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Reducing treatment burden is a priority for people with cystic fibrosis, whose health has benefited from using new modulators that substantially increase CFTR protein function. The SIMPLIFY study aimed to assess the effects of discontinuing nebulised hypertonic saline or dornase alfa in individuals using the CFTR modulator elexacaftor plus tezacaftor plus ivacaftor (ETI).The SIMPLIFY study included two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials at 80 participating clinics across the USA in the Cystic Fibrosis Therapeutics Development Network. We included individuals with cystic fibrosis aged 12-17 years with percent predicted FEVFrom Aug 25, 2020, to May 25, 2022, a total of 672 unique participants were screened for eligibility for one or both trials, resulting in 847 total random assignments across both trials with 594 unique participants. 370 participants were randomly assigned in the hypertonic saline trial and 477 in the dornase alfa trial. Participants across both trials had an average ppFEVIn individuals with cystic fibrosis on ETI with relatively well preserved pulmonary function, discontinuing daily hypertonic saline or dornase alfa for 6 weeks did not result in clinically meaningful differences in pulmonary function when compared with continuing treatment.

BACKGROUND Despite steady gains in life expectancy, individuals with cystic fibrosis (CF) lung disease still experience rapid pulmonary decline throughout their clinical course, which can ultimately end in respiratory failure. Point-of-care tools for accurate and timely information regarding the risk of rapid decline is essential for clinical decision support. OBJECTIVE This study aims to translate a novel algorithm for earlier, more accurate prediction of rapid lung function decline in patients with CF into an interactive web-based application that can be integrated within electronic health record systems, via collaborative development with clinicians. METHODS Longitudinal clinical history, lung function measurements, and time-invariant characteristics were obtained for 30,879 patients with CF who were followed in the US Cystic Fibrosis Foundation Patient Registry (2003-2015). We iteratively developed the application using the R Shiny framework and by conducting a qualitative study with care provider focus groups (N=17). RESULTS A clinical conceptual model and 4 themes were identified through coded feedback from application users: (1) ambiguity in rapid decline, (2) clinical utility, (3) clinical significance, and (4) specific suggested revisions. These themes were used to revise our application to the currently released version, available online for exploration. This study has advanced the application’s potential prognostic utility for monitoring individuals with CF lung disease. Further application development will incorporate additional clinical characteristics requested by the users and also a more modular layout that can be useful for care provider and family interactions. CONCLUSIONS Our framework for creating an interactive and visual analytics platform enables generalized development of applications to synthesize, model, and translate electronic health data, thereby enhancing clinical decision support and improving care and health outcomes for chronic diseases and disorders. A prospective implementation study is necessary to evaluate this tool’s effectiveness regarding increased communication, enhanced shared decision-making, and improved clinical outcomes for patients with CF.

Background Shortcomings of inhaled antibiotic treatments for Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF) include poor drug penetration, inactivation by sputum, poor efficiency due to protective biofilm, and short residence in the lung. Methods Eligible patients with forced expiratory volume in 1 s (FEV1) ≥25% of predicted value at screening and CF with chronic P. aeruginosa infection were randomly assigned to receive 3 treatment cycles (28 days on, 28 days off) of amikacin liposome inhalation suspension (ALIS, 590 mg QD) or tobramycin inhalation solution (TIS, 300 mg BID). The primary endpoint was noninferiority of ALIS vs TIS in change from baseline to day 168 in FEV1 (per-protocol population). Secondary endpoints included change in respiratory symptoms by Cystic Fibrosis Questionnaire-Revised (CFQ-R). Results The study was conducted February 2012 to September 2013. ALIS was noninferior to TIS (95% CI, −4.95 to 2.34) for relative change in FEV1 (L) from baseline. The mean increases in CFQ-R score from baseline on the Respiratory Symptoms scale suggested clinically meaningful improvement in both arms at the end of treatment in cycle 1 and in the ALIS arm at the end of treatment in cycles 2 and 3; however, the changes were not statistically significant between the 2 treatment arms. Treatment-emergent adverse events (TEAEs) were reported in most patients (ALIS, 84.5%; TIS, 78.8%). Serious TEAEs occurred in 17.6% and 19.9% of patients, respectively; most were hospitalisations for infective pulmonary exacerbation of CF. Conclusions Cyclical dosing of once-daily ALIS was noninferior to cyclical twice-daily TIS in improving lung function. ClinicalTrials.gov Identifier: NCT01315678

U.S. companies are now reportedly earning record-high operating returns on capital while at the same time continuing to set new records both for corporate cash holdings and distributions to investors in the form of dividends and stock repurchases. But are most of these companies really maximizing value? And what role, if any, do these large distributions play in creating value? These are the two main questions that are addressed by a small group that includes two senior corporate executives and two representatives of well-known activist investors. A number of panelists suggest that many companies, in misguided efforts to maximize returns on capital, have been using hurdle rates that are too high and so sacrificing value-adding investment opportunities. As evidence for this claim, they cite evidence that, in recent years, the companies that have achieved the highest stock market returns appear to have made conscious decisions to reduce their returns on capital to pursue higher growth. Another increasingly common charge against U.S. companies is their tendency to pay out excessive capital to investors, especially in the form of stock repurchases at prices that turn out to be too high. But this last practice, however widespread, may not be as troubling as it has been made out to be. Although it involves a wealth transfer from existing to selling shareholders, overall investor value is lost only if such buybacks lead to corporate underinvestment. But, as a number of panelists (including the activist investors) point out, such payouts of capital have generally functioned as a demonstration of corporate managers' commitment to investing and operating with the optimal, or value-maximizing, level of capital�neither too much nor too little.

A multi-user integrated suite of instruments designed to optimize the search for evidence of life on Mars is described. The package includes: • ∗ Surface inspection and surface environment analysis to identify the potential Mars landing sites, to inspect the surface geology and mineralogy, to search for visible surficial microbial macrofossils, to study the surface radiation budget and surface oxidation processes, to search for niches for extant life. • ∗ Analysis of surface and subsurface minerals and organics to characterize the surface mineralogy, to analyse the surface and subsurface oxidants, to analyze the mineralogy of subsurface aliquots, to analyze the organics present in the subsurface aliquots (elemental and molecular composition, isotopes, chirality). • ∗ Macroscopic and microscopic inspection of subsurface aliquots to search for life's indicators (paleontological, biological, mineralogical) and to characterize the mineralogy of the subsurface aliquots. The study is led by ESA Manned Spaceflight and Microgravity Directorate.

Cystic fibrosis (CF) is caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR functions as an anion channel and is known to interact with a number of other cellular proteins involved in ion transport. To date more than 1,800 mutations are known, most of which result in various degrees of impaired transport function of the gene product. Due to the high inter-individual variability of disease onset and progression, CF still is a diagnostic challenge. Implemented almost 20 years ago, the measurement of electrolyte transport function of rectal biopsies is a useful ex vivo tool to diagnose CF. In this chapter we will review the different approaches to perform ion transport measurements and try to highlight the advantages and limitations of these techniques.

†‡ PhD 4-Space sarl, Paris 75015, France The European Space Agency (ESA) is evaluating an underground isolation laboratory for simulating long duration human space missions with 6-person crews confined to the laboratory for periods of 100 days and perhaps substantially longer. ESA is evaluating a remote location over 200 metres underground in an existing tunnel network in Belgium with the intent of increasing the laboratory’s physical isolation. This paper describes a design for the laboratory that fits snugly into a portion of the tunnels, making the most of the confined and limited volume available. The tunnel system is operated by Studiecentrum voor Kernenegie ‐ Centre d’Etude de l’Energie Nucleaire (SCK-CEN) at Mol in Belgium. SCKCEN originally built the tunnels for subterranean geological studies concerned with the underground storage of radioactive nuclear waste (though no such waste was ever stored there). An end gallery in the tunnel system is available for the isolation laboratory. Many challenges exist in utilizing the tunnels for this purpose: delivery of all construction elements must take place down two lift shafts with construction and installation by hand; the end gallery site has one entrance/exit, raising crew emergency evacuation and safety concerns; the end gallery volume is below an accepted human habitability standard for long duration missions; there is minimal residual volume available for environmental control & life support (ECLS) systems. Despite these challenges, it is possible to achieve a feasible design utilizing modular and repetitive construction elements, a choice of open or closed ECLS systems and an interior accommodation and outfitting approach with life-cycle adaptability, all at relatively low cost. The laboratory has the potential to provide Europe with its own long duration spaceflight simulator to support international human missions to deep space, such as the “flexible path” exploration missions currently under study at NASA. The project design and engineering team comprised 4CON Space Ltd. (Paris), Altus Associates (Los Angeles), RFR (Paris), EADS-Astrium (Bremen) and Davis Langdon LLP (London). I. Introduction HE European Space Agency is considering the development of an underground isolation laboratory for simulating long duration human space missions. The simulated missions would involve 6-person crews confined to the laboratory for periods of 100 or possibly 150 days. ESA is studying a remote site over 200 metres underground in an existing tunnel network in Belgium with the intent of increasing the laboratory’s physical isolation from the surface. The tunnel system is operated by Studiecentrum voor Kernenegie ‐ Centre d’Etude de l’Energie Nucleaire (SCK-CEN) at Mol in Belgium. SCK-CEN originally built the tunnels for subterranean geological studies concerned with the underground storage of radioactive nuclear waste under Belgium’s nuclear energy programme. Subsequently, the storage of nuclear waste in the tunnels never occurred, though geological research into the long-term behaviour of the soil continues in tunnels. SCK-CEN has proposed to ESA that an end gallery in the tunnel system is converted into the isolation laboratory.

The International Space Station (ISS) is the largest international cooperative science and technology project ever undertaken. Involving the United States, Russia, Japan, Canada and 10 ESA Member States, it is now rapidly becoming a reality in orbit, offering unprecedented access for research and applications under space conditions. Europe has invested heavily in this endeavour and plans to exploit that investment by a vigorous utilisation of the ISS for life and physical sciences research and applications, space science, Earth observation, space technology development, the promotion of commercial access to space, and the use of space for educational purposes. In recent years, ESA has engaged in an intensive promotional effort to encourage potential user communities to exploit the novel opportunities that the ISS offers. It has also made significant financial commitments to develop both multi-user facilities for life and physical sciences studies in the Columbus Laboratory, and observational and technology exposure instruments using the external Columbus mounting locations, as well as giving financial support to promote commercial and educational activities. ESA has now elaborated a European Strategy for the efficient utilisation of the ISS by European scientists and other users, which is being coordinated with the Agency's Member States contributing to the ISS Programme, and with the European Science Foundation (ESF). In cooperation with the European Commission, ESA is also fostering synergy with the European Commission's Framework Programmes in terms of shared RD objectives. This article describes the plan that has been evolved to integrate all of these various elements.

A multi-user integrated suite of instruments designed to optimize the search for evidence of life on Mars is described. The package includes: - Surface inspection and surface environment analysis to identify the potential Mars landing sites, to inspect the surface geology and mineralogy, to search for visible surficial microbial macrofossils, to study the surface radiation budget and surface oxidation processes, to search for niches for extant life. - Subsurface sample acquisition by core drilling- Analysis of surface and subsurface minerals and organics to characterize the surface mineralogy, to analyse the surface and subsurface oxidants, to analyse the mineralogy of subsurface aliquots, to analyse the organics present in the subsurface aliquots (elemental and molecular composition, isotopes, chirality). - Macroscopic and microscopic inspection of subsurface aliquots to search for life's indicators (paleontological, biological, mineralogical) and to characterize the mineralogy of the subsurface aliquots. The study is led by ESA Manned Spaceflight and Microgravity Directorate.

Coronary angioplasty was performed on 14 high-risk patients supported with venoarterial partial cardiopulmonary bypass. Hemodynamic, metabolic and physiologic parameters were monitored to assess the effect of cardiopulmonary support in conscious patients. Cardiopulmonary support caused a decrease in systolic (45 ± 17 to 27 ± 14 mm Hg, p < 0.001), diastolic (23 ± 12 to 14 ± 8 mm Hg, p < 0.005) and mean (29.7 ± 13.2 to 18 ± 9 mm Hg, p < 0.001) pulmonary artery pressures. Aortic systolic (129 ± 18 to 106 ± 17 mm Hg, p < 0.001), mean (89 ± 19 to 84 ± 19 mm Hg, p < 0.05) and pulse (64 ± 17 to 37 ± 16 mm Hg, p < 0.00001) pressures also decreased. Heart rate and aortic diastolic pressures were unchanged. End-systolic wall stress (122 ± 48 × 103 to 96 ± 44 × 103 dynes/cm2, p < 0.001) and left ventricular end-diastolic diameter (5.7 ± 0.8 to 5.5 ± 0.9 cm, p < 0.05) were reduced during partial cardiopulmonary bypass. After initiation of cardiopulmonary support, normal lactate extraction across the coronary circulation was diminished or converted to lactate production (38 ± 23 to 2 ± 29%, p < 0.005). There was a marked reduction in hematocrit (41 ± 4 to 28 ± 5%, p < 0.0001) and platelet count (259,000 ± 57,600/ml to 145,900 ± 46,000/ml, p < 0.0001) after bypass. Cardiopulmonary bypass successfully supported all patients during balloon inflation, for an optimal angioplasty result. During balloon inflation, 6 of 8 patients with interpretable electrocardiograms had ST shifts suggestive of ischemia and 1 developed ventricular tachycardia. During balloon inflation, pulse pressure decreased from a mean of 38 ± 15 to 25 ± 15 mm Hg (p < 0.01). It is concluded that cardiopulmonary support provides excellent systemic support but induces cardiac anaerobic metabolism in patients with severe coronary artery disease. Myocardial ischemia when coronary blood flow is interrupted during balloon inflation is still observed despite effective cardiopulmonary support.

Similarities in the early histories of Mars and Earth suggest the possibility that life may have arisen on Mars as it did on Earth. If this were the case, early deterioration of the environment on Mars (loss of surface water, decrease in temperature) may have inhibited further evolution of life. Thus, life on Mars would probably be similar to the simplest form of life on Earth, the prokaryotes. We present a hypothetical strategy to search for life on Mars consisting of (i) identifying a suitable landing site with good exobiological potential, and (ii) searching for morphological and biogeochemical signatures of extinct and extant life on the surface, in the regolith subsurface, and within rocks. The platform to be used in this theoretical exercise is an integrated, multi-user instrument package, distributed between a lander and rover, which will observe and analyse surface and subsurface samples to obtain the following information: 1. environmental data concerning the surface geology and mineralogy, UV radiation and oxidation processes; 2. macroscopic to microscopic morphological evidence of life; 3. biogeochemistry indicative of the presence of extinct or extant life; 4. niches for extant life.