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A prospective study has been carried out in 172 women to determine the sensitivity of methods to detect occult metastatic disease in the skeleton and liver. With the exception of bone scintiscans, the results of these tests bore little relationship to recurrence rates. On the other hand, knowledge of the histopathology of the lower axillary (pectoral) lymph nodes is of value in this respect.A follow-up study is also reported which confirms the importance of accurate measurements of the primary tumour clinical node status and oestrogen receptor contact of the tumour in defining prognostic groups. Elastosis (estimated in 165 tumours) did not prove to be a useful prognostic index. [ABSTRACT FROM AUTHOR]

The mass spectra of the hops derived humulinic acids, isohumulones and hulupones are discussed. The fragmentations are in accordance with those found for model compounds. [ABSTRACT FROM AUTHOR]

The Mass spectra of some 1,3-cyclopentanediones and 1,2,4-cyclopentanetriones, related to compounds encountered in the chemistry of hops bitter constituents have been determined. Methyl substituted compounds mostly show ring degradation, while for longer alkyl groups and acyl groups, fragmentations in the side chain carry most of the total ionization. When both alkyl (> 2C) and acyl substituents are present, fragmentations in the alkyl group always occur before those in the acyl side chain. The observed degradation processes are useful for the interpretation of the spectra of hop bitter acids and derived products. [ABSTRACT FROM AUTHOR]

The mass spectra of 2- and 4-substituted 1,3-cyclopentanediones are discussed. Methyl substituted compounds display mostly ring degradation, while for longer alkyl groups fragmentations in the side chain are responsible for most of the total ionization. As was found for other 1,3-diketones the spectra of 1,3-cyclopentanediones show typical and separate fragmentations for both diketoand enol-molecular ions. [ABSTRACT FROM AUTHOR]

Rationale: The inflammasome is a key regulatory complex of the inflammatory response leading to interleukin-1β (IL-1β) release and activation. IL-1β amplifies inflammatory responses and induces mucus secretion and hyperconcentration in other diseases. The role of IL-1β in bronchiectasis has not been investigated., Objectives: To characterise the role of airway IL-1β in bronchiectasis, including the association with mucus properties, ciliary function, airway inflammation, microbiome and disease severity., Methods: Stable bronchiectasis patients were enrolled in an international cohort study (n=269). IL-1β was measured in sputum supernatant. A validation cohort also had sputum rheology and hydration measured (n=53). For analysis, patients were stratified according to the median value of IL-1β in the population (high versus low) to compare disease severity, airway infection, microbiome (16S rRNA sequencing), inflammation and caspase-1 activity. Primary human nasal epithelial cells grown in air-liquid interface culture were used to study the effect of IL-1β on cilia function., Results: Patients with high sputum IL-1β had more severe disease, increased caspase-1 activity and an increased T-helper type 1, T-helper type 2 and neutrophil inflammatory response compared with patients with low IL-1β. The active-dominant form of IL-1β was associated with increased disease severity. High IL-1β was related to higher relative abundance of Proteobacteria in the microbiome and increased mucus solid content and viscoelastic properties. Chronic IL-1β treatment reduced the functionality of cilia and tight junctions of epithelial cells in vitro ., Conclusions: A subset of stable bronchiectasis patients show increased airway IL-1β, suggesting pulmonary inflammasome activation is linked with more severe disease, airway infection, mucus dehydration and epithelial dysfunction., Competing Interests: Conflict of interest: M. Shteinberg reports consulting fees from GSK, Boehringer Ingelheim, Kamada and Zambon; payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, Boehringer Ingelheim, GSK, AstraZeneca, Teva, Novartis, Kamada and Sanofi; support for attending meetings and/or travel from Novartis, Actelion, Boehringer Ingelheim, GSK and Rafa; participation on a data safety monitoring board or advisory board for Bonus Therapeutics, Israel; leadership roles for EMBARC Management, Israel Pulmonology Society Board, Israel Society for TB and Mycobacterial Diseases; receipt of equipment, materials, drugs, medical writing, gifts or other services from Trudell Medical Int; and is an associate editor of the American Journal of Respiratory and Critical Care Medicine. P.C. Goeminne reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, GSK and Chiesi; support for attending meetings and/or travel from Chiesi; and participation on a data safety monitoring board or advisory board for Boehringer, GSK and Pfizer. E. Polverino reports grants or contracts from Grifols; consulting fees from Insmed, Bayer, Chiesi and Zambon; payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Chiesi, Grifols, GSK, Insmed, Menarini and Zambon; and support for attending meetings and/or travel from Insmed, Pfizer and Moderna. F. Blasi reports grants or contracts from AstraZeneca, Chiesi and Insmed; consulting fees from Menarini; and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Chiesi, GSK, Guidotti, Grifols, Insmed, Menarini, Novartis, OM Pharma, Pfizer, Sanofi, Viatris, Vertex and Zambon. S. Aliberti reports grants or contracts from Insmed Incorporated, Chiesi, Fisher and Paykel and GSK; royalties or licences from McGraw Hill; consulting fees from Insmed Incorporated, Insmed Italy, Insmed Ireland Ltd, Zambon Spa, AstraZeneca UK Ltd, AstraZeneca Pharmaceutical LP, CSL Behring GmbH, Grifols, Fondazione Internazionale Menarini, Moderna, Chiesi, MCD Italis SrL, Brahms, Physioassist SAS and GSK SpA; payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK SpA, Thermofisher Scientific, Insmed Italy, Insmed Ireland, Zambon and Fondazione Internazionale Menarini; and participation on a data safety monitoring board or advisory board for Insmed Incorporated, Insmed Italy, AstraZeneca UK Ltd and MSD Italia SrL. J.D. Chalmers reports grants or contracts from AstraZeneca, Boehringer Ingelheim, Genentech, Gilead Sciences, GSK, Grifols, Insmed, LifeArc and Novartis; and consulting fees from AstraZeneca, Chiesi, GSK, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio and Zambon. A. Shoemark reports consulting fees from Spirovant and Translate Bio; payment or honoraria for lectures, presentations, manuscript writing or educational events from Translate Bio, Ethris and Insmed; and a leadership role in European Respiratory Society Clinical Research Collaborations (EMBARC, BEATPCD, AMR). The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Rationale: Bronchiectasis is characterized by acute exacerbations, but the biological mechanisms underlying these events are poorly characterized. Objectives: To investigate the inflammatory and microbial characteristics of exacerbations of bronchiectasis. Methods: A total of 120 patients with bronchiectasis were enrolled and presented with acute exacerbations within 12 months. Spontaneous sputum samples were obtained during a period of clinical stability and again at exacerbation before receipt of antibiotic treatment. A validated rapid PCR assay for bacteria and viruses was used to classify exacerbations as bacterial, viral, or both. Sputum inflammatory assessments included label-free liquid chromatography-tandem mass spectrometry and measurement of sputum cytokines and neutrophil elastase activity. 16 s rRNA sequencing was used to characterize the microbiome. Measurements and Main Results: Bronchiectasis exacerbations showed profound molecular heterogeneity. At least one bacterium was identified in 103 samples (86%), and a high bacterial load (total bacterial load > 10 7 copies/g) was observed in 81 patients (68%). Respiratory viruses were identified in 55 (46%) patients, with rhinovirus being the most common virus (31%). PCR testing was more sensitive than culture. No consistent change in the microbiome was observed at exacerbation. Exacerbations were associated with increased neutrophil elastase, proteinase-3, IL-1β, and CXCL8. These markers were particularly associated with bacterial and bacterial plus viral exacerbations. Distinct inflammatory and microbiome profiles were seen between different exacerbation subtypes, including bacterial, viral, and eosinophilic events in both hypothesis-led and hypothesis-free analysis using integrated microbiome and proteomics, demonstrating four subtypes of exacerbation. Conclusions: Bronchiectasis exacerbations are heterogeneous events with contributions from bacteria, viruses, and inflammatory dysregulation.

Polymer powder bed fusion (PBF) is becoming increasingly popular for the fabrication of lightweight, high-performance parts, particularly for medical and aerospace applications. This study investigates the effect of powder re-use and material aging on the coalescence behaviour, melt flowability, and isothermal crystallisation kinetics of polyamide-12 (PA-12) powder. With increased powder re-use, a progressive reduction in melt flowability and material coalescence is observed; at 200 °C, the particle consolidation time increases from 15 s in virgin powder to 180 s in powder recovered from build 6. The observed changes in the behaviour of PA-12 were attributed to polycondensation and cross-linking; these aging phenomena also create structural defects, which hinder the rate and extent of primary crystallisation. At an isothermal crystallisation temperature of 165 °C, the crystallisation half-time increased from 12.78 min in virgin powder to 23.95 min in powder re-used across six build cycles. As a result, the commonly used Avrami model was found to be unsuitable for modelling the crystallisation behaviour of aged PA-12 powder, with the co-efficient of determination (R 2 ) reducing from >0.995 for virgin powder to as low as 0.795 for re-used powder. On the other hand, an alternative method, the Hay model, is able to successfully track full phase transformation within re-used powder (R 2 > 0.99). These results highlight the importance of selecting the most appropriate model for analysing the crystallisation kinetics of PA-12 powder re-used across multiple build cycles. This understanding is crucial for obtaining the strong mechanical properties and dimensional precision required for the fabrication of functional, end-use parts within PBF.

Rationale: Although inflammation and infection are key disease drivers in bronchiectasis, few studies have integrated host inflammatory and microbiome data to guide precision medicine. Objectives: To identify clusters among patients with bronchiectasis on the basis of inflammatory markers and to assess the association between inflammatory endotypes, microbiome characteristics, and exacerbation risk. Methods: Patients with stable bronchiectasis were enrolled at three European centers, and cluster analysis was used to stratify the patients according to the levels of 33 sputum and serum inflammatory markers. Clusters were compared in terms of microbiome composition (16S ribosomal RNA sequencing) and exacerbation risk over a 12-month follow-up. Measurements and Main Results: A total of 199 patients were enrolled (109 [54.8%] female; median age, 69 yr). Four clusters of patients were defined according to their inflammatory profiles: cluster 1, milder neutrophilic inflammation; cluster 2, mixed-neutrophilic and type 2; cluster 3, most severe neutrophilic; and cluster 4, mixed-epithelial and type 2. Lower microbiome diversity was associated with more severe inflammatory clusters ( P  < 0.001), and β-diversity analysis demonstrated distinct microbiome profiles associated with each inflammatory cluster ( P  = 0.001). Proteobacteria and Pseudomonas at phylum and genus levels, respectively, were more enriched in clusters 2 and 3 than in clusters 1 and 4. Furthermore, patients in cluster 2 (rate ratio [RR], 1.49; 95% confidence interval [CI], 1.16-1.92) and cluster 3 (RR, 1.61; 95% CI, 1.12-2.32) were at higher risk of exacerbation over a 12-month follow-up compared with cluster 1, even after adjustment for prior exacerbation history. Conclusions: Bronchiectasis inflammatory endotypes are associated with distinct microbiome profiles and future exacerbation risk.

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by defects in motile cilia, which play an important role in several organ systems. Lung disease is a hallmark of PCD, given the essential role of cilia in airway surface defense. Diagnosis of PCD is complicated due to its reliance on complex tests that are not utilized by every clinic and also its phenotypic overlap with several other respiratory diseases. Nonetheless, PCD is increasingly being recognized as more common than once thought. The disease is genetically complex, with several genes reported to be associated with PCD. There is no cure for PCD, but gene therapy remains a promising therapeutic strategy. In this review, we provide an overview of the clinical symptoms, diagnosis, genetics, and current treatment regimens for PCD. We also describe PCD model systems and discuss the therapeutic potential of different gene therapeutics for targeting the intended cellular target, the ciliated cells of the airway.

Rationale: Bronchiectasis and chronic obstructive pulmonary disease (COPD) are two disease entities with overlapped clinical features, and codiagnosis frequently occurs (termed the "COPD-bronchiectasis association"). Objectives: To investigate the sputum microbiome and proteome in patients with bronchiectasis, COPD, and the COPD-bronchiectasis association with the aim of identifying endotypes that may inform treatment. Methods: Sputum microbiome and protein profiling were carried out using 16S rRNA amplicon sequencing and a label-free proteomics workflow, respectively, in a cohort comprising patients with COPD ( n  = 43), bronchiectasis ( n  = 30), and the COPD-bronchiectasis association ( n  = 48). Results were validated in an independent cohort of 91 patients ( n  = 28-31 each group) using targeted measurements of inflammatory markers, mucins, and bacterial culture. Measurements and Main Results: Principal component analysis of sputum microbiome and protein profiles showed a partial separation between the COPD and the "COPD-bronchiectasis association" group. Further analyses revealed that patients with the "COPD-bronchiectasis association" had a higher abundance of proteobacteria, higher expression of mucin-5AC and proteins from the "neutrophil degranulation" pathway compared to those with COPD. In contrast, patients with COPD had an elevated expression of mucin-5B and several peptidase inhibitors, higher abundance of common commensal taxa, and a greater microbiome diversity. The profiles of "COPD-bronchiectasis association" and bronchiectasis groups were largely overlapping. Five endotypes were proposed with differential inflammatory, mucin, and microbiological features. The key features related to the "COPD-bronchiectasis association" were validated in an independent cohort. Conclusions: Neutrophilic inflammation, differential mucin expression, and Gram-negative infection are dominant traits in patients with the "COPD-bronchiectasis association."

Powder bed fusion (PBF) is an additive manufacturing (AM) technique which offers efficient part-production, light-weighting, and the ability to create complex geometries. However, during a build cycle, multiple aging and degradation processes occur which may affect the reusability of the Polyamide 12 (PA-12) powder. Limited understanding of these phenomena can result in discarding re-usable powder unnecessarily, or the production of parts with insufficient properties, both of which lead to significant amounts of waste. This paper examines the thermal, chemical, and mechanical characteristics of PA-12 via an oven storage experiment that simulates multi jet fusion (MJF) conditions. Changes in the properties of PA-12 powder during oven storage showed two separate, time-dependent trends. Initially, differential scanning calorimetry showed a 4.2 °C increase in melting temperature (T m ) and a rise in crystallinity (X c ). This suggests that secondary crystallisation is occurring instead of, or in addition to, the more commonly reported further polycondensation process. However, with extended storage time, there were substantial reductions in T m and X c , whilst an 11.6 °C decrease in crystallisation temperature was observed. Fourier transform infrared spectroscopy, a technique rarely used in PBF literature, shows an increased presence of imide bonds-a key marker of thermo-oxidative degradation. Discolouration of samples, an 81% reduction in strength and severe material embrittlement provided further evidence that thermo-oxidative degradation becomes the dominant process following extended storage times beyond 100 h. An additional pre-drying experiment showed how moisture present within PA-12 can also accelerate degradation via hydrolysis.

Rationale: Bronchiectasis is classically considered a neutrophilic disorder, but eosinophilic subtypes have recently been described. Objectives: To use multiple datasets available through the European Multicentre Bronchiectasis Audit and Research Collaboration to characterize eosinophilic bronchiectasis as a clinical entity focusing on the impact of eosinophils on bronchiectasis exacerbations. Methods: Patients were included from five countries to examine the relationships between blood eosinophil counts and clinical phenotypes after excluding coexisting asthma. 16S rRNA sequencing was used to examine relationships between eosinophil counts and the sputum microbiome. A post hoc analysis of the PROMIS (Inhaled Promixin in the Treatment of Non-Cystic Fibrosis Bronchiectasis) phase 2 trial was used to examine the impact of blood eosinophil counts on exacerbations in patients with Pseudomonas aeruginosa infection. Measurements and Main Results: A relationship between sputum and blood eosinophil counts was demonstrated in two cohorts. In analysis of 1,007 patients from five countries, 22.6% of patients had blood eosinophil counts of ⩾300 cells/μl. Counts of <100 cells/μl were associated with higher bronchiectasis severity and increased mortality. There was no clear relationship with exacerbations. Blood eosinophil counts of ⩾300 cells/μl were associated with both Streptococcus - and Pseudomonas -dominated microbiome profiles. To investigate the relationship of eosinophil counts with exacerbations after controlling for the confounding effects of infection, 144 patients were studied in a clinical trial after treatment with antipseudomonal antibiotics. Compared with patients with blood eosinophil counts of <100 cells/μl (reference), elevated eosinophil counts of 100-299 cells/μl (hazard ratio, 2.38; 95% confidence interval, 1.33-4.25; P  = 0.003) and ⩾300 cells/μl (hazard ratio, 3.99; 95% confidence interval, 2.20-7.85; P  < 0.0001) were associated with shorter time to exacerbation. Conclusions: Eosinophilic bronchiectasis affects approximately 20% of patients. After accounting for infection status, raised blood eosinophil counts are associated with shortened time to exacerbation.

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)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Neutrophil elastase activity in sputum can identify patients at high risk of airway infection and exacerbations in bronchiectasis. Application of this biomarker in clinical practice is limited, because no point-of-care test is available. We tested whether a novel semi-quantitative lateral flow device (neutrophil elastase airway test stick - NEATstik®) can stratify bronchiectasis patients according to severity, airway infection and exacerbation risk., Methods: Sputum samples from 124 patients with stable bronchiectasis enrolled in the UK and Spain were tested using the NEATstik®, which scores neutrophil elastase concentration from 0 (<8 µg·mL -1 elastase activity) to 10 (maximum detectable neutrophil elastase activity). High neutrophil elastase activity was regarded as a NEATstik® grade >6. Severity of disease, airway infection from sputum culture and exacerbations over the 12 months were recorded. An independent validation was conducted in 50 patients from Milan, Italy., Measurements and Main Results: Patients had a median age of 69 years and forced expiratory volume in 1 s (FEV 1 ) 69%. High neutrophil elastase activity was associated with worse bronchiectasis severity using the bronchiectasis severity index (p=0.0007) and FEV 1 (p=0.02). A high NEATstik® grade was associated with a significant increase in exacerbation frequency, incident rate ratio 2.75 (95% CI 1.63-4.64, p<0.001). The median time to next exacerbation for patients with a NEATstik® grade >6 was 103 days compared to 278 days. The hazard ratio was 2.59 (95% CI 1.71-3.94, p<0.001). Results were confirmed in the independent validation cohort., Conclusions: A novel lateral flow device provides assessment of neutrophil elastase activity from sputum in minutes and identifies patients at increasing risk of airway infection and future exacerbations., Competing Interests: Conflict of interest: A. Shoemark has nothing to disclose. Conflict of interest: E. Cant has nothing to disclose. Conflict of interest: L. Carreto has nothing to disclose. Conflict of interest: A. Smith has nothing to disclose. Conflict of interest: M. Oriano has nothing to disclose. Conflict of interest: H.R. Keir has nothing to disclose. Conflict of interest: L. Perea has nothing to disclose. Conflict of interest: E. Canto has nothing to disclose. Conflict of interest: L. Terranova has nothing to disclose. Conflict of interest: S. Vidal has nothing to disclose. Conflict of interest: K. Moffitt was employed by Proaxsis, during the conduct of the study. Conflict of interest: S. Aliberti has nothing to disclose. Conflict of interest: O Sibila has nothing to disclose. Conflict of interest: J.D. Chalmers reports grants and personal fees from GlaxoSmithKline, Boehringer Ingelheim, Pfizer, Bayer Healthcare, Grifols and Insmed, grants from AstraZeneca, personal fees from Napp and Aradigm Corporation, outside the submitted work., (Copyright ©ERS 2019.)

"Early" breast cancer is a systemic disease in the majority of cases. Progress has been and is being made toward the determination of those women at risk of recurrence. Attractive as it seems, the value of systemic adjuvant therapy, given at the time of minimal tumour load i.e., after mastectomy, is not proven. Therefore, for the average case it is better to treat the cancer locally and to observe and leave further evaluation of systemic therapy to those centres which are able to conduct controlled, randomized trails.

Estrogen receptor assays were performed on human myometrium in order to determine optimal conditions for certain steps of the assay. The findings indicate that: (1) tissue should be snap-frozen in liquid nitrogen prior to assay, (2) dithiothreitol does not increase measurable binding site numbers, (3) estrogen receptors in the cytosol fraction are unstable and should be stored in excess of 1 day; (4) if storage prior to receptor assay is unavoidable, tissue should be stored at -20 degrees C or -70 degrees C for no longer than 1 week.

Measurements of teat end expansion and contraction times from step changes in pressure suggest that teat ends require a minimal duration of liner closure for response. Effect of duration of liner closure per pulsation cycle on susceptibility of the udder to infection was tested. Four durations of liner closure (liner more than half closed) were applied: zero, .17, .34, and .51 s per pulsation cycle. For the latter three treatments, duration of the liner more than half open was .66 s per pulsation cycle, resulting in pulsation rates of 72.3, 60.0, and 51.3 pulsations per min. Four groups, each of 10 British Friesian cows, were in a 4-wk experiment. High bacterial exposure of all teats was ensured by dipping them before and after each milking in a suspension of Streptococcus agalactiae and Streptococcus dysgalactiae. Numbers of quarters becoming infected per treatment group were 20, 11, 4, and 5. This result represents both a significant inverse linear and quadratic relationship between proportion of quarters becoming infected and duration of liner closure. We conclude that a sufficient duration of liner closure, i.e., one-third of a second or more, per pulsation cycle contributes to reducing risk of new mammary gland infections.