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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.

†‡ 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.

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.