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Summary Background Infection is a key component of bronchiectasis pathophysiology. Characterisation of the microbiome offers a higher degree of sensitivity and resolution than does traditional culture methods. We aimed to evaluate the role of the microbiome in determining the risk of exacerbation and long-term outcomes, including all-cause mortality, in bronchiectasis. Methods We did a prospective observational cohort study of patients with bronchiectasis from eastern Scotland. Patients were enrolled from Sept 11, 2012, to Dec 21, 2015, and followed until Jan 8, 2019, for long-term outcomes. Patients were included if they were aged 18 years or older, and had a high-resolution CT-confirmed diagnosis of bronchiectasis and clinical symptoms consistent with the disease. Sputum samples were obtained when patients were clinically stable. Repeat sputum samples were taken at stable and exacerbation visits during follow-up. The V3–V4 region of the bacterial 16S rRNA gene was sequenced using the Illumina MiSeq platform. The dominant bacterial genus in each sample was assigned on the basis of a previously published method. Microbiome characteristics were analysed for their association with measures of clinical disease severity and long-term outcomes using PERMANOVA, random forest, and survival analyses. Findings Sequencing data were obtained from the sputum samples of 281 patients with bronchiectasis who were included in the stable baseline cohort. 49 (17%) of 281 patients provided more than one sample when clinically stable and were included in the longitudinal analysis. 64 (23%) patients provided both stable and exacerbation samples. In both stable bronchiectasis and during exacerbations, a sputum microbiome dominated by Proteobacteria and Firmicutes was observed. Individual patients' microbiome profiles were relatively stable over time, during exacerbations and at disease stability. Lower microbiome diversity, measured using the Shannon-Wiener diversity index, was associated with more severe bronchiectasis defined by the bronchiectasis severity index, lower FEV1, and more severe symptoms. Random forest analysis of baseline samples identified Pseudomonas, Enterobacteriaceae, and Stenotrophomonas as being associated with severe bronchiectasis (bronchiectasis severity index ≥9) and greater lung inflammation and Pseudomonas and Enterobacteriaceae with more frequent exacerbations. Patients in whom Pseudomonas was dominant (n=35) were at increased risk of all-cause mortality (hazard ratio 3·12, 95% CI 1·33–7·36; p=0·0091) and had more frequent exacerbations (incident rate ratio 1·69, 95% CI 1·07–2·67; p=0·024) during follow-up compared with patients with other dominant genera (n=246). Interpretation A reduction in microbiome diversity, particularly one associated with dominance of Pseudomonas, is associated with greater disease severity, higher frequency and severity of exacerbations, and higher risk of mortality. The microbiome might therefore identify subgroups of patients at increased risk of poor outcomes who could benefit from precision treatment strategies. Further research is required to identify the mechanisms of reduced microbiome diversity and to establish whether the microbiome can be therapeutically targeted. Funding British Lung Foundation and European Respiratory Society EMBARC2 consortium.

Rationale: Bronchiectasis guidelines regard treatment to prevent exacerbation and treatment of daily symptoms as separate objectives.Objectives: We hypothesized that patients with greater symptoms ...

Background: Randomized Trials in bronchiectasis may have been underpowered due to unexpectedly large “placebo effects”. We used a combination of meta-analysis and analysis of the European Bronchiectasis Registry (EMBARC) to quantify “placebo effects” in randomized trials in bronchiectasis Method: We searched electronic databases from 1990-2019, to identify double blind, randomized, placebo-controlled trials of drug treatment in bronchiectasis. We defined the “placebo effects” by comparing the outcomes at the end of placebo treatment and at baseline prior to treatment. EMBARC registry data were employed to model changes in exacerbation rate and quality of life (QoL) Result: 27 trials were included for meta-analysis (N=1739 placebo-treated patients). Placebo treatment was associated with significantly reduced exacerbation rate (mean difference [MD] -1.79, -2.03 to -1.56; p Conclusion: Placebo treatment was associated with improved QoL and reduced exacerbation in bronchiectasis. Enrolling patients with 1 or more exacerbation may be an optimal inclusion criteria

Background: Bronchiectasis guidelines regard treatment to prevent exacerbation and relieve symptom as separate objective. We hypothesized that patients with greater symptoms would be at higher risk of exacerbation and therefore a treatment aimed at reducing symptoms would reduce exacerbations in highly symptomatic patients. Methods: An observational cohort of 333 patients are analyzed. Symptoms were either modelled as a continuous variable or patients were classified as high, moderate and low symptom burden (>70, 40-70 and Results: In the observational cohort symptoms were a significant predictor of future exacerbations (rate ratio [RR] 1.10, 95% confidence interval [CI] 1.03-1.17, P=0.005). Patients with high symptom scores had higher exacerbation rates (RR 1.74, 95% CI 1.12-2.72, P=0.01) over 12 months follow-up compared to those with low symptoms. Inhaled mannitol improved the time to first exacerbation (hazard ratio 0.56; 95% CI 0.40-0.77; P Conclusions: Highly symptomatic patients are at increased risk of exacerbations and have exacerbation benefit with inhaled mannitol.

Background: The MUSIC study is testing the impact of inhaled corticosteroid (ICS) and bronchodilator (LABA/LAMA) treatment on the upper and lower airway microbiome in patients with COPD (NCT02972476). Patients receiving ICS at baseline withdrew therapy for one month, followed by randomization to 3 different ICS regimes or combined LABA/LAMA for 3 months. Here we report rates of patients experiencing exacerbations during the withdrawal period Methods: Multicentre randomized controlled trial. Patients were aged >=40 years, current or exsmokers, FEV1/FVC Results: 122 patients were enrolled from 6 study sites. 52.5% of patients were male, mean age 67 years (standard deviation(SD) 8.1), and mean post-bronchodilator FEV1 54.9% predicted (SD 20.7). 48 patients had blood eosinophil counts 300cells/ul (18.0%). 57 patients experienced an exacerbation or adverse event leading to withdrawal during month 1., Rates of failure ranged from 42-69% with no differences between sites (p=0.52). Failure rates were 56.3% in low, 46.2% in moderate, 45.5% in high eosinophil groups (p=0.54). Failure rates were significantly higher in patients with FEV1 50% (41.8%), (odds ratio 2.23 95% CI 1.06 – 4.67,p=0.034). Conclusion: We found a high failure rate during 1 month switch to LABA/LAMA, particularly in patients with severe and very severe lung function impairment.

Summary Background Bronchiectasis is predominantly a neutrophilic inflammatory disease. There are no established therapies that directly target neutrophilic inflammation because little is understood of the underlying mechanisms leading to severe disease. Neutrophil extracellular trap (NET) formation is a method of host defence that has been implicated in multiple inflammatory diseases. We aimed to investigate the role of NETs in disease severity and treatment response in bronchiectasis. Methods In this observational study, we did a series of UK and international studies to investigate the role of NETs in disease severity and treatment response in bronchiectasis. First, we used liquid chromatography-tandem mass spectrometry to identify proteomic biomarkers associated with disease severity, defined using the bronchiectasis severity index, in patients with bronchiectasis (n=40) in Dundee, UK. Second, we validated these biomarkers in two cohorts of patients with bronchiectasis, the first comprising 175 patients from the TAYBRIDGE study in the UK and the second comprising 275 patients from the BRIDGE cohort study from centres in Italy, Spain, and UK, using an immunoassay to measure NETs. Third, we investigated whether pathogenic bacteria had a role in NET concentrations in patients with severe bronchiectasis. In a separate study, we enrolled patients with acute exacerbations of bronchiectasis (n=20) in Dundee, treated with intravenous antibiotics for 14 days and proteomics were used to identify proteins associated with treatment response. Findings from this cohort were validated in an independent cohort of patients who were admitted to the same hospital (n=20). Fourth, to assess the potential use of macrolides to reduce NETs in patients with bronchiectasis, we examined two studies of long-term macrolide treatment, one in patients with bronchiectasis (n=52 from the UK) in which patients were given 250 mg of azithromycin three times a week for a year, and a post-hoc analysis of the Australian AMAZES trial in patients with asthma (n=47) who were given 500 mg of azithromycin 3 times per week for a year. Findings Sputum proteomics identified that NET-associated proteins were the most abundant and were the proteins most strongly associated with disease severity. This finding was validated in two observational cohorts, in which sputum NETs were associated with bronchiectasis severity index, quality of life, future risk of hospital admission, and mortality. In a subgroup of 20 patients with acute exacerbations, clinical response to intravenous antibiotic treatment was associated with successfully reducing NETs in sputum. Patients with Pseudomonas aeruginosa infection had a lessened proteomic and clinical response to intravenous antibiotic treatment compared with those without Pseudomonas infections, but responded to macrolide therapy. Treatment with low dose azithromycin was associated with a significant reduction in NETs in sputum over 12 months in both bronchiectasis and asthma. Interpretation We identified NETs as a key marker of disease severity and treatment response in bronchiectasis. These data support the concept of targeting neutrophilic inflammation with existing and novel therapies. Funding Scottish Government, British Lung Foundation, and European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC).

BackgroundCoronavirus disease 2019 (COVID-19) is an international emergency that has been addressed in many countries by changes in and restrictions on behaviour. These are often collectively labelled social distancing and lockdown. On the 23rd June 2020, Boris Johnson, the Prime Minister of the United Kingdom announced substantial easings of restrictions. This paper examines some of the data he presented.MethodsGeneralised additive models, with negative binomial errors and cyclic term representing day-of-week effects, were fitted to data on the daily numbers of new confirmed cases of COVID-19. Exponential rates for the epidemic were estimated for different periods, and then used to calculate R, the reproduction number, for the disease in different periods.ResultsAfter an initial stabilisation, the lockdown reduced R to around 0.81 (95% CI: 0.79, 0.82). This value increased to around 0.94 (95% CI 0.89, 0.996) for the fortnight from the 9th June 2020.ConclusionsOfficial UK data, presented as the easing of the lockdown was announced, shows that R was already more than half way back to 1 at that point. That suggests there was little scope for the announced changes to be implemented without restarting the spread of the disease.

Germline SDHA mutations are reported in a minority of pheochromocytoma/paraganglioma (PPGL) cases but are associated with an increased risk of malignancy, leading some to advocate cascade genetic testing and surveillance screening of "at-risk" first-degree relatives. However, such approaches rely on accurate estimates of variant pathogenicity and disease penetrance, which may have been subject to ascertainment and reporting biases, although the recent provision of large population-based DNA sequence data sets may provide a potentially unbiased resource to aid variant interpretation. Thus, the aim of the current study was to evaluate the pathogenicity and penetrance of SDHA variants reported in literature-based PPGL cases by comparing their frequency to those occurring in the Genome Aggregation Database (GnomAD) data set, which provides high-quality DNA sequence data on 138,632 individuals. In total, 39 different missense or loss-of-function (LOF) SDHA variants were identified in 95 PPGL index cases. Notably, many of the PPGL-associated SDHA alleles were observed at an unexpectedly high frequency in the GnomAD cohort, with ~1% and ~0.1% of the background population harboring a rare missense or LOF variant, respectively. Although the pathogenicity of several SDHA alleles was supported by significant enrichment in PPGL cases relative to GnomAD controls, calculations of disease penetrance based on allele frequencies in the respective cohorts resulted in much lower estimates than previously reported, ranging from 0.1% to 4.9%. Thus, although this study provides support for the etiological role of SDHA in PPGL formation, it suggests that most variant carriers will not manifest PPGLs and are unlikely to benefit from periodic surveillance screening.

COPD exacerbations are associated with worsening symptoms including cough, shortness of breath, sputum production and worsening airflow obstruction. Increased number of exacerbations is associated with morbidity and mortality [1]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Keir has nothing to disclose. Conflict of interest: Dr. Dicker has nothing to disclose. Conflict of interest: Dr. Lonergan has nothing to disclose. Conflict of interest: Dr. Crichton has nothing to disclose. Conflict of interest: Dr. Miller reports other from GSK, outside the submitted work. Conflict of interest: Dr. Tal-Singer reports other from GSK, outside the submitted work. Conflict of interest: Dr. Chalmers reports grants from Glaxosmithkline, during the conduct of the study; grants and personal fees from Glaxosmithkline, grants and personal fees from Boehringer-Ingelheim, grants from Astrazeneca, grants and personal fees from Pfizer, grants and personal fees from Bayer Healthcare, grants and personal fees from Grifols, personal fees from Napp, personal fees from Aradigm corporation, grants and personal fees from Insmed, outside the submitted work.

Inhaled antibiotics may improve symptom scores, but it is not known which specific symptoms improve with therapy. Item-level analysis of questionnaire data may allow us to identify which specific symptoms respond best to treatment.Aztreonam improved cough (difference 0.22, 95% CI 0.08-0.37; p=0.002), sputum production (0.30, 95% CI 0.15-0.44; p0.0001) and sputum colour (0.29, 95% CI 0.15-0.43; p0.0001)Baseline bronchitic symptoms predict response to inhaled aztreonam in bronchiectasis. More sensitive tools to measure bronchitic symptoms may be useful to better identify inhaled antibiotic responders and to evaluate patient response to treatment.

Re-examination of the large dataset collected and meta-analysed by Dr Chu and his colleagues contradicts their conclusions about the effects of separation distance on infection risk. Their conclusion was based on misunderstandings of the datasets. Each of these estimated risk relative to that incurred when touching infected individuals. Allowing for this suggests that the main advantage of social distancing, a perhaps 78% (95% CI 24, 92) reduction in risk of infection, occurs at distances below 1m. The data imply an 11% chance of further distances reducing the risk, with any effects likely to be small. However the limitations of the dataset do limit the strength of these conclusions.

Background: Bronchiectasis is predominantly a neutrophilic inflammatory disease. There are no established therapies that directly target neutrophilic inflammation because of a lack of understanding of the underlying mechanisms leading to severe disease. Neutrophil extracellular trap (NET) formation is a mode of host defence that has been implicated in multiple inflammatory diseases. Methods: We conducted a series of UK and international studies to investigate the role of NETs in disease severity and treatment response in bronchiectasis. Nano LC/MS-MS was used to identify proteomic markers associated with disease severity, defined using the bronchiectasis severity index (BSI) (n=40). These were validated in two cohorts (n=175 and n=275) using a validated immunoassay to measure NETs. 20 patients with acute exacerbations of bronchiectasis were treated with intravenous antibiotics for 14 days and proteomics used to identify proteins associated with treatment response. Two studies of long-term macrolide treatment, one in bronchiectasis and a post-hoc analysis of the AMAZES trial in asthma, investigated the effect of macrolide treatment on NETs. Findings: 96 proteins were differentially expressed in sputum between severe and mild bronchiectasis. The most abundant and most discriminating were proteins known to be NET proteins. This was validated in two observational cohorts where sputum NETs were associated with BSI, quality of life, lung function, future risk of hospital admissions and mortality. Antibiotic treatment in 20 patients was associated with 23 significantly down-regulated and 16 up-regulated proteins, with the “neutrophil degranulation” pathway being most strongly implicated in response. Patients with Pseudomonas aeruginosa infection had a blunted proteomic and clinical response to treatment. Treatment with low dose azithromycin was associated with a significant reduction in NETs in sputum over 12 months in both bronchiectasis and asthma. Interpretation: NETs are identified as a key marker of disease severity and treatment response in bronchiectasis. Funding: Supported by the Scottish Government Chief Scientist Office (Senior Clinical Fellowship to JDC) and British Lung Foundation through the BLF Chair of Respiratory Research. Supported by the European Bronchiectasis Network (EMBARC), a European Respiratory Society Clinical Research Collaboration. Declaration of Interests: None to declare Ethics Approval Statement: The studies were approved by local research ethics committees and patients provided informed consent.

Background The sputum microbiome has a potential role in disease phenotyping and risk stratification in chronic obstructive pulmonary disease (COPD), but few large longitudinal cohort studies exist. Objective Our aim was to investigate the COPD sputum microbiome and its association with inflammatory phenotypes and mortality. Methods 16S ribosomal RNA gene sequencing was performed on sputum from 253 clinically stable COPD patients (4-year median follow-up). Samples were classified as Proteobacteria or Firmicutes (phylum level) and Haemophilus or Streptococcus (genus level) dominant. Alpha diversity was measured by using Shannon-Wiener diversity and Berger-Parker dominance indices. Survival was modeled by using Cox proportional hazards regression. A subset of 78 patients had label-free liquid chromatography with tandem mass spectrometry performed, with partial least square discriminant analysis integrating clinical, microbiome, and proteomics data. Results Proteobacteria dominance and lower diversity was associated with more severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease classification system (P = .0015), more frequent exacerbations (P = .0042), blood eosinophil level less than or equal to 100 cells/μL (P Conclusion The sputum microbiome is associated with clinical and inflammatory phenotypes in COPD. Reduced microbiome diversity, associated with Proteobacteria (predominantly Haemophilus) dominance, is associated with neutrophil-associated protein profiles and an increased risk of mortality.

Background: Bronchiectasis (BE) guidelines recommend long term macrolide treatment for patients with ≥3 exacerbations/year without P aeruginosa infection. Randomized controlled trials (RCTs) suggest that long term macrolide treatment can prevent exacerbations in adult patients with BE but these studies have been too small to conduct meaningful subgroup analyses. Aims: To explore macrolide benefit in subpopulations, including those where macrolide therapy is not currently recommended, using individual patient data (IPD) meta-analysis. Methods: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched to identify RCT’s of macrolide antibiotics for at least 3 months with a primary outcome of BE exacerbations. IPD meta-analysis was performed using fixed effects models adjusting for age, sex, FEV1 and trial. Results: IPD was obtained for 341 participants in 3 RCTs. Macrolides reduced the frequency of exacerbations adjusted incidence rate ratio (IRR) 0.49 95% CI 0.36-0.66,p Conclusions: Long-term macrolide treatment significantly reduces the rate of exacerbations in patients with BE with similar benefits observed in all subgroups based on patient characteristics.

Introduction: Bronchiectasis and COPD are two disease entities with overlapped clinical features but whether underlying biology supports a “treatable traits” approach is unknown. Aim: To investigate the endotypic differences in sputum microbiome and proteome between patients with BE, COPD, and the overlap. Methods: Patients with BE (n=61, age 72±8 years, FEV1(pred) 85±23), COPD (n=56, age 72±9 years, FEV1(pred) 67±22%), and the overlap (n=63, age 72±8 years, FEV1(pred) 66±24%) were included. Sputum microbiome and protein profiling were carried out using 16S rRNA sequencing and a label-free proteomics workflow, respectively. Results: Principle component analysis of combined sputum microbiome (1,393 OTUs) and proteome profiles (614 proteins) revealed two clusters that partially separate COPD patients with BE from those without (Figure). COPD patients with BE were co-clustered with patients with BE. Patients with BE (regardless of COPD status) were predominantly associated with a proteobacteria dominant microbiome profile and a proteome profile over-represented with the “neutrophil degranulation” pathway (over-representation p=8E-13). In contrast, COPD patients without BE displayed a higher microbiome diversity, a firmicutes dominant microbiome profile and higher expression of IGK, PIGR, AZGP1 and TCN1. Conclusion: Independent of COPD status, BE is a dominant trait associated with a proteobacteria and neutrophilic endotype.

Introduction: COPD is a heterogenous disease which makes identifying patients more likely to respond to a particular treatment or at higher risk of poor clinical outcomes challenging. Methods: Microbiome characterization by 16S bacterial rRNA gene sequencing was performed on sputum samples obtained from 297 COPD patients studied during stable disease with a median follow up of 4 years. Samples were classified at the phyla level as proteobacteria or firmicutes dominant whilst at the genera level samples were classed as Haemophilus or Streptococcus dominant. If no phyla or genera was represented at greater than 40% these were classed as “balanced microbiomes”. The results were compared to clinical characteristics to determine the utility of stable disease microbiome in predicting outcomes. Results: Proteobacteria dysbiosis and loss of microbiota diversity (Shannon-Wiener Diversity Index) was associated with more severe COPD by GOLD stage (P=0.0007), more frequent prior exacerbations (P=0.0057), low blood eosinophil counts ( Proteobacteria dysbiosis was associated with an increased risk of mortality (HR 2.39 95% CI 1.23-4.66, p=0.01) compared to those with a balanced or firmicutes dominated microbiome. Uniquely among Firmicutes, patients with a Streptococcus dominated microbiome had an increased mortality risk (HR 2.58 95% CI 1.03-6.46, p= 0.043) when compared to those with balanced microbiomes. Conclusions: Reduced microbiome diversity, driven by Proteobacteria (predominantly Haemophilus) or Streptococcus dysbiosis is associated with increased mortality and may indicate COPD endotypes at increased risk of negative outcomes. Funder: GSK

Funding: part-funded by the UK Natural Environment Research Council to SMRU (Grant no. SMRU1001). 1. Grey seals (Halichoerus grypus) were the first mammals to be protected by an Act of Parliament in the UK and are currently protected under UK, Scottish, and EU conservation legislation. Reporting requirements under each of these statutes requires accurate and timely population estimates. Monitoring is principally conducted by aerial surveys of the breeding colonies; these are used to produce estimates of annual pup production. Translating these data to estimates of adult population size requires information about demographic parameters such as fecundity and sex ratio. 2. An age‐structured population dynamics model is presented, which includes density dependence in pup survival, with separate carrying capacities in each of the four breeding regions considered (North Sea, Inner Hebrides, Outer Hebrides, and Orkney). This model is embedded within a Bayesian state–space modelling framework, allowing the population model to be linked to available data and the use of informative prior distributions on demographic parameters. A computer‐intensive fitting algorithm is presented based on particle filtering methods. 3. The model is fitted to region‐level pup production estimates from 1984 to 2010 and an independent estimate of adult population size, derived from aerial surveys of hauled‐out seals in 2008. The fitted model is used to estimate total population size from 1984 to 2010. 4. The population in the North Sea region has increased at a near‐constant rate; growth in the other three regions began to slow in the mid‐1990s and these populations appear to have reached carrying capacity. The total population size of seals aged 1 year or older in 2010 was estimated to be 116 100 (95% CI 98 400–138 600), an increase of

We are grateful to Professor Morice for his reminder of the limits of observational data, and the need for caution in its interpretation [1]. And we accept that it is unlikely to ever be proved conclusively that the dramatic restrictions imposed as countries locked down caused the dramatic changes in epidemic trajectories, even though the epidemiological changes seemed to follow the behavioural changes. However, there is also a large logical leap from observing the Swedish data to inferring that social distancing “measures can only have had a minor effect”., There are limitations to inferring causality from observational data, but lockdowns have almost certainly saved lives worldwide

By 21st May 2020, SARS-CoV-2 had caused more than 5 million cases of COVID-19 across more than 200 countries. Most countries with significant outbreaks have introduced social distancing or “lockdown” measures to reduce viral transmission. So the key question now is when, how, and to what extent, these measures can be lifted. Publically available data, on daily numbers of newly-confirmed cases and mortality, were used to fit regression models estimating trajectories, doubling times and the reproduction number (R0) of the disease, before and under the control measures. These data ran up to 21st May 2020, and were sufficient for analysis in 89 countries. The estimates of R0, before lockdown, based on these data were broadly consistent with those previously published: between 2.0 and 3.7 in the countries with the largest number of cases available for analysis (USA, Italy, Spain, France and UK). There was little evidence to suggest that the restrictions had reduced R far below 1 in many places, with France having the most rapid reductions – R0 0.76 (95%CI 0.72–0.82), based on cases and 0.77 (95%CI 0.73–0.80) based on mortality. Intermittent lockdown has been proposed as a means of controlling the outbreak while allowing periods of increase freedom and economic activity. These data suggest that few countries could have even 1 week per month unrestricted without seeing resurgence of the epidemic. Similarly, restoring 20% of the activity that has been prevented by the lockdowns looks difficult to reconcile with preventing the resurgence of the disease in most countries., Data from multiple countries show that current restrictions on behaviour barely contain the spread of COVID19. Resuming 20% of the currently excluded contact between individuals looks sufficient to restart the epidemic's progression in many countries.

Rationale: The principal underlying inhaled antibiotic treatment in bronchiectasis is that airway bacterial load drives inflammation, and therefore antibiotic treatment will reduce symptoms. Objectives: To determine the relationship between bacterial load and clinical outcomes, assess the stability of bacterial load over time, and test the hypothesis that response to inhaled antibiotics would be predicted by baseline bacterial load. Methods: We performed three studies. Studies 1 and 2 were prospective studies including adults with bronchiectasis. Study 3 was a post hoc analysis of a randomized trial of inhaled aztreonam. A priori patients were divided into low (= 10(7) cfu/g) using quantitative sputum culture. Measurements and Main Results: Bacterial load was a stable trait associated with worse quality of life and more airway inflammation in studies 1, 2, and 3. In study 3, patients with high bacterial load showed an improvement in the primary endpoint (Quality of Life-Bronchiectasis-Respiratory Symptoms Score at Week 4) in favor of aztreonam (mean difference of 9.7 points; 95% confidence interval, 3.4-16.0; P = 0.003). The proportion of patients who achieved an increase above the minimum clinically important difference was higher in the aztreonam group at Week 4 (63% vs. 37%; P = 0.01) and at Week 12 (62% vs. 38%; P = 0.01) only in high bacterial load patients. Conclusions: Improvement of quality of life with inhaled aztreonam was only evident in patients with high bacterial load. Bacterial load may be a useful biomarker of severity of disease and treatment response.

Background: Bronchiectasis guidelines recommend long-term macrolide treatment for patients with three or more exacerbations per year without Pseudomonas aeruginosa infection. Randomised controlled trials suggest that long-term macrolide treatment can prevent exacerbations in adult patients with bronchiectasis, but these individual studies have been too small to do meaningful subgroup analyses. We did a systematic review and individual patient data (IPD) meta-analysis to explore macrolide benefit in subpopulations, including those in which macrolide therapy is not currently recommended. Methods: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science from Jan 1, 2000, to Sept 30, 2018, to identify double blind, randomised, placebo-controlled trials of macrolide antibiotics in adult patients with bronchiectasis. We applied no language restrictions. Randomised controlled trials were eligible if treatment was defined a priori as long term and had a primary or secondary outcome of bronchiectasis exacerbations. Studies in patients with cystic fibrosis bronchiectasis were excluded. The primary outcome of the meta-analysis was frequency of exacerbations requiring treatment with antibiotics. Secondary endpoints were time to first exacerbation, change in quality of life according to the St George's Respiratory Questionnaire (SGRQ), and change in FEV1. IPD meta-analysis was done using fixed effects models adjusting for age, sex, FEV1, and trial. We did prespecified subgroup analyses for each of the primary and secondary endpoints using one-step meta-analysis only. Subgroups were defined by age, sex, previous exacerbation frequency, smoking status, inhaled corticosteroid use at baseline, body-mass index at baseline, cause, C-reactive protein at baseline, baseline FEV1 percentage of predicted, SGRQ total score, and Pseudomonas aeruginosa in sputum culture at baseline. The meta-analysis is registered with the PROSPERO international register of systematic reviews, number CRD42018102908. Findings: Of 234 identified studies, we included three randomised controlled trials, and IPD was obtained for 341 participants. Macrolide antibiotics reduced the frequency of exacerbations (adjusted incidence rate ratio [IRR] 0·49, 95% CI 0·36 to 0·66; p

Introduction: Infection is a key component of the pathophysiology of bronchiectasis. Characterisation of the microbiome offers a higher degree of sensitivity and resolution than traditional culture to evaluate the importance of infection in determining the risk of exacerbation and long-term outcomes, including mortality, in bronchiectasis. Methods: Sputum samples from 281 patients with bronchiectasis included in a longitudinal cohort of patients from two hospitals in the East of Scotland underwent 16S rRNA amplicon sequencing. Sputum supernatant was used to measure neutrophil elastase activity by immunoassay. Patients were enrolled from 2012-2015 and followed up until January 2019 for long term outcomes. Repeat sputum samples were obtained at exacerbation and stable visits during follow-up. Dominant genera was assigned based on a previously published method. Microbiome characteristics were compared to measures of clinical disease severity and long term outcomes. Results: In both stable bronchiectasis and during exacerbations, a microbiome dominated by Proteobacteria and Firmicutes was observed. Beta diversity analysis indicated that patients' microbiomes were relatively stable over time and showed less variation than that observed between patients. During disease stability, reduced Shannon-Wiener Diversity Index was associated with higher bronchiectasis severity (P

IntroductionInhaled antibiotics may improve symptom scores, but it is not known which specific symptoms improve with therapy. Item-level analysis of questionnaire data may allow us to identify which specific symptoms respond best to treatment.MethodsPost hoc analysis of the AIR-BX1 studies and two trials of inhaled aztreonam versus placebo in bronchiectasis. Individual items from the quality of life bronchiectasis (QOL-B) respiratory symptom scale, were extracted as representing severity of nine distinct symptoms. Generalised linear models were used to evaluate changes in symptoms with treatment versus placebo from baseline to end of first on-treatment cycle and mixed models were used to evaluate changes across the full 16-week trial.ResultsAztreonam improved cough (difference 0.22, 95% CI 0.08–0.37; p=0.002), sputum production (0.30, 95% CI 0.15–0.44; pversus placebo equating to a 20% improvement in cough and 25% improvement in sputum production and colour. Similar results were observed for cough, sputum production and sputum purulence across the trial duration (all pConclusionBaseline bronchitic symptoms predict response to inhaled aztreonam in bronchiectasis. More sensitive tools to measure bronchitic symptoms may be useful to better identify inhaled antibiotic responders and to evaluate patient response to treatment.

Germline SDHA mutations are reported in a minority of pheochromocytoma/paraganglioma (PPGL) cases but are associated with an increased risk of malignancy, leading some to advocate cascade genetic testing and surveillance screening of “at-risk” first-degree relatives. However, such approaches rely on accurate estimates of variant pathogenicity and disease penetrance, which may have been subject to ascertainment and reporting biases, although the recent provision of large population-based DNA sequence data sets may provide a potentially unbiased resource to aid variant interpretation. Thus, the aim of the current study was to evaluate the pathogenicity and penetrance of SDHA variants reported in literature-based PPGL cases by comparing their frequency to those occurring in the Genome Aggregation Database (GnomAD) data set, which provides high-quality DNA sequence data on 138,632 individuals. In total, 39 different missense or loss-of-function (LOF) SDHA variants were identified in 95 PPGL index cases. Notably, many of the PPGL-associated SDHA alleles were observed at an unexpectedly high frequency in the GnomAD cohort, with ~1% and ~0.1% of the background population harboring a rare missense or LOF variant, respectively. Although the pathogenicity of several SDHA alleles was supported by significant enrichment in PPGL cases relative to GnomAD controls, calculations of disease penetrance based on allele frequencies in the respective cohorts resulted in much lower estimates than previously reported, ranging from 0.1% to 4.9%. Thus, although this study provides support for the etiological role of SDHA in PPGL formation, it suggests that most variant carriers will not manifest PPGLs and are unlikely to benefit from periodic surveillance screening., Germline SDHA variants are enriched in patients with pheochromocytoma/paraganglioma but are associated with very low disease penetrance such that most variant carriers will not manifest disease.

OBJECTIVEThe impact of taking oral glucose-lowering medicines intermittently, rather than as recommended, is unclear. We conducted a retrospective cohort study using community-acquired U.K. clinical data (Clinical Practice Research Database [CPRD] and GoDARTS database) to examine the prevalence of nonadherence to treatment for type 2 diabetes and investigate its potential impact on HbA1c reduction stratified by type of glucose-lowering medication.RESEARCH DESIGN AND METHODSData were extracted for patients treated between 2004 and 2014 who were newly prescribed metformin, sulfonylurea, thiazolidinedione, or dipeptidyl peptidase 4 inhibitors and who continued to obtain prescriptions over 1 year. Cohorts were defined by prescribed medication type, and good adherence was defined as a medication possession ratio ≥0.8. Linear regression was used to determine potential associations between adherence and 1-year baseline-adjusted HbA1c reduction.RESULTSIn CPRD and GoDARTS, 13% and 15% of patients, respectively, were nonadherent. Proportions of nonadherent patients varied by the oral glucose-lowering treatment prescribed (range 8.6% [thiazolidinedione] to 18.8% [metformin]). Nonadherent, compared with adherent, patients had a smaller HbA1c reduction (0.4% [4.4 mmol/mol] and 0.46% [5.0 mmol/mol] for CPRD and GoDARTs, respectively). Difference in HbA1c response for adherent compared with nonadherent patients varied by drug (range 0.38% [4.1 mmol/mol] to 0.75% [8.2 mmol/mol] lower in adherent group). Decreasing levels of adherence were consistently associated with a smaller reduction in HbA1c.CONCLUSIONSReduced medication adherence for commonly used glucose-lowering therapies among patients persisting with treatment is associated with smaller HbA1c reductions compared with those taking treatment as recommended. Differences observed in HbA1c responses to glucose-lowering treatments may be explained in part by their intermittent use.

Aerial surveys have detected alarming declines in counts of harbour seals in several regions across Scotland. Demographic data and simple models were used to examine the recent decline in the numbers of harbour seals counted in one population within a Special Area of Conservation (SAC) on the east coast of Scotland. The models suggest that the continuation of current trends would result in the species effectively disappearing from this area within the next 20 years. While the cause of the decline is unknown, it must be reducing adult survival because the high rate of decline cannot be wholly accounted for by changes in other demographic parameters. Recovery of the population to the abundance recorded at the time the SAC was designated (2005) is likely to take at least 40 years, even if the cause of the decline is immediately identified and removed. The models suggest that partial removal of the cause can have only limited benefits to population recovery, and there are unlikely to be any long-term benefits from introducing or reintroducing additional individuals while the underlying problem persists. Therefore, if the population of harbour seals in this area is to recover it is essential that the sources of the increased mortality are identified and measures are put in place to manage these. Copyright © 2015 John Wiley & Sons, Ltd.

OBJECTIVE The choice of therapy for type 2 diabetes after metformin is guided by overall estimates of glycemic response and side effects seen in large cohorts. A stratified approach to therapy would aim to improve on this by identifying subgroups of patients whose glycemic response or risk of side effects differs markedly. We assessed whether simple clinical characteristics could identify patients with differing glycemic response and side effects with sulfonylureas and thiazolidinediones. RESEARCH DESIGN AND METHODS We studied 22,379 patients starting sulfonylurea or thiazolidinedione therapy in the U.K. Clinical Practice Research Datalink (CPRD) to identify features associated with increased 1-year HbA1c fall with one therapy class and reduced fall with the second. We then assessed whether prespecified patient subgroups defined by the differential clinical factors showed differing 5-year glycemic response and side effects with sulfonylureas and thiazolidinediones using individual randomized trial data from ADOPT (A Diabetes Outcome Progression Trial) (first-line therapy, n = 2,725) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) (second-line therapy, n = 2,222). Further replication was conducted using routine clinical data from GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) (n = 1,977). RESULTS In CPRD, male sex and lower BMI were associated with greater glycemic response with sulfonylureas and a lesser response with thiazolidinediones (both P < 0.001). In ADOPT and RECORD, nonobese males had a greater overall HbA1c reduction with sulfonylureas than with thiazolidinediones (P < 0.001); in contrast, obese females had a greater HbA1c reduction with thiazolidinediones than with sulfonylureas (P < 0.001). Weight gain and edema risk with thiazolidinediones were greatest in obese females; however, hypoglycemia risk with sulfonylureas was similar across all subgroups. CONCLUSIONS Patient subgroups defined by sex and BMI have different patterns of benefits and risks on thiazolidinedione and sulfonylurea therapy. Subgroup-specific estimates can inform discussion about the choice of therapy after metformin for an individual patient. Our approach using routine and shared trial data provides a framework for future stratification research in type 2 diabetes.

Detailed models have the potential to reveal important processes underlying patterns in data. However, model fitting depends on the availability of sufficient data, and the results obtained from the models depend on detailed assumptions. In a recent paper, Matthiopoulos et al. fitted Bayesian state space models to a limited dataset and attempted to explain the recent trajectory of the harbour seal population in the Moray Firth, in northern Scotland. They went on to suggest that the results could help explain recent declines in other nearby populations. This Comment describes the implications of understating the uncertainty that the model required for convergence, questions the robustness of the results, highlights the differences between the areas, and cautions against extrapolating across these populations. The distinction between models that can be fitted to a dataset and those that provide useful information about the systems that generated the data is also considered.

A method of dating the marine growth circuli on Atlantic salmon (Salmo salar L.) scales is presented. Data were available for 54 salmon, intercepted as smolts at the completion of their downstream migration in the River North Esk, Scotland. Smolts were tagged, released, and recaptured as return adults after either one (1SW) or two (2SW) winters at sea. Dating of circuli was achieved by fitting a simple quadratic model to the circuli pertaining to fixed points on the scale. For 1SW fish, the latter were the dates of river emigration and completion of marine migration, and the midpoint circulus (equal to the winter solstice) of the winter annulus. For 2SW salmon, these were the date of emigration and the two winter annulus midpoints. A key assumption is that winter annulus formation arises from constraints of light availability on foraging, and hence, reduced growth rate. Comparative analyses indicate the method to be robust and effectively transferable to salmon of known capture date — but of unknown smolt emigration date — by assuming a fixed date of emigration; in such cases, circuli could still be allocated with confidence to a calendar month.

The premise for stratified medicine is that drug efficacy, drug safety, or both, vary between groups of patients, and biomarkers can be used to facilitate more targeted prescribing, with the aim of improving the benefit:risk ratio of treatment. However, many factors can contribute to the variability in response to drug treatment. Inadequate characterisation of the nature and degree of variability can lead to the identification of biomarkers that have limited utility in clinical settings. Here, we discuss the complexities associated with the investigation of variability in drug efficacy and drug safety, and how consideration of these issues a priori, together with standardisation of phenotypes, can increase both the efficiency of stratification procedures and identification of biomarkers with the potential for clinical impact.

Todd, C. D., Friedland, K. D., MacLean, J. C., Whyte, B. D., Russell, I. C., Lonergan, M. E., and Morrissey, M. B. 2012. Phenological and phenotypic changes in Atlantic salmon populations in response to a changing climate. – ICES Journal of Marine Science, 69: 1686–1698. Atlantic salmon (Salmo salar) of southern European origin migrating to the Norwegian Sea currently encounter anomalously high sea-surface temperatures, and returning adults are of low mean condition factor. For the River North Esk (Scotland), time-series changes in river age-structure of emigrant smolts and returning one- and two-sea-winter (1SW and 2SW) adults are assessed. A comparison of the river age-structure of returning adults (1977–1999) with that of their respective annual emigrant smolt cohorts shows no evidence of river age-related bias in survivorship at sea. Evidence is presented of a possible transgenerational, or maternal, influence (poor somatic condition of spawners) driving reduced quality of emigrant S2 smolts in the North Esk. This effect is concurrent with an influence of freshwater climate as indicated by the North Atlantic Oscillation Index (NAOI). The maternal influence and NAOI variation in the winter immediately prior to smolt migration jointly explain approximately 29 (S2) and 17% (S3), respectively, of the variation in the mean size of smolts over the period 1975–2010. Run-timing of 1SW adult cohorts returning to Scotland shows recent delays. Variation in river flow did influence mean return date for the River Tweed, but adult condition factor, which itself shows temporal trends likely to be associated with ocean climate change, was the primary significant explanatory variable for run-timing in the rivers North Esk and Tweed. Overall, in years of poorer adult condition, 1SW salmon stay at sea longer.

Estimates of both absolute abundance and trends in abundance are among the most basic pieces of information required for planning the conservation and management of wildlife populations. They are important for understanding both the current situation of species and potential risks to them. This study presents estimates of the size of the harbour seal (Phoca vitulina) population associated with the Orkney Islands, a part of northern Scotland that used to contain one of the largest concentrations of this species in Europe. The numbers of animals counted during aerial surveys of this area have decreased substantially over the period 2001–2010. ARGOS transmitters attached to flipper tags were used to rescale the counts into estimates of abundance and to confirm the rate of decline of this population. Females hauled out for more of the survey window (0.84; bootstrap 95% CI: 0.63–0.99) than males (0.61; bootstrap 95% CI: 0.34–0.86). The animals hauled out less during weekends (0.57; bootstrap 95% CI: 0.40–0.74) than during the week (0.76; bootstrap 95% CI: 0.58–0.91). The sex-ratios of this population is unknown. Assuming it was close to 1:1, then there were around 3586 (bootstrap 95% CI: 2970–4542) harbour seals in Orkney in 2010. A female-skewed sex-ratio would reduce the population estimate, and a changing sex-ratio might mean the counts understate the real decline. The mean annual rate of decline in the Orkney population of harbour seals, over the period 2001–2010, is estimated at 13% (95% CI: 10.8–14.8). Similar data for Arisaig, on the west coast of Scotland, shows an increase of around 2% (95% CI: 1.5–2.4) and, assuming an equal sex-ratio, 923 animals (95% CI: 765–1169) in 2007. Copyright © 2012 John Wiley & Sons, Ltd.

Lonergan, M., Duck, C. D., Thompson, D., Moss, S., and McConnell, B. 2011. British grey seal (Halichoerus grypus) abundance in 2008: an assessment based on aerial counts and satellite telemetry. – ICES Journal of Marine Science, 68: 2201–2209. Recent estimates of the total size of the British grey seal population have been based on fitting age-structured models to estimates of pup production. The estimates were sensitive to whether density-dependence was considered to act on fecundity or pup survival. This study provides an alternative estimate for abundance in 2008: 91 800 animals (95% confidence interval, CI, 78 400–109 900). The estimate is consistent with the results of existing models where population density influences pup survival. It suggests that reductions in fecundity are unlikely to have been the cause of the recent slowing of the rate of growth of the population. The estimate presented is based on aerial surveys of the entire Scottish coast and the east coast of England. The surveys were carried out in August of 2007–2009 and restricted to the 2 h each side of daylight low water. Data from 107 electronic tags deployed between 1995 and 2008 were used to estimate the proportion of animals hauled out during the surveys. Overall, the animals hauled out for 31% (95% CI 15–50%) of the survey windows. No significant effects on the proportion of animals hauled out were detected from year, location, age, sex, temperature, rainfall, or the timing of low tide.

The management of marine mammal populations requires the balancing of conflicting interests and also compliance with national legislation and international agreements. These conflicts are intensifying and it is becoming urgent that management goals, and justifications, are clear and explicit. This paper summarises six methods currently used to assess the status of marine mammal populations: the IUCN Red List Criteria; the regulations under the European Union Habitats Directive; PBR; the IWC's Revised Management Procedure; HELCOM's approach to managing seals; and the Canadian Objective-Based Fisheries Management system for harp seals. It compares the assumptions and implications of the methods then describes how one of them, PBR, can be re-presented to make explicit the subjective choice at its centre, and push the decision about conservation targets back from scientists to policymakers, where it belongs.

In 1988 and 2002 dramatic and well-documented phocine distemper epizootics occurred in Europe. While their progression and impact were remarkably similar and consistent over much of Europe, mortality in the UK varied greatly between and within the 2 epizootics. We use antibody lev- els in blood samples to show that 51% (Bayesian 95% CI: 41 to 61%) of the individuals alive in 5 UK harbour seal populations at the end of the 1988 epizootic had been exposed to the virus, and that the equivalent figure after the 2002 outbreak was 22% (95% CI: 16 to 30%). Antibody prevalence was significantly higher in females than males after the 2002 epizootic. Combining these estimates with information on reductions in the numbers of animals observed hauled out during surveys of the Wash, Moray Firth, and Orkney populations and a simple epidemiological model, suggests that the differences between the 2 epizootics were primarily due to a 27% (95% CI: 8 to 43%) fall in R0, the basic reproductive rate of the virus. The large geographic variation in population effects observed within the UK during each epizootic appears to have been mainly due to differences in case mortal- ity, with R0 being remarkably similar in all the populations investigated.

1.Compliance with conservation legislation requires knowledge on the behaviour, abundance and distribution of protected species. Seal life history is characterized by a combination of marine foraging and a requirement to haul out on a solid substrate for reproduction and moulting. Thus understanding the use of haul out sites, where seals are counted, as well as their at-sea movements is crucial for designing effective monitoring and management plans. 2.This study used satellite transmitters deployed on 24 harbour seals in western Scotland to examine movements and haul-out patterns. 3.The proportion of time harbour seals spent hauled out (daily means of between 11 and 27%) varied spatially, temporally and according to sex. The mean haul-out duration was 5 h, with a maximum of over 24 h. 4.Patterns of movement were observed at two geographical scales; while some seals travelled over 100 km, 50% of trips were within 25 km of a haul-out site. These patterns are important for the identification of a marine component to designated protected areas for the species. 5.On average seals returned to the haul-out sites they last used during 40% of trips, indicating a degree of site fidelity, though there was wide variation between different haul-out sites (range 0% to >75%). 6.Low fidelity haul-out sites could form a network of land-based protected areas, while high fidelity sites might form appropriate management units. Copyright © 2008 John Wiley & Sons, Ltd.

The Global Positioning System (GPS) gives precise estimates of location. However, the investigation of animal movement and behavior often requires interpolation to examine events between such fixes. We obtained 6,288 GPS locations from an electronic tag deployed for 170 d on an adult male gray seal (Halichoerus grypus) that ranged freely off the east coast of Scotland, and interpolated between subsamples of these data to investigate the growth of uncertainty within the intervals between observations. Average uncertainty over the path increased linearly as the interval between interpolating locations increased, reaching 12 km in longitude and 6 km in latitude at 2-d separation. The decrease in precision caused by duty-cycling, only collecting data in part of the day, was demonstrated. Adding noise to the GPS locations to simulate data from the ARGOS satellite system had little effect on the total errors for observations separated by more than 12 h. While the rate of growth in interpolation error is likely to vary between species, these results suggest that frequent, and preferably evenly spaced, location fixes are required to take full advantage of the precision of GPS data in the reconstruction of animal tracks.

Ocean climate impacts on survivorship and growth of Atlantic salmon are complex, but still poorly understood. Stock abundances have declined over the past three decades and 1992–2006 has seen widespread sea surface temperature (SST) warming of the NE Atlantic, including the foraging areas exploited by salmon of southern European origin. Salmon cease feeding on return migration, and here we express the final growth condition of year-classes of one-sea winter adults at, or just before, freshwater re-entry as the predicted weight at standard length. Two independent 14-year time series for a single river stock and for mixed, multiple stocks revealed almost identical temporal patterns in growth condition variation, and an overall trend decrease of 11–14% over the past decade. Growth condition has fallen as SST anomaly has risen, and for each yearclass the midwinter (January) SST anomalies they experienced at sea correlated negatively with their final condition on migratory return during the subsequent summer months. Stored lipids are crucial for survival and for the prespawning provisioning of eggs in freshwater, and we show that under-weight individuals have disproportionately low reserves. The poorest condition fish (� 30% under-weight) returned with lipid stores reduced by � 80%. This study concurs with previous analyses of other North Atlantic top consumers (e.g. somatic condition of tuna, reproductive failure of seabirds) showing evidence of major, recent climate-driven changes in the eastern North Atlantic pelagic ecosystem, and the likely importance of bottom-up control processes. Because salmon abundances presently remain at historical lows, fecundity of recent year-classes will have been increasingly compromised. Measures of year-class growth condition should therefore be incorporated in the analysis and setting of numerical spawning escapements for threatened stocks, and conservation limits should be revised upwards conservatively during periods of excessive ocean climate warming.