Bronchiectasis with Chronic Rhinosinusitis Is Associated with Eosinophilic Airway Inflammation and Is Distinct from Asthma.

Rationale: Bronchiectasis is an airway inflammatory disease that is frequently associated with chronic rhinosinusitis (CRS). An eosinophilic endotype of bronchiectasis has recently been described, but detailed testing to differentiate eosinophilic bronchiectasis from asthma has not been performed. Objectives: This prospective observational study aimed to test the hypotheses that bronchiectasis with CRS is enriched for the eosinophilic phenotype in comparison with bronchiectasis alone and that the eosinophilic bronchiectasis phenotype exists as a separate entity from bronchiectasis associated with asthma. Methods: People with idiopathic or postinfectious bronchiectasis were assessed for concomitant CRS. We excluded people with asthma or primary ciliary dyskinesia and smokers. We assessed sputum and blood cell counts, nasal NO and fractional excreted NO, methacholine reactivity, skin allergy testing and total and specific immunoglobulin (Ig) E, cytokines in the sputum and serum, and the microbiome in the sputum and nasopharynx. Results: A total of 22 people with CRS (BE + CRS) and 17 without CRS (BE - CRS) were included. Sex, age, Reiff score, and bronchiectasis severity were similar. Median sputum eosinophil percentages were 0% (IQR, 0-1.5%) in BE - CRS and 3% (1-12%) in BE + CRS (P = 0.012). Blood eosinophil counts were predictive of sputum eosinophilia (counts ⩾3%; area under the receiver operating characteristic curve, 0.68; 95% confidence interval, 0.50-0.85). Inclusion of CRS improved the prediction of sputum eosinophilia by blood eosinophil counts (area under the receiver operating characteristic curve, 0.79; 95% confidence interval, 0.65-0.94). Methacholine tests were negative in 85.7% of patients in the BE - CRS group and 85.2% of patients in the BE + CRS group (P > 0.99). Specific IgE and skin testing were similar between the groups, but total IgE levels were increased in people with increased sputum eosinophils. Microbiome analysis demonstrated distinct microbiota in nasopharyngeal and airway samples in the BE + CRS and BE - CRS groups, without significant differences between groups. However, interactome analysis revealed altered interactomes in individuals with high sputum eosinophil counts and CRS. Conclusions: Bronchiectasis with CRS is associated with an eosinophilic airway inflammation that is distinct from asthma.

Biogeochemical impacts of sewage effluents in predominantly rural river catchments: Are point source inputs distinct to background diffuse pollution?

Discharge of treated sewage effluent to rivers can degrade aquatic ecosystem quality, interacting with multiple stressors in the wider catchment. In predominantly rural catchments, the river reach influence of point source effluents is unknown relative to complex background pressures. We examined water column, sediment and biofilm biogeochemical water quality parameters along river transects (200 m upstream to 1 km downstream) during summer at five wastewater treatment works (WWTW) in Scotland. Treated sewage effluent (subset, n = 3) pollutant concentrations varied between sites. Downstream concentration profiles of water and sediment biogeochemical parameters showed complex spatial changes. A hypothesised point source signature of elevated concentrations of pollution immediately downstream of WWTW then a decaying pollution 'plume' did not commonly occur. Instead, elevated soluble reactive phosphorus (SRP), ammonium and coliforms (maximum 0.23 mgP/l, 0.33 mgN/l and >2 × 106 MPN/100 ml) occurred immediately downstream of two WWTW, whereas some downstream pollutant concentrations decreased. Microbial substrate respiration responses only differed 1 km downstream. Significantly greater concentrations of sediment metal occurred >500 m downstream, likely due to the redeposition of historic contaminated sediments. Significantly lowered chlorophyll-a downstream of one WWTW coincided with elevated metals, despite water SRP and sediment P increases. Overall, stress caused to microbes and algae by effluent contaminants outweighed the subsidy effect of WWTW nutrients. We observed variable effluent flows to the rivers limited localised pollution downstream of WWTW and overall influence of arable land cover on river water quality. Together, this challenges views of consistently discharging point sources impacting low dilution sensitive rivers in summer contrasting with 'diffuse' sources. Thus, river water column and benthic compartments are altered at varying scales by point source effluents in combination with rural catchment pollution sources, both discrete (e.g. farmyards and septic tanks) and diffuse.

Dual ß-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition.

The aim of the study was to determine the efficacy of dual ß-lactam combination treatments derived from eight approved drugs against Galleria mellonella larvae infected with MDR strains of P. aeruginosa. Carbapenem-resistant P. aeruginosa NCTC 13437 and an unrelated clinical isolate were used to infect G. mellonella larvae and the efficacy of twenty-eight dual ß-lactam combination therapies were compared to their constituent monotherapies. For the most potent combinations identified, penicillin-binding protein (PBP) inhibition profiles were measured and compared with each constituent antibiotic. Five of the dual ß-lactam combinations resulted in greater than 70% survival of infected G. mellonella. Two combinations showed potent, enhanced efficacy versus both strains - ceftazidime + meropenem and aztreonam + meropenem. Comparison of PBP inhibition profiles revealed that the enhanced efficacy of these two dual ß-lactam combinations could not be explained by more potent inhibition of PBPs or inhibition of a broader range of PBPs. A possible contribution to the enhanced efficacy of the combinations could be stimulation of innate immunity via increased haemocyte numbers compared to their constituent monotherapies. Combinations of ß-lactam antibiotics show promise in overcoming MDR P. aeruginosa and are worthy of additional study and development.