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(1) Background: We have previously shown that sputum rheology can discriminate between patients with COPD and other muco-obstructive lung diseases, and that it is correlated with mucin content and sputum eosinophilia. We now hypothesize that it could be a more-accurate guide than clinical evaluation for the prescription of azithromycin to prevent exacerbations of COPD and to reduce exposure to antibiotics; (2) Methods: “COPD CaRhe” is a multicentric, randomized, controlled trial comparing outcomes in two parallel arms (36 vs. 36 patients). Patients will be recruited in the university hospitals of Montpellier, Bordeaux, and Toulouse, in France, and they should have a diagnosis of COPD with frequent exacerbations (≥3/year). Enrollment will occur during a routine visit to a respiratory department, and follow-up visits will occur every 3 months for a period of 1 year. At each visit, a 3-month prescription of azithromycin will be provided to those patients who obtain a score of 39 on a rheological assessment of sputum, depending upon their randomization group. The primary outcome will be the number of exacerbations of COPD; (3) Discussion: By using sputum rheology, the COPD CaRhe study may provide clinicians with an objective biomarker to guide the prescription of azithromycin while reducing the cumulative exposure to macrolides.

Additional file 1: Figs. S1-S11. Supplementary Figure S1. Transduction of the HY03 hiPSC line with LF-ZsGreen particles allows transient ZsGreen expression and does not affect pluripotency. Supplementary Figure S2. LF-ZsGreen particles allow the highly efficient delivery of RNA in different hiPSC lines. Supplementary Figure S3. Characterization of the HY03-GFP non-clonal reporter hiPSC line. Supplementary Figure S4. NGS analysis of DNAH5 indel size distribution. Supplementary Figure S5. LentiFlash�� particle-based transduction of the CRISPR/Cas9 system to target the GFP fluorescent reporter sequence in a HCT116-GFP cell line that contains one GFP copy per cell. Supplementary Figure S6. Characterization of hiPSC clones in which DNAH5 or MCIDAS was knocked out by CRISPR/Cas9 gene editing using the LentiFlash�� system. Supplementary Figure S7. LentiFlash�� particle-based transduction of the CRISPR/Cas9 components to target specific genes results in high indel formation in different hiPSC lines. Supplementary Figure S8. Interallelic gene conversion following iPSC electroporation and following LentiFlash�� transduction of neural progenitors obtained from the PCD_02:30 hiPSC line results. Supplementary Figure S9. Characterization of hiPSC clonal lines harboring DNAH5 heterozygous mutations. Supplementary Figure S10. Specifically targeting the wild-type allele in hiPSC clones harboring a DNAH5 heterozygous mutation results in interallelic gene conversion. Supplementary Figure S11. Schematic representation of the expression cassettes carried by the plasmids used to produce the integrative lentiviral vector (ILV) that expresses the GFP reporter and of the expression cassettes carried by the plasmids used to produce non-integrative lentiviral particles (LentiFlash��) that express the ZsGreen reporter or the CRISPR/Cas9 systems. Supplementary Tables S1-3. Supplementary Table S1. sgRNA sequences. Supplementary Table S2. PCR primers. Supplementary Table S3. antibodies

Additional file 2: Supplemental Digital Content – Table 2. Definition of ICD-10 Codes.

Additional file 3: Supplemental Digital Content – Table 3. PDs of patients in the groups derived from propensity scoring.

Additional file 4: Supplemental Digital Content – Table 4. PDs of deceased patients in the propensity score groups.

Additional file 1: Supplemental Digital Content – Table 1. Definition of hospital stays in resuscitation / ICUs for COPD exacerbation based on ICD-10 codes.

As burden of chronic respiratory diseases is constantly increasing, improving in vitro lung models is essential in order to reproduce as closely as possible the complex pulmonary architecture, responsible for oxygen uptake and carbon dioxide clearance. The study of diseases that affect the respiratory system has benefited from in vitro reconstructions of the respiratory epithelium with inserts in air/liquid interface (2D) or in organoids able to mimic up to the arborescence of the respiratory tree (3D). Recent development in the fields of pluripotent stem cells-derived organoids and genome editing technologies has provided new insights to better understand pulmonary diseases and to find new therapeutic perspectives.Les organoïdes pulmonaires.L’impact en santé publique des pathologies respiratoires chroniques ne cesse de croître. Dans ce contexte, il paraît indispensable d’améliorer les modèles d’études du poumon afin de reproduire au plus proche l’architecture pulmonaire complexe, garante des fonctions d’oxygénation et d’épuration du gaz carbonique. Les connaissances actuelles en physiopathologie respiratoire résultent en partie des études de modèles de reconstitution d’épithélium bronchique in vitro à partir de cellules primaires, en deux dimensions sur des inserts, ou en trois dimensions, en organoïdes mimant jusqu’à l’arborescence pulmonaire. Le développement de ces modèles in vitro a connu un nouvel essor grâce aux organoïdes pulmonaires issus de cellules souches pluripotentes et la démocratisation des outils d’édition du génome. Ces apports technologiques récents offrent de nouvelles perspectives en matière de thérapeutiques ou de compréhension physiopathologique et pourraient, dans le futur, ouvrir les portes de la médecine régénératrice pulmonaire.

Primary Ciliary Dyskinesia (PCD) is a rare heterogeneous genetic disorder affecting motile cilia structure and function leading to lung disease. We generated induced pluripotent stem cells (iPSCs) from dermal fibroblasts of a female PCD patient carrying disease-causing variants in the CCDC40 gene. Reprogramming was performed with the human OSKM transcription factors using the Sendai-virus delivery system. The resulting transgene free iPSCs had normal karyotype, expressed pluripotency markers, could differentiate into the three germ layers in vivo and retained the disease-causing CCDC40 mutations. This iPSC line could be useful to model PCD disease and test gene therapy strategies.Resource TableUnlabelled TableUnique stem cell line identifierUHOMi001-AAlternative name(s) of stem cell lineiPCD02.30InstitutionInstitute for Regenerative Medicine & Biotherapy (IRMB), Montpellier, FRANCEContact information of distributorJohn De Vos john.devos@inserm.frType of cell lineiPSCOriginhumanAdditional origin infoAge: 34Sex: FemaleCell SourceDermal fibroblastsClonalityClonalMethod of reprogramminghOCT4, hSOX2, hC-MYC, hKLF4 (CytoTune™-iPS 2.0 Sendai Reprogramming Kit - Invitrogen, Thermo Fisher Scientific Inc.)Genetic ModificationYESType of ModificationSpontaneous mutationAssociated diseasePrimary Ciliary DyskinesiaGene/locusCompound Heterozygous mutations the Coiled-Coil Domain Containing 40 Gene (CCDC40): c.1116_1117delCT (Exon 7) and c.3180 + 1G > A (Intron 19)Method of modificationN/AName of transgene or resistanceN/AInducible/constitutive systemN/ADate archived/stock date2018-02-12Cell line repository/bankN/AEthical approvalThe study was approved by the regional scientific ethical committee (CPP Sud Med IV) under the number ID-RCB: 2013-A00892–43/CILIPS, Promoter University Hospital Of Montpellier) and informed consent was obtained from the patient.

Background To examine trends in mortality, costs and in-hospital management and outcomes of severe COPD exacerbations admitted in France. Methods Patients hospitalized from 2007 to 2012 with COPD exacerbation as the primary diagnosis were identified from the exhaustive French medico-administrative hospitalizations database records. Four groups of severe COPD exacerbations were defined: hospitalisation in a general ward (GW) without acute respiratory failure (ARF), GW with ARF, ICU without invasive mechanical ventilation (MV), and ICU with MV. Results A 15.48 % increase in admissions from 113 276 in 2007 to 133 497 in 2012 was recorded. Age (+9.9 months), gender (−2.5 % of male) and length of stay (−0.29 day) slightly changed while the number of ICU admissions increased markedly (+41.78 %). In-hospital mortality rates increased (+8.06 %, p