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Linzy Houchen-Wolloff,1 Johanna EA Williams,1 Ruth H Green,2 Gerrit Woltmann,2 Michael C Steiner,1,2 Louise Sewell,1 Michael DL Morgan,1,2 Sally J Singh1 1NIHR Leicester Biomedical Research Centre – Respiratory, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester, 2Department of Respiratory Medicine, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester, UK Rationale: Pulmonary rehabilitation (PR) in patients with COPD has consistently been shown to produce benefits in exercise capacity, symptoms, and health status. The data surrounding survival following PR are less clear. Our aims were to compare the long-term survival in two cohorts of patients referred for PR; those who successfully completed PR, and a comparator group constructed from patients who either did not complete PR or did not start the program. Additionally, we compared survival between those people who were able to achieve a clinically meaningful improvement in exercise capacity (incremental shuttle walking test) following PR with those who were not. Methods: A retrospective longitudinal analysis of clinical service outcomes was conducted to compare the long-term survival in “completers” and “non-completers” of rehabilitation at two hospitals within the University Hospitals of Leicester NHS Trust from January 1, 2000 to February 23, 2012. For “completers”, we also analyzed survival in those meeting (and not meeting) the desired level of change in the incremental shuttle walking test (≥50 m vs 50 m change in walking distance) was also associated with improved survival. Keywords: survival, COPD, exercise

A decision aid to assist the development of a linear valuation function for multiple attribute problems is proposed, based on a linear programming formulation using a constraint set structured in a similar manner to data envelopment analysis (DEA). Value functions which favour each decision option are calculated, and efficient, potentially optimal, options identified. These are used to help a decision maker progressively to articulate preferences, indicators of his/her values, in an interactive, structurally flexible manner. As preference indications are provided, candidate value functions and hitherto efficient options inconsistent with his/her declarations are eliminated, thus proceeding towards an explicit value function and, if needed a corresponding complete option order. Keywords: decision analysis; value function; preferences; linear programming; data envelopment analysis

Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) are heterogeneous with respect to inflammation and etiology.Objectives: Investigate biomarker expression in COPD exacerbations to identify biologic clusters and determine biomarkers that recognize clinical COPD exacerbation phenotypes, namely those associated with bacteria, viruses, or eosinophilic airway inflammation.Methods: Patients with COPD were observed for 1 year at stable and exacerbation visits. Biomarkers were measured in sputum and serum. Viruses and selected bacteria were assessed in sputum by polymerase chain reaction and routine diagnostic bacterial culture. Biologic phenotypes were explored using unbiased cluster analysis and biomarkers that differentiated clinical exacerbation phenotypes were investigated.Measurements and Main Results: A total of 145 patients (101 men and 44 women) entered the study. A total of 182 exacerbations were captured from 86 patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed “pauciinflammatory.” Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1β, 0.89 (area under receiver operating characteristic curve) (95% confidence interval [CI], 0.83–0.95); serum CXCL10, 0.83 (95% CI, 0.70–0.96); and percentage peripheral eosinophils, 0.85 (95% CI, 0.78–0.93), respectively.Conclusions: The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1β, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil-associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation. [ABSTRACT FROM AUTHOR]

Rationale: The importance of Aspergillus fumigatus sensitization and colonization of the airways in patients with asthma is unclear.Objectives: To define the relationship between the clinical and laboratory features of A. fumigatus-associated asthma.Methods: We studied 79 patients with asthma (89% classed as GINA 4 or 5) classified into 3 groups according to A. fumigatus sensitization: (1) IgE-sensitized (immediate cutaneous reactivity > 3 mm and/or IgE > 0.35 kU/L); (2) IgG-only-sensitized (IgG > 40 mg/L); and (3) nonsensitized. These were compared with 14 healthy control subjects. Sputum culture was focused toward detection of A. fumigatus and compared with clinical assessment data.Measurements and Main Results: A. fumigatus was cultured from 63% of IgE-sensitized patients with asthma (n = 40), 39% of IgG-only-sensitized patients with asthma (n = 13), 31% of nonsensitized patients with asthma (n = 26) and 7% of healthy control subjects (n = 14). Patients sensitized to A. fumigatus compared with nonsensitized patients with asthma had lower lung function (postbronchodilator FEV₁ % predicted, mean [SEM]: 68 [±5]% versus 88 [±5]%; P < 0.05), more bronchiectasis (68% versus 35%; P < 0.05), and more sputum neutrophils (median [interquartile range]: 80.9 [50.1-94.1]% versus 49.5 [21.2-71.4]%; P < 0.01). In a multilinear regression model, A. fumigatus-IgE sensitization and sputum neutrophil differential cell count were important predictors of lung function (P = 0.016), supported by culture of A. fumigatus (P = 0.046) and eosinophil differential cell count (P = 0.024).Conclusions: A. fumigatus detection in sputum is associated with A. fumigatus-IgE sensitization, neutrophilic airway inflammation, and reduced lung function. This supports the concept that development of fixed airflow obstruction in asthma is consequent upon the damaging effects of airway colonization with A. fumigatus. [ABSTRACT FROM AUTHOR]

Rationale: Heterogeneity in asthma expression is multidimensional, including variability in clinical, physiologic, and pathologic parameters. Classification requires consideration of these disparate domains in a unified model.Objectives: To explore the application of a multivariate mathematical technique, k-means cluster analysis, for identifying distinct phenotypic groups.Methods: We performed k-means cluster analysis in three independent asthma populations. Clusters of a population managed in primary care (n = 184) with predominantly mild to moderate disease, were compared with a refractory asthma population managed in secondary care (n = 187). We then compared differences in asthma outcomes (exacerbation frequency and change in corticosteroid dose at 12 mo) between clusters in a third population of 68 subjects with predominantly refractory asthma, clustered at entry into a randomized trial comparing a strategy of minimizing eosinophilic inflammation (inflammation-guided strategy) with standard care.Measurements and Main Results: Two clusters (early-onset atopic and obese, noneosinophilic) were common to both asthma populations. Two clusters characterized by marked discordance between symptom expression and eosinophilic airway inflammation (early-onset symptom predominant and late-onset inflammation predominant) were specific to refractory asthma. Inflammation-guided management was superior for both discordant subgroups leading to a reduction in exacerbation frequency in the inflammation-predominant cluster (3.53 [SD, 1.18] vs. 0.38 [SD, 0.13] exacerbation/patient/yr, P = 0.002) and a dose reduction of inhaled corticosteroid in the symptom-predominant cluster (mean difference, 1,829 mug beclomethasone equivalent/d [95% confidence interval, 307-3,349 mug]; P = 0.02).Conclusions: Cluster analysis offers a novel multidimensional approach for identifying asthma phenotypes that exhibit differences in clinical response to treatment algorithms. [ABSTRACT FROM AUTHOR]

Rationale: Current asthma guidelines recommend adjusting antiinflammatory treatment on the basis of the results of lung function tests and symptom assessment, neither of which are closely associated with airway inflammation. Objectives: We tested the hypothesis that titrating corticosteroid dose using the concentration of exhaled nitric oxide in exhaled breath (Fe(NO)) results in fewer asthma exacerbations and more efficient use of corticosteroids, when compared with traditional management. Methods: One hundred eighteen participants with a primary care diagnosis of asthma were randomized to a single-blind trial of corticosteroid therapy based on either Fe(NO) measurements (n = 58) or British Thoracic Society guidelines (n = 60). Participants were assessed monthly for 4 months and then every 2 months for a further 8 months. The primary outcome was the number of severe asthma exacerbations. Analyses were by intention to treat. Measurements and Main Results: The estimated mean (SD) exacerbation frequency was 0.33 per patient per year (0.69) in the Fe(NO) group and 0.42 (0.79) in the control group (mean difference, -21%; 95% confidence interval [CI], -57 to 43%; p = 0.43). Overall the Fe(NO) group used 11% more inhaled corticosteroid (95% CI, -17 to 42%; p = 0.40), although the final daily dose of inhaled corticosteroid was lower in the Fe(NO) group (557 vs. 895 mug; mean difference, 338 mug; 95% CI, -640 to -37; p = 0.028). Conclusions: An asthma treatment strategy based on the measurement of exhaled nitric oxide did not result in a large reduction in asthma exacerbations or in the total amount of inhaled corticosteroid therapy used over 12 mo, when compared with current asthma guidelines. Clinical trial registered with www.controlled-trials.com (ISRCTN08067387). [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVES: Sputum induction is increasingly used as a research technique and as a clinical tool. In order to evaluate abnormal results, normal ranges need to be fully developed. Although a number of studies have described normal ranges, none have investigated the effect of the age of the subject on these results. This study was undertaken to assess whether there are age-related differences in sputum cell differential cell counts in a population of normal, healthy volunteers. STUDY DESIGN AND PARTICIPANTS: Induced sputum samples were obtained from 66 healthy, nonsmoking subjects (24 men) with a mean age of 44 years (age range, 18 to 74 years). Differential cell counts were related to age. RESULTS: Sputum neutrophil counts were found to correlate significantly with the age of the volunteers (r = 0.58; p < 0.001). Macrophage counts showed a proportionate, inverse correlation with increasing age (p < 0.01), but no correlation was seen for any other cell type. On subanalysis according to age range, the mean neutrophil differential increased from 26.9% (SD, 19.8%) [17 patients] in the group of patients who were 0 to 29 years of age to 68.5% (SD, 20.6%) [11 patients] in the group of patients who were > 60 years of age. CONCLUSION: In our healthy volunteer population, the induced sputum differential neutrophil count increased significantly with age. These findings highlight the need for age matching in controlled studies. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma has less than a 5% 5-year survival rate, and metastatic disease is associated with a median survival of 4.5 months. A typical presentation often includes evidence of biliary obstruction, abdominal pain, jaundice, and weight loss. Significant ascites is not commonly seen at initial presentation and, when present, is typically associated with a low serum albumin ascites gradient (SAAG). We discuss a patient who presented with high-SAAG ascites as her initial presentation, only to be later diagnosed with metastatic pancreatic adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background: The role of TNFalpha in cancer is complex with both pro-tumourigenic and anti-tumourigenic roles proposed. We hypothesised that anatomical microlocalisation is critical for its function.Methods: This study used immunohistochemistry to investigate the expression of TNFalpha in the tumour islets and stroma with respect to survival in 133 patients with surgically resected NSCLC.Results: TNFalpha expression was increased in the tumour islets of patients with above median survival (AMS) compared to those with below median survival (BMS)(p = 0.006), but similar in the stroma of both groups. Increasing tumour islet TNFalpha density was a favorable independent prognostic indicator (p = 0.048) while stromal TNFalpha density was an independent predictor of reduced survival (p = 0.007). Patients with high TNFalpha expression (upper tertile) had a significantly higher 5-year survival compared to patients in the lower tertile (43% versus 22%, p = 0.01). In patients with AMS, 100% of TNFalpha+ cells were macrophages and mast cells, compared to only 28% in the islets and 50% in the stroma of BMS patients (p < 0.001).Conclusions: The expression of TNFalpha in the tumour islets of patients with NSCLC is associated with improved survival suggesting a role in the host anti-tumour immunological response. The expression of TNFalpha by macrophages and mast cells is critical for this relationship. [ABSTRACT FROM AUTHOR]

Background: The development of tumor necrosis factor alpha (TNF-alpha) antagonists has made it feasible to investigate the role of this cytokine in refractory asthma. Methods: We measured markers of TNF-alpha activity on peripheral-blood monocytes in 10 patients with refractory asthma, 10 patients with mild-to-moderate asthma, and 10 control subjects. We also investigated the effects of treatment with the soluble TNF-alpha receptor etanercept (25 mg twice weekly) in the patients with refractory asthma in a placebo-controlled, double-blind, crossover pilot study. Results: As compared with patients with mild-to-moderate asthma and controls, patients with refractory asthma had increased expression of membrane-bound TNF-alpha, TNF-alpha receptor 1, and TNF-alpha-converting enzyme by peripheral-blood monocytes. In the clinical trial, as compared with placebo, 10 weeks of treatment with etanercept was associated with a significant increase in the concentration of methacholine required to provoke a 20 percent decrease in the forced expiratory volume in one second (FEV1) (mean difference in doubling concentration changes between etanercept and placebo, 3.5; 95 percent confidence interval, 0.07 to 7.0; P=0.05), an improvement in the asthma-related quality-of-life score (by 0.85 point; 95 percent confidence interval, 0.16 to 1.54 on a 7-point scale; P=0.02), and a 0.32-liter increase in post-bronchodilator FEV1 (95 percent confidence interval, 0.08 to 0.55; P=0.01). Conclusions: Patients with refractory asthma have evidence of up-regulation of the TNF-alpha axis. (ClinicalTrials.gov number, NCT00276029.). [ABSTRACT FROM AUTHOR]

Background: Adults living with severe asthma have lower physical activity levels, particularly high-intensity physical activity, compared with their healthy peers. Physical inactivity is associated with increased morbidity and mortality., Objective: To understand patient and health care professional attitudes toward exercise and physical activity to inform future strategies for the improvement of healthy lifestyle behaviors, including exercise., Methods: Participants recruited from a specialist difficult asthma service were interviewed individually, and health care professionals (HCPs) from primary care, secondary care, and a tertiary center were invited to attend focus groups. Interviews and focus groups were transcribed verbatim. We performed thematic analysis on interviews and focus groups separately, followed by an adapted framework analysis to analyze datasets together., Results: Twenty-nine people with severe asthma participated in a semi-structured interview. A total of 51 HCPs took part in eight focus groups across the East Midlands, United Kingdom. Final analysis resulted in three major themes: barriers to exercise and exercise counseling - in which patients and HCPs identified disease and non-disease factors affecting those living with severe asthma; attitudes toward HCP support for exercise - highlighting education needs for HCPs and preference for supervised exercise programs; and areas for system improvement in supporting patients and HCPs - challenges exist across health sectors that limit patient support are described., Conclusions: Patients identified the important role of HCPs in supporting and advising on lifestyle change. Despite a preference for supervised exercise programs, both patient and HCP barriers existed. To meet patients' varied support needs, improved integration of services is required and HCP skills need extending., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The use of demographic variables in the medical literature has been a topic of much recent debate. Recent studies found that race and socioeconomic status (SES) are inconsistently reported. Best-practice use of sex and gender has been contentious. We aimed to characterise the state of medical demographic reporting in greater detail, especially regarding geography and specific terms used in articles., Methods: Original articles were included from issues of the New England Journal of Medicine ( NEJM ), JAMA , The Lancet , and the American Journal of Epidemiology ( AJE ) published from 1 January to 31 December 2020 (n = 640). Articles without human participants, case reports, or with only aggregate data were excluded, leaving 594 articles. Use of age, sex, gender, race, ethnicity, and SES were coded, as well as corresponding author and participant geography., Findings: 99.0% of articles reported age. While 92.9% reported sex alone, only 4.7% used the term gender and 1.0% transgender. 47.8% of articles reported race and 29.6% reported ethnicity. Studies with U.S. corresponding authors or participants were significantly more likely to report race (72.9% and 73.7% respectively) or ethnicity (47.3% and 45.3% respectively) than those without (25.9% and 25.6% for race, 14.2% and 16.3% for ethnicity), p < 0.01 for all. Of articles reporting race, 40.9% used only a Black-white binary; of those reporting ethnicity, 85.2% included two or fewer terms. Under 5.0% of all articles used Office of Management and Budget (OMB) categories. Across all articles, 33.0% reported SES, from 15.2% in NEJM to 80.2% in AJE ., Interpretation: We found that while some factors (age, sex) are reported consistently, others (gender, race, ethnicity, SES) are not, despite recent attention. Authors often rely on binary or limited categories that inadequately capture human diversity. The presence of U.S. researchers or participants increased the reporting of race and/or ethnicity, highlighting wide variations that persist even as multinational collaborations become widespread. Researchers should reflect on their use of these terms, justify their decisions, and report results with care., Funding: None., Competing Interests: The authors declare that no conflicts of interest exist in relation to this work., (© 2023 The Authors.)

Coral reefs have evolved over millennia to survive disturbances. Yet, in just a few decades chronic local pressures and the climate catastrophe have accelerated so quickly that most coral reefs are now threatened. Rising ocean temperatures and recurrent bleaching pose the biggest threat, affecting even remote and well-managed reefs on global scales. We illustrate how coral bleaching is altering reefs by contrasting the dynamics of adjacent reef systems over more than two decades. Both reef systems sit near the edge of northwest Australia's continental shelf, have escaped chronic local pressures and are regularly affected by tropical storms and cyclones. The Scott reef system has experienced multiple bleaching events, including mass bleaching in 1998 and 2016, from which it is unlikely to fully recover. The Rowley Shoals has maintained a high cover and diversity of corals and has not yet been impacted by mass bleaching. We show how the dynamics of both reef systems were driven by a combination of local environment, exposure to disturbances and coral life history traits, and consider future shifts in community structure with ongoing climate change. We then demonstrate how applying knowledge of community dynamics at local scales can aid management strategies to slow the degradation of coral reefs until carbon emissions and other human impacts are properly managed., (© 2021 The Ecological Society of America.)

Background: Currently, the acceptability and efficacy of pulmonary rehabilitation for adults with severe asthma is unknown., Objective: To investigate the feasibility of performing a randomized controlled trial of asthma-tailored pulmonary rehabilitation (AT-PR) versus usual care (UC)., Methods: Adults with severe asthma were recruited and randomized 2:1 to AT-PR and UC. The primary outcomes were recruitment, retention, and serious adverse event rates. Secondary outcome measures included those for a future trial assessing the feasibility of collecting data. Assessments were performed at baseline, 12 weeks, and 9 months including measures of physical performance, health-related quality of life, and asthma control. A recruitment rate of 30% was estimated with 95% CI of ±7%, a retention rate of 75% ± 14% if we recruited 40 patients to AT-PR, and a serious adverse event rate of 2.5%., Results: Sixty-one (26%) of 238 eligible patients were recruited (38 women; mean age, 54 ± 13 years; body mass index, 32 ± 7 kg/m 2 ; FEV 1 , 1.9 ± 0.7 L; FEV 1 /forced vital capacity, 69% ± 11%). Fifty-one patients were randomized to AT-PR (n = 34) and UC (n = 17). The retention rate was 62% for the AT-PR group and 53% for the UC group, with a serious adverse event rate of 3.3% related to the study visits. Overall collection of the outcome measures was feasible. The results of the AT-PR group were suggestive of improvements in exercise performance, health-related quality of life, and asthma control, but the UC group results were either unchanged or worsened., Conclusions: Both recruitment and retention rates were within the a priori estimated 95% CI. Our results indicate that AT-PR may be efficacious for adults with severe asthma but any future intervention and trial design would need further modifications to improve acceptability and retention rate., (Copyright © 2020. Published by Elsevier Inc.)

Background: The management of severe asthma poses many challenges related to treatment, adherence, and psychosocial morbidity. There is little direct data from the patient perspective to understand and negotiate the complexities of managing severe asthma., Objective: To explore the patient perceptions of living with severe asthma and the experience of managing severe asthma, in order to better understand the support that might promote more effective self-management for severe asthma., Methods: Participants were recruited from a specialist Difficult Asthma Service. Semistructured interviews were conducted by researchers independent of the patient's care. Interviews were transcribed verbatim and inductive thematic analysis was performed., Results: Twenty-nine participants (13 male: mean [standard deviation] age, 49.5 [13.6] years: mean Asthma Control Questionnaire 2.2 [1.2]) participated in an interview. Analysis resulted in 4 major themes describing the experience and challenges to managing severe asthma: understanding of severe asthma, emotional impact of living with severe asthma (subtheme: fear of hospitalization), public perceptions of asthma, and concerns about medications., Conclusions: Health care professionals need to consider and discuss with patients their perceptions of severe asthma and the relevant treatments; particular attention should focus around education of disease control and actively exploring thoughts around hospitalization. Our data highlight the potential for psychological and social support to enhance self-management by directly addressing the wide-ranging individual challenges patients face. There is also a need for greater public awareness and education about severe asthma to minimize patient distress particularly in the work environment., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background and Objective: We investigated the repeatability and validity of the incremental shuttle walk test (ISWT) distance compared to peak oxygen uptake (VO 2pk ) during maximal incremental cycle ergometer (ICE) and treadmill (ITM) tests in adults with severe asthma., Methods: Adults with severe asthma, Medical Research Council (MRC) dyspnoea ≥2, were recruited from specialists caring for patients with severe asthma. All participants performed three ISWT (familiarization and two subsequent tests on the same day), an ICE and an ITM in a randomized order, on separate days, to intolerance with expiratory gas analysis., Results: A total of 50 patients (32 females, mean (SD), age: 54 (13) years, forced expiratory volume in 1 s (FEV 1 ): 1.9 (0.8) L and body mass index (BMI): 32 (6) kg/m 2 ) completed all five tests. The mean (SD) ISWT distance for each test was 400 (156), 418 (142) and 438 (157) m (P = 0.001), respectively. There was a strong correlation between the ISWT distance with VO 2pk derived from ITM (r = 0.74, P < 0.001) and ICE (r = 0.75, P < 0.001)., Conclusion: There was a small increase in the mean ISWT distance on sequential testing. In clinical practice, the coefficient of repeatability and heteroscedasticity need to be considered when assessing whether a true change has occurred within an individual patient. The ISWT has validity compared to VO 2pk on both ICE and ITM, but they are not interchangeable., (© 2019 Asian Pacific Society of Respirology.)

Objective: Major changes in the design and delivery of clinical academic training in the United Kingdom have occurred yet there has been little exploration of the perceptions of integrated clinic academic trainees or educators. We obtained the views of a range of key stakeholders involved in clinical academic training in the East Midlands., Design: A qualitative study with inductive iterative thematic content analysis of findings from trainee surveys and facilitated focus groups., Setting: The East Midlands School of Clinical Academic Training., Participants: Integrated Clinical Academic Trainees, clinical and academic educators involved in clinical academic training., Main Outcome Measures: The experience, opinions and beliefs of key stakeholders about barriers and enablers in the delivery of clinical academic training., Results: We identified key themes many shared by both trainees and educators. These highlighted issues in the systems and process of the integrated academic pathways, career pathways, supervision and support, the assessment process and the balance between clinical and academic training., Conclusions: Our findings help inform the future development of integrated academic training programmes.