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Richard N van Zyl-Smit,1 Kenneth R Chapman,2 Huib AM Kerstjens,3 Christian Gessner,4 Hironori Sagara,5 Ana-Maria Tanase,6 Motoi Hosoe,6 Abhijit Pethe,7 David Lawrence,6 Hanns-Christian Tillmann,8 Peter D’Andrea7 1Division of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africa; 2Division of Respiratory Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 3Department of Pulmonology, University of Groningen, University Medical Center Groningen, and Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands; 4Universitätsklinikum Leipzig, Germany POIS Leipzig GbR, Leipzig, Germany; 5Department of Medicine, Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Tokyo, Japan; 6Novartis Pharma AG, Basel, Switzerland; 7Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 8Novartis Institutes for BioMedical Research, Translational Medicine, Basel, SwitzerlandCorrespondence: Ana-Maria Tanase, Novartis Pharma AG, Fabrikstrasse 4, Novartis Campus, Basel, Switzerland, Tel +41 79 899 98 22, Email ana-maria.tanase@novartis.comBackground: Once-daily, single-inhaler mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY, an ICS/LABA/LAMA) and MF/IND (an ICS/LABA) via Breezhaler® have been approved for the maintenance treatment of patients with asthma inadequately controlled with medium-or high-dose ICS or medium-or high-dose ICS/LABA treatment.Objective: Once-daily (o.d.) formulations of MF/IND/GLY and MF/IND at different MF dose strengths have been compared with twice-daily (b.i.d.) fluticasone propionate/salmeterol xinafoate (FLU/SAL), and b.i.d. FLU/SAL+ o.d. tiotropium (TIO) in the PALLADIUM, IRIDIUM and ARGON studies.Methods: The similarity in study design and consistent outcomes in these studies prompted the pooling of data in this review to better characterise these novel once-daily controller formulations.Results: Pooled data from PALLADIUM and IRIDIUM studies showed comparable or greater efficacy with o.d. MF/IND formulations versus b.i.d. FLU/SAL. The o.d. MF/IND/GLY was superior to b.i.d. FLU/SAL in the IRIDIUM study, and similar to, if not more efficacious than b.i.d. FLU/SAL + o.d. TIO in the ARGON study.Conclusion: These formulations therefore provide novel once-daily treatment options for patients across asthma severity and flexibility for clinicians to step-up or step-down the treatment using the same device and formulations.Keywords: mometasone/indacaterol/glycopyrronium, mometasone/indacaterol, fluticasone/salmeterol, tiotropium, bronchodilator, lung function, asthma control, exacerbation

Kai Michael Beeh,1 Anne-Marie Kirsten,2 Ana-Maria Tanase,3 Alexia Richard,3 Weihua Cao,4 Bettina Hederer,3 Jutta Beier,1 Oliver Kornmann,5 Richard N van Zyl-Smit6 1Insaf Respiratory Research Institute Wiesbaden, Wiesbaden, Germany; 2Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 5IKF Pneumologie, Clinical Research Centre Respiratory Diseases, Frankfurt, Germany; 6Division of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africa Background and purpose: Fixed-dose combinations of a long-acting beta agonist and an inhaled corticosteroid are more effective than the individual components in COPD. The primary study objective was to demonstrate that the combination indacaterol acetate/mometasone furoate (IND/MF [QMF149]) was non-inferior to the twice-daily combination salmeterol xinafoate/fluticasone propionate (Sal/Flu) in terms of trough FEV1 at week 12 (day 85). Secondary objectives were to compare the efficacy of IND/MF (QMF149) vs Sal/Flu with respect to other lung function parameters, COPD exacerbations, symptoms and dyspnea, health status/health-related quality of life, and rescue medication use.Materials and methods: This was a 12-week multicenter, randomized, double-blind, double-dummy, parallel-group, Phase II study in patients with moderate-to-very-severe COPD, who were randomized (1:1) to IND/MF (QMF149) (150/160 µg once daily; n=316) or Sal/Flu (50/500 µg twice daily; n=313).Results: Over 90% of patients completed the study: 94.6% in the IND/MF (QMF149) group and 92.0% in the Sal/Flu group. The primary objective of non-inferiority of IND/MF (QMF149) to Sal/Flu for trough FEV1 at week 12 (day 85) was met: the lower limit of the CI (95% CI: 27.7, 83.3 mL) was greater than -60 mL. The analysis for superiority of IND/MF (QMF149) to Sal/Flu demonstrated superiority of IND/MF (QMF149), with a difference of 56 mL (P

Introduction: GINA guidelines recommend increasing the dose of inhaled corticosteroids (ICS) as a step-up option for patients with inadequately controlled asthma at GINA step 4 [inadequately controlled asthma on medium-dose ICS/long-acting beta-2 agonist (LABA)]. The aim of this study was to compare the efficacy and safety of long-acting muscarinic antagonists (LAMA) add-on to medium-dose ICS/LABA in patients at GINA 2022 step 4., Methods: This post hoc analysis of the IRIDIUM study evaluated the change from baseline in trough forced expiratory volume (FEV 1 ) in patients receiving medium-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL at Week 26. Other outcomes included improvement in lung functions [peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow between 25% and 75% of the FVC (FEF) 25-75% )], asthma control [Asthma Control Questionnaire (ACQ-7)], responder analysis (≥ 0.5 unit improvement in ACQ-7), and reduction in asthma exacerbations at Weeks 26 and 52., Results: A total of 1930 patients were included in this analysis. Medium-dose MF/IND/GLY improved trough FEV 1 versus high-dose MF/IND (Δ 41 mL; 95% CI - 7-90) and high-dose FLU/SAL (Δ 88 mL; 95% CI 39-137) at Week 26 which were sustained until Week 52. Exacerbation rates were 16% lower with medium-dose MF/IND/GLY versus high-dose MF/IND for all (mild, moderate, and severe) exacerbations and 21-30% lower versus high-dose FLU/SAL for all (mild, moderate, and severe), moderate or severe, and severe exacerbations over 52 weeks. Further improvements in other lung functions were observed with medium-dose MF/IND/GLY. No new safety signals were identified., Conclusion: Medium-dose MF/IND/GLY improved lung function and reduced asthma exacerbations compared to high-dose ICS/LABA and may be an undervalued option in patients at GINA 2022 step 4., Trial Registration: ClinicalTrials.gov Identifier: NCT02571777., (© 2023. The Author(s).)

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction is associated with mucus accumulation and worsening chronic obstructive pulmonary disease (COPD) symptoms. Objectives: The aim of this phase IIb dose-finding study was to compare a CFTR potentiator, icenticaftor (QBW251), with placebo in patients with COPD and chronic bronchitis. Methods: Patients with COPD on triple therapy for at least three months were randomized to six treatment arms (icenticaftor 450, 300, 150, 75, or 25 mg or placebo twice daily [b.i.d.]) in a 24-week, multicenter, parallel-group, double-blind study. The primary endpoint was change from baseline in trough FEV 1 after 12 weeks. Secondary endpoints included change from baseline in trough FEV 1 and Evaluating Respiratory Symptoms in COPD (E-RS) total and cough and sputum scores after 24 weeks. Multiple comparison procedure-modeling was conducted to characterize dose-response relationship. Rescue medication use, exacerbations, and change in serum fibrinogen concentration after 24 weeks were assessed in exploratory and post hoc analyses, respectively. Measurements and Main Results: Nine hundred seventy-four patients were randomized. After 12 weeks of icenticaftor treatment, no dose-response relationship for change from baseline in trough FEV 1 was observed; however, it was observed for E-RS cough and sputum score. A dose-response relationship was observed after 24 weeks for trough FEV 1 , E-RS cough and sputum and total scores, rescue medication use, and fibrinogen. A dose of 300 mg b.i.d. was consistently the most effective. Improvements for 300 mg b.i.d. versus placebo were also seen in pairwise comparisons of these endpoints. All treatments were well tolerated. Conclusions: The primary endpoint was negative, as icenticaftor did not improve trough FEV 1 over 12 weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV 1 ; reduced cough, sputum, and rescue medication use; and lowered fibrinogen concentrations at 24 weeks. Clinical trial registered with www.clinicaltrials.gov (NCT04072887).

Background: A novel, once-daily, fixed-dose combination of mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY) delivered via Breezhaler® is the first inhaled corticosteroid/long-acting ꞵ 2 -agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) therapy approved for the maintenance treatment of asthma in adults inadequately controlled on ICS/LABA combination. In patients with asthma and persistent airflow limitation (PAL), maximal treatment, especially with combination is suggested. This post hoc analysis of data from the IRIDIUM study assessed the efficacy of MF/IND/GLY in asthma patients with and without PAL., Methods: Patients with post-bronchodilator FEV 1 ≤80% of predicted and FEV 1 /FVC ratio of ≤0.7 were categorised as PAL subgroup and the remaining as the non-PAL subgroup. Lung function parameters (FEV 1 , PEF, and FEF 25%-75% ) and annualised asthma exacerbations rates were evaluated in both subgroups across the treatment arms: once-daily high-dose MF/IND/GLY (160/150/50 μg), high-dose MF/IND (320/150 μg) and twice-daily high-dose fluticasone/salmeterol (FLU/SAL; 500/50 μg)., Results: Of the 3092 randomised patients, 64% (n = 1981) met the criteria for PAL. Overall, there was no evidence of treatment difference between PAL and non-PAL subgroups (interaction P-value for FEV 1 , FEF 25%-75% , PEF, moderate or severe exacerbations, severe exacerbations and all exacerbations were 0.42, 0.08, 0.43 0.29, 0.35 and 0.12, respectively). In the PAL subgroup, high-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL improved trough FEV 1 (mean difference: 102 mL [P < 0.0001] and 137 mL [P < 0.0001]) and reduced moderate or severe (16% and 32%), severe (25% and 39%) and all exacerbations (19% and 38%), respectively., Conclusions: Once-daily fixed-dose MF/IND/GLY was efficacious in asthma patients with and without persistent airflow limitation., Competing Interests: Declaration of competing interest RVZS reports personal fees from Aspen/GSK, Pfizer, Roche, MSD, AstraZeneca, Novartis, Glenmark, Boehringer Ingelheim and Cipla, outside the submitted work. HAK reports grants and consultancy/advisory board participation from/for Novartis during the conduct of the study, grants and consultancy/advisory board participation from/for GlaxoSmithKline and Boehringer Ingelheim, and a grant from Chiesi, outside the submitted work. All were paid to his institution. JFM reports personal fees and grants from Novartis during the conduct of the study, personal fees from AstraZeneca, grants and personal fees from Sanofi and personal fees from ImmunoTek. KK reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Novartis and Menarini; personal fees from Sanofi; and grants from NuvoAir, outside the submitted work, and was an employee of Novartis Pharma AG until October 31, 2018. KRC reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, Sanofi, Regeneron, Novartis and Takeda; personal fees from CSL Behring, Inhibrx and Kamada; and grants from Vertex, outside the submitted work. MH, AMT, KM, DB and DL are employees of Novartis Pharma AG. PD is an employee of Novartis Pharmaceutical Corporation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Sarcoidosis is a multisystem disease, characterised by the infiltration of various organs by non-necrotising granulomas. The disease's heterogeneity complicates the study of patients' experiences., Objective: To gather insight into life experiences, unmet needs and views on hypothetically emerging treatment options among patients living with sarcoidosis., Methods: Multinational, virtual, interactive, moderated discussion of specific questions between people with sarcoidosis, with experienced clinicians participating., Results: Nine patients with sarcoidosis from Australia, Denmark, Germany, Italy, Japan and the US, and three clinicians took part. All patients had pulmonary sarcoidosis, self-assessed as mild by five patients. The path to diagnosis was convoluted, with up to four physicians and a large number of tests involved. There was agreement that the process would be improved by earlier referral to specialists. The patients made a clear distinction between 'living with a condition' (adapting to the disease) and 'being ill'. The concept of remission was viewed sceptically as disease might develop in multiple organs. Panellists had a pragmatic attitude to therapies: side effects during a treatment course were accepted if overall symptoms improved. When considering hypothetical new therapies, improved quality of life (QoL) was the most important need; improved tolerability had lower priority. New therapies should be targeted on reducing disease progression and improving symptoms and QoL rather than corticosteroid withdrawal., Conclusions: The interactive exchange provided insights into the need for earlier specialist referrals, distrust of the concept of remission in sarcoidosis, and the need for therapies targeted on reducing disease progression and improving symptoms and QoL., Competing Interests: Competing interest MAJ reports consulting fees from Bohringer-Ingelheim and receipt of grants for his institution from aTyr, Kinevant, Mallinckrodt, and Star Therapeutics. PS reports personal fees from Novartis during the conduct of the study and personal fees from Behring and Chiesi outside the submitted work. RS has no conflicts to disclose. GF reports personal fees from Foundation for Sarcoidosis Research - Industry Patient Roundtable, outside the submitted work. FP and AMT are employees of Novartis. RPB reports consulting fees from ATYR, Actelion, Bellephron, Kinevant, Novartis and Xentria, and research grants from ATYR, Actelion, Bellephron and Genentech., (Copyright © 2023. Published by Elsevier Ltd.)

High-throughput screening (HTS) methods for characterization of microbial production of polyhydroxyalkanoates (PHA) are currently under investigated, despite the advent of such systems in related fields. In this study, phenotypic microarray by Biolog PM1 screening of Halomonas sp. R5-57 and Pseudomonas sp. MR4-99 identified 49 and 54 carbon substrates to be metabolized by these bacteria, respectively. Growth on 15 (Halomonas sp. R5-57) and 14 (Pseudomonas sp. MR4-99) carbon substrates was subsequently characterized in 96-well plates using medium with low nitrogen concentration. Bacterial cells were then harvested and analyzed for putative PHA production using two different Fourier transform infrared spectroscopy (FTIR) systems. The FTIR spectra obtained from both strains contained carbonyl-ester peaks indicative of PHA production. Strain specific differences in the carbonyl-ester peak wavenumber indicated that the PHA side chain configuration differed between the two strains. Confirmation of short chain length PHA (scl-PHA) accumulation in Halomonas sp. R5-57 and medium chain length PHA (mcl-PHA) in Pseudomonas sp. MR4-99 was done using Gas Chromatography-Flame Ionization Detector (GC-FID) analysis after upscaling to 50 mL cultures supplemented with glycerol and gluconate. The strain specific PHA side chain configurations were also found in FTIR spectra of the 50 mL cultures. This supports the hypothesis that PHA was also produced in the cells cultivated in 96-well plates, and that the HTS approach is suitable for analysis of PHA production in bacteria. However, the carbonyl-ester peaks detected by FTIR are only indicative of PHA production in the small-scale cultures, and appropriate calibration and prediction models based on combining FTIR and GC-FID data needs to be developed and optimized by performing more extensive screenings and multivariate analyses., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Christensen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: The 52-week long-term safety of once-daily indacaterol acetate/glycopyrronium bromide/mometasone furoate (IND/GLY/MF) high-dose (150/50/160 µg) and IND/MF high-dose (150/320 µg) was evaluated in two studies enrolling Japanese patients with inadequately controlled asthma., Methods: Study 1 (IND/GLY/MF) and Study 2 (IND/MF) were 52-week, phase III, open-label, single-arm, multicenter studies conducted in Japanese adult patients with inadequately controlled asthma. The primary endpoint was incidence and severity of treatment-emergent adverse events (AEs) over 52-weeks., Results: In Study 1, 94 patients received IND/GLY/MF high-dose and 84 (89.4%) patients completed the 52-week study treatment; in Study 2, 51 patients received IND/MF high-dose and 48 (94.1%) patients completed the 52-week study treatment. In Study 1, 68.1% and 6.4% of 94 patients reported ≥1 AE and ≥1 serious AE (SAE) respectively. In Study 2, 78.4% of 51 patients reported ≥1 AE; no patients reported SAEs. The most commonly reported AEs were asthma (exacerbation; 30.9% and 54.9%) and nasopharyngitis (18.1% and 29.4%) in Study 1 and Study 2, respectively. Severe AEs including asthma (exacerbation) were reported in 13.8% and 13.7% of patients in Study 1 and Study 2, respectively. In Study 1, 10 patients (10.6%) reported treatment-related AEs, of which dysphonia (9 patients [9.6%]) was the most commonly reported; no treatment-related AEs were reported in Study 2. In Study 1, one death (not study drug-related) was reported after study discontinuation (92 days after last dose of study medication)., Conclusions: Once-daily IND/GLY/MF and IND/MF high-dose were well-tolerated in Japanese patients with inadequately controlled asthma. No unexpected safety findings were observed., Supplemental data for this article is available online at.

Anode modification with carbon nanomaterials is an important strategy for the improvement of microbial fuel cell (MFC) performance. The presence of nitrogen in the carbon network, introduced as active nitrogen functional groups, is considered beneficial for anode modification. In this aim, nitrogen-containing carbon nanostructures (NCNs) with different morphologies were obtained via carbonization of polyaniline and were further investigated as anode modifiers in MFCs. The present study investigates the influence of NCN morphology on the changes in the anodic microbial community and MFC performance. Results show that the nanofibrillar morphology of NCNs is beneficial for the improvement of MFC performance, with a maximum power density of 40.4 mW/m 2 , 1.25 times higher than the anode modified with carbonized polyaniline with granular morphology and 2.15 times higher than MFC using the carbon cloth-anode. The nanofibrillar morphology, due to the well-defined individual nanofibers separated by microgaps and micropores and a better organization of the carbon network, leads to a larger specific surface area and higher conductivity, which can allow more efficient substrate transport and better bacterial colonization with greater relative abundances of Geobacter and Thermoanaerobacter , justifying the improvement of MFC performance.

A novel, once-daily (o.d.), fixed-dose combination (FDC) of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF), delivered by the inhaler Breezhaler ® device, is the first long-acting beta2-adrenergic agonist/long-acting muscarinic antagonist/inhaled corticosteroid (LABA/LAMA/ICS) therapy to be approved for maintenance treatment of asthma in adults inadequately controlled on LABA/ICS. The approval of IND/GLY/MF in the European Union (EU) also included an optional electronic sensor and smartphone (or other suitable device) application, making it the first "digital companion" that can be prescribed with an asthma medication. As a result, the European Medicines Agency included this approval as one of the "outstanding contributions to public health" (for Pneumology/Allergology) in their 2020 highlights report. Alongside IND/GLY/MF, an o.d. LABA/ICS FDC, IND/MF, was also developed and approved. This review outlines the unique strategy used in the accelerated development of IND/GLY/MF that combined various approaches: (1) selecting individual components with established efficacy/safety, (2) bridging doses to optimize efficacy/safety of IND/GLY/MF and IND/MF delivered via the Breezhaler ®  device, (3) developing IND/GLY/MF and IND/MF in parallel, and (4) submission for regulatory approval before formal completion of the pivotal phase III studies. IND/GLY/MF and IND/MF were combined in a single-development plan (PLATINUM program), which comprised four phase III studies: QUARTZ and PALLADIUM evaluated IND/MF while IRIDIUM and ARGON evaluated IND/GLY/MF. A unique feature was the inclusion of two LABA/ICS comparators in the pivotal IRIDIUM study-IND/MF as an internal comparator, and high-dose salmeterol xinafoate/fluticasone propionate (SAL/FLU) as a marketed comparator. In the ARGON study, IND/GLY/MF was compared against o.d. tiotropium (via Respimat ® ) plus twice-daily (b.i.d.) high-dose SAL/FLU (via Diskus ® ). As a result of this development strategy, the development and approval of IND/GLY/MF was accelerated by ca. 4 years as against what would be expected from a traditional approach, novel data were generated, and a unique optional digital companion was approved in the EU. A Video Abstract by Dr Dominic Brittain, Global Drug Development, Novartis. (MP4 228293 kb)., (© 2022. The Author(s).)

Background: QMF149 is an inhaled fixed-dose combination of indacaterol acetate and mometasone furoate (MF) delivered via Breezhaler®, under development for once-daily treatment of asthma. MF delivered via Twisthaler® is approved as Asmanex® Twisthaler® for the treatment of asthma. Bridging of MF delivered via Twisthaler® to MF delivered via Breezhaler® was undertaken as part of QMF149 development to enable dose comparisons between the devices. Pharmacokinetics (PK) of MF were characterized in two studies; a single dose PK study in healthy volunteers and a pharmacokinetic/pharmacodynamic (PK/PD) study in asthma patients., Objectives: The PK study in healthy volunteers evaluated the PK of single doses of MF via Breezhaler® (50-400 μg) and compared systemic exposure of MF following administration via Breezhaler® and Twisthaler® 400 μg (2 inhalations of 200 μg). The study in patients with asthma characterized the MF PK profile following once-daily inhalation of MF via Breezhaler® and Twisthaler® devices for 4 weeks., Methods: In the open-label, single-dose, crossover study, healthy subjects sequentially received MF via Twisthaler® (400 μg, medium-dose inhaled corticosteroid [ICS]) and escalating doses via Breezhaler® (50, 100, 200, 400 μg). PK data were obtained up to 72 h post-dose. In the double-blind, double-dummy, parallel-group study, asthma patients were randomised to receive either MF 80 μg (low-dose ICS) or 320 μg (high-dose ICS) via Breezhaler®, or 200 μg (low-dose ICS) or 800 μg (2 inhalations of 400 μg; high-dose ICS) via Twisthaler® once daily for 4 weeks. PK sampling was performed on Days 1 and 28 at pre-dose and up to 24 h post-dose., Results: In the healthy volunteer PK study, 20 healthy subjects completed all treatments. Dose-normalised AUC last of MF was 1.8-1.9-fold higher when delivered via Breezhaler® versus Twisthaler®. AUC and C max of MF increased in a dose-proportional manner over the range of 50-400 μg via Breezhaler®. Results from this study guided dose selection of MF via Breezhaler® for the asthma study. In the asthma study, in a subset of 96 patients, mean systemic exposure (AUC last and C max ) for MF 80 and 320 μg via Breezhaler® was comparable with MF 200 and 800 μg via Twisthaler®, respectively, on Day 28., Conclusion: PK characterization in a healthy volunteer PK study and subsequently an asthma study enabled selection of 80 μg (low), 160 μg (medium), and 320 μg (high) delivered via Breezhaler® as MF doses comparable to the 200 μg, 400 μg and 800 μg doses delivered by Twisthaler®, respectively, as part of QMF149 formulation development., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Despite currently available standard-of-care inhaled corticosteroid (ICS)/long-acting β 2 -agonist therapies, a substantial proportion of patients with asthma remain inadequately controlled. This pooled analysis evaluated efficacy and safety of mometasone furoate/indacaterol acetate (MF/IND) versus fluticasone propionate/salmeterol xinafoate (FLU/SAL) in patients with inadequately controlled asthma., Methods: This analysis included patients from PALLADIUM (NCT02554786) and IRIDIUM (NCT02571777) studies who received high-dose MF/IND (320/150 µg) or medium-dose MF/IND (160/150 µg) one time a day or high-dose FLU/SAL (500/50 µg) two times a day for 52 weeks. Reduction in asthma exacerbations, improvement in lung function, asthma control, and safety were evaluated for 52 weeks., Results: In total, 3154 patients (high-dose MF/IND, n=1054; medium-dose MF/IND, n=1044; high-dose FLU/SAL, n=1056) were included. High-dose MF/IND showed 26%, 22% and 19% reductions in rate of severe, moderate or severe, and all (mild, moderate and severe) exacerbations versus high-dose FLU/SAL, respectively, over 52 weeks (all, p<0.05). High-dose MF/IND improved trough FEV 1 versus high-dose FLU/SAL at weeks 26 (Δ, 43 mL, p=0.001) and 52 (Δ, 51 mL, p<0.001). Reductions in asthma exacerbation rate and improvement in trough FEV 1 with medium-dose MF/IND were comparable with high-dose FLU/SAL over 52 weeks. All treatments improved Asthma Control Questionnaire-7 score from baseline to 52 weeks with no difference between treatments. Safety was comparable between high-dose MF/IND and high-dose FLU/SAL., Conclusions: One time a day, single-inhaler, high-dose MF/IND reduced asthma exacerbations and improved lung function versus two times a day, high-dose FLU/SAL in patients with inadequately controlled asthma. Similarly, improved outcomes were seen with one time a day, medium-dose MF/IND and two times a day, high-dose FLU/SAL, but at a lower ICS dose., Competing Interests: Competing interests: Authors received no compensation related to development of the manuscript. KC reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, Novartis, Regeneron, Sanofi, and Takeda, grants from Vertex, and personal fees from CSL Behring, Inhibrx, and Kamada, all outside of the submitted work. RvZ-S reports receiving personal fees from Aspen–GlaxoSmithKline, Pfizer, Roche, AstraZeneca, Novartis, Merck Sharp & Dohme, and Cipla, outside of the submitted work. JM reports grants and personal fees from Novartis, during the conduct of the study, grants and personal fees from Sanofi, and personal fees from AstraZeneca and ImmunoTek. HAMK reports grants and fees for consultancy or advisory board participation from Novartis, during the conduct of the study; and grants and fees for consultancy or advisory board participation from GlaxoSmithKline and Boehringer Ingelheim, and a grant from Chiesi, outside of the submitted work. All were paid to his institution. YG reports receiving personal fees from Novartis, GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim, outside the submitted work. MH and A-MT are employees of Novartis Pharma. AP, XS, and PD are employees of Novartis Pharmaceuticals., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS) and long-acting β 2 -adrenoceptor agonists (LABA) are considered safe and efficacious in asthma management. Most available FDCs require twice-daily dosing to achieve optimum therapeutic effect. The objective of the PALLADIUM study was to assess the efficacy and safety of once-daily FDC of mometasone furoate plus indacaterol acetate (MF-IND) versus mometasone furoate (MF) monotherapy in patients with inadequately controlled asthma., Methods: This 52-week, double-blind, triple-dummy, parallel-group, phase 3 study recruited patients from 316 centres across 24 countries. Patients aged 12 to 75 years with a documented diagnosis of asthma for at least 1 year, percentage of predicted FEV 1 of 50-85%, and an Asthma Control Questionnaire 7 score of at least 1·5 despite treatment with medium-dose or high-dose ICS or low-dose ICS plus LABA were included. A history of asthma exacerbations was not a study requirement. Participants were randomily assigned (1:1:1:1:1) via interactive response technology to receive one of the following treatments for 52 weeks: high-dose MF-IND (320 μg, 150 μg) or medium-dose MF-IND (160 μg, 150 μg) once daily via Breezhaler; high-dose MF (800 μg [400 μg twice daily]) or medium-dose MF (400 μg once daily) via Twisthaler; or high-dose fluticasone propionate-salmeterol xinafoate (FLU-SAL; 500 μg, 50 μg) twice daily via Diskus. Participants received placebo via inhalation through the Breezhaler, Twisthaler, or Diskus devices in the mornings and evenings, as appropriate. The primary endpoint was improvement in trough FEV 1 with high-dose and medium-dose MF-IND versus respective MF doses from baseline at 26 weeks, analysed in the full analysis set by means of a mixed model for repeated measures. High-dose MF-IND once daily was compared with high-dose FLU-SAL twice daily for non-inferiority on improving trough FEV 1 at week 26 with a margin of -90 mL using mixed model for repeated measures as one of the secondary endpoints. Safety was assessed in all patients who had received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02554786, and is completed., Findings: Between Dec 29, 2015, and May 4, 2018, 2216 patients were randomly assigned (high-dose MF-IND, n=445; medium-dose MF-IND, n=439; high-dose MF, n=442; medium-dose MF, n=444; high-dose FLU-SAL, n=446), of which 1973 (89·0%) completed the study treatment and 234 (10·6%) prematurely discontinued study treatment. High-dose MF-IND (treatment difference [Δ] 132 mL [95% CI 88 to 176]; p<0·001) and medium-dose MF-IND (Δ 211 mL [167 to 255]; p<0·001) showed superiority in improving trough FEV 1 over corresponding MF doses from baseline at week 26. High-dose MF-IND was non-inferior to high-dose FLU-SAL in improving trough FEV 1 from baseline at week 26 (Δ 36 mL [-7 to 80]; p=0·101). Overall, the incidence of adverse events was similar across the treatment groups., Interpretation: Once-daily FDC of ICS and LABA (MF-IND) significantly improved lung function over ICS monotherapy (MF) at week 26; high-dose MF-IND was non-inferior to twice-daily combination of ICS and LABA (high-dose FLU-SAL) for improvement in trough FEV 1 . The combination of MF-IND provides a novel once-daily dry powder option for asthma control., Funding: Novartis Pharmaceuticals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Patients with asthma who are inadequately controlled on inhaled corticosteroid-long-acting β 2 -adrenoceptor agonist (ICS-LABA) combinations might benefit from the addition of a long-acting muscarinic receptor antagonist. The aim of the IRIDIUM study was to assess the efficacy and safety of a once-daily, single-inhaler combination of mometasone furoate, indacaterol acetate, and glycopyrronium bromide (MF-IND-GLY) versus ICS-LABA in patients with inadequately controlled asthma., Methods: In this 52-week, double-blind, double-dummy, parallel-group, active-controlled phase 3 study, patients were recruited from 415 sites across 41 countries. Patients aged 18 to 75 years with symptomatic asthma despite treatment with medium-dose or high-dose ICS-LABA, at least one exacerbation in the previous year, and a percentage of predicted FEV 1 of less than 80% were included. Enrolled patients were randomly assigned (1:1:1:1:1) via interactive response technology to receive medium-dose or high-dose MF-IND-GLY (80 μg, 150 μg, 50 μg; 160 μg, 150 μg, 50 μg) or MF-IND (160 μg, 150 μg; 320 μg, 150 μg) once daily via Breezhaler, or high-dose fluticasone-salmeterol (FLU-SAL; 500 μg, 50 μg) twice daily via Diskus. The primary outcome was change from baseline in trough FEV 1 with MF-IND-GLY versus MF-IND at week 26 in patients in the full analysis set, analysed by means of a mixed model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02571777, and is completed., Findings: Between Dec 8, 2015, and Jun 14, 2019, 3092 of 4851 patients screened were randomly assigned (medium-dose MF-IND-GLY, n=620; high-dose MF-IND-GLY, n=619; medium-dose MF-IND, n=617; high-dose MF-IND, n=618; high-dose FLU-SAL, n=618). 2747 (88·8%) patients completed the 52-week treatment and 321 (10·4%) started but discontinued study treatment prematurely. Medium-dose MF-IND-GLY (treatment difference [Δ] 76 mL [95% CI 41-111]; p<0·001) and high-dose MF-IND-GLY (Δ 65 mL [31-99]; p<0·001) showed superior improvement in trough FEV 1 versus corresponding doses of MF-IND at week 26. Improvements in trough FEV 1 were greater for both medium-dose MF-IND-GLY (99 mL [64-133]; p<0·001) and high-dose MF-IND-GLY (119 mL [85-154]; p<0·001) than for high-dose FLU-SAL at week 26. Overall, the incidence of adverse events was balanced across the treatment groups. Seven deaths were reported (one with medium-dose MF-IND-GLY, two with high-dose MF-IND-GLY, and four with high-dose MF-IND) during the study; none of these deaths was considered by the investigators to be caused by study drugs or other study-related factors., Interpretation: Once-daily, single-inhaler MF-IND-GLY improved lung function versus ICS-LABA combinations (MF-IND and FLU-SAL) in patients with inadequately controlled asthma. The safety profile was similar across treatment groups. MF-IND-GLY therefore constitutes a good treatment option in these patients., Funding: Novartis Pharmaceuticals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Mometasone furoate (MF) is the inhaled corticosteroid (ICS) component in the long-acting β 2 -agonist (LABA)/ICS fixed-dose combination of indacaterol/MF, delivered via Breezhaler®, in development for asthma. MF at low (80 μg) and high (320 μg) doses delivered via Breezhaler® is expected to be comparable to MF at low (200 μg) and high (800 μg) doses respectively, delivered via Twisthaler®., Methods: This was a randomized, double-blind, double-dummy, four-week, parallel-group study of 739 adolescents and adults with persistent asthma. Eligible patients were receiving ICS treatment up to the maximum dose per day on a stable regimen for at least four weeks before screening. The study population was enriched for patients who were responsive to ICS therapy. The primary objective of the present study was to show non-inferiority of these doses, i.e. the low (80 μg) and high (320 μg) doses of MF delivered via Breezhaler® once daily, compared with the corresponding low (200 μg) and high (800 μg) doses of MF delivered via Twisthaler® once daily. The primary endpoint was 24 h post-dose trough forced expiratory volume in 1 s (FEV 1 ), after four weeks of treatment in patients with asthma. A secondary objective was to evaluate the efficacy of MF 80 μg and 320 μg delivered via Breezhaler®, and MF 200 μg and 800 μg delivered via Twisthaler® in terms of Asthma Control Questionnaire-5 (ACQ-5) after one, two, three and four weeks of treatment., Results: The LS mean difference in trough FEV 1 after four weeks of treatment between MF low dose 80 μg (Breezhaler®) and MF low dose 200 μg (Twisthaler®) was 27 mL (95% CI -34, 89); for MF high dose 320 μg (Breezhaler®) and MF high dose 800 μg (Twisthaler®) the difference was 0 mL (95% CI -60, 61). These differences were neither clinically nor statistically significant. All treatment arms provided similar clinically relevant improvements in ACQ-5 after four weeks of treatment compared with baseline. Both treatments showed a similar safety profile with a low incidence of adverse events., Conclusion: The similarities in effects on lung function and ACQ after four weeks of treatment demonstrate the comparability of MF at low (80 μg) and high (320 μg) doses delivered with Breezhaler® with MF at low (200 μg) and high (800 μg) doses delivered with Twisthaler®, respectively. The study formally demonstrated that MF, delivered via Breezhaler®, is non-inferior to MF, delivered via Twisthaler® at corresponding ICS doses., Competing Interests: Declarations of competing interest RB reports grants to Mainz University and personal fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche, as well as personal fees from AstraZeneca, Chiesi, Cipla, Sanofi and Teva, all outside the submitted work. AMT, MH, ID, FP, BH and HCT are employees of Novartis Pharma AG and own Novartis Pharma AG shares. WC is an employee of Novartis Pharmaceuticals Corporation. CB and JJ are employees of Novartis Pharma AG. DZ is an employee of Novartis Pharma AG and owns Novartis Pharma AG shares. DZ has led the development of Breezhaler® dry powder inhaler and was the technical project leader for the development of the Breezhaler® mometasone drug product. FK reports personal grants or fees for scientific work, presentations and Advisory boards in the last 5 years from Mundipharma, Astra Zeneca, Novartis and TEVA. However, all of these are outside the submitted work., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In this work, an alkalophilic bacterium (LVX-4) capable of using p-cresol as sole source of carbon and energy was screened and isolated from soil polluted by used oil. Phylogenetic (16S rRNA) and phenotypic characterization using Biolog GN microplates and API 20NE strips indicated that LVX-4 strain is a new Advenella species. It showed both the capability to degrade of p-cresol at high concentrations (750 mg/L) and to use p-cresol for growth in a pH from 7 to 10, although the optimum pH was 9. Moreover bioaugmentation of activated sludge with this strain lead to the complete removal of p-cresol in less than 100 h. This is the first study that shows the potential of Advenella sp. to be bioaugmented in activated sludge system for p-cresol biodegradation., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Genomic analysis of hepatocellular carcinoma (HCC) has been shown to provide clues about local risk factors. In the last decades, the mortality from malignant liver tumors increased sharply in Romania, where both hepatitis viruses and environmental pollutants are known to be highly prevalent. To date, HCC from this country has not been subject to molecular characterization. We analyzed a series of 48 consecutive HCC cases. Point mutations were searched in 9 nuclear genes and the mitochondrial D-loop. Oxidative stress response was monitored through measurement of gene expression (NRF2, KEAP1, SRXN1, and CES1) by qRT-PCR. An atypical mutation spectrum was observed, as more than 40% of DNA changes were oxidative stress-associated T>C or T>G lesions (T>S). These mutations affected primarily genes encoding for β-catenin and NRF2 (P<0.0001). Besides, tumors from patients born in Greater Bucharest carried TP53 mutations more frequently than others (45 vs 10%, P=0.02). Finally, a R249S mutation of TP53, well-known hallmark of aflatoxin B1 exposure, was found. Our findings indicate, therefore, that distinct mutagenic processes affect Romanian patients with HCC. Further analyses are now warranted in order to identify causal lifestyle or environmental factors.

Background: The global risk of hepatocellular carcinoma (HCC) is largely due to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. In recent years, however, an increased prevalence of non-viral HCC has been noted. The clinical impact of the presence/absence of viral infections in HCC remains controversial. The present study aimed to assess the effect of hepatitis viruses on demographics, clinical and pathological features and long-term outcome in a large cohort of Romanian patients who underwent surgery for HCC., Methods: The study included 404 patients with HCC who had undergone resection, transplantation or radiofrequency ablation at a single institution between 2001 and 2010. The patients were divided into four groups: 85 patients with hepatitis B virus infection (HBV group), 164 patients with hepatitis C virus infection (HCV group), 39 patients with hepatitis B and C virus co-infection (HBCV group), and 116 patients without viral infection (non-BC group)., Results: The patients of both HBV (56.0+/-11.3 years) and HBCV groups (56.0+/-9.9 years) were significantly younger than those of the HCV (61.0+/-8.5 years, P=0.001) and non-BC groups (61.0+/-13.0 years, P=0.002). Interestingly, the prevalence of liver cirrhosis was significantly lower in the non-BC group (47%) than in any other subsets (72%-90%, P<0.002). Furthermore, the non-BC patients were more advanced according to the Barcelona Clinic Liver Cancer stages than the patients of the HCV or HBCV groups (P<0.020); accordingly, they were more frequently assessed beyond the Milan criteria than any other groups (P=0.001). No significant differences in the disease-free or overall survival rates were observed among these groups., Conclusions: Patients with non-viral HCC are diagnosed at advanced ages and stages, a situation plausibly due to the poor effectiveness of cancer surveillance in community practice. The presence of viral infections does not appear to impair the long-term prognosis after surgical treatment in patients with HCC; however, there is a trend for worse disease-free survival rates in HBCV patients, though statistical significance was not reached.