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Barcoded amplicon sequencing is rapidly becoming a standard method for profiling microbial communities, including the human respiratory microbiome. While this approach has less bias than standard cultivation, several steps can introduce variation including the type of DNA extraction method used. Here we assessed five different extraction methods on pediatric bronchoalveolar lavage (BAL) samples and a mock community comprised of nine bacterial genera to determine method reproducibility and detection limits for these typically low complexity communities. Additionally, using the mock community, we were able to evaluate contamination and select a relative abundance cut-off threshold based on the geometric distribution that optimizes the trade off between detecting bona fide operational taxonomic units and filtering out spurious ones. Using this threshold, the majority of genera in the mock community were predictably detected by all extraction methods including the hard-to-lyse Gram-positive genus Staphylococcus. Differences between extraction methods were significantly greater than between technical replicates for both the mock community and BAL samples emphasizing the importance of using a standardized methodology for microbiome studies. However, regardless of method used, individual patients retained unique diagnostic profiles. Furthermore, despite being stored as raw frozen samples for over five years, community profiles from BAL samples were consistent with historical culturing results. The culture-independent profiling of these samples also identified a number of anaerobic genera that are gaining acceptance as being part of the respiratory microbiome. This study should help guide researchers to formulate sampling, extraction and analysis strategies for respiratory and other human microbiome samples.

1. Community ecology is frequently invoked as complementary to and useful for guiding ecological restoration. While the conceptual literature is devoted to this unification, first-hand accounts from practitioners and ecologists suggest that integration may be weak in practice. To date, there have been no analyses of how extensively community ecology theory appears in the empirical restoration literature. 2. We address this knowledge gap with the first quantitative assessment of the extent to which community ecology concepts appear in empirical restoration literature by analysing the use of community ecology theories, concepts and conceptually derived tools in the design and interpretation of 1,000+ experimental ecological restoration studies over time (20 years) across all global regions. We also gauge general trends in author demographics, focal ecosystems and taxa targeted by these studies. 3. We found that the incorporation of community ecology into restoration research has increased significantly in recent years. 4. Community assembly and succession theories were the community ecology concepts integrated most often, while the functional traits framework and evolutionary theory have increased in usage recently. 5. Synthesis and applications. Restoration endeavours are increasingly infused with elements of community ecology. Our results highlight the widespread application of deterministic models of community structure in restoration design and the rise of ecosystem service and function-focused restoration. With this diagnostic summary of these applications, ecologists and restoration practitioners can move forward while directly exploring underdeveloped synergies between theory and practice.

Progressive lung disease accounts for the majority of morbidity and mortality observed in cystic fibrosis (CF). Beyond secondhand smoke exposure and socio-economic status, the effect of specific environmental factors on CF lung function is largely unknown. Multivariate regression was used to assess correlation between specific environmental factors, the presence of pulmonary pathogens, and variation in lung function using subjects enrolled in the U.S. CF Twin and Sibling Study (CFTSS: n = 1378). Significant associations were tested for replication in the U.S. CF Foundation Patient Registry (CFF: n = 16439), the Australian CF Data Registry (ACFDR: n = 1801), and prospectively ascertained subjects from Australia/New Zealand (ACFBAL: n = 167). In CFTSS subjects, the presence of Pseudomonas aeruginosa (OR = 1.06 per °F; p<0.001) was associated with warmer annual ambient temperatures. This finding was independently replicated in the CFF (1.02; p<0.001), ACFDR (1.05; p = 0.002), and ACFBAL (1.09; p = 0.003) subjects. Warmer temperatures (-0.34 points per °F; p = 0.005) and public insurance (-6.43 points; p<0.001) were associated with lower lung function in the CFTSS subjects. These findings were replicated in the CFF subjects (temperature: -0.31; p<0.001; insurance: -9.11; p<0.001) and similar in the ACFDR subjects (temperature: -0.23; p = 0.057). The association between temperature and lung function was minimally influenced by P. aeruginosa. Similarly, the association between temperature and P. aeruginosa was largely independent of lung function. Ambient temperature is associated with prevalence of P. aeruginosa and lung function in four independent samples of CF patients from two continents.

1. Climate change is predicted to have profound consequences for multispecies coexistence, and thus, patterns of biological diversity. These consequences will be mediated by direct and indirect impacts of environmental change on species' vital rates and interactions. While the impacts of environmental change on individual species has received much attention to date, the consequences for coexistence mediated by changes in the strength and direction of multispecies interactions are not as well understood. 2. To investigate how coexistence dynamics may be sensitive to environmental change, we conducted a field experiment in a diverse semi-arid annual plant system. We imposed a water manipulation treatment in two sites that vary in aridity and associated rainfall. Focusing on four common annual plant species in these sites, we quantified the fecundity (seed production) of individuals in response to a gradient of intra-and interspecific competitor densities and aridity. We then used these fecundities to parameterize an annual plant population model and examine the influence of aridity and species identity on resultant coexistence dynamics (as a function of stabilizing niche differences and fitness inequalities). 3. While the responses of some vital rates and competitive impacts to watering varied somewhat predictably across sites, coexistence metrics encapsulating changes in these vital rates and interaction strengths did not. Fitness inequalities among our focal species were driven largely by differences in sensitivity to competition, which were almost always much greater than the magnitude of stabilizing niche differences. These findings were surprising given observational evidence suggesting that these species do coexist at local scales in these natural communities. 4. Synthesis. Our study is one of the first to explicitly consider the influence of environmental variation on the individual components of coexistence outcomes. We show that environmental change has the ability to influence coexistence not only through direct pathways (i.e., vital rates), but also indirect pathways (i.e., species interactions). Despite the consistency of many of the responses of these individual components to environmental variation, their combined influence on predictions of both current and future coexistence remains unclear.

Rapid germination or flexible germination cues may be key traits that facilitate the invasion of exotic plant species in new environments. We investigated whether robustness or plasticity in response to environmental cues were more commonly exhibited by exotic than native species during germination, evidenced by (1) exhibiting consistently greater germination rate under a variety of conditions (robustness), or (2) increasing germination rate more strongly than native species in response to favorable conditions (plasticity). We conducted growth chamber germination trials of 12 native and 12 exotic species common to coastal sage scrub, a shrub-dominated Mediterranean-type ecosystem in California. Time to germination and percentage germination were recorded in response to variation in three environmental cues: temperature, day length, and soil moisture. Exotic species, especially annuals, displayed consistently higher germination percentages and more rapid germination than native species. Exotic germination percentages also responded more strongly when conditions were favorable (warm temperatures and high soil moisture), and germinated earlier than natives when conditions were indicative of typical growing season conditions in Mediterranean ecosystems (short day length and cool temperatures). Exotic species had more rapid and prolific germination across a variety of environmental cues and in response to increased resource availability compared with native species, indicating both germination plasticity and robustness. These traits may enable colonization of novel environments, particularly if they allow exotic species to establish earlier in the growing season than native species, setting the stage for seasonal priority effects.

Ivacaftor, a potentiator of CFTR, was studied in patients with cystic fibrosis (CF) who had mutations that reduced the function of the CFTR protein. Ivacaftor significantly improved FEV 1 and reduced pulmonary exacerbations; it holds promise in the treatment of selected patients with CF. Cystic fibrosis, the most common lethal genetic disease in whites, affects approximately 70,000 people worldwide. 1 – 3 There is no cure for this disease, and the progressive lung disease associated with it is the leading cause of death. Current treatments for cystic fibrosis target the secondary effects of dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The CFTR protein is an epithelial ion channel contributing to the regulation of absorption and secretion of salt and water in various tissues, including the lung, sweat glands, pancreas, and gastrointestinal tract. 4 , 5 Cystic fibrosis is caused by mutations in CFTR that affect . . .

Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, has been shown to improve lung function, pulmonary exacerbation rate, respiratory symptoms, and weight gain compared with placebo in patients with cystic fibrosis aged 12 years or older with a G551D-CFTR mutation. This randomized, double-blind, placebo-controlled trial evaluated ivacaftor in patients with cystic fibrosis aged 6-11 years with a G551D-CFTR mutation on at least one allele. Patients were randomly assigned to receive ivacaftor administered orally at 150 mg (n = 26) or placebo (n = 26) every 12 hours for 48 weeks in addition to existing prescribed cystic fibrosis therapies. Despite near-normal mean baseline values in FEV1, patients receiving ivacaftor had a significant increase in percent predicted FEV1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P < 0.001). Effects on pulmonary function were evident by 2 weeks, and a significant treatment effect was maintained through Week 48. Patients treated with ivacaftor gained, on average, 2.8 kg more than those receiving placebo at Week 48 (P < 0.001). The change from baseline through Week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor was -53.5 mmol/L (P < 0.001) versus placebo. The incidence of adverse events was similar in the two groups. In patients who are younger and healthier than those in previously studied populations, ivacaftor demonstrated a significant improvement in pulmonary function, weight, and CFTR activity compared with placebo. Clinical trial registered with www.clinicaltrials.gov (NCT00909727).

1. The timing of seasonal activity (i.e. phenology) may play an important role in plant invasions. In ecosystems characterized by seasonal rainfall, early-active exotic species may pre-empt resources and attain competitive dominance via a seasonal 'priority advantage'. Exotic annual grasses in California are often active earlier than native species, potentially because they possess greater germination plasticity. While these problematic invaders may usually benefit from having early phenology, their flexible germination cues might be manipulated as a restoration strategy to germinate seeds far in advance of favourable growing conditions, leading to a 'priority disadvantage'. 2. We manipulated the start of the growing season in an invaded California coastal sage scrub community characterized by a Mediterranean-type climate to (i) identify whether early-season phenology confers a performance advantage and (ii) test whether rainfall timing could be manipulated to favour native species. We compared the performance of seeded native and exotic focal species under ambient rainfall timing (winter rains) vs. with a pre-growing season (late-summer) watering event. 3. Under ambient rainfall timing, exotic annual grasses and forbs germinated earlier and reached higher levels of abundance than native species, consistent with a seasonal priority advantage. Many exotic annual grasses germinated with pre-season watering, but none survived until the onset of natural rains. Observations suggest that early-germinating seedlings suffered mortality via herbivory. The watering pulse thus depleted the exotic seedbank, fewer exotic individuals germinated with winter rains, and exotic species attained lower abundance than under the natural rainfall timing. 4. Native species, whether annual or perennial, did not germinate with the pre-season watering pulse, suggesting they may have more constrained germination cues than the exotic species. 5. Synthesis and applications. Our results suggest that phenology is an important factor influencing invasion success, and that this could be manipulated to favour native species. Manipulation of the start of the growing season, for example through a pre-growing season watering event, could be a successful restoration strategy for native species in some ecosystems.

A key measure of lung function in people with Cystic Fibrosis (CF) is Forced Expiratory Volume in the first second FEV 1 percent predicted (FEV 1 pp). This study aimed to address challenges in identifying predictors of FEV 1 pp, specifically dealing with non-linearity and the censoring effect of death. Data was obtained from a large multi-centre Australian Cystic Fibrosis Data Registry (ACFDR). A linear mixed model was used to study FEV 1 pp as the endpoint. There were 3655 patients (52.4% male) included in our study. Restricted cubic splines were used to fit the non-linear relationship between age of visit and FEV 1 pp. The following predictors were found to be significant in the multivariate model: age of patient at visit, BMI z-score, age interaction with lung transplantation, insulin dependent diabetes, cirrhosis/portal hypertension, pancreatic insufficiency, Pseudomonas aeruginosa infection and baseline variability in FEV 1 pp. Those with P. aeruginosa infection had a lower mean difference in FEV 1 pp of 4.7 units, p  < 0.001 compared to those who did not have the infection. Joint modelling with mortality outcome did not materially affect our findings. These models will prove useful for to study the impact of CFTR modulator therapies on rate of change of lung function among patients with CF.

Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV1) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV1 decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life. Spirometry-based classifications of ‘normal’ (FEV1≥90% predicted) and ‘mild lung disease’ (FEV1 70%–89% predicted) are inappropriate, given the failure of spirometry to detect significant structural or functional abnormalities shown by more sensitive imaging and lung function techniques. The state and readiness of two imaging (CT and MRI) and two functional (multiple breath washout and oscillometry) tools for the detection and monitoring of early lung disease in children and adults with CF are discussed in this article.Prospective research programmes and technological advances in these techniques mean that well-designed interventional trials in early lung disease, particularly in young children and infants, are possible. Age appropriate, randomised controlled trials are critical to determine the safety, efficacy and best use of new therapies in young children. Regulatory bodies continue to approve medications in young children based on safety data alone and extrapolation of efficacy results from older age groups. Harnessing the complementary information from structural and functional tools, with measures of inflammation and infection, will significantly advance our understanding of early CF lung disease pathophysiology and responses to therapy. Defining clinical utility for these novel techniques will require effective collaboration across multiple disciplines to address important remaining research questions. Future impact on existing management burden for patients with CF and their family must be considered, assessed and minimised.To address the possible role of these techniques in early lung disease, a meeting of international leaders and experts in the field was convened in August 2019 at the Australiasian Cystic Fibrosis Conference. The meeting entitiled ‘Shaping imaging and functional testing for early disease detection of lung disease in Cystic Fibrosis’, was attended by representatives across the range of disciplines involved in modern CF care. This document summarises the proceedings, key priorities and important research questions highlighted.