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Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant ( = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group. Thus, selective TORC1 inhibition has the potential to improve immune function and reduce infections in the elderly.

In this study, we evaluated the performance of a humidified nasal high-flow system (Optiflow™, Fisher and Paykel Healthcare) by measuring delivered FiO2 and airway pressures. Oxygraphy, capnography and measurement of airway pressures were performed through a hypopharyngeal catheter in healthy volunteers receiving Optiflow™ humidified nasal high flow therapy at rest and with exercise. The study was conducted in a non-clinical experimental setting. Ten healthy volunteers completed the study after giving informed written consent. Participants received a delivered oxygen fraction of 0.60 with gas flow rates of 10, 20, 30, 40 and 50 l/minute in random order. FiO2, FEO2, FECO2 and airway pressures were measured. Calculation of FiO2 from FEO2 and FECO2 was later performed. Calculated FiO2 approached 0.60 as gas flow rates increased above 30 l/minute during nose breathing at rest. High peak inspiratory flow rates with exercise were associated with increased air entrainment. Hypopharyngeal pressure increased with increasing delivered gas flow rate. At 50 l/minute the system delivered a mean airway pressure of up to 7.1 cmH2O. We believe that the high gas flow rates delivered by this system enable an accurate inspired oxygen fraction to be delivered. The positive mean airway pressure created by the high flow increases the efficacy of this system and may serve as a bridge to formal positive pressure systems.

BackgroundThis study investigated the long-term effects of humidified high-flow nasal cannula (HFNC) in COPD patients with chronic hypoxemic respiratory failure treated with long-term oxygen therapy (LTOT).Patients and methodsA total of 200 patients were randomized into usual care ± HFNC. At inclusion, acute exacerbation of COPD (AECOPD) and hospital admissions 1 year before inclusion, modified Medical Research Council (mMRC) score, St George’s Respiratory Questionnaire (SGRQ), forced expiratory volume in 1 second (FEV1), 6-minute walk test (6MWT) and arterial carbon dioxide (PaCO2) were recorded. Patients completed phone interviews at 1, 3 and 9 months assessing mMRC score and AECOPD since the last contact. At on-site visits (6 and 12 months), mMRC, number of AECOPD since last contact and SGRQ were registered and FEV1, FEV1%, PaCO2 and, at 12 months, 6MWT were reassessed. Hospital admissions during the study period were obtained from hospital records. Hours of the use of HFNC were retrieved from the high-flow device.ResultsThe average daily use of HFNC was 6 hours/day. The HFNC group had a lower AECOPD rate (3.12 versus 4.95/patient/year, p<0.001). Modeled hospital admission rates were 0.79 versus 1.39/patient/year for 12- versus 1-month use of HFNC, respectively (p<0.001). The HFNC group had improved mMRC scores from 3 months onward (p<0.001) and improved SGRQ at 6 and 12 months (p=0.002, p=0.033) and PaCO2 (p=0.005) and 6MWT (p=0.005) at 12 months. There was no difference in all-cause mortality.ConclusionHFNC treatment reduced AECOPD, hospital admissions and symptoms in COPD patients with hypoxic failure.

Long-term humidification therapy significantly reduced exacerbation days, increased time to first exacerbation, improved lung function and quality of life in patients with COPD and bronchiectasis. Clinical trial registered with www.actr.org.au; Number ACTRN2605000623695.

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Background Nasal High Flow (NHF) therapy delivers flows of heated humidified gases up to 60 LPM (litres per minute) via a nasal cannula. Particles of oral/nasal fluid released by patients undergoing NHF therapy may pose a cross-infection risk, which is a potential concern for treating COVID-19 patients. Methods Liquid particles within the exhaled breath of healthy participants were measured with two protocols: (1) high speed camera imaging and counting exhaled particles under high magnification (6 participants) and (2) measuring the deposition of a chemical marker (riboflavin-5-monophosphate) at a distance of 100 and 500 mm on filter papers through which air was drawn (10 participants). The filter papers were assayed with HPLC. Breathing conditions tested included quiet (resting) breathing and vigorous breathing (which here means nasal snorting, voluntary coughing and voluntary sneezing). Unsupported (natural) breathing and NHF at 30 and 60 LPM were compared. Results Imaging: During quiet breathing, no particles were recorded with unsupported breathing or 30 LPM NHF (detection limit for single particles 33 μm). Particles were detected from 2 of 6 participants at 60 LPM quiet breathing at approximately 10% of the rate caused by unsupported vigorous breathing. Unsupported vigorous breathing released the greatest numbers of particles. Vigorous breathing with NHF at 60 LPM, released half the number of particles compared to vigorous breathing without NHF. Chemical marker tests: No oral/nasal fluid was detected in quiet breathing without NHF (detection limit 0.28 μL/m3). In quiet breathing with NHF at 60 LPM, small quantities were detected in 4 out of 29 quiet breathing tests, not exceeding 17 μL/m3. Vigorous breathing released 200–1000 times more fluid than the quiet breathing with NHF. The quantities detected in vigorous breathing were similar whether using NHF or not. Conclusion During quiet breathing, 60 LPM NHF therapy may cause oral/nasal fluid to be released as particles, at levels of tens of μL per cubic metre of air. Vigorous breathing (snort, cough or sneeze) releases 200 to 1000 times more oral/nasal fluid than quiet breathing (p < 0.001 with both imaging and chemical marker methods). During vigorous breathing, 60 LPM NHF therapy caused no statistically significant difference in the quantity of oral/nasal fluid released compared to unsupported breathing. NHF use does not increase the risk of dispersing infectious aerosols above the risk of unsupported vigorous breathing. Standard infection prevention and control measures should apply when dealing with a patient who has an acute respiratory infection, independent of which, if any, respiratory support is being used. Clinical trial registration ACTRN12614000924651

Awareness of drug‐drug interactions is critical in organ transplant recipient management. However, biologic agents interfering with monoclonal antibodies is not widely considered. We report the effect of high‐dose intravenous immunoglobulin (IVIg) on safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the human anti‐C5 monoclonal antibody tesidolumab (LFG316) in end‐stage renal disease patients awaiting kidney transplant. In this single‐center, phase 1, open‐label, parallel‐group study, 8 patients were assigned to receive either single‐dose tesidolumab + IVIg or tesidolumab alone, with 56‐day follow‐up. Within‐group PK parameters were consistent. Mean tesidolumab exposure decreased 34%, clearance increased 63%, and half‐life decreased 41% comparing tesidolumab + IVIg to tesidolumab alone. IVIg influence on tesidolumab elimination was most evident in the first 3 weeks. Complete suppression of both total and alternative complement activities was maintained for 4 weeks in the tesidolumab alone group and for 2 weeks in the tesidolumab + IVIg group. Tesidolumab was well tolerated. IVIg infused before tesidolumab affected tesidolumab PK and PD, resulting in a shortened period of full complement activity inhibition. These findings suggest a clinically relevant impact of IVIg on monoclonal antibody clearance and indirectly hint at an IVIg mechanism of action in treating autoimmune diseases and allosensitization by accelerating pathogenic IgG antibody degradation. Trial registration number: NCT02878616.