BACKGROUND-Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508delminimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.METHODS-We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV 1 ) at week 4.

To understand the pathogenesis of chronic inflammatory disease, we analyzed an experimental mouse model of a chronic lung disease that resembles asthma and chronic obstructive pulmonary disease (COPD) in humans. In this model, chronic lung disease develops after infection with a common type of respiratory virus is cleared to trace levels of noninfectious virus. Unexpectedly, the chronic inflammatory disease arises independently of an adaptive immune response and is driven by IL-13 produced by macrophages stimulated by CD1d-dependent TCR-invariant NKT cells. This innate immune axis is also activated in the lungs of humans with chronic airway disease due to asthma or COPD. These findings provide new insight into the pathogenesis of chronic inflammatory disease with the discovery that the transition from respiratory viral infection into chronic lung disease requires persistent activation of a novel NKT cell-macrophage innate immune axis. It has been widely speculated that infections are linked to the development of chronic inflammatory diseases. Although the connection between infection and chronic disease is uncertain, it likely depends on an aberrant immune response. In particular, it is believed that the innate immune system mediates the acute response to an infectious agent 1 , while an atypical adaptive immune response may cause chronic inflammation 2. Furthermore, infectioninduced alterations in the adaptive immune response that produce T cell or antibody-mediated

The panel formulated and provided a rationale for the direction as well as for the strength of each recommendation to establish the diagnosis of PCD.

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Cystic Fibrosis (CF) exhibits morbidity in several organs, including progressive lung disease in all patients and intestinal obstruction at birth (meconium ileus) in ~15%. Individuals with the same causal CFTR mutations show variable disease presentation which is partly attributed to modifier genes. With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10 -10 ); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on chromosome 1, (min p<2.2x10 -16 , 2.81x10 −11 , respectively); and replicated a suggestive locus on chromosome 7 near PRSS1 (min p = 2.55x10 -7 ). PRSS1 is exclusively expressed in the exocrine pancreas and was previously associated with non-CF pancreatitis with functional characterization demonstrating impact on PRSS1 gene expression. We thus asked whether the other meconium ileus modifier loci impact gene expression and in which organ. We developed and applied a colocalization framework called the Simple Sum (SS) that integrates regulatory and genetic association information, and also contrasts colocalization evidence across tissues or genes. The associated modifier loci colocalized with expression quantitative trait loci (eQTLs) for ATP12A (p = 3.35x10 -8 ), SLC6A14 (p = 1.12x10 -10 ) and SLC26A9 (p = 4.48x10 -5 ) in the pancreas, even though meconium ileus manifests in the intestine. The meconium ileus susceptibility locus on chromosome X appeared shifted in location from a previously identified locus for CF lung disease severity. Using the SS we integrated the lung disease association locus with eQTLs from nasal epithelia of 63 CF participants and demonstrated evidence of colocalization with airway-specific regulation of SLC6A14 (p = 2.3x10 -4 ). Cystic Fibrosis is realizing the promise of personalized medicine, and identification of the contributing organ and understanding of tissue specificity for a gene modifier is essential for the next phase of personalizing therapeutic strategies.

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a b s t r a c tAim: Extracorporeal resuscitation during cardiopulmonary resuscitation (ECPR) deploys rapid cardiopulmonary bypass to sustain oxygenated circulation until the return of spontaneous circulation (ROSC). The purpose of this systematic review is to address the defining elements and outcomes (quality survival and organ donation) of currently active protocols for ECPR in refractory out-of-hospital cardiac arrest (OHCA) of cardiac origin in adult patients. The results may inform policy and practices for ECPR and help clarify the corrresponding intersection with deceased organ donation. Methods: We searched Medline, Embase, Cochrane and seven other electronic databases from 2005 to 2015, with no language restrictions. Internal validity and the quality of the studies reporting outcomes and guidelines were assessed. The review was included in the international prospective register of systematic reviews (Prospero, CRD42014015259). Results: One guideline and 20 outcome studies were analyzed. Half of the studies were prospective observational studies assessed to be of fair to good methodological quality. The remainder were retrospective cohorts, case series, and case studies. Ages ranged from 16 to 75 years and initial shockable cardiac rhythms, witnessed events, and a reversible primary cause of cardiac arrest were considered favorable prognostic factors. CPR duration and time to hospital cannulation varied considerably. Coronary revascularization, hemodynamic interventions and targeted temperature management neuroprotection were variable. A total of 833 patients receiving this ECPR approach had an overall reported survival rate of Abbreviations: ECPR, extracorporeal resuscitation; ROSC, return of spontaneous circulation; OHCA, out-of-hospital cardiac arrest; CPC, cerebral performance category; GOS, Glasgow Outcome Scale; LOE, level of evidence; ILCOR, International Liaison Committee on Resuscitation; RCTs, randomized controlled trials; TTM, targeted temperature management; IABP, intra-aortic balloon pump; DBD, donation after brain death; cDCD, controlled donation after circulatory determination of death; ELSO, extracorporeal life support organization. I. Ortega-Deballon et al. / Resuscitation 101 (2016) 12-20 13 22%, including 13% with good neurological recovery. Additionally, 88 potential and 17 actual deceased organ donors were identified among the non-survivor population in 8 out of 20 included studies. Study heterogeneity precluded a meta-analysis preventing any meaningful comparison between protocols, interventions and outcomes. Conclusions: ECPR is feasible for refractory OHCA of cardiac origin in adult patients. It may enable neurologically good survival in selected patients, who practically have no other alternative in order to save their lives with quality of life, and contribute to organ donation in those who die. Large, prospective studies are required to clarify patient selection, modifiable outcome variables, risk-benefit and cost-effectiveness.