetes. We used a central randomisation schedule derived from a Geigy random number table to assign patients 1:1 to receive insulin or repaglinide, stratified by sex and age (10–15 years or >15 years). The primary outcome was glycaemic control assessed by mean change in HbA 1c concentration from baseline after 24 months of treatment. Differences between groups were assessed by linear models. The primary and safety analyses were done in the modified intention-to-treat population (including patients who stopped treatment early because of lack of efficacy). This trial is registered with ClinicalTrials.gov, number NCT00662714. Findings We enrolled 34 patients in the repaglinide group and 41 in the insulin group, of whom 30 and 37, respectively, were included in the analyses. At 24 months, glycaemic control was similar in the repaglinide and insulin groups (mean change in HbA 1c concentration from baseline 0·2% [SD 0·7%], 1·7 mmol/mol [8·1 mmol/mol] with repaglinide vs −0·2% [1·3%], −2·7 mmol/mol, [14·5 mmol/mol] with insulin; mean difference between groups −0·4%, (95% CI −1·1 to 0·2 [−4·4 mmol/mol, −11·5 to 2·7], p=0·15). The most frequent adverse events were pulmonary events (43 [40%] of 107 in the repaglinide group and 60 [45%] of 133 in the insulin group), and the most frequent serious adverse events were pulmonary events leading to hospital admission (five [50%] of ten and seven [54%] of 13, respectively). Interpretation Repaglinide for glycaemic control in patients with cystic-fibrosis-related diabetes is as efficacious and safe as insulin. Funding Mukoviszidose eV, Vaincre la Mucoviscidose, ABCF Association, and Novo Nordisk.

Background Newborn screening (NBS) for cystic fibrosis (CF) is a well-established public health strategy with international standards. The aim of this study was to provide an update on NBS for CF in Europe and assess performance against the standards. Methods Questionnaires were sent to key workers in each European country. Results In 2016, there were 17 national programmes, 4 countries with regional programmes and 25 countries not screening in Europe. All national programmes employed different protocols, with IRT-DNA the most common strategy. Five countries were not using DNA analysis. In addition, the processing and structure of programmes varied considerably. Most programmes were achieving the ECFS standards with respect to timeliness, but were less successful with respect to sensitivity and specificity. Conclusions There has been a steady increase in national CF NBS programmes across Europe with variable strategies and outcomes that reflect the different approaches.

Resume Les tumeurs desmoides (TD) sont des tumeurs rares, infiltrant les tissus, denuees de potentiel metastatique. Elles sont le plus souvent sporadiques et dans 5 a 10 % des cas associees aux polyposes adenomateuses familiales (PAF). Elles apparaissent habituellement chez l’adulte jeune, plus rarement chez l’enfant. Nous rapportons le cas d’une adolescente de 14 ans qui avait subi une procto-colectomie totale en raison d’une PAF avec mutation de novo du gene APC, habituellement non associee aux TD. Trois ans plus tard, elle a presente des douleurs a la defecation. Le scanner a mis en evidence 2 TD intra-abdominales. Une exerese chirurgicale ayant ete ecartee en raison du risque de resection etendue du grele, un traitement par anti-estrogene et anti-inflammatoire non steroidien a ete instaure. Le scanner realise a 18 mois a montre une stabilisation des TD, mais l’adolescente gardait des douleurs chroniques difficiles a controler. Une surveillance radiologique reguliere a ete effectuee. Cette observation rappelle l’importance d’un depistage regulier des TD chez les sujets atteints de PAF, notamment apres une chirurgie, et ce quel que soit l’âge et le type de mutation. Des progres restent a faire pour determiner les facteurs de risque d’apparition d’une TD chez ces sujets et pour les traiter efficacement. La prise en charge therapeutique actuelle reste difficile du fait du caractere infiltrant et recidivant de ces tumeurs et necessite un avis pluridisciplinaire.

International audience; Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting.Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations.Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

This report contains information on five selected locations that may be utilized for industrial collection of drinking water, and provides the technical background for the second licensing round of the Greenland Government in its Strategy for Export of Ice and Water. This report is not aimed at addressing any technical or engineering questions posed by the locations or water treatment, but only concerns the natural environment and the quality of the water as it was sampled. A prerequisite in the investigation has been that the water should be at least partly derived from meltwater originating either from the Greenland Ice Sheet or from local glaciers and ice caps. The identification and selection process for locations was de-scribed in detail in Ahlstrøm et al. (2018) and updated in Kjeldsen et al. (2019). Locations are defined as outlets of a significant meltwater river to accessible fjords in the southwestern part of Greenland, to minimize potential sea ice and iceberg interference. Catchments for each location or river outlet were derived employing advanced hydrological methods, using the most recent elevation models available.The five selected locations represent different catchment sizes with varying amounts of discharge, ranging from roughly 290,000 million litres per year, down to slightly over 10,000 million litres per year. The rivers at all locations are, on average, discharging water from May to November with the vast majority of water discharging in the period June-September. A comparison between modelled discharge for the catchments for the two periods 1980-1991 and 2006-2017, showed an increase in the discharge at all sites except one, which was stable. A similar method was also used to examine the change in discharge over the last few decades, showing a promising overall melt increase of more than 50 % for the region.The five selected locations were visited by boat to sample the water and collect additional data. The field visits were conducted in June and September in either 2018 or 2019, to capture the seasonal variability in the water quality. Two locations drain ice sheet catch-ments and three locations drain catchments with local mountain glaciers and ice caps.An extensive analysis of chemical, physical and microbiological parameters was performed on the water samples. Some types of analyses had to be performed on-site, some were performed at GEUS laboratories, and some at certified commercial laboratories.All of the locations provide large amounts of meltwater during the summer from June-September, with river outlets being relatively near deep fjord waters. The meltwater con-tains varying amounts of sediment derived from glacier erosion of the bedrock, requiring filtration of the meltwater before use. For all five locations, inorganic parameters are below drinking water requirements and guidelines in filtered water samples. Gentle UV-treatment of the water is recommended, as is commonly required for surface water, as microbiological parameters generally exceed the guideline limits at all locations.While the water quality can be expected to vary over the season, the results provide a strong indication of the potential for export of drinking water from meltwater rivers in Greenland.

Resume Introduction Le traitement de la mucoviscidose est reste longtemps symptomatique. Des therapeutiques ciblant la proteine CFTR defectueuse commencent a etre disponibles. Etat des connaissances Les resultats de la therapie genique restent modestes mais une etude clinique recente montre un benefice sur le VEMS. Les avancees concernent surtout les therapies ciblant la proteine CFTR. Une amelioration respiratoire importante (gain de VEMS d’environ 10 % et baisse des exacerbations respiratoires) a ete obtenue sous ivacaftor, potentiateur de CFTR, chez les patients porteurs de mutations gating, aboutissant a l’obtention d’une Autorisation de mise sur le marche (en 2012 pour la mutation G551D et en 2015 pour des mutations plus rares). Chez les patients homozygotes phe508del, l’association de l’ivacaftor a un correcteur de CFTR (lumacaftor) permet une amelioration respiratoire plus modeste. L’efficacite de l’ataluren chez des patients porteurs de mutations non-sens est en cours d’evaluation. Perspectives De nouveaux correcteurs et potentiateurs de CFTR sont en developpement. Ils pourraient changer le cours de la maladie mais les enjeux medicoeconomiques ne doivent pas etre sous-estimes. Conclusion L’ivacaftor peut etre prescrit chez les patients porteurs d’une mutation de classe 3 a partir de l’âge de 6 ans. Prochainement, l’Orkambi® sera disponible pour les patients homozygotes phe508del a partir de 12 ans.

Streszczenie Specjalistyczna opieka nad chorymi na mukowiscydoze doprowadzila do znaczącej poprawy przezycia: w ciągu ostatnich czterech dekad bylo ono istotnie wyzsze niz wśrod ogolnej populacji pacjentow w analogicznym wcześniejszym okresie. Wprowadzenie badan przesiewowych noworodkow w wielu krajach Europy sprawilo, ze w coraz wiekszej liczbie ośrodkow prowadzeni są pacjenci z minimalnymi zmianami plucnymi w momencie rozpoznania, ktorzy w efekcie mogą potencjalnie cieszyc sie doskonalą jakością zycia i wyzszą średnią dlugością zycia niz w przeszlości. W celu zapewnienia wysokiej jakości opieki medycznej w Europie, w 2005 roku opublikowano przelomową prace ustanawiającą standardy opieki. Niniejszy artykul opiera sie na tamtym dokumencie, wyznaczając standardy dotyczące najlepszych praktyk dla kluczowych aspektow leczenia mukowiscydozy. Celem naszej pracy jest zapewnienie szerokiego przeglądu standardow dotyczących badan przesiewowych, diagnostyki, leczenia ograniczajacego chorobe pluc, zywienia, leczenia powiklan, przeszczepienia, opieki u schylku zycia i wsparcia psychologicznego. W tabeli I umieszczono odniesienia do najnowszego konsensusu europejskiego, wytycznych i innych dokumentow zawierających kompleksowe informacje dotyczące opieki medycznej w mukowiscydozie. Mamy nadzieje, ze niniejszy dokument opisujący najlepsze praktyki bedzie uzytecznym narzedziem dla zespolow klinicznych zarowno w krajach, w ktorych opieka nad pacjentami z mukowiscydozą jest dopiero rozwijana, jak i tych, w ktorych istnieją juz specjalistyczne ośrodki.

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gating mutation G551D prevents sufficient ion transport due to reduced channel-open probability. Ivacaftor, an oral CFTR potentiator, increases the channel-open probability.To further analyze improvements in weight and body mass index (BMI) in two studies of ivacaftor in patients aged a parts per thousand yen6 years with CF and the G551D mutation.Patients were randomized 1:1 to ivacaftor 150 mg or placebo every 12 h for 48 weeks. Primary end point (lung function) was reported previously. Other outcomes included weight and height measurements and CF Questionnaire-Revised (CFQ-R).Studies included 213 patients (aged a parts per thousand currency sign 20 years, n = 105; aged > 20 years, n = 108). In patients a parts per thousand currency sign20 years, adjusted mean change from baseline to week 48 in body weight was 4.9 versus 2.2 kg (ivacaftor vs. placebo, p = 0.0008). At week 48, change from baseline in mean weight-for-age z-score was 0.29 versus -0.06 (p 20 years, adjusted mean change from baseline to week 48 in body weight was 2.7 versus -0.2 kg (p = 0.0003). Mean BMI change at week 48 was 0.9 versus -0.1 kg/m(2) (p = 0.0003). There was no linear correlation evident between changes in body weight and improvements in lung function or sweat chloride. Significant CFQ-R improvements were seen in perception of eating, body image, and sense of ability to gain weight.Nutritional status improved following treatment with ivacaftor for 48 weeks.

To evaluate nutritional status and associated factors in a cystic fibrosis (CF) cohort diagnosed by newborn screening and followed up to month 24.A prospective longitudinal multicenter study assessing nutritional status according to pancreatic status, feeding modalities, prescriptions, pulmonary outcome, and biological nutritional parameters.One hundred and five infants were recruited and 99 completed the study. Nutritional care management prevented undernutrition and stunting in those with exocrine pancreatic sufficiency (EPS), but affected (13/87) 15% and (21/86) 24%, respectively, of infants with exocrine pancreatic insufficiency (EPI). The logistic regression model found a positive association between both weight and length z scores "at risk" at month 24, and initial pulmonary symptoms (odds ratio [OR] 0.06, P 0.01 and OR 0.08, P 0.01, respectively); these symptoms were less frequent when age at first visit was earlier than 1.2 months (33% vs 67%, P = 0.02); stunting was also associated with high-calorie density intake and Staphylococcus aureus (OR 0.05, P = 0.01 and OR 0.17, P 0.01). Pulmonary outcome did not differ according to pancreatic status; breast-feeding for at least 3 months delayed first acquisition of Pseudomonas aeruginosa. Despite sodium and fat-soluble vitamin supplementation, half of both cohorts had low urinary sodium output and half of the EPI cohort had low vitamin D levels.Our data shed light on the fact that stunting was more frequent than undernutrition, while both parameters involved only patients with pancreatic insufficiency. Modalities of feeding were not associated with nutritional status; breast-feeding may provide some protection against acquisition of P aeruginosa.

Developments in managing CF continue to drive dramatic improvements in survival. As newborn screening rolls-out across Europe, CF centres are increasingly caring for cohorts of patients who have minimal lung disease on diagnosis. With the introduction of mutation-specific therapies and the prospect of truly personalised medicine, patients have the potential to enjoy good quality of life in adulthood with ever-increasing life expectancy. The landmark Standards of Care published in 2005 set out what high quality CF care is and how it can be delivered throughout Europe. This underwent a fundamental re-write in 2014, resulting in three documents; center framework, quality management and best practice guidelines. This document is a revision of the latter, updating standards for best practice in key aspects of CF care, in the context of a fast-moving and dynamic field. In continuing to give a broad overview of the standards expected for newborn screening, diagnosis, preventative treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support, this consensus on best practice is expected to prove useful to clinical teams both in countries where CF care is developing and those with established CF centres. The document is an ECFS product and endorsed by the CF Network in ERN LUNG and CF Europe.

Meltwater from Greenland is an increasingly attractive resource of pure freshwater. To at-tract investments from the industry, an extensive effort has been launched to map possible extraction locations, determine the quality of the meltwater, and review the existing ice and water export legislation. This report presents results from mapping- and water quality anal-ysis of five selected locations, visited by boat in June 2017. Two locations drain ice sheet catchments and three locations drain catchments with local mountain glaciers.The mapping includes catchment delineation, ice- and land runoff modelling, ice-dynamic modelling of the age of the melting ice, collection of fjord depth data and an assessment of the risk from glacial lake outburst floods. An extensive analysis of chemical, physical and microbiological parameters were performed on the water samples collected during field-work. Some types of analysis had to be performed on-site, some were performed at GEUS laboratories, and some at certified commercial laboratories.Greenland has a diverse geology including areas with potential for mining of metals and radioactive isotopes. The existence of such areas could influence the water quality in melt-water rivers. The 2017 survey, however, showed excellent water quality at all locations with regards to inorganics like metal ions and radioisotopes. Toxic metals like arsenic, cadmium and nickel were well below the lowest criterion at all locations and so was fluoride, which may be an indicator for a number of toxic metals in Southern Greenland. Radioactivity was below the detection limit of the commercial laboratory at all locations. The seasonal varia-tion of metals and radioisotopes is not yet known, but so far the locations look promising with regards to these quality parameters.Biology is another factor that may influence water quality of meltwater rivers. Of most con-cern are cyanobacteria in lakes and rivers and bacteria from the gut of animals. Cyanobac-teria produce toxins like microcystins and Anatoxin-A. These compounds were not detected at any of the locations. Coliforms and enterococci were chosen as indicator bacteria. Coli-forms were not found at any location. Enterococcaceae were detected only at one location (2 per 5 mL). Total colony forming units (CFU) at 22 and 36°C were also analysed. While some CFU were found at 22°C (7-115 per mL) almost none were found at 36°C (0-2 per mL), which is a good safety indication. The bacterial parameters generally indicated good water quality, but some sort of simple disinfection should be considered, as is the case for all surface water for human consumption.In summary, the results indicate an excellent water quality at all five locations, with all pa-rameter values below the required drinking water standards for the European Union, the United States and The International Council of Bottled Water Associations (ICBWA) .

Introduction L’efficacite de l’ivacaftor, un modulateur de la proteine CFTR, chez les patients atteints de mucoviscidose (MV) a ete demontree dans des essais randomises controles de phase 3. L’etude BRIO est une etude observationnelle evaluant l’efficacite de l’ivacaftor chez des patients atteints de MV et porteurs de mutations repondant a l’ivacaftor, en France. Cette analyse decrit l’impact de l’ivacaftor sur l’utilisation des ressources en sante (URS) chez des patients de plus de 6 ans. Methodes L’etude BRIO est une etude observationnelle et multicentrique en cours dans 33 centres. Les patients atteints de MV, deja traites ou nouvellement traites par ivacaftor sont eligibles. Les donnees des patients sont recueillies de maniere prospective au cours des deux ans suivant l’inclusion et de maniere retrospective au cours des 12 mois precedant le debut de l’ivacaftor et jusqu’a leur inclusion dans l’etude. L’analyse decrit l’URS : les hospitalisations, toutes causes confondues, et l’utilisation d’antibiotiques (voie orale/IV/inhalee) pour exacerbation respiratoire (ER) dans les 12 mois pre- et post-debut de l’ivacaftor. L’analyse statistique a utilise un modele binomial negatif ajuste selon la duree dans l’etude sur les 12 mois (reference : date de debut de l’ivacaftor). Resultats Sur 107 patients inclus, 100 ont recu au moins 12 mois de traitement par ivacaftor. A l’inclusion, l’âge moyen (ecart-type) etait de 21,1 (14,3) ans et 56 % des patients etaient de sexe masculin. Le taux d’hospitalisation, toutes causes confondues, par patients-annees (PA) a significativement diminue dans les 12 mois post- par rapport aux 12 mois pre-debut de l’ivacaftor (rapport des taux : 0,40 ; intervalle de confiance [IC] a 95 % : 0,26–0,61). Le nombre de jours d’hospitalisation par PA a diminue de 5,3 jours avant l’ivacaftor a 2,5 jours apres le debut de l’ivacaftor (rapport des taux : 0,46 ; IC 95 % : 0,22–0,95). Le nombre de traitements antibiotiques par PA pour les ER a baisse dans les 12 mois post- par rapport aux 12 mois pre-ivacaftor (rapport des taux : 0,47 ; IC 95 % : 0,32–0,68). Le nombre de jours de traitements d’antibiotiques en PA a baisse de 20,9 jours a 11,4 jours pre-/post-ivacaftor (rapport des taux : 0,54 ; IC 95 % : 0,40–0,72). Conclusion Le traitement des patients atteints de MV par l’ivacaftor en vie reelle en France a entraine une reduction de l’URS : diminution des hospitalisations toutes causes confondues et des traitements antibiotiques pour ER. Promoteur : Vertex Pharmaceuticals Incorporated.

Summary Introduction The gastrointestinal tract is a major source of morbidity in adults with cystic fibrosis (CF), with a wide range of complications, some of them being specific to the underlying disease. State of knowledge Abnormal CFTR function, with reduced bicarbonate and other ion transport levels through the apical surface of epithelial cells, affects the intestinal tract including the pancreas and the liver. Similarly to what is observed in the respiratory tract, gastrointestinal CFTR dysfunction leads to mucus accumulation, dysmotility, small bowel bacterial overgrowth and inflammation with alteration of innate immune responses, all of which being likely to be interrelated. In developed countries, almost half of patients with CF are adults followed in multidisciplinary CF care centres by pneumologists who often have to manage gastrointestinal complications. Conclusion It therefore appears essential that adult gastroenterologists develop the expertise needed for managing CF gastrointestinal complications in close collaboration with multidisciplinary CF care centre teams to improve the quality of life of adults with CF.

Summary Clinical studies in patients with cystic fibrosis and G551D-CFTR showed that the group treated with ivacaftor had improved clinical outcomes. To better understand the effect of ivacaftor therapy across the distribution of individual FEV1 responses, data from Phase 3 studies (STRIVE/ENVISION) were re-examined. In this post-hoc analysis of patients (n = 209) who received 48 weeks of ivacaftor or placebo, patients were assigned to tertiles according to FEV1 response. These groups were then used to evaluate response (FEV1, sweat chloride, weight, CFQ-R, and pulmonary exacerbation). The number needed to treat (NNT) was calculated for specific thresholds for each outcome. Across all tertiles, numerical improvements in FEV1, sweat chloride, CFQ-R and the frequency of pulmonary exacerbations were observed in ivacaftor-treated patients: the treatment difference versus placebo was statistically significant for all outcomes in the upper tertile and for some outcomes in the lower and middle tertiles. The NNT for a ≥ 5% improvement in %predicted FEV1 was 1.90, for a ≥ 5% body weight increase was 5.74, and to prevent a pulmonary exacerbation was 3.85. This analysis suggests that the majority of patients with clinical characteristics similar to STRIVE/ENVISION patients have the potential to benefit from ivacaftor therapy. Pediatr Pulmonol. 2015; 50:447–455. © 2015 Wiley Periodicals, Inc.

Background and Aims Catheter venous thrombosis may result in life-threatening embolic complications. Recently, a thrombophilic tendency was described in cystic fibrosis (CF), the significance of which remains unclear. The aims of this study were to (1) document the frequency of catheter venous thrombosis detected by colour-Doppler-ultrasound (Doppler-US), (2) assess genetic and acquired thrombophilia risk factors for catheter venous thrombosis and hypercoagulability status and (3) provide recommendations on laboratory screening when considering insertion of a totally implantable vascular access device (TIVAD) in CF patients. Methods We designed a multicentre prospective study in patients selected at the time of catheter insertion. Doppler-US was scheduled at 1 and 6months after insertion and before insertion in case of a previous central line. Blood samplings were drawn at insertion and at 1 and 6months later. Results One-hundred patients received a TIVAD and 90 completed the 6-month study. Prevalence of thrombophilia abnormalities and hypercoagulability was found in 50% of the cohorts. Conversely, catheter venous thrombosis frequency was low (6.6%). Conclusion Our data do not support biological screening at the time of a TIVAD insertion. We emphasise the contribution of a medical history of venous thromboembolism and prospective Doppler-US for identifying asymptomatic catheter venous thrombosis to select patients who may benefit from biological screening and possible anticoagulant therapy.

Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, is approved for the treatment of patients with cystic fibrosis aged 6 years or older with Gly551Asp-CFTR. We assessed the safety and efficacy of ivacaftor during 96 weeks of PERSIST in patients with cystic fibrosis who completed a previous 48-week, placebo-controlled trial of the drug (STRIVE or ENVISION).In this phase 3, open-label extension study, patients received ivacaftor 150 mg every 12 h in addition to their prescribed cystic fibrosis therapies. Patients who received placebo in their previous study initiated ivacaftor in this extension study. Patients were eligible if they had a Gly551Asp-CFTR mutation on at least one allele. The primary objective was to assess the long-term safety profile of ivacaftor as assessed by adverse events, clinical laboratory assessments, electrocardiograms, vital signs, and physical examination; secondary measures included change in forced expiratory volume in one second (FEV1), weight, and pulmonary exacerbations. This study is registered with ClinicalTrials.gov, number NCT01117012 and EudraCT, number 2009-012997-11.Between July 8, 2010, and April 8, 2013, 144 adolescents/adults (≥12 years) from STRIVE and 48 children (6-11 years) from ENVISION were enrolled. Across both trials, 38 (20%) patients had a serious adverse event during the first 48 weeks and 44 (23%) during the subsequent 48 weeks. Two adults (1%) and one child (1%) discontinued because of adverse events. The most common adverse events were pulmonary exacerbation, cough, and upper respiratory tract infection. Patients previously treated with ivacaftor had sustained improvements in FEV1, weight, and rate of pulmonary exacerbations for up to 144 weeks of treatment. Among adolescents/adults and children who previously received ivacaftor, absolute change in FEV1 at week 96 (144 weeks ivacaftor) was 9·4 and 10·3 % points and absolute increase in weight was 4·1 kg and 14·8 kg, respectively. For adolescents/adults only, the pulmonary exacerbation rate remained suppressed compared with that of patients who received placebo in the placebo-controlled study.At 144 weeks of treatment, ivacaftor was well tolerated, with no new safety concerns. Ivacaftor also provided durable effects for 144 weeks in patients who had received active treatment in the placebo-controlled study. Those patients who previously received placebo had improvements comparable to those of patients treated with ivacaftor in the placebo-controlled study.Vertex Pharmaceuticals Inc.

Objectives To evaluate the French cystic fibrosis newborn screening algorithm, based on data tracked by a centralized monitoring process, from 2002 to 2014. The programme aimed to attain European Standards in terms of positive predictive value, sensitivity, the ratio of screen positive patients diagnosed with cystic fibrosis to infants who screen positive but with inconclusive diagnosis (CFSPID), and time to diagnosis. Methods Retrospective analysis of programme performance, compliance with the algorithm, and changes in screening strategy. Results Modifications in the flow chart protocol improved the positive predictive value to 0.31 while maintaining the sensitivity at 0.95. Among infants diagnosed with cystic fibrosis, or identified as CFSPID, sweat test results were obtained for 94%, and two mutations were identified after exhaustive screening for the gene, when applicable, in 99.6%. The rate of pending diagnosis was very low (0.5%). The ratio of infants with cystic fibrosis:CFSPID was 6.3:1. Age at initial visit at the CF centre was ≤ 35 days, respectively, in 53%/26%. Conclusion Performances were in agreement with European standards, but timeliness of initial visit needed improvement. Our data complement an accumulating body of evidence demonstrating that attention must be paid to such ethical considerations as limiting carrier detection and inconclusive diagnosis. Newborn screening programmes should have a rigorous centralized monitoring process to warrant adjustments for improving performance to attain consensus guidelines.

Background Ivacaftor has been shown to improve lung function and body weight in patients with CF and a gating mutation. Real-world evaluation is warranted to examine its safety and effectiveness over the long term. Methods A retrospective observational multicentre study collected clinical data in the year before and the 2years after ivacaftor initiation in patients with CF and a Gly551Asp- CFTR mutation. Results Fifty-seven patients were included. Mean absolute change in FEV 1 % predicted improved from baseline to Year 1 (8.4%; p Pseudomonas aeruginosa and Staphylococcus aureus positive cultures, and decreased IV antibiotics and maintenance treatment prescriptions (including azithromycin, Dornase alpha and nutritional supplements). No significant adverse events were reported. Conclusion The clinical benefits of ivacaftor reported in previous clinical trials were confirmed in a real-world setting two years post-initiation, also reducing treatment burden.