SummaryMycobacteria have a unique outer membrane (OM) that is thicker than any other known biological membrane. Nutrients cross this permeability barrier by diffusion through porins. MspA is the major porin of Mycobacterium smegmatis . In this study we showed that three paralogues of MspA, namely MspB, MspC and MspD are also porins. However, only the mspA and mspC genes were expressed in the wild-type strain. None of the single deletion mutants displayed a significant OM permeability defect except for the mspA mutant. Deletion of the mspA gene caused activation of transcription of mspB and/or mspD in three independent strains by unknown chromosomal mutations. It is concluded that mspB and mspD provide backup porins for M. smegmatis . This also indicated that a minimal porin-mediated OM permeability is essential for survival of M. smegmatis . Electron microscopy in combination with quantitative image analysis of protein gels revealed that the number of pores per cell dropped from 2400 to 800 and 150 for the Δ Δ Δ Δ mspA and Δ Δ Δ Δ mspA Δ Δ Δ Δ mspC mutant (ML10) respectively. The very low number of pores correlated well with the at least 20-fold lower channel activity of detergent extracts of the ML10 strain and its 15-and 75-fold lower permeability to nutrient molecules such as serine and glucose respectively. The amount of Msp porin and the OM permeability of the triple porin mutant lacking mspA , mspC and mspD was not altered. The growth rate of M. smegmatis dropped drastically with its porin-mediated OM permeability in contrast to porin mutants of Escherichia coli . These results show that porin-mediated influx of nutrients is a major determinant of the growth rate of M. smegmatis .

Many patients with chronic obstructive pulmonary disease (COPD) receive inhaled corticosteroids (ICSs) without a clear indication, and thus, the impact of ICS withdrawal on disease control is of great interest. DACCORD is a prospective, noninterventional 2-year study in the primary and secondary care throughout Germany. A subgroup of patients were taking ICS prior to entry – 1,022 patients continued to receive ICS for 2 years; physicians withdrew ICS on entry in 236 patients. Data from these two subgroups were analyzed to evaluate the impact of ICS withdrawal. Patients aged ≥40 years with COPD, initiating or changing COPD maintenance medication were recruited, excluding patients with asthma. Demographic and disease characteristics, prescribed COPD medication, COPD Assessment Test, exacerbations, and lung function were recorded. There were few differences in baseline characteristics; ICS withdrawn patients had shorter disease duration and better lung function, with 74.2% of ICS withdrawn patients not exacerbating, compared with 70.7% ICS-continued patients. During Year 1, exacerbation rates were 0.414 in the withdrawn group and 0.433 in the continued group. COPD Assessment Test total score improved from baseline in both groups. These data suggest that ICS withdrawal is possible with no increased risk of exacerbations in patients with COPD managed in the primary and secondary care.

In conclusion, DACCORD is a large, prospective, non-interventional study that provides an informative and intriguing picture of the typical COPD patient in Germany.

BackgroundPhysical activity limitation is common in chronic obstructive pulmonary disease (COPD), and is associated with worse health status, and increased hospitalisation and mortality. Long-acting bronchodilators, either alone or in combination, have been shown to improve exercise intolerance. However, none of these studies were designed with physical activity as primary outcome.This study assessed the effect of indacaterol/glycopyrronium fixed dose combination (IND/GLY) 110/50 μg once daily (OD) versus placebo on lung hyperinflation (inspiratory capacity [IC]) and physical activity in patients with moderate-to-severe COPD.MethodsIn this multicentre, randomised, double-blind, placebo-controlled crossover study, patients received IND/GLY or placebo OD in two 21-day treatment periods (14-day washout between periods). Eligible patients were ≥40 years of age, current or ex-smokers (smoking history ≥10 pack-years), with post-salbutamol forced expiratory volume in 1 s (FEV1) 40–80 % predicted, and FEV1:forced vital capacity <0.70.The co-primary endpoints were peak IC after 21 days and average daily activity-related energy expenditure. Key secondary endpoints were average number of steps per day and the duration of at least moderate activity per day. Peak IC and FEV1 on Day 1, and trough IC and FEV1 after 21 days were other secondary endpoints.ResultsA total of 194 patients were randomised (65.5 % male, mean age 62.8 years, mean FEV1 61.6 % predicted), with 183 (94.3 %) completing the study.Compared with placebo, IND/GLY significantly increased peak IC after 21 days (difference 202 mL, p < 0.0001), activity-related energy expenditure (difference 36.7 kcal/day, p = 0.040), and the average number of steps per day (difference 358, p = 0.029), with a trend towards an improvement in the duration of at least moderate activity (difference 4.4 min, p = 0.264). IND/GLY was associated with statistically significant improvements versus placebo in peak IC and FEV1 on Day 1, and trough IC and FEV1 after 21 days. The incidence of treatment-emergent adverse events was 22.8 % with IND/GLY and 22.9 % with placebo.ConclusionsIn this study, compared with placebo, IND/GLY reduced hyperinflation, and, despite no patient education or lifestyle advice, improved daily physical activity levels. This suggests that IND/GLY has the potential to impact two of the main clinical concerns in the care of patients with COPD.Trial registrationClinicalTrials.gov number: NCT01996319.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-016-0256-7) contains supplementary material, which is available to authorized users.

Overall, the 2-year follow-up data from DACCORD suggest that for most patients with COPD exacerbations are a rare event. For the majority of patients, the focus should be on managing symptoms, and the impact that these symptoms have on their daily lives. Even for those patients who do exacerbate, although prevention of exacerbations is an important factor, management of symptoms should be a key consideration. DACCORD also suggests that COPD disease progression is not inevitable - providing patients are receiving pharmacological treatment.

IntroductionRandomized interventional trials generally recruit highly selected patients. In contrast, long-term, noninterventional studies can reflect standard of care of real-life populations. DACCORD (Die ambulante Versorgung mit langwirksamen Bronchodilatatoren: COPD-Register in Deutschland [Outpatient Care With Long-Acting Bronchodilators: COPD Registry in Germany]) is an ongoing observational study, conducted in primary and secondary care in Germany, aiming to describe the impact of disease and treatments on real-life patients with chronic obstructive pulmonary disease (COPD).MethodsPatients had a clinical and spirometry diagnosis of COPD, were aged ≥40 years, and were initiating or changing COPD maintenance medication. The only exclusion criteria were asthma and participation in a randomized clinical trial. Exacerbation data were collected every 3 months. COPD medication, COPD Assessment Test, and forced expiratory volume in 1 second (FEV1) were recorded at the end of the 1 year period.ResultsIn the 6 months prior to baseline, 26.5% of the 3,974 patients experienced ≥1 exacerbation, compared with 26.1% over the 1-year follow-up (annualized rate 0.384). Importantly, only previous exacerbations and not poor lung function alone predicted an increased exacerbation risk. There was a general shift to lower disease severity from baseline to 1 year, predominantly as a consequence of a lower proportion of patients considered at high risk due to exacerbations. COPD Assessment Test mean change from baseline was −1.9, with 48.9% of patients reporting a clinically relevant improvement. Overall persistence to medication was high, with 77.2% of patients still receiving the same class of medication at 1 year.ConclusionDACCORD suggests that in clinical practice, the large majority of COPD patients are symptomatic but seldom exacerbate and that widely used tools and treatment recommendations do not reflect this fully.

In the EU, five biologics have been approved as add-on therapy for patients with severe asthma. Until recently, none of the biologics was approved for home use and had to be administered under medical supervision, a time-consuming schedule for both patients and physicians, accompanied by greater expenditure. However, over the last year, four out of the five biologics have been granted approval for patient self-administration at home. The objective of this multiple-choice survey was to understand how patients with severe asthma treated with omalizumab and their treating physicians view the potential home use of biologics exemplified by omalizumab. The questionnaires were answered by 120 physicians and 432 patients (response rate: 51.7 % and 20.6 %, respectively). Overall, 44.7 % of patients were in favour of self-administration at home while 30.6 % opposed this method of administration and 23.8 % of patients were neutral. Especially teenagers and young adults had a positive attitude towards self-administration. 76.7 % of the questioned physicians were in favour of home use for certain patients. Time saving was the main advantage for self-administration mentioned by patients (53.2 %) as well as by physicians (72.5 %). The main concern for patients was ‘making a mistake while injecting’ (43.8 %) while ‘forgetting to inject omalizumab’ (73.3 %) was the main concern for physicians. 44.4 % of patients expressed a wish for individual training and 70.8 % of physicians agreed with this statement. The latter group also considered a starter kit including several information materials (54.2 %) as well as an electronic reminder system (50.8 %) as useful. In conclusion, self-administration of biologics has the potential to be timesaving for both patients and physicians.

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